Artigos de revistas sobre o tema "Philip Johnson Associates"

Background:Tildrakizumab (TIL), an anti–interleukin (IL)-23p19 monoclonal antibody, is approved in the US, EU, and Australia for treatment of moderate-to-severe plaque psoriasis.1A randomised, double-blind, placebo-controlled, multiple-dose, phase 2b study (NCT02980692) evaluating efficacy and safety of TIL for treatment of psoriatic arthritis (PsA) was recently completed.Objectives:To evaluate the effect of TIL in PsA, using the DAS28-CRP responses up to week (W)52.Methods:Patients (pts) ≥18 years old with PsA2and ≥3 tender and ≥3 swollen joints were randomised 1:1:1:1:1 to receive TIL (200 mg once every 4 weeks [Q4W], 200 mg every 12 weeks [Q12W], 100 mg Q12W, or 20 mg Q12W) or placebo (PBO Q4W) to W24. Thereafter, PBO Q4W and TIL 20 mg Q12W arms crossed over to TIL 200 mg Q12W to W52. DAS28-CRP was shown to be reliable in PsA studies,3and pts achieving scores <3.2 satisfied responder criteria. Adverse events (AEs), including treatment-emergent AEs (TEAEs) and serious AEs (SAEs), were monitored throughout the study.Results:Overall, 391/500 pts screened met the inclusion criteria; 55% were female with a mean age of 48.8 years. At baseline, disease characteristics were generally consistent across treatment arms (Table).At W24, DAS28-CRP response rates increased across all TIL treatment arms relative to PBO (Figure). After W24, response rates continued to increase and were sustained through W52, including in pts who switched from PBO to TIL.From W0–W24/W25–W52, 50.4%/39.9% and 2.3%/1.0% of pts experienced a TEAE and SAE, respectively. There were no reports of candidiasis, inflammatory bowel disease, major adverse cardiac events or elevated liver enzymes. From W0–W24, 1 pt (0.3%) had urinary tract infection (TIL 100 mg Q12W). From W25–W52, 1 pt (0.3%) had an intraductal proliferative breast lesion (TIL 20→200 mg Q12W). One pt (0.3%) discontinued before 24 weeks due to hypertension. No deaths were reported.Table.Baseline disease characteristics related to DAS28-CRPTIL 200 mg Q4Wn = 78TIL 200 mg Q12Wn = 79TIL 100 mg Q12Wn = 77TIL 20→200 mg Q12Wn = 78PBO→TIL 200 mg Q12Wn = 79hsCRP, mg/L7.8 ± 18.610.5 ± 14.410.6 ± 20.010.7 ± 14.013.0 ± 20.8ESR, mm/h*22.8 ± 18.922.5 ± 19.824.7 ± 19.827.2 ± 20.726.9 ± 20.5Swollen joint count (66)10.4 ± 7.410.0 ± 8.011.0 ± 8.29.4 ± 6.411.8 ± 9.8Tender joint count (68)16.6 ± 11.919.5 ± 13.921.3 ± 14.819.0 ± 13.019.7 ± 14.7PtGA57.8 ± 18.361.1 ± 20.760.3 ± 20.261.9 ± 17.465.2 ± 18.1Data are reported as mean ± standard deviation unless otherwise stated.*Total pts analysed (n) = 71, 69, 70, 68, 62, respectively.ESR, erythrocyte sedimentation rate; hsCRP, high-sensitivity C-Reactive Protein; PBO, placebo; PtGA, Patient Global Assessment; pts, patients; Q4W, every 4 weeks; Q12W, every 12 weeks; TIL tildrakizumab.Conclusion:Treatment with all doses of TIL increased the rate of DAS28-CRP responders in pts with active PsA and was well tolerated, suggesting a reduction in PsA-related disease activity for up to 52 weeks of treatment. Ongoing analyses will assess whether DAS28-CRP responses correlate with baseline clinical characteristics.References:[1]Reich K, et al.Lancet. 2017;390(10091):276−88.[2]Taylor W, et al.Arthritis Rheum. 2006; 54(8):2665−73.[3]Fransen J, et al.Ann Rheum Dis. 2004; 62:151.Disclosure of Interests:Saima Chohan Employee of: Partner/physician at Arizona Arthritis and Rheumatology Associates, Arthur Kavanaugh Grant/research support from: AbbVie, Amgen, Eli Lilly, Novartis, Janssen, Pfizer, Gilead, UCB, Consultant of: AbbVie, Amgen, Eli Lilly, Novartis, Janssen, Pfizer, Gilead, UCB, Vibeke Strand Consultant of: AbbVie, Amgen, Biogen, Celltrion, Consortium of Rheumatology Researchers of North America, Crescendo Bioscience, Eli Lilly, Genentech/Roche, GlaxoSmithKline, Hospira, Janssen, Merck, Novartis, Pfizer, Regeneron Pharmaceuticals, Inc., Sanofi, UCB, Richard C Chou Consultant of: Sun Pharmaceutical Industries, Inc, Alan M Mendelsohn Shareholder of: Johnson and Johnson, Employee of: Sun Pharmaceutical Industries, Inc, Stephen Rozzo Employee of: Sun Pharmaceutical Industries, Inc, Philip J Mease Grant/research support from: Abbott, Amgen, Biogen Idec, BMS, Celgene Corporation, Eli Lilly, Novartis, Pfizer, Sun Pharmaceutical, UCB – grant/research support, Consultant of: Abbott, Amgen, Biogen Idec, BMS, Celgene Corporation, Eli Lilly, Novartis, Pfizer, Sun Pharmaceutical, UCB – consultant, Speakers bureau: Abbott, Amgen, Biogen Idec, BMS, Eli Lilly, Genentech, Janssen, Pfizer, UCB – speakers bureau

BackgroundLupus nephritis (LN) is one of the most common severe clinical manifestations of systemic lupus erythematosus (SLE), occurring in 21%–48% of SLE patients.[1]The kidney is the major organ affected in SLE, with persistent inflammation leading to progressive loss of renal function and chronic kidney disease (CKD). The decline in kidney function leads to an accumulation of metabolic waste products normally cleared by the kidneys, known as uremic toxins. Uremic toxins negatively affect multiple organ systems, causing increased cardiovascular and kidney damage, among other effects.[2]Given the clear link to kidney function, uremic toxins may serve as biomarkers of kidney damage and of treatment response.Anifrolumab, a monoclonal antibody that targets the type I interferon (IFN) receptor subunit 1, is approved for moderate to severe SLE treatment[3]and intensified dosing is being evaluated in a phase 3 study for LN treatment.ObjectivesIn this study, we conducted unbiased metabolomic serum profiling to identify novel biomarkers of treatment response and provide insights into the mechanism of action of anifrolumab in LN.MethodsIn the 52-week phase 2 clinical trial TULIP-LN (NCT02547922), 147 patients with active LN were randomized 1:1:1 to receive intravenous anifrolumab every 4 weeks at standard SLE dosing (basic regimen [BR], 300 mg), intensified dosing (intensified regimen [IR], 900 mg for the first 3 doses, 300 mg thereafter), or placebo in addition to standard therapy.[4]Serum samples were obtained from 140 of these patients at baseline (BL) and Weeks 12, 24, and 52. Serum metabolites were analyzed using an unbiased liquid chromatography–mass spectrometry-based approach. Metabolites that were differentially modulated in the anifrolumab IR vs placebo group were identified using a mixed effects model evaluating the interaction of metabolite levels and treatment, adjusted for patients’ IFN gene signature (IFNGS) status (high/low) and 24-hour urine protein–creatinine ratio (UPCR >3 or ≤3). Relationships between BL metabolite level and clinical characteristics of kidney damage were assessed by Spearman’s correlation. Association of BL metabolite levels with complete renal response were evaluated by logistic regression, adjusted for IFNGS and UPCR status.ResultsOur unbiased metabolomic approach identified 2 metabolites significantly impacted by anifrolumab treatment compared with placebo (Figure 1). Cytosine (Cyt) and indoxyl sulfate (IS) levels were significantly reduced following anifrolumab IR treatment compared with placebo, while an intermediate, non-significant reduction was observed longitudinally with anifrolumab BR. At baseline, Cyt and IS serum levels were positively correlated with serum creatinine and negatively correlated with estimated glomerular filtration rate. Baseline IS levels were also associated with complete renal response at Week 52. Compared to the trend observed in nonresponders, IS levels in responders were reduced from BL to Week 52. A trend in reduction of multiple uremic toxins not limited to IS was detected in the anifrolumab-treated group.ConclusionIn patients with LN, anifrolumab treatment reduced levels of multiple circulating uremic toxins including IS, a known inducer of cardiovascular damage in CKD.[5]Together, correlations with kidney damage measures at baseline and reductions in IS levels in responders vs nonresponders at Week 52 suggest improvements in kidney function following anifrolumab treatment. Overall, our results contribute to a deeper understanding of how inhibition of type I IFN affects renal disease in LN.References[1] Wang H, et al.Arch Rheumatol.2017;33:17–25.[2] Rosner MH, et al.Clin J Am Soc Nephrol.2021;16:1918–28.[3] AstraZeneca. Saphnelo prescribing information. 2021.[4] Jayne D, et al.Ann Rheum Dis.2022;81:496–506.[5] Zoccali C, et al.Nat Rev Nephrol.2017;13:344–58.AcknowledgementsWriting assistance by Katey Glunt, PhD, of JK Associates Inc., part of Fishawack Health.This study was sponsored by AstraZeneca.Disclosure of InterestsDavid Jayne Shareholder of: Aurinia, Speakers bureau: GSK, CSL Vifor, Consultant of: AstraZeneca, Chemocentryx, CSL Vifor, GSK, Novartis, Roche, Takeda, Grant/research support from: GSK, Roche, Patrick Gavin Employee of: AstraZeneca, Erik Allman Shareholder of: Primarily AstraZeneca but others through various Exchange Traded Funds (ETFs), Employee of: Previously, Janssen/Johnson & Johnson. Currently, AstraZeneca, Cristina Di Poto Shareholder of: AstraZeneca, Employee of: AstraZeneca, Xiang Tian Shareholder of: AstraZeneca, Employee of: AstraZeneca, Sonja Hess Shareholder of: AstraZeneca, Employee of: AstraZeneca, Madhu Ramaswamy Shareholder of: GSK, Employee of: AstraZeneca (until Jan 2023), GSK (from Jan 2023), Mark Lazarus Consultant of: Paid consulting for Novartis and Sandoz over 2 years ago, Employee of: AstraZeneca, Philip Z Brohawn Shareholder of: AstraZeneca, Employee of: AstraZeneca, Daniel Muthas Shareholder of: AstraZeneca, Employee of: AstraZeneca, Adam Platt Shareholder of: AstraZeneca, Employee of: AstraZeneca, Hussein Al-Mossawi Shareholder of: AstraZeneca, UCB, GSK, Speakers bureau: Novartis, Pfizer, UCB, Consultant of: Novartis, UCB, AbbVie, Grant/research support from: UCB, Employee of: UCB (Previous), AstraZeneca (Current), Catharina Lindholm Shareholder of: AstraZeneca, Employee of: AstraZeneca, Nicola Ferrari Shareholder of: AstraZeneca, Employee of: AstraZeneca.

Abstract Background The pathogenesis of inflammatory bowel disease (IBD) which includes Crohn’s disease (CD) and ulcerative colitis (UC), is believed to involve activation of the intestinal immune system in response to the gut microbiome among genetically susceptible hosts. IBD has been historically regarded as a disease of developed nations, though in the past two decades there has been a reported shift in the epidemiological pattern of disease. High-income nations with known high prevalence of disease are seeing a stabilization of incident cases, while a rapid rise of incident IBD is being observed in developing nations. This suggests that environmental exposures may play a role in mediating the risk of developing IBD. The potential environmental determinants of IBD across various regions is vast, though medications have been increasingly recognized as one broad category of risk factors. Purpose Several medications have been considered to contribute to the etiology of IBD. This study assessed the association between medication use and risk of developing IBD using the Prospective Urban Rural Epidemiology (PURE) cohort. Method This was a prospective cohort study of 133,137 individuals between the ages of 20-80 from 24 countries. Country-specific validated questionnaires documented baseline and follow-up medication use. Participants were followed prospectively at least every 3 years. The main outcome was development of IBD, including CD and UC. Short-term (baseline but not follow-up use) and long-term use (baseline and subsequent follow-up use) was evaluated. Results are presented as adjusted odds ratios (aOR) with 95% confidence intervals (CI). Result(s) During the median follow-up of 11.0 years [interquartile range (IQR) 9.2-12.2], we recorded 571 incident cases of IBD (143 CD and 428 UC). Higher risk of incident IBD was associated with baseline antibiotic use [aOR: 2.81 (95% CI: 1.67-4.73), p=0.0001] and hormonal medication use [aOR: 4.43 (95% CI: 1.78-11.01), p=0.001]. Among females, previous or current oral contraceptive use was also associated with IBD development [aOR: 2.17 (95% CI: 1.70-2.77), p=5.02E-10]. NSAID users were also observed to have increased risk of IBD [aOR: 1.80 (95% CI: 1.23-2.64), p=0.002], which was driven by long-term users [aOR: 5.58 (95% CI: 2.26-13.80), p&lt;0.001]. All significant results were consistent in direction for CD and UC with low heterogeneity. Conclusion(s) Antibiotics, hormonal medications, oral contraceptives, and long-term NSAID use were associated with increased odds of incident IBD after adjustment for covariates. Please acknowledge all funding agencies by checking the applicable boxes below Other Please indicate your source of funding below: Salim Yusuf is supported by the Heart & Stroke Foundation/Marion W. Burke Chair in Cardiovascular Disease. The PURE Study is an investigator-initiated study funded by the Population Health Research Institute, the Canadian Institutes of Health Research (CIHR), Heart and Stroke Foundation of Ontario, support from CIHR’s Strategy for Patient Oriented Research (SPOR) through the Ontario SPOR Support Unit, as well as the Ontario Ministry of Health and Long-Term Care and through unrestricted grants from several pharmaceutical companies, with major contributions from AstraZeneca (Canada), Sanofi-Aventis (France and Canada), Boehringer Ingelheim (Germany and Canada), Servier, and GlaxoSmithkline, and additional contributions from Novartis and King Pharma and from various national or local organisations in participating countries; these include: Argentina: Fundacion ECLA; Bangladesh: Independent University, Bangladesh and Mitra and Associates; Brazil: Unilever Health Institute, Brazil; Canada: Public Health Agency of Canada and Champlain Cardiovascular Disease Prevention Network; Chile: Universidad de la Frontera; China: National Center for Cardiovascular Diseases; Colombia: Colciencias, grant number 6566-04-18062; India: Indian Council of Medical Research; Malaysia: Ministry of Science, Technology and Innovation of Malaysia, grant numbers 100 -IRDC/BIOTEK 16/6/21 (13/2007) and 07-05-IFN-BPH 010, Ministry of Higher Education of Malaysia grant number 600 -RMI/LRGS/5/3 (2/2011), Universiti Teknologi MARA, Universiti Kebangsaan Malaysia (UKM-Hejim-Komuniti-15-2010); occupied Palestinian territory: the UN Relief and Works Agency for Palestine Refugees in the Near East, occupied Palestinian territory; International Development Research Centre, Canada; Philippines: Philippine Council for Health Research & Development; Poland: Polish Ministry of Science and Higher Education grant number 290/W-PURE/2008/0, Wroclaw Medical University; Saudi Arabia: the Deanship of Scientific Research at King Saud University, Riyadh, Saudi Arabia (research group number RG -1436-013); South Africa: the North-West University, SANPAD (SA and Netherlands Programme for Alternative Development), National Research Foundation, Medical Research Council of SA, The SA Sugar Association (SASA), Faculty of Community and Health Sciences (UWC); Sweden: grants from the Swedish state under the Agreement concerning research and education of doctors; the Swedish Heart and Lung Foundation; the Swedish Research Council; the Swedish Council for Health, Working Life and Welfare, King Gustaf V’s and Queen Victoria Freemasons Foundation, AFA Insurance, Swedish Council for Working Life and Social Research, Swedish Research Council for Environment, Agricultural Sciences and Spatial Planning, grant from the Swedish State under the Läkar Utbildnings Avtalet agreement, and grant from the Västra Götaland Region; Turkey: Metabolic Syndrome Society, AstraZeneca, Turkey, Sanofi Aventis, Turkey; United Arab Emirates (UAE): Sheikh Hamdan Bin Rashid Al Maktoum Award For Medical Sciences and Dubai Health Authority, Dubai UAE. Disclosure of Interest C. Pray: None Declared, N. Narula Grant / Research support from: Neeraj Narula holds a McMaster University Department of Medicine Internal Career Award. Neeraj Narula has received honoraria from Janssen, Abbvie, Takeda, Pfizer, Merck, and Ferring, E. C. Wong: None Declared, J. K. Marshall Grant / Research support from: John K. Marshall has received honoraria from Janssen, AbbVie, Allergan, Bristol-Meyer-Squibb, Ferring, Janssen, Lilly, Lupin, Merck, Pfizer, Pharmascience, Roche, Shire, Takeda and Teva., S. Rangarajan: None Declared, S. Islam: None Declared, A. Bahonar: None Declared, K. F. Alhabib: None Declared, A. Kontsevaya: None Declared, F. Ariffin: None Declared, H. U. Co: None Declared, W. Al Sharief: None Declared, A. Szuba: None Declared, A. Wielgosz: None Declared, M. L. Diaz: None Declared, R. Yusuf: None Declared, L. Kruger: None Declared, B. Soman: None Declared, Y. Li: None Declared, C. Wang: None Declared, L. Yin: None Declared, M. Erkin: None Declared, F. Lanas: None Declared, K. Davletov: None Declared, A. Rosengren: None Declared, P. Lopez-Jaramillo: None Declared, R. Khatib: None Declared, A. Oguz: None Declared, R. Iqbal: None Declared, K. Yeates: None Declared, Á. Avezum: None Declared, W. Reinisch Consultant of: Speaker for Abbott Laboratories, Abbvie, Aesca, Aptalis, Astellas, Centocor, Celltrion, Danone Austria, Elan, Falk Pharma GmbH, Ferring, Immundiagnostik, Mitsubishi Tanabe Pharma Corporation, MSD, Otsuka, PDL, Pharmacosmos, PLS Education, Schering-Plough, Shire, Takeda, Therakos, Vifor, Yakult, Consultant for Abbott Laboratories, Abbvie, Aesca, Algernon, Amgen, AM Pharma, AMT, AOP Orphan, Arena Pharmaceuticals, Astellas, Astra Zeneca, Avaxia, Roland Berger GmBH, Bioclinica, Biogen IDEC, Boehringer-Ingelheim, Bristol-Myers Squibb, Cellerix, Chemocentryx, Celgene, Centocor, Celltrion, Covance, Danone Austria, DSM, Elan, Eli Lilly, Ernest & Young, Falk Pharma GmbH, Ferring, Galapagos, Genentech, Gilead, Grünenthal, ICON, Index Pharma, Inova, Janssen, Johnson & Johnson, Kyowa Hakko Kirin Pharma, Lipid Therapeutics, LivaNova, Mallinckrodt, Medahead, MedImmune, Millenium, Mitsubishi Tanabe Pharma Corporation, MSD, Nash Pharmaceuticals, Nestle, Nippon Kayaku, Novartis, Ocera, Omass, Otsuka, Parexel, PDL, Periconsulting, Pharmacosmos, Philip Morris Institute, Pfizer, Procter & Gamble, Prometheus, Protagonist, Provention, Robarts Clinical Trial, Sandoz, Schering-Plough, Second Genome, Seres Therapeutics, Setpointmedical, Sigmoid, Sublimity, Takeda, Therakos, Theravance, Tigenix, UCB, Vifor, Zealand, Zyngenia, and 4SC, Advisory board member for Abbott Laboratories, Abbvie, Aesca, Amgen, AM Pharma, Astellas, Astra Zeneca, Avaxia, Biogen IDEC, Boehringer-Ingelheim, Bristol-Myers Squibb, Cellerix, Chemocentryx, Celgene, Centocor, Celltrion, Danone Austria, DSM, Elan, Ferring, Galapagos, Genentech, Grünenthal, Inova, Janssen, Johnson & Johnson, Kyowa Hakko Kirin Pharma, Lipid Therapeutics, MedImmune, Millenium, Mitsubishi Tanabe Pharma Corporation, MSD, Nestle, Novartis, Ocera, Otsuka, PDL, Pharmacosmos, Pfizer, Procter & Gamble, Prometheus, Sandoz, Schering-Plough, Second Genome, Setpointmedical, Takeda, Therakos, Tigenix, UCB, Zealand, Zyngenia, and 4SC, P. Moayyedi: None Declared, S. Yusuf: None Declared

Background:DISCOVER 1 & 2 are phase 3 psoriatic arthritis (PsA) trials investigating guselkumab (GUS), an IL-23 inhibitor that specifically binds the IL-23p19 subunit. In both studies, GUS showed significant improvement vs placebo (PBO) through week (W) 24 in the PBO-controlled period.1,2Objectives:To present integrated safety results of DISC 1 & 2 through the PBO-controlled periods.Methods:Adult patients (pts) with active PsA despite standard therapy were enrolled. All pts were biologic-naïve, except ~30% in DISC 1 with previous exposure to 1-2 TNF inhibitors. Pts were randomized to SC GUS 100 mg Q4W; GUS 100 mg at W0, W4, then Q8W; or PBO. Adverse events (AEs) and lab results were analyzed from pooled data.Results:The rates of pts experiencing ≥1 AE, serious AE, infection, serious infection, and discontinuation due to an AE were similar between GUS and PBO (Table 1). There were 2 deaths, 3 malignancies, 2 Major Adverse Cardiac Events (MACE), and no opportunistic infections (treatment group not shown to prevent unblinding). Among the AEs reported by ≥5% pts in any group (Table 1), nasopharyngitis and elevated serum hepatic aminotransferases were more common with GUS vs PBO. Laboratory ALT and AST elevations were mostly mild, transient, and not associated with significant bilirubin elevation. There was a trend to decreased neutrophil count (mostly Grade 1, transient, and not associated with infection) with GUS vs PBO (Table 2). Low rates of injection-site reactions were seen with GUS vs PBO. Anti-drug antibody development was also low (Table 1).Table 1.Patient Reported AEs, n (%)GUS100 mgQ8WGUS100 mgQ4WPBON375373372≥1 AE182 (48.5)182 (48.8)176 (47.3)≥1 Serious AE7 (1.9)8 (2.1)12 (3.2)Discontinuation due to AE5 (1.3)8 (2.1)7 (1.9)≥1 Infection73 (19.5)80 (21.4)77 (20.7)≥1 Serious infection1 (0.3)3 (0.8)3 (0.8)≥1 Opportunistic Infection (including Candida)000Active Tuberculosis000≥1 Injection-site reaction5 (1.3)4 (1.1)1 (0.3)Anti-GUS antibody +, n/N (%)6/373 (1.6)9/371 (2.4)--AEs* reported by ≥5% of patients in any treatment groupNasopharyngitis26 (6.9)19 (5.1)17 (4.6)Upper respiratory tract infection13 (3.5)23 (6.2)17 (4.6)Increased ALT23 (6.1)28 (7.5)14 (3.8)Increased AST23 (6.1)14 (3.8)9 (2.4)*Medical Dictionary for Regulatory Activities (MedDRA) preferred termTable 2.Lab Results*GUS100 mgQ8WGUS100 mgQ4WPBON373371370ALT Increased (%)Grade 128.235.030.121.12.71.43-40.81.10.8Neutrophil Count Decreased (%)Grade 15.65.93.221.61.60.83-400.30.3*NCI toxicity gradeALT=Alanine aminotransferaseConclusion:GUS was safe and well tolerated through the PBO-controlled period in 2 randomized, phase 3 trials of patients with active PsA. There were no meaningful safety differences between the Q8W and Q4W groups, no significant safety issues identified when comparing GUS to PBO, and no safety signals with regards to infections, malignancy, and MACE. The safety profile of GUS Q4W and Q8W in PsA pts was generally consistent with that in the Phase 3 trials of GUS Q8W for psoriasis.3,4References:[1]Deodhar et al. ACR 2019 (#807). Arth Rheum 2019;71 S10:1386[2]Mease et al. ACR 2019 (#L13). Arth Rheum 2019;71 S10:5247[3]Blauvelt et al. J Am Acad Derm 2017;76:405[4]Reich et al. J Am Acad Derm 2017;76:418Acknowledgments:NoneDisclosure of Interests:Proton Rahman Grant/research support from: Janssen and Novartis, Consultant of: Abbott, AbbVie, Amgen, BMS, Celgene, Lilly, Janssen, Novartis, and Pfizer., Speakers bureau: Abbott, AbbVie, Amgen, BMS, Celgene, Lilly, Janssen, Novartis, Pfizer, Christopher T. Ritchlin Grant/research support from: UCB Pharma, AbbVie, Amgen, Consultant of: UCB Pharma, Amgen, AbbVie, Lilly, Pfizer, Novartis, Gilead, Janssen, Philip Helliwell: None declared, Wolf-Henning Boehncke Grant/research support from: Janssen Research & Development, LLC, Consultant of: Janssen, Philip J Mease Grant/research support from: Abbott, Amgen, Biogen Idec, BMS, Celgene Corporation, Eli Lilly, Novartis, Pfizer, Sun Pharmaceutical, UCB – grant/research support, Consultant of: Abbott, Amgen, Biogen Idec, BMS, Celgene Corporation, Eli Lilly, Novartis, Pfizer, Sun Pharmaceutical, UCB – consultant, Speakers bureau: Abbott, Amgen, Biogen Idec, BMS, Eli Lilly, Genentech, Janssen, Pfizer, UCB – speakers bureau, Alice B Gottlieb Grant/research support from:: Research grants, consultation fees, or speaker honoraria for lectures from: Pfizer, AbbVie, BMS, Lilly, MSD, Novartis, Roche, Sanofi, Sandoz, Nordic, Celltrion and UCB., Consultant of:: Research grants, consultation fees, or speaker honoraria for lectures from: Pfizer, AbbVie, BMS, Lilly, MSD, Novartis, Roche, Sanofi, Sandoz, Nordic, Celltrion and UCB., Speakers bureau:: Research grants, consultation fees, or speaker honoraria for lectures from: Pfizer, AbbVie, BMS, Lilly, MSD, Novartis, Roche, Sanofi, Sandoz, Nordic, Celltrion and UCB., Shelly Kafka Employee of: Janssen Scientific Affairs, LLC, Alexa Kollmeier Shareholder of: Johnson & Johnson, Employee of: Janssen Research & Development, LLC, Elizabeth C Hsia Shareholder of: Johnson & Johnson, Employee of: Janssen Research & Development, LLC, Xie L Xu Shareholder of: Johnson & Johnson, Employee of: Janssen Research & Development, LLC, May Shawi Shareholder of: Johnson & Johnson, Employee of: Janssen Research & Development, LLC, Shihong Sheng Shareholder of: Johnson & Johnson, Employee of: Janssen Research & Development, LLC, Prasheen Agarwal Shareholder of: Johnson & Johnson, Employee of: Janssen Research & Development, LLC, Bei Zhou Shareholder of: Johnson & Johnson, Employee of: Janssen Research & Development, LLC, Paraneedharan Ramachandran Employee of: Janssen Research & Development, LLC, Iain McInnes Grant/research support from: Bristol-Myers Squibb, Celgene, Eli Lilly and Company, Janssen, and UCB, Consultant of: AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly and Company, Gilead, Janssen, Novartis, Pfizer, and UCB

BackgroundFatigue, one of the top 3 patient (pt)-reported symptoms of psoriatic arthritis (PsA) and a recent PsA outcome domain,1 causes impaired health-related quality-of-life, diminished productivity, and disability.1-3 Although the origins of fatigue are multifactorial, inflammation is hypothesized to play an important role.4 In pts with active PsA, treatment with guselkumab (GUS) led to clinically meaningful and sustained improvements in fatigue through 1 year in DISCOVER-1 (D1) and DISCOVER-2 (D2).5ObjectivesTo identify 1) factors associated with fatigue and 2) factors associated with change in fatigue among pts with PsA treated with GUS.MethodsIn the Phase 3 D1 (N=381, biologic-naïve and tumor necrosis factor inhibitor-experienced) and D2 (N=739, biologic-naïve) studies, pts with active PsA despite standard therapies and/or biologic disease-modifying antirheumatic drugs were randomized 1:1:1 to GUS 100 mg every 4 weeks (Q4W); GUS 100 mg at W0, W4, then Q8W; or placebo (PBO) with crossover to GUS 100 mg Q4W at W24. The pt-reported Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) scale measured fatigue (scored 0-52). In these post-hoc analyses of D1 and D2 pts, a principal component analysis (PCA) was performed using W0 data to identify the underlying baseline factors associated with fatigue. Additionally, linear regression analyses were performed to identify covariates associated with change in fatigue from W0 to W24.ResultsIn 1120 pts (mean age 47 yrs, mean disease duration 5.9 yrs, 48% female), mean FACIT-Fatigue scores at baseline ranged from 29.1 to 31.4 (vs 43.6 for the general US population).5 PCA showed that 62% of the variability in fatigue could be explained by 3 components (Figure 1). The first component, explaining 34% of variability in fatigue, largely comprised systemic disease activity and function measures such as pain, pt global assessment of disease activity (PtGDA), physician’s global assessment of disease activity, and Health Assessment Questionnaire-Disability Index (HAQ-DI). The second component, explaining 16% of variability, comprised joint manifestations including swollen joint count (SJC) and tender joint count (TJC). Skin involvement as assessed by Psoriasis Area and Severity Index (PASI) and systemic inflammation (C-reactive protein [CRP]) could explain 12% of the variability in fatigue (Figure 1 and Table 1). In a multivariate linear regression analysis, after adjusting for effects from other variables, improvement in CRP, physical function (HAQ-DI), PtGDA, and PASI score were significantly associated with fatigue improvement in GUS-treated pts at W24 (all p<0.001).Table 1.PCA of Pts With Active PsA in D1+D2 (N=1120; Pooled W0 data): Factor Loading Estimates by CovariatesComponent1 Systemic Disease Activity and FunctionComponent 2 Joint ManifestationsComponent 3 Skin Involvement and InflammationPsA disease duration, yr0.100.140.25PASI total score (0-72)0.220.230.74CRP, mg/dL0.36-0.130.55HAQ-DI score (0-3)0.73-0.09-0.19Pain (0-10 VAS)0.83-0.35-0.13PtGDA (0-10 VAS)0.82-0.36-0.16Physician global assessment of disease activity (0-10 VAS)0.65-0.180.23SJC (0-66)0.500.74-0.12TJC (0-68)0.540.70-0.18VAS=Visual Analog Scale.ConclusionAmong pts with PsA, measures of systemic disease activity and function, followed by joint manifestations, and skin involvement/inflammation accounted for 62% of the variability in fatigue. The large residual effect (38%) that was unexplained by the current model suggests the need for further research to identify additional factors (eg, distinct molecular pathways) contributing to the fatigue reported by PsA pts.References[1]Leung YY, et al. J Rheumatol (Suppl). 2020;96:46-9.[2]Gudu T, et al. Joint Bone Spine. 2016;83:439-43.[3]Husted JA, et al. Ann Rheum Dis. 2009;68:1553-8.[4]Krajewska-Włodarczyk M, et al. Reumatologia. 2017;55:125-30.[5]Rahman P, et al. Arthritis Res Ther. 2021;23:190.Disclosure of InterestsProton Rahman Consultant of: AbbVie, Amgen, Bristol Myers Squibb, Celgene, Eli Lilly, Janssen, Merck, Novartis, Pfizer, and UCB, Grant/research support from: Janssen and Novartis, Philip J Mease Speakers bureau: AbbVie, Amgen, Eli Lilly, Janssen, Novartis, Pfizer, Sun Pharma, and UCB, Consultant of: AbbVie, Aclaris, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Galapagos, Gilead, GSK, Inmagene, Janssen, Novartis, Pfizer, Sun Pharma, and UCB, Grant/research support from: AbbVie, Amgen, Bristol Myers Squibb, Eli Lilly, Galapagos, Gilead, Janssen, Novartis, Pfizer, Sun Pharma, and UCB, Atul Deodhar Speakers bureau: AbbVie, Eli Lilly, Janssen, Novartis, Pfizer, and UCB, Consultant of: AbbVie, Amgen, Aurinia, Bristol Myers Squibb, Celgene, Eli Lilly, GlaxoSmithKline, Janssen, MoonLake, Novartis, Pfizer, and UCB, Grant/research support from: AbbVie, Eli Lilly, GlaxoSmithKline, Novartis, Pfizer, and UCB, Arthur Kavanaugh Consultant of: AbbVie, Amgen, Bristol Myers Squibb, Eli Lilly, Genentech, Janssen, Merck, Novartis, Pfizer and UCB, Soumya D Chakravarty Shareholder of: Johnson & Johnson, Employee of: Janssen Scientific Affairs, LLC, Alexa Kollmeier Shareholder of: Johnson & Johnson, Employee of: Janssen Research & Development, LLC, Yan Liu Shareholder of: 3 Johnson & Johnson, Employee of: Janssen Research & Development, LLC, May Shawi Shareholder of: Johnson & Johnson, Employee of: Janssen Pharmaceutical Companies of Johnson & Johnson, Chenglong Han Shareholder of: Johnson & Johnson, Employee of: Janssen Research & Development, LLC.

Background:Guselkumab (GUS) is a human monoclonal antibody specific to the p19-subunit of interleukin-23. GUS significantly improved signs and symptoms of PsA through Week24 (Wk24), and improvements were maintained through Wk52 in the Phase 3 DISCOVER-11 and DISCOVER-22 studies.Objectives:Assess GUS efficacy through Wk52 in both studies utilizing composite indices.Methods:Adult patients (pts) enrolled had active PsA despite standard therapies. Pts in DISCOVER-1 had ≥3 swollen and ≥3 tender joints and C-reactive protein (CRP) ≥0.3 mg/dL; in DISCOVER-2, pts had ≥5 swollen and ≥5 tender joints and CRP ≥0.6 mg/dL. 31% of DISCOVER-1 pts received 1-2 prior tumor necrosis factor inhibitors; DISCOVER-2 pts were biologic-naïve. Pts were randomized 1:1:1 to GUS 100 mg every 4 weeks (Q4W); GUS 100 mg at Wk0, Wk4, then every 8 weeks (Q8W); or placebo (PBO); PBO pts crossed over to GUS 100 mg Q4W at Wk24. Composite endpoints pooled across the two studies were: Disease Activity Index for Psoriatic Arthritis (DAPSA), Psoriatic Arthritis Disease Activity Score (PASDAS), Minimal Disease Activity (MDA), and Very Low Disease Activity (VLDA). GUS vs PBO comparisons through Wk24 employed a Cochran-Mantel-Haenszel test with baseline stratification factors or Fisher’s exact test; no treatment group comparisons were performed beyond Wk24. P-values were not adjusted for multiplicity. From Wk24 -Wk52, pts with missing data were considered nonresponders (>90% of pts completed study treatment through Wk52).Results:In randomized and treated pts from DISCOVER-1 (N=381) and DISCOVER-2 (N=739), pooled baseline characteristics were generally well-balanced across treatment groups and reflected active disease. Differences in response rates between GUS Q4W or Q8W and PBO were seen as early as Wk8 and increased over time through Wk24. In pts continuing GUS Q4W or Q8W, respectively, post-Wk24 response rates associated with these composite indices continued to increase through Wk52, at which time they were 54.2% and 52.5% for DAPSA LDA, 45.3% and 41.9% for PASDAS LDA, 35.9% and 30.7% for MDA, 18.2% and 17.6% for DAPSA remission, and 13.1% and 14.4% for VLDA, with no discernable difference between the GUS Q4W and Q8W dosing regimens (Table 1 and Figure 1). After PBO pts crossed over to GUS Q4W at Wk24, response rates increased through Wk52.Conclusion:GUS 100 mg Q4W and Q8W provided robust and sustained benefits to pts with active PsA across multiple domains, indicating that GUS may provide an alternative treatment option for the diverse manifestations of PsA.References:[1]Ritchlin CR et al. RMD Open 2021; 1–11. doi: rmdopen-2020-001457[2]McInnes IB, et al. Arthritis Rheumatol 2020 Oct 11. doi: 10.1002/art.41553.Table 1.Pooled response rates for DISCOVER-1 and DISCOVER-2 randomized and treated patients.DISCOVER-1&2GUS Q4WGUS Q8WPBO -->GUS Q4W1Randomized and treated patients, n373375372PASDAS2LDAWk 2427.9%**30.1%**8.9%Wk 5245.3%41.9%36.8%MDA3Wk 2422.8%**24.3%**7.8%Wk 5235.9%30.7%28.2%DAPSA4RemissionWk 2410.2%**8.3%**2.2%Wk 5218.2%17.6%11.0%VLDA3Wk 246.4%**4.3%*1.3%Wk 5213.1%14.4%8.3%Data reported as proportions of patients, %. Unadjusted p values at Wk24 vs PBO: *p<0.05; **p<0.001.1 Pts randomized to PBO crossed over to GUS Q4W at Wk24.2 PASDAS is derived from Pt global assessment of arthritis and psoriasis (0-100), Physician global assessment (0-100), swollen joint count (0-66), tender joint count (0-68), CRP (mg/L), Leeds enthesitis index score, tender dactylitis count, and the 36-item Short-Form Health Survey Physical Component Summary score. PASDAS LDA ≤3.2.3 MDA is 5/7 criteria met; VLDA is 7/7 criteria met: tender joint count ≤1, swollen joint count ≤1, Psoriasis Activity and Severity Index ≤1, Pt assessment of pain ≤15 (0-100), Pt global assessment of disease activity ≤20 (0-100), Health Assessment Questionnaire-Disability Index score ≤0.5, Tender entheseal points ≤1.4 DAPSA Remission: score ≤4 (definition in Figure 1 legend).Disclosure of Interests:Laura C Coates Consultant of: AbbVie, Amgen, Biogen, Bristol Myers Squibb, Boehringer Ingelheim, Celgene, Domain, Eli Lilly, Gilead, Janssen, Medac, Novartis, Pfizer and UCB, Grant/research support from: AbbVie, Amgen, Celgene, Eli Lilly, Gilead, Novartis, Pfizer, Christopher T. Ritchlin Consultant of: Amgen, AbbVie, Eli Lilly, Gilead, Janssen, Novartis, Pfizer, and UCB, Grant/research support from: AbbVie, Amgen, and UCB, Laure Gossec Consultant of: AbbVie, Amgen, Bristol Myers Squibb, Biogen, Celgene, Eli Lilly, Gilead, Janssen, Novartis, Pfizer, Samsung Bioepis, Sanofi-Aventis, and UCB., Grant/research support from: Amgen, Eli Lilly, Galapagos, Janssen, Pfizer, Sandoz, and Sanofi, Philip Helliwell Consultant of: Galapagos, Janssen, and Novartis, Grant/research support from: AbbVie, Janssen, Pfizer, Proton Rahman Speakers bureau: AbbVie, Eli Lilly, Janssen, Novartis, Pfizer, and UCB, Consultant of: AbbVie, Amgen, Bristol Myers Squibb, Celgene, Eli Lilly, Janssen, Novartis, Pfizer, Roche, and UCB, Grant/research support from: Janssen and Novartis, Elizabeth C Hsia Shareholder of: Johnson & Johnson, Employee of: Janssen Research & Development, LLC, Alexa Kollmeier Shareholder of: Johnson & Johnson, Employee of: Janssen Research & Development, LLC, Xie L Xu Shareholder of: Johnson & Johnson, Employee of: Janssen Research & Development, LLC, Chetan Karyekar Shareholder of: Johnson & Johnson, Employee of: Janssen Global Services, LLC, May Shawi Shareholder of: Johnson & Johnson, Employee of: Janssen Global Services, LLC, Wim Noel Shareholder of: Johnson & Johnson, Employee of: Janssen Scientific Affairs, LLC, Yusang Jiang Employee of: Cytel, Inc. providing statistical support (funded by Janssen), Shihong Sheng Shareholder of: Johnson & Johnson, Employee of: Janssen Research & Development, LLC, Yanli Wang Employee of: IQVIA providing statistical support (funded by Janssen), Philip J Mease Consultant of: AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Galapagos, Gilead, GlaxoSmithKline, Janssen, Novartis, Pfizer, SUN, and UCB, Grant/research support from: AbbVie, Amgen, Bristol Myers Squibb, Eli Lilly, Galapagos, Gilead, Janssen, Novartis, Pfizer, SUN, and UCB.

Background:Psoriatic arthritis (PsA) is a chronic inflammatory disease characterized by peripheral arthritis, axial inflammation, dactylitis, enthesitis, & skin/nail psoriasis. Patients (pts) with PsA often experience reduced health-related quality of life (HRQoL) due to these features.Objectives:Using EuroQoL-5 dimension-5 level (EQ-5D-5L) questionnaire index & visual analog scale (EQ-VAS) scores, we assessed HRQoL in pts with PsA & its association with pt characteristics & clinical features of PsA, including fatigue.Methods:The Phase 3 DISCOVER-2 trial evaluated guselkumab (GUS), a human monoclonal antibody targeting the IL-23p19-subunit, in bio-naïve adults with active PsA (swollen joint count [SJC] ≥5, tender joint count [TJC] ≥5, C-reactive protein [CRP] ≥0.6 mg/dL) despite standard therapies.1 Pts were randomized 1:1:1 to GUS 100 mg every 4 weeks (Q4W); GUS 100 mg at Week 0 (W0), W4, then Q8W; or placebo (PBO). EQ-5D-5L index assesses mobility, self-care, usual activities, pain/discomfort, & anxiety/depression. EQ-VAS assesses pt health state. Spearman correlation testing was used to evaluate relationships between baseline (BL) pt characteristics & PsA clinical features & BL EQ-5D-5L index & EQ-VAS scores (Figure 1). Employing absolute observed scores at both W0 & W24, univariate linear regression was used to assess the association between EQ-5D-5L index & EQ-VAS scores & pt characteristics/PsA clinical features. Variables with p<0.20 in the univariate analysis were included in a multivariate analysis employing mixed-effect model for repeated measures (MMRM), controlling for all other variables; resulting p values <0.05 were considered statistically significant. Least-squares (LS) mean changes in EQ-5D-5L index & EQ-VAS were assessed at W24 using MMRM.Results:Among 738 pts, BL EQ-5D-5L index & EQ-VAS scores were moderately to strongly correlated (ie, ≥0.4) with BL pt-reported pain (0-10 VAS), physical function (Health Assessment Questionnaire-Disability Index [HAQ-DI]), fatigue (Functional Assessment of Chronic Illness Therapy-Fatigue [FACIT-F] scale), & 36-item Short Form Health Survey (SF-36) physical & mental component summary (PCS & MCS) scores & weakly correlated with other variables (Figure 1). Based on univariate analyses (p<0.20) & evaluation of collinearity between variables, attributes at W0 & W24 included in the multivariate models were age, sex, CRP, FACIT-F, pain, psoriasis area & severity index (PASI) score, TJC, SJC, enthesitis, & dactylitis. In the final model, CRP, FACIT-F, pain, PASI score, & the presence of dactylitis were significantly associated with EQ-5D-5L index & EQ-VAS scores. A higher TJC was significantly associated with a worse EQ-5D-5L index score. A higher SJC was significantly associated with a worse EQ-VAS score (Table 1). For reference, in the GUS Q4W (N=244), GUS Q8W (N=246), & PBO (N=244) groups, the LS mean changes from baseline at W24 were 0.12, 0.12, & 0.05, respectively, for EQ-5D-5L index & 18.1, 18.4, & 6.8, respectively, for EQ-VAS.Conclusion:Joint & skin symptoms, dactylitis, fatigue, pain, & elevated levels of CRP were significantly associated with reduced HRQoL (measured by EQ-5D-5L index & EQ-VAS) in bio-naïve pts with active PsA. Treatment of multiple PsA domains may help optimize HRQoL. Improvement across clinical domains1 & in HRQoL has been observed in GUS-treated pts with PsA.References:[1]Mease P, et al. Lancet 2020;395:1126-36.Table 1.Multivariate analysis of pt characteristics/clinical features & EQ-5D-5L index & EQ-VAS scores at W0 & W24ParameterEQ-5D-5L IndexEQ-VASEstimatep valueEstimatep valueAge (y)-0.00010.690.060.12Female-0.0030.531.110.20CRP (mg/dL)-0.005<0.001-0.510.007FACIT-F (0-52)0.007<0.0010.57<0.001Pain (0-10)-0.02<0.001-3.47<0.001PASI (0-72)-0.0010.03-0.17<0.001SJC (0-66)-0.0010.21-0.170.02TJC (0-68)-0.0010.04-0.040.41Dactylitis (Y/N)0.010.021.740.49Enthesitis (Y/N)-0.0040.33-0.980.22Disclosure of Interests:Jeffrey Curtis Consultant of: AbbVie, Amgen, Bristol-Myers Squibb, Corrona, Eli Lilly, Janssen, Myriad, Pfizer, Regeneron, Roche, and UCB, Grant/research support from: AbbVie, Amgen, Bristol-Myers Squibb, Corrona, Eli Lilly, Janssen, Myriad, Pfizer, Regeneron, Roche, and UCB, Iain McInnes Consultant of: AbbVie, Bristol Myers Squibb, Celgene, Eli Lilly, Gilead, Janssen, Novartis, Pfizer, and UCB, Grant/research support from: Bristol Myers Squibb, Celgene, Eli Lilly, Janssen, and UCB, Dafna D Gladman Consultant of: Abbvie, Amgen, Bristol Myers Squibb, Eli Lilly, Galapagos, Gilead, Janssen, Novartis, Pfizer and UCB, Grant/research support from: Abbvie, Amgen, Bristol Myers Squibb, Eli Lilly, Galapagos, Gilead, Janssen, Novartis, Pfizer and UCB, Feifei Yang Shareholder of: Johnson & Johnson, Employee of: Janssen Global Services, LLC, Steve Peterson Shareholder of: Johnson & Johnson, Employee of: Janssen Global Services, LLC, Prasheen Agarwal Shareholder of: Johnson & Johnson, Employee of: Janssen Research & Development, LLC, Alexa Kollmeier Shareholder of: Johnson & Johnson, Employee of: Janssen Research & Development, LLC, Elizabeth C Hsia Shareholder of: Johnson & Johnson, Employee of: Janssen Research & Development, LLC, Chenglong Han Shareholder of: Johnson & Johnson, Employee of: Janssen Research & Development, LLC, May Shawi Shareholder of: Johnson & Johnson, Employee of: Janssen Global Services, LLC, William Tillett Speakers bureau: AbbVie, Amgen, Celgene, Eli Lilly, Janssen, Novartis, Pfizer, and UCB, Consultant of: AbbVie, Amgen, Celgene, Eli Lilly, Janssen, Novartis, MSD, Pfizer, and UCB, Grant/research support from: AbbVie, Celgene, Eli Lilly, Janssen, Novartis, Philip J Mease Consultant of: AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Galapagos, Gilead, GlaxoSmithKline, Janssen, Novartis, Pfizer, SUN, and UCB, Grant/research support from: AbbVie, Amgen, Bristol Myers Squibb, Eli Lilly, Galapagos, Gilead, Janssen, Novartis, Pfizer, SUN, and UCB, Proton Rahman Speakers bureau: AbbVie, Eli Lilly, Janssen, Novartis, Pfizer, and UCB, Consultant of: AbbVie, Amgen, Bristol Myers Squibb, Celgene, Eli Lilly, Janssen, Novartis, Pfizer, Roche, and UCB, Grant/research support from: Janssen and Novartis.

BackgroundGuselkumab (GUS), an IL-23p19 inhibitor, has demonstrated efficacy in psoriatic arthritis (PsA) across key Group for Research and Assessment of Psoriasis (PsO) and Psoriatic Arthritis (GRAPPA)-recommended domains[1,2]. Skin disease and enthesitis have been identified as disease manifestations with earlier response times than others[3].ObjectivesIn this analysis we: (a) Determined whether early skin and/or entheseal response predicts future response in other PsA domains; (b) Evaluated the trajectory for achieving skin/entheseal responses by 52 weeks (W) in patients (pts) without early responses.MethodsPts in the DISCOVER-1 and DISCOVER-2 (D1/2) studies were adults with active PsA despite standard therapies. D1 pts had ≥3 swollen and ≥3 tender joints (SJC/TJC) and C-reactive protein (CRP) ≥0.3 mg/dL; D2 pts had SJC ≥5, TJC ≥5, and CRP ≥0.6 mg/dL. 31% of D1 pts received 1-2 prior TNF inhibitors; D2 pts were biologic-naïve. Pts were randomized 1:1:1 to GUS 100 mg every 4 weeks (Q4W); GUS 100 mg at W0, W4, then every 8 weeks (Q8W); or placebo. These post hoc analyses included only pooled GUS Q4W and Q8W pts (N=748). Early skin response was defined as PsO Area and Severity Index (PASI) score ≤1 at W16 or skin visual analogue scale (VAS) ≤15mm at W8 among pts with a baseline (BL) PASI score >1 and skin VAS >15mm (first assessment time for both); early entheseal response was defined as Leeds Enthesitis Index (LEI) score ≤1 at W8; and categories of early response were defined as skin VAS ≤15mm only vs LEI score ≤1 only vs combined skin VAS ≤15mm & LEI score ≤1 vs none at W8. Potential responses at W24 & W52 included achievement of minimal disease activity (MDA), Disease Activity in PsA (DAPSA) low disease activity (LDA) or remission, DAPSA50, and enthesitis/dactylitis resolution. Associations between early skin/entheseal response and W24/W52 response were assessed with crosstabulations and logistic regression.ResultsEarly skin response associated with greater odds of achieving W24 MDA, DAPSA LDA, DAPSA remission, and DAPSA50, but not enthesitis or dactylitis resolution (Figure 1). Early entheseal response associated with greater odds of achieving all W24 outcomes, including resolution of enthesitis or dactylitis, with the exception of DAPSA remission; DAPSA remission was achieved by a greater proportion of early responders, though the association was significant only at W52. In pts with both BL PsO and enthesitis, early responders in both domains were even more likely to subsequently demonstrate MDA, DAPSA LDA, DAPSA50, DAPSA remission only at W52, and dactylitis resolution than pts with individual responses. Among pts who did not achieve early responses, approximately half did so by W52.ConclusionEarly skin and entheseal responses predicted long-term clinical response, including disease remission. A synergistic effect was observed, in which pts with BL PsO and enthesitis exhibiting early response in both domains were more likely to achieve later clinical response. These results highlight the importance of early response in these two domains on the trajectory of long-term pt outcome.References[1]Deodhar A et al. Lancet. 2020;395(10230):1115-25[2]Mease PJ et al. Lancet. 2020;395(10230):1125-36[3]Coates LC et al. A893. EULAR 2022, DenmarkAcknowledgements:NIL.Disclosure of InterestsLaura Coates Speakers bureau: AbbVie, Amgen, Biogen, Celgene, Eli Lilly, Galapagos, Gilead, Janssen, Medac, Novartis, Pfizer and UCB, Consultant of: AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Eli Lilly, Gilead, Galapagos, Janssen, Novartis, Pfizer, and UCB, Grant/research support from: AbbVie, Amgen, Celgene, Eli Lilly, Janssen, Novartis, Pfizer, and UCB, Julio Ramírez Speakers bureau: AbbVie, Amgen, Eli Lilly, Janssen, Novartis, and UCB, Consultant of: AbbVie, Amgen, Eli Lilly, Janssen, Novartis, and UCB, Dennis McGonagle Grant/research support from: AbbVie, Amgen, Bristol Myers Squibb, Celgene, Eli Lilly, Gilead, Janssen, Novartis, Pfizer, and UCB, Sibel Aydin Grant/research support from: AbbVie, Celgene, Eli Lilly, Janssen, Novartis, Pfizer, and UCB, Miriam Zimmermann Shareholder of: Johnson & Johnson, Employee of: Janssen Scientific Affairs, LLC, Francois Nantel Shareholder of: Johnson & Johnson, Consultant of: Janssen, May Shawi Shareholder of: Johnson & Johnson, Employee of: Janssen Pharmaceutical Companies of Johnson & Johnson, Emmanouil Rampakakis Consultant of: Janssen, Employee of: JSS Medical Research, Peter Nash Grant/research support from: AbbVie, Boehringher-Ingelheim, Eli Lilly, Galapagos, Gilead, GSK, Janssen, MSD, Novartis, Pfizer, Samsung, Sun Pharma, and UCB, Philip J Mease Speakers bureau: AbbVie, Amgen, Eli Lilly, Janssen, Novartis, Pfizer, Sun Pharma, and UCB, Consultant of: AbbVie, Aclaris, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Galapagos, Gilead, GlaxoSmithKline, Inmagene, Janssen, Novartis, Pfizer, Sun Pharma, and UCB, Grant/research support from: AbbVie, Amgen, Bristol Myers Squibb, Eli Lilly, Galapagos, Gilead, Janssen, Novartis, Pfizer, Sun Pharma, and UCB.

Background:Guselkumab (GUS), a novel monoclonal antibody that specifically binds to the p19-subunit of IL-23, demonstrated efficacy in the Ph 3 DISCOVER-1 (D1) & DISCOVER-2 (D2) trials of pts with active psoriatic arthritis (PsA).1,2Dactylitis & enthesitis, key PsA clinical manifestations, can be difficult to treat and may portend more significant disease burden.3,4Objectives:In pts with dactylitis or enthesitis at baseline, assess: 1) changes in symptoms over time and 2) relationships between improvements in dactylitis or enthesitis and other PsA domains.Methods:Adults with active PsA despite standard therapies were eligible for D1 & D2. Approx. 30% of D1 pts previously received 1-2 TNF inhibitors; D2 pts were biologic-naïve. Pts were randomized 1:1:1 to GUS 100mg Q4W; GUS 100mg at W0, W4, Q8W; or PBO. Independent assessors evaluated dactylitis (total score: 0-60) & enthesitis (Leeds Enthesitis Index [LEI]; total score 0-6). Dactylitis and enthesitis findings through W24 were prespecified to be pooled across D1 & D2. P-values are unadjusted. We assessed changes in dactylitis and LEI scores over time (ANCOVA); associations between dactylitis or enthesitis resolution and ACR/PASI responses at W24 (Chi-square); and correlations between dactylitis or LEI and HAQ-DI/SF-36 change scores at W24 (Spearman’s correlation). AEs through W24 were reported.1,2Results:At W0, 42% of pooled D1+D2 pts had dactylitis; 65% had enthesitis. GUS improved dactylitis and LEI scores vs PBO at W8, W16, W24. GUS vs PBO differences were significant for dactylitis changes at W16 & W24 and LEI changes at W8 (Q4W only), W16 & W24; no dose response was observed (Fig). Rates of dactylitis or enthesitis resolution by W24 were consistently significantly (p<0.001) associated with ACR20/50/70 and PASI75/90 response (Table). In GUS-treated pts at W24, significant correlations were observed between dactylitis change scores and PASI (p<0.001 Q4W; p=0.006 Q8W) and SF-36 MCS (p=0.038 Q4W; p=0.003 Q8W) changes, and between LEI and HAQ-DI change scores (p<0.001 Q4W; p=0.005 Q8W). No consistent correlations/associations were observed between dactylitis or LEI scores and other clinical outcomes.Conclusion:In PsA pts with dactylitis or enthesitis at W0, GUS improved dactylitis or LEI scores vs PBO by W8; treatment differences were significant at W16 & W24. Resolution of dactylitis or enthesitis was significantly associated with clinically meaningful improvements in PsA joint & skin symptoms. Improved dactylitis scores correlated with improved skin symptoms and mental health; improved LEI scores correlated with improved physical function.References:[1]Deodhar A (A#807),[2]Mease P (A#L13), Arthritis Rheumatol 2019;71(suppl 10);[3]DOI: 10.1186/s13075-017-1399-5;4DOI: 10.1016/j.semarthrit.2018.02.002Table.Pooled DISCOVER-1&2: associations between dactylitis/enthesitis resolution and joint/skin responseACR20ACR50ACR70PASI75aPASI90aDactylitis resolutionbN%pts%pts%ptsN%pts%pts Q4W37355*34*16*12178*55* Q8W37553*31*16*11680*65* PBO37226*12*5*11519*10*Enthesitis resolutionc Q4W24334*31*11*18782*63* Q8W23040*7*12*16277*62* PBO25514*13*5*18219*9** p < 0.001 (Chi-square)aIn pts with ≥3% BSA psoriasis & IGA ≥2 at W0bIn pts with D at W0cIn pts with E at W0Acknowledgments:NoneDisclosure of Interests:Dennis McGonagle Grant/research support from: Janssen Research & Development, LLC, Iain McInnes Grant/research support from: Bristol-Myers Squibb, Celgene, Eli Lilly and Company, Janssen, and UCB, Consultant of: AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly and Company, Gilead, Janssen, Novartis, Pfizer, and UCB, Atul Deodhar Grant/research support from: AbbVie, Eli Lilly, GSK, Novartis, Pfizer, UCB, Consultant of: AbbVie, Amgen, Boehringer Ingelheim, Bristol Myer Squibb (BMS), Eli Lilly, GSK, Janssen, Novartis, Pfizer, UCB, Speakers bureau: AbbVie, Amgen, Boehringer Ingelheim, Bristol Myer Squibb (BMS), Eli Lilly, GSK, Janssen, Novartis, Pfizer, UCB, Georg Schett Speakers bureau: AbbVie, BMS, Celgene, Janssen, Eli Lilly, Novartis, Roche and UCB, Philip J Mease Grant/research support from: Abbott, Amgen, Biogen Idec, BMS, Celgene Corporation, Eli Lilly, Novartis, Pfizer, Sun Pharmaceutical, UCB – grant/research support, Consultant of: Abbott, Amgen, Biogen Idec, BMS, Celgene Corporation, Eli Lilly, Novartis, Pfizer, Sun Pharmaceutical, UCB – consultant, Speakers bureau: Abbott, Amgen, Biogen Idec, BMS, Eli Lilly, Genentech, Janssen, Pfizer, UCB – speakers bureau, May Shawi Shareholder of: Johnson & Johnson, Employee of: Janssen Research & Development, LLC, Shelly Kafka Employee of: Janssen Scientific Affairs, LLC, Chetan Karyekar Shareholder of: Johnson & Johnson, Consultant of: Janssen, Employee of: Janssen Global Services, LLC. Previously, Novartis, Bristol-Myers Squibb, and Abbott Labs., Alexa Kollmeier Shareholder of: Johnson & Johnson, Employee of: Janssen Research & Development, LLC, Elizabeth C Hsia Shareholder of: Johnson & Johnson, Employee of: Janssen Research & Development, LLC, Xie L Xu Shareholder of: Johnson & Johnson, Employee of: Janssen Research & Development, LLC, Shihong Sheng Shareholder of: Johnson & Johnson, Employee of: Janssen Research & Development, LLC, Prasheen Agarwal Shareholder of: Johnson & Johnson, Employee of: Janssen Research & Development, LLC, Bei Zhou Shareholder of: Johnson & Johnson, Employee of: Janssen Research & Development, LLC, Christopher T. Ritchlin Grant/research support from: UCB Pharma, AbbVie, Amgen, Consultant of: UCB Pharma, Amgen, AbbVie, Lilly, Pfizer, Novartis, Gilead, Janssen, Proton Rahman Grant/research support from: Janssen and Novartis, Consultant of: Abbott, AbbVie, Amgen, BMS, Celgene, Lilly, Janssen, Novartis, and Pfizer., Speakers bureau: Abbott, AbbVie, Amgen, BMS, Celgene, Lilly, Janssen, Novartis, Pfizer

BackgroundPsoriatic arthritis (PsA), a chronic inflammatory disease characterized by peripheral arthritis, axial inflammation, dactylitis, enthesitis, and skin/nail psoriasis, is associated with reduced health-related quality of life (HRQoL).ObjectivesTo assess long-term effect of guselkumab (GUS), a human monoclonal antibody that selectively targets the interleukin (IL)-23p19 subunit, on HRQoL of bio-naïve PsA patients (pts) who participated in the Phase 3 2-year DISCOVER-2 trial.1MethodsPts with active PsA despite nonbiologic disease-modifying antirheumatic drugs (DMARDs) and/or nonsteroidal anti-inflammatory drugs (NSAIDs) received GUS 100 mg every 4 weeks (Q4W); GUS 100 mg at W0, W4, then Q8W; or placebo (PBO). At W24, PBO pts crossed over to GUS 100 mg Q4W. HRQoL was assessed using the pt-reported EuroQoL-5 Dimension-5 Level (EQ-5D-5L) questionnaire index and EuroQol Visual Analog Scale (EQ-VAS), widely used and complimentary tools that allow pts to provide a global assessment of their HRQoL. The EQ-5D-5L index assesses mobility, self-care, usual activities, pain/discomfort, and anxiety/depression; an index score is derived ranging from 0 (death) to 1 (perfect health).2 EQ-VAS assesses pt health state on a scale of 0-100, with higher scores indicating better health. Using mixed effects models for repeated measures (MMRM), least squares (LS) mean changes from baseline in the EQ-5D-5L index and EQ-VAS through W100 were assessed. Observed changes from baseline were evaluated; in pts who met treatment failure rules before W24 and in pts who discontinued with missing data after W24, changes from baseline were imputed as 0.ResultsGUS-treated pts achieved greater improvements in pt-reported health status than PBO at both W16 and W24 when evaluated using both the EQ-5D-5L index score and the EQ-VAS. The improvements by GUS in EQ-5D-5L index scores through W24 (0.12 for GUS Q4W/Q8W vs 0.05 for PBO; each nominal p<0.0001) were maintained with continued GUS through 2 years (0.15 for GUS Q4W/Q8W) (Table 1). PBO-treated pts who started GUS at W24 reported comparable improvements in their HRQoL by W52 (0.12), with maintenance though W100 (0.14). Similar results were observed with EQ-VAS (Figure 1). W24 improvements in EQ-VAS scores were greater following GUS treatment (18.2/18.4 GUS Q4W/Q8W) vs PBO (6.8; nominal p<0.0001). EQ-VAS scores continued to improve with GUS through 2 years (25.0/24.6 GUS Q4W/Q8W). Likewise, PBO-treated pts who crossed over to GUS at W24 experienced improvements in HRQoL by W52 (18.8), with maintenance through W100 (21.2).Table 1.LS mean change from baseline through W100 in EQ-5D-5L indexGUS 100mg Q4W(W0-100)GUS 100mg Q8W(W0-100)PBO → GUS 100 mg Q4WPBO(W0-24)GUS(W24-100)Week162410016241001624100N243244243247246248244244244LS mean change (95% CI)0.10 (0.09,0.12)0.12 (0.1,0.13)0.15 (0.13,0.16)0.11 (0.1,0.13)0.12 (0.1,0.13)0.15 (0.13,0.17)0.06 (0.04,0.07)0.05 (0.04,0.07)0.14 (0.12,0.16) Diff vs. PBO0.04 (0.02,0.06)0.06 (0.04,0.09)--0.05 (0.03,0.07)0.06 (0.04,0.08)-------- Nominal p-value<0.0001<0.0001--<0.0001<0.0001--------CI=Confidence interval; Diff=DifferenceConclusionIn bio-naïve pts with active PsA receiving GUS, earlier improvements (at the first timepoint assessed) in self-reported HRQoL measures were sustained through 2 years.References[1]Mease PJ, et al. Lancet. 2020;395:1126–36.[2]EuroQol Group. 1990;16:199-208.Disclosure of InterestsJeffrey Curtis Consultant of: AbbVie, Amgen, Bristol-Myers Squibb, CorEvitas, Eli Lilly, Janssen, Myriad, Novartis, Pfizer, Sanofi, and UCB, Grant/research support from: AbbVie, Amgen, Bristol-Myers Squibb, CorEvitas, Eli Lilly, Janssen, Myriad, Novartis, Pfizer, Sanofi, and UCB, Iain McInnes Shareholder of: Causeway Therapeutics, and Evelo Compugen, Consultant of: Astra Zeneca, AbbVie, Amgen, Bristol-Myers Squibb, Cabaletta, Compugen, Eli Lilly, Gilead, GSK, Janssen, Novartis, Pfizer, Roche, Sanofi, and UCB, Grant/research support from: Astra Zeneca, Amgen, Bristol-Myers Squibb, Eli Lilly, GSK, Janssen, Novartis, Roche, and UCB, Proton Rahman Consultant of: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Eli Lilly, Janssen, Merck, Novartis, Pfizer, and UCB, Grant/research support from: Janssen and Novartis, Dafna D Gladman Consultant of: AbbVie, Amgen, Bristol-Myers Squibb, Eli Lilly, Galapagos, Gilead, Janssen, Novartis, Pfizer, and UCB, Grant/research support from: AbbVie, Amgen, Eli Lilly, Janssen, Pfizer, and UCB, Feifei Yang Shareholder of: Johnson & Johnson, Employee of: Janssen Global Services, LLC (a wholly owned subsidiary of Johnson & Johnson), Steve Peterson Shareholder of: Johnson & Johnson, Employee of: Janssen Global Services, LLC (a wholly owned subsidiary of Johnson & Johnson), Alexa Kollmeier Shareholder of: Johnson & Johnson, Employee of: Janssen Research & Development, LLC (a wholly owned subsidiary of Johnson & Johnson), Natalie Shiff Shareholder of: AbbVie, Gilead, and Johnson & Johnson, Employee of: Janssen Scientific Affairs, LLC (a wholly owned subsidiary of Johnson & Johnson), Chenglong Han Shareholder of: Johnson & Johnson, Employee of: Janssen Research & Development, LLC (a wholly owned subsidiary of Johnson & Johnson), May Shawi Shareholder of: Johnson & Johnson, Employee of: Immunology Global Medical Affairs, Janssen Pharmaceutical Companies (a wholly owned subsidiary of Johnson & Johnson), William Tillett Speakers bureau: AbbVie, Amgen, Eli Lilly, Janssen, MSD, Novartis, Pfizer, and UCB, Consultant of: AbbVie, Amgen, Eli Lilly, Janssen, MSD, Novartis, Pfizer, and UCB, Grant/research support from: AbbVie, Amgen, Eli Lilly, Janssen, and UCB, Philip J Mease Speakers bureau: AbbVie, Amgen, Eli Lilly, Janssen, Novartis, Pfizer, SUN Pharma, and UCB, Consultant of: AbbVie, Aclaris, Amgen, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Galapagos, Gilead, GSK, Inmagene, Janssen, Novartis, Pfizer, SUN Pharma, and UCB, Grant/research support from: AbbVie, Amgen, Bristol-Myers Squibb, Eli Lilly, Galapagos, Gilead, Janssen, Novartis, Pfizer, SUN Pharma, and UCB

BackgroundImprovement in health-related quality of life (HRQoL) is a key goal of psoriatic arthritis (PsA) therapy.[1,2]Here, we assess whether early clinical response predicts long-term improvement in HRQoL for patients (pts) with PsA and inadequate response to 1–2 tumour necrosis factor inhibitors (TNFi-IR).ObjectivesAssess the association between early clinical response across various PsA domains and HRQoL at Week (W)48, as well as identify baseline (BL) characteristics that could predict early response in guselkumab (GUS)-treated TNFi-IR PsA pts in the Phase 3b COSMOS trial.MethodsIn the randomized controlled COSMOS trial (NCT03796858),[3]adults with active PsA (swollen/tender joint counts [SJC/TJC] each ≥3) and TNFi-IR were randomized 2:1 to receive subcutaneous injections of either GUS 100 mg (at W0, W4, then every 8 weeks through W44) or placebo (at W0, W4, W12, W20, followed by GUS at W16 [early escape] or at W24 [planned], W28, W36, W44). Only pts randomized to GUS were included in this analysis. Long-term improvements in HRQoL were defined as changes from BL to W48 in 36-item short-form survey (SF-36) physical and mental component summary (PCS and MCS) and Dermatology Life Quality Index (DLQI) scores. Early clinical response was defined as achievement of the following criteria at W4 or W8: American College of Rheumatology (ACR)20, pt pain on a visual analogue scale (VAS) ≤15,SJC ≤1, skin VAS ≤20, and health assessment questionnaire – disability index.(HAQ-DI) ≤0.5. In addition, Psoriasis Area and Severity Index (PASI) ≤1 was considered at W16 – the earliest PASI assessment. Analyses were restricted to pts not meeting the respective early response criteria at BL. Long-term HRQoL improvements were compared between pts achieving vs not achieving early response criteria by means of Student’s.t-test and by multivariate linear regression models adjusting for demographic and BL pt disease characteristics. Results from the multivariate linear regression analyses are presented here. Demographic and BL pt disease characteristics predicting early clinical response were investigated using multivariate logistic regression.ResultsOverall, 189 pts were randomized to GUS, with a mean age of 49.1 years, and 45.5% were male. Among pts not meeting the respective early response criteria at BL, GUS led to.2.7–19.0% and 4.3–38.4% of pts achieving one of the clinical responses of interest as early as W4 and W8, respectively. SF-36 PCS improvement from BL to W48 was significantly associated with ACR20 response, SJC ≤1 and HAQ-DI ≤0.5 achievement at W4 as well as at W8. There were no significant findings for SF-36 MCS. DLQI improvement from BL to W48 was significantly associated with ACR20 and skin VAS ≤20 at W8 (Figure 1). Improvements in SF-36 PCS, SF-36 MCS and DLQI at W48 were all significantly associated with achievement of PASI ≤1 at W16. Multivariate logistic regression identified significant (P<0.05) associations between males and early clinical response at W8 (ACR20: odds ratio [OR]=1.98; HAQ-DI ≤0.5: OR=3.71), BL SJC and.SJC ≤1 at W8 (OR=0.84), BL HAQ-DI and HAQ-DI ≤0.5 at W8 (OR=0.23), and BL skin VAS and skin VAS ≤20 at W8 (OR=0.98).ConclusionFor pts receiving GUS, ACR20 response at W4 and W8 was positively associated with SF-36 PCS improvement from BL to W48, and also at W8 with DLQI improvement from BL to W48. Therefore, early clinical response is relevant for HRQoL improvements over time. These results may help in shared decision-making processes.References[1]Gossec Let al Ann Rheum Dis2020;79:700–12[2]Coates LCet al. Nat Rev Rheumatol2022;18:465–79[3]Coates LCet al Ann Rheum Dis2022;81:359–69Acknowledgements:NIL.Disclosure of InterestsLaure Gossec Consultant of: AbbVie, Amgen, BMS, Celltrion, Galapagos, Janssen, Lilly, MSD, Novartis, Pfizer, Sandoz, UCB, Grant/research support from: Sandoz, UCB, Daniel Aletaha Speakers bureau: Abbvie, Gilead, Galapagos, Eli Lilly, Janssen, Merck, Novartis, Pfizer, Sandoz, and Sanofi, Consultant of: Abbvie, Gilead, Galapagos, Eli Lilly, Janssen, Merck, Novartis, Pfizer, Sandoz, and Sanofi, Grant/research support from: Abbvie, Gilead, Galapagos, Eli Lilly, Janssen, Merck, Novartis, Pfizer, Sandoz, and Sanofi, Philipp Sewerin Speakers bureau: AXIOM Health, Amgen, AbbVie, Biogen, Bristol-Myers Squibb, Celgene, Chugai Pharma Marketing Ltd./ Chugai Europe, Deutscher Psoriasis-Bund, Gilead Sciences, Hexal Pharma, Janssen-Cilag, Johnson & Johnson, Lilly/ Lilly Europe/ Lilly Global, medi-login, Mediri GmbH, Novartis Pharma, Onkowissen GmbH, Pfizer, Roche Pharma, Rheumazentrum Rhein-Ruhr, Sanofi-Genzyme, Spirit Medical Communications, Swedish Orphan Biovitrum, UCB Pharma, Consultant of: AXIOM Health, Amgen, AbbVie, Biogen, Bristol-Myers Squibb, Celgene, Chugai Pharma Marketing Ltd./ Chugai Europe, Deutscher Psoriasis-Bund, Gilead Sciences, Hexal Pharma, Janssen-Cilag, Johnson & Johnson, Lilly/ Lilly Europe/ Lilly Global, medi-login, Mediri GmbH, Novartis Pharma, Onkowissen GmbH, Pfizer, Roche Pharma, Rheumazentrum Rhein-Ruhr, Sanofi-Genzyme, Spirit Medical Communications, Swedish Orphan Biovitrum, UCB Pharma, Grant/research support from: AXIOM Health, Amgen, AbbVie, Biogen, Bristol-Myers Squibb, Celgene, Chugai Pharma Marketing Ltd./ Chugai Europe, Deutscher Psoriasis-Bund, Gilead Sciences, Hexal Pharma, Janssen-Cilag, Johnson & Johnson, Lilly/ Lilly Europe/ Lilly Global, medi-login, Mediri GmbH, Novartis Pharma, Onkowissen GmbH, Pfizer, Roche Pharma, Rheumazentrum Rhein-Ruhr, Sanofi-Genzyme, Spirit Medical Communications, Swedish Orphan Biovitrum, UCB Pharma, Alen Zabotti Speakers bureau: AbbVie, Novartis, Janssen, Lilly, UCB, Amgen, Paid instructor for: AbbVie, Novartis, UCB, Filip van den Bosch Consultant of: AbbVie, Amgen, Eli Lilly, Galapagos, Janssen, Moonlake, Novartis, Pfizer and UCB, Michela Efficace Shareholder of: Janssen Pharmaceutical Companies of Johnson and Johnson, Employee of: Janssen Pharmaceutical Companies of Johnson and Johnson, Frederic Lavie Shareholder of: Johnson & Johnson, Abbvie, Employee of: The Janssen Pharmaceutical Companies of Johnson & Johnson, Miriam Zimmermann Employee of: Janssen Pharmaceutical Companies of Johnson and Johnson, Mohamed Sharaf Employee of: Janssen Pharmaceutical Companies of Johnson and Johnson, Iain McInnes Speakers bureau: Abbvie, Consultant of: Amgen Abbvie, Astra Zeneca, GSK, Lilly, Sanofi, Evelo, Compugen, Cabaletta, UCB, Novartis, BMS, Causeway Therapeutics, Gilead, Moonlake, Pfizer, Janssen, Grant/research support from: Amgen, AstraZeneca, BMS, Lilly Novartis, Janssen, GSK, UCB, Pfizer.

Background:In OA, there is a close association of meniscus and cartilage pathologies. Meniscus degeneration and lesioning are critical risk factors for development of early OA. Hence, thisex-vivostudy assessed the responses to standardized loading of human meniscus samples as a function of degeneration and based on changes in their T1, T2 and T1ρ maps (as surrogate parameters of the tissue’s functionality).Objectives:Can meniscus functionality be visualized by serial quantitative MRI mapping technics?Methods:During total knee replacements, 45 meniscus samples of variable degeneration were harvested from the center of the lateral meniscus body (Fig. 1a1-a3). After preparation to standard, samples were subject to force-controlled loading using an MRI-compatible lever device that created compressive loading by torque ((Fig. 1a4-a5). For each sample and loading position, MRI measurements (as detailed below) were performed in the unloaded (δ0) and loaded configurations, i.e. loaded to 2 bar (δ1, 37.1 N compressive force, 0.67 Nm torque) and to 4 bar (δ2, 69.1 N, 1.24 Nm). Throughout all loading positions, morphological and quantitative imaging was performed using Proton Density-weighted and T1, T1ρ, and T2 mapping sequences (3.0 T, Achieva, Philips) based on standard turbospin-echo, inversion-recovery, spin-lock multi-gradient-echo, and multi-spin-echo sequences. For reference purposes, histological (i.e. Pauli classification) and biomechanical measures (i.e. Elastic Modulus) were obtained for each sample. Based on Pauli sum scores, samples were trichotomized as grossly intact, (n=14), mildly degenerated (n=16), and moderate-to-severely degenerated (n=15).Figure 1.Preparation of meniscus samples and details of the MRI-compatible loading device. The lateral meniscus (a1) was cut to standard size by use of a dedicated cutting block (a2) to eventually obtain lateral meniscus samples (from the body region) of standard dimensions (a3). These samples were then placed in a dedicated MRI-compatible loading device for pressure-controlled, quasi-static and torque-induced loading under simultaneous MR imaging (a4). Two parallel support beams allowed standardized positioning in the MRI scanner‘s bore (a5).Results:Morphologically, loading induced deformation and flattening in all samples (Fig. 2a). For T1, homogeneous loading-induced decreases in all samples were found, irrespective of degeneration (Fig. 2b). For T1ρ, increases in the apical zones of intact samples were observed, and decreases in degenerated samples (Fig. 2c). For T2, changes were ambiguous and incoherent (Fig. 2d).Figure 2.Serial morphological images and functional maps of histologically moderately degenerative human meniscus as a function of force-controlled loading. Serial PDw (a), T1 (b), T1ρ (c), and T2 maps (d) are displayed at increasing loading intensity (δ0: unloaded [a1-d1]; δ1: loaded to 2 bar [a2-d2]; δ2: loaded to 4 bar [a3-d3]). Histologically, this sample demonstrated signs of severe surface desintegration and disruption. Pauli sum score 12, i.e. moderate to severe degeneration (Pauli Grade III). In b – d, color-coded parameter value maps are overlaid onto the corresponding morphological images. Histological sections are stained with Hematoxylin-Eosin (e1) and Safranin O (e2).Conclusion:Meniscus functionality may be visualized using serial quantitative MRI mapping techniques. T1ρ may provide an imaging biomarker of relevant intra-tissue adaptations that seem to be associated with histological degeneration. The perspective evaluation of meniscus functionality may be indicative of incipient or manifest load transmission failure to the adjacent cartilage layer.Disclosure of Interests:Philipp Sewerin Grant/research support from: AbbVie Deutschland GmbH & Co. KGBristol-Myers Squibb Celgene GmbHLilly Deutschland GmbHNovartis Pharma GmbH Pfizer Deutschland GmbHRheumazentrum Rhein-Ruhr, Consultant of: AMGEN GmbH AbbVie Deutschland GmbH & Co. KG Biogen GmbHBristol-Myers Squibb Celgene GmbH Chugai Pharma arketing Ltd. / Chugai Europe GmbHHexal Pharma Janssen-CilagGmbH Johnson & Johnson Deutschland GmbHLilly Deutschland GmbH / Lilly Europe / Lilly Global Novartis Pharma GmbH Pfizer Deutschland GmbH Roche Pharma Rheumazentrum Rhein-Ruhr Sanofi-Genzyme Deutschland GmbH Swedish Orphan Biovitrum GmbH UCB Pharma GmbH, Speakers bureau: AMGEN GmbH AbbVie Deutschland GmbH & Co. KG Biogen GmbHBristol-Myers Squibb Celgene GmbH Chugai Pharma arketing Ltd. / Chugai Europe GmbHHexal Pharma Janssen-CilagGmbH Johnson & Johnson Deutschland GmbHLilly Deutschland GmbH / Lilly Europe / Lilly Global Novartis Pharma GmbH Pfizer Deutschland GmbH Roche Pharma Rheumazentrum Rhein-Ruhr Sanofi-Genzyme Deutschland GmbH Swedish Orphan Biovitrum GmbH UCB Pharma GmbH, Lisa Dötsch: None declared, Daniel Truhm: None declared, Daniel Abrar: None declared, Sven Nebelung: None declared

BackgroundIn patients (pts) with mono/oligoarticular psoriatic arthritis (PsA), swelling or tenderness of specific joints can be associated with poorer pt-reported outcomes (PROs) and physician global assessment[1]. We hypothesize that location of affected entheseal points may also have differential impact on PROs or time to enthesitis resolution with guselkumab (GUS).Objectives(1) Describe the distribution of affected entheseal points in pts with active polyarticular PsA; (2) evaluate the impact of anatomical location of enthesitis and Leeds enthesitis index (LEI) score on pt-reported pain (PtP), pt global assessment (PtGA), and functional status; and (3) compare the time to resolution of each entheseal point following treatment with GUS.MethodsThis post-hoc analysis used pooled data from adults with active PsA, despite standard therapies, from the DISCOVER-1 and -2 studies who were randomized to GUS 100 mg every 4 weeks (Q4W) or at W0, W4, then Q8W. Only pts with baseline (BL) enthesitis were included (N=473). Proportions of pts with enthesitis were determined for each entheseal point assessed by LEI score. Longitudinal impact of LEI score and location of individual entheseal points on PtP, PtGA, and health assessment questionnaire disability index (HAQ-DI), upon adjusting for potential confounders (age, sex, body mass index, prior TNFi use, BL PsA duration, SJC, TJC), was assessed with mixed models for repeated measures through W52. Time to resolution of enthesitis at each anatomical location was assessed with Kaplan-Meier survival analysis.ResultsApproximately half (49.5%) of GUS-randomized pts with BL enthesitis had an LEI score of 1 or 2. The most commonly affected entheseal point was Achilles tendon insertion among both pts with BL enthesitis and pts with an LEI score of 1 or 2. Through W52, higher BL LEI score was associated with increased PtP, PtGA, and HAQ-DI scores (Table 1). Of the individual entheseal points assessed, enthesitis of Achilles tendon insertion had the greatest impact on all PROs and enthesitis of medial femoral condyle the least. Following GUS treatment, median time to enthesitis resolution was W8 for each of the three anatomical locations assessed by the LEI (Figure 1).ConclusionIn this population of pts with active polyarticular PsA, Achilles tendon insertion was the most commonly affected entheseal point and more highly associated with worse PtP, PtGA, and functional status. GUS treatment was associated with rapid enthesitis resolution, including resolution of Achilles enthesitis.Reference[1]Ayan G. Int J Rheum Dis. 2020;23(8):1094-9.Table 1.Parameter Estimates§(95% Confidence Limits) of Association of LEI Score or Individual Entheseal Points with PROs (Higher Parameter Estimates Indicate Greater Association)DeterminantPresence/ # of pointsPtP (0-100)PtGA (0-100)HAQ-DI (0-3)LEI Score0.8 (0.3, 1.2)†1.7 (1.1, 2.3)‡0.01 (0.004, 0.02)†Enthesitis of Achilles Tendon InsertionYes vs. No¥3.7 (1.8, 5.6)†2.0 (-0.5, 4.6)0.04 (-0.001, 0.08)2 vs. 0¥2.3 (0.7, 4.0)†4.6 (2.4, 6.8)‡0.04 (0.01, 0.08)*1 vs. 0¥3.5 (1.9, 5.1)‡3.2 (1.1, 5.4)†0.05 (0.02, 0.08)†Enthesitis of Lateral Epicondyle HumerusYes vs. No¥3.0 (1.0, 4.9)†0.9 (-1.6, 3.4)0.02 (-0.02, 0.06)2 vs. 0¥1.8 (0.1, 3.6)*3.8 (1.6, 6.1)†0.02 (-0.02, 0.05)1 vs. 0¥2.5 (0.9, 4.0)†1.8 (-0.2, 3.8)0.03 (0.001, 0.07)*Enthesitis of Medial Femoral CondyleYes vs. No¥1.0 (-1.0, 3.0)-0.04 (-2.7, 2.6)-0.01 (-0.05, 0.03)2 vs. 0¥0.3 (-1.4, 1.9)2.0 (-0.2, 4.1)0.02 (-0.01, 0.06)1 vs. 0¥0.1 (-1.5, 1.8)1.6 (-0.5, 3.7)-0.02 (-0.05, 0.01)§Parameter estimates correspond to the incremental increase in each PRO for ‘Yes vs No’, ‘2 vs 0’, and ‘1 vs 0’ or for every increase in LEI score by one unit.¥Categories ‘No’ and ‘0’ correspond to pts with BL enthesitis who do not have enthesitis of the individual entheseal point.*p <0.05;†p <0.01;‡p ≤0.0001. Bold text=statistical significance.Acknowledgements:NIL.Disclosure of InterestsLaura Coates Speakers bureau: AbbVie, Amgen, Biogen, Celgene, Eli Lilly, Galapagos, Gilead, Janssen, Medac, Novartis, Pfizer, and UCB, Consultant of: AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Eli Lilly, Gilead, Galapagos, Janssen, Novartis, Pfizer, and UCB, Grant/research support from: AbbVie, Amgen, Celgene, Eli Lilly, Janssen, Novartis, Pfizer, and UCB, Iain McInnes Shareholder of: Causeway Therapeutics, Evelo Compugen, Consultant of: AbbVie, Amgen, Astra Zeneca, Bristol Myers Squibb, Eli Lilly, Cabaletta, Compugen, GSK, Gilead, Janssen, Novartis, Pfizer, Sanofi, Roche, and UCB, Grant/research support from: Amgen, Astra Zeneca, Bristol Myers Squibb, Eli Lilly, GSK, Janssen, Novartis, Roche, and UCB, Sibel Aydin Consultant of: AbbVie, Celgene, Eli Lilly, Novartis, Pfizer, and UCB, Grant/research support from: AbbVie, Celgene, Eli Lilly, Novartis, Pfizer, and UCB, Mitsumasa Kishimoto Speakers bureau: AbbVie, Amgen, Asahi-Kasei Pharma, Astellas, Ayumi Pharma, Bristol Myers Squibb, Chugai, Daiichi-Sankyo, Eisai, Eli Lilly, Gilead, Janssen, Kyowa Kirin, Novartis, Ono, Pfizer, Tanabe-Mitsubishi, and UCB, Consultant of: AbbVie, Amgen, Asahi-Kasei Pharma, Astellas, Ayumi Pharma, Bristol Myers Squibb, Chugai, Daiichi-Sankyo, Eisai, Eli Lilly, Gilead, Janssen, Kyowa Kirin, Novartis, Ono, Pfizer, Tanabe-Mitsubishi, and UCB., Philip J Mease Speakers bureau: AbbVie, Amgen, Eli Lilly, Janssen, Novartis, Pfizer, Sun Pharma, and UCB, Consultant of: AbbVie, Aclaris, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Galapagos, Gilead, GSK, Inmagene, Janssen, Novartis, Pfizer, Sun Pharma, and UCB, Grant/research support from: AbbVie, Amgen, Bristol Myers Squibb, Eli Lilly, Galapagos, Gilead, Janssen, Novartis, Pfizer, Sun Pharma, and UCB, May Shawi Shareholder of: Johnson & Johnson, Employee of: Immunology Global Medical Affairs, Janssen Pharmaceutical Companies of Johnson & Johnson, Miriam Zimmermann Shareholder of: Johnson & Johnson, Employee of: Janssen Research & Development, LLC, Emmanouil Rampakakis Consultant of: Janssen, Employee of: JSS Medical Research, Inc., Frederic Lavie Shareholder of: Johnson & Johnson, Employee of: Immunology Global Medical Affairs, Janssen Pharmaceutical Companies of Johnson & Johnson, Dennis McGonagle Consultant of: AbbVie, Amgen, Bristol Myers Squibb, Celgene, Eli Lilly, Gilead, Janssen, Novartis, Pfizer, and UCB, Grant/research support from: AbbVie, Amgen, Bristol Myers Squibb, Celgene, Eli Lilly, Gilead, Janssen, Novartis, Pfizer, and UCB.

Background:DISCOVER-2 was a Phase 3 trial of the first-in-class anti-IL-23-specific mAb guselkumab (GUS) in patients (pts) with psoriatic arthritis (PsA). PsA impacts patients’ productivity at work and in daily activity.1Objectives:To evaluate the effect of GUS on work productivity and daily activity in DISCOVER-2 through 1 year using the Work Productivity and Activity Impairment Questionnaire: PsA (WPAI- PsA).Methods:Bio-naïve adults with active PsA despite nonbiologic DMARDs &/or NSAIDs received subcutaneous GUS 100 mg every 4 weeks (Q4W); GUS 100 mg W0, W4, then Q8W; or placebo (PBO). At W24, PBO pts crossed over to GUS 100 mg Q4W. WPAI-PsA assesses PsA-related work time missed (absenteeism), impairment while working (presenteeism), impaired overall work productivity (absenteeism + presenteeism), and daily activity during the previous week. A shift analysis evaluated proportions of pts employed vs unemployed (regardless of desire to work) over time. Among pts working at baseline, least-squares (LS) mean changes from baseline in WPAI-PsA domains were determined using a mixed-effects model for repeated measures analysis, whereby mean changes in WPAI-PsA domains were calculated for each multiple imputation (MI) dataset using an analysis of covariance (ANCOVA); the reported LSmean is the average of all MI datasets. Also, among pts employed at baseline, indirect savings from improved overall work productivity were estimated using 2020 EU mean yearly wage estimate (all occupations).2Results:In pts working at baseline, significant improvement in work productivity and non-work activity vs PBO was observed at W24. Productivity gains seen with GUS at W24 continued to improve through 1 year (Table 1). Shift analysis showed relatively stable employment in pts employed at baseline (62% of shift analysis cohort) through 1 year of GUS (>91% continued to work when assessed at W16, W24, and W52 [data not shown]). For those unemployed at baseline (38% of cohort), the proportion of pts working increased by ~10% following 1 year of GUS (Figure 1). Potential yearly indirect savings from improved overall work productivity were: €7409 GUS Q4W and €7039 GUS Q8W vs €4075 PBO at W24 and were €8520 GUS Q4W, €9632 GUS Q8W, and €6668 PBO→GUS Q4W at W52.Conclusion:Improvement in work productivity and non-work activity was greater with GUS vs PBO among pts with active PsA through W52. Improvements demonstrated may result in reduction in PsA costs associated with work productivity.References:[1]Tillett W et al. Rheumatol (Oxford). 2012;51:275–83.[2]OECD (2020). Average wages (indicator). https://data.oecd.org/earnwage/average-wages.htmTable 1.Model-based estimates of LSmean changea (95% CI) from baseline in WPAI-PsA domains among pts working at baseline and with an observed change through W24 (N=474) and W52 (N=475)Change from baselineGUS 100mg Q4WGUS 100mg Q8WPBO(W0-24)PBO → GUS 100 mg Q4W (W24-52)VisitW24W52W24W52W24W52Absenteeism, N145145147147162163LSmean-3.4 (-6.5,-0.3)-4.1 (-6.8,-1.5)-3.0 (-6.0,0.1)-4.0 (-6.6,-1.3)-3.0 (-6.0, 0.04)-3.0 (-5.5,-0.4)Diff vs. PBO-0.4 (-4.6,3.8)-0.01 (-4.2, 4.2)Presenteeism, N145145147147162163LSmean-20.1 (-23.7,-16.6)-22.4 (-26.3,-18.6)-19.6 (-23.2,-16.1)-25.7 (-29.5,-21.8)-10.5 (-13.9,-7.0)-18.5 (-22.2,-14.7)Diff vs PBO-9.7* (-14.4,-5.0)-9.2* (-13.9,-4.5)Work productivity, N145145147147162163LSmean-20.1 (-24.1,-16.1)-22.6 (-26.8,-18.3)-19.2 (-23.1,-15.2)-25.9 (-30.0,-21.7)-10.6 (-14.4,-6.8)-17.6 (-21.7,-13.6)Diff vs PBO-9.5* (-14.8,-4.2)-8.6* (-13.9,-3.3)Non-work Activity, N242242246246245245LSmean-20.5 (-23.3,-17.7)-25.7 (-28.6,-22.7)-21.2 (-23.9,-18.4)-25.4 (-28.4,-22.5)-9.9 (-12.6,-7.1)-22.3 (-25.3,-19.4)Diff vs PBO-10.6* (-14.4,-6.8)-11.3* (-15.1,-7.5)CI=Confidence intervala. LSmean for each MI dataset is calculated based on an ANCOVA model for the change from baseline at W24/W52. The combined LSmean, which is the average of the LSmean, taken over all the MI datasets, is presented.*p<0.05Disclosure of Interests:Jeffrey Curtis Consultant of: AbbVie, Amgen, Bristol-Myers Squibb, Corrona, Janssen, Lilly, Myriad, Pfizer, Regeneron, Roche, and UCB, Grant/research support from: AbbVie, Amgen, Bristol-Myers Squibb, Corrona, Janssen, Lilly, Myriad, Pfizer, Regeneron, Roche, and UCB, Iain McInnes Consultant of: AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly and Company, Gilead, Janssen, Novartis, Pfizer, and UCB, Grant/research support from: Bristol-Myers Squibb, Celgene, Eli Lilly and Company, Janssen, and UCB, Steve Peterson Shareholder of: Johnson & Johnson, Employee of: Janssen Global Services, LLC, Prasheen Agarwal Shareholder of: Johnson & Johnson, Employee of: Janssen Research & Development, LLC, Feifei Yang Shareholder of: Johnson & Johnson, Employee of: Janssen Global Services, LLC, Alexa Kollmeier Shareholder of: Johnson & Johnson, Employee of: Janssen Research & Development, LLC, Elizabeth C Hsia Shareholder of: Johnson & Johnson, Employee of: Janssen Research & Development, LLC, Chenglong Han Shareholder of: Johnson & Johnson, Employee of: Janssen Research & Development, LLC, William Tillett Speakers bureau: AbbVie, Amgen, Celgene, Lilly, Janssen, Novartis, Pfizer Inc, and UCB, Consultant of: AbbVie, Amgen, Celgene, Lilly, Janssen, Novartis, MSD, Pfizer Inc, and UCB, Grant/research support from: AbbVie, Celgene, Eli Lilly, Janssen, Novartis, Pfizer Inc, and UCB, Philip J Mease Speakers bureau: Boehringer Ingelheim and GlaxoSmithKline, Grant/research support from: AbbVie, Amgen, Bristol Myers Squibb, Eli Lilly, Galapagos, Gilead, Janssen, Novartis, Pfizer, SUN, and UCB, Proton Rahman Speakers bureau: AbbVie, Eli Lilly, Janssen, Novartis, Pfizer, and UCB, Consultant of: AbbVie, Amgen, Bristol Myers Squibb, Celgene, Eli Lilly, Janssen, Novartis, Pfizer, Roche, and UCB, Grant/research support from: Janssen and Novartis.

BackgroundPain in PsA has multifaceted origins (e.g., peripheral joint inflammation, axial involvement [axPsA], skin lesions, dactylitis, enthesitis, underlying conditions) and can be difficult to treat. Guselkumab (GUS), a fully human IL-23p19 subunit inhibitor, is effective in treating multiple PsA domains and elicited durable improvement in patient (pt)-reported pain (PtP) in the DISCOVER (D)-1&2 trials[1,2].ObjectivesAssess association between improvement in key PsA manifestations and PtP using 1-year D1&2 data.MethodsD1&2 enrolled adults with active PsA despite standard therapies[3,4]. Pts were randomized 1:1:1 to GUS 100 mg every 4 weeks (Q4W); GUS 100 mg at W0, W4, then Q8W; or placebo with crossover to GUS 100 mg Q4W at W24. Treatment groups were pooled (N=1120). Longitudinal associations of improvement in SJC (0-66), TJC (0-68), Leeds enthesitis index (LEI), dactylitis severity score (DSS), Psoriasis Area and Severity Index (PASI), axPsA (N=312), and improvement in overall PtP (0-100 mm) and spinal pain (BASDAI question 2 in pts with axPsA) were assessed. Longitudinal associations of improvement in these PsA manifestations with ≥30%/50%/70% improvements in PtP (PtP-30/50/70) were assessed.ResultsMean (SD) BL PtP of 61.2 (19.8) indicated substantial burden. Upon adjusting for potential confounders, greater improvement in PASI, SJC, and TJC (mutually adjusted) were each associated with significantly greater improvement in PtP and higher odds of achieving PtP-30 through W52(Table 1). PASI reduction was also associated with greater odds of PtP-50, as was TJC improvement for PtP-50/70. In pts with BL enthesitis, LEI, PASI, and TJC improvements were each associated with greater PtP improvement and attaining PtP-30/50/70; SJC reduction was only associated with PtP-30. In pts with BL dactylitis, PASI and TJC reductions were significantly associated with PtP improvement. Overall, axPsA presence did not impact the extent of PtP improvement (data not shown). In pts with axPsA, significant associations were observed between spinal pain improvement and TJC and LEI improvement.ConclusionImprovements in key PsA manifestations were significantly associated with pain reduction, although to varying extents. TJC reduction had the greatest impact on PtP improvement, likely due to overlap of the construct measured. Psoriasis improvement had a greater impact on pain relief than SJC improvement, highlighting the sensory burden of skin lesions, while enthesitis improvement showed a significant association with both overall and spinal pain relief. These findings underscore the importance of utilizing treatments effective across manifestations to address recalcitrant PsA symptoms.References[1]Ritchlin CT. RMD Open 2022;8:e002195[2]Nash P. ACR Convergence 2021 (PO1333)[3]Deodhar A. Lancet 2020;395:1115[4]Mease PJ. Lancet 2020;395:1126Table 1.Adjusted1Associations Between Improvements in Key PsA Manifestations and Pain Improvement Through W52Pt PopulationPredictor (Δ)Δ PtP (β)2Odds Ratio (OR)3Δ Spinal Pain (β)2,4PtP-30PtP-50PtP-70All (N=1120)PASI0.41‡1.05†1.04†1.040.03SJC0.28†1.03*1.031.060.03TJC0.55‡1.05‡1.08‡1.12‡0.06‡BL Enthesitis (N=728)LEI1.62‡1.19‡1.25‡1.32‡0.18†PASI0.47‡1.06†1.06†1.06*0.02SJC0.28†1.03*1.031.030.03TJC0.39‡1.04‡1.05‡1.08‡0.05‡BL Dactylitis (N=473)DSS-0.040.97*1.011.070.01PASI0.31†1.04*1.05*1.050.02SJC0.191.031.031.020.05*TJC0.60‡1.05‡1.06‡1.11‡0.05†*p<0.05;†p<0.01;‡p≤0.00011Adjusted for BL values, age, gender, BMI, SF-36 Mental Component Summary score, presence of TJC – SJC ≥7 (central pain sensitization proxy), FACIT-Fatigue score, and treatment group2β correspond to the incremental increase in pain improvement;3ORs correspond to the incremental increase in the odds of achieving pain endpoints, for every increase in improvement in key PsA manifestations or in the presence (vs absence) of axPsA. Higher β = greater impact on pain improvement4N=312Acknowledgements:NIL.Disclosure of InterestsPeter Nash Consultant of: AbbVie, Boehringer-Ingelheim, Eli Lilly, Gilead/Galapagos, GSK, Janssen, MSD, Novartis, Pfizer, Samsung, Sun Pharma, and UCB, Grant/research support from: AbbVie, Boehringer-Ingelheim, Eli Lilly, Gilead/Galapagos, GSK, Janssen, MSD, Novartis, Pfizer, Samsung, Sun Pharma, and UCB, Iain McInnes Shareholder of: Causeway Therapeutics and Evelo Compugen, Consultant of: AbbVie, Amgen, Astra Zeneca, Bristol-Myers Squibb, Cabaletta, Compugen, Eli Lilly, Gilead, GSK, Janssen, Novartis, Pfizer, Roche, Sanofi, and UCB, Grant/research support from: Amgen, Astra Zeneca, Bristol-Myers Squibb, Eli Lilly, GSK, Janssen, Novartis, Roche, and UCB, Christopher T. Ritchlin Consultant of: AbbVie, Amgen, Eli Lilly, Gilead, Janssen, Novartis, Pfizer, and UCB, Grant/research support from: AbbVie, Amgen, and UCB, Lai-Shan Tam Consultant of: AbbVie, Boehringer-Ingelheim, Eli Lilly, Janssen, Pfizer, and Sanofi, Grant/research support from: Amgen, Boehringer-Ingelheim, GSK, Janssen, Novartis, and Pfizer, Enrique Soriano Speakers bureau: AbbVie, Amgen, Bristol-Myers Squibb, Eli Lilly, Janssen, Novartis, Roche, and UCB, Consultant of: AbbVie, Janssen, Novartis, and Roche, Grant/research support from: AbbVie, Janssen, Novartis, Pfizer, Roche, and UCB, Michael Starr Consultant of: AbbVie, Eli Lilly, Janssen, Novartis, Pfizer, and UCB, Emmanouil Rampakakis Consultant of: Janssen, Employee of: JSS Medical Research, Inc., Frederic Lavie Shareholder of: Johnson & Johnson, Employee of: Immunology Global Medical Affairs, Janssen Pharmaceutical Companies of Johnson & Johnson, May Shawi Shareholder of: Johnson & Johnson, Employee of: Immunology Global Medical Affairs, Janssen Pharmaceutical Companies of Johnson & Johnson, Xenofon Baraliakos Speakers bureau: AbbVie, Biocad, Chugai, Eli Lilly, Janssen, MSD, Novartis, Pfizer, Roche, and UCB, Consultant of: AbbVie, Biocad, Chugai, Eli Lilly, Janssen, MSD, Novartis, Pfizer, Roche, and UCB, Grant/research support from: AbbVie, Biocad, Chugai, Eli Lilly, Janssen, MSD, Novartis, Pfizer, Roche, and UCB, Philip J Mease Speakers bureau: AbbVie, Amgen, Eli Lilly, Janssen, Novartis, Pfizer, Sun Pharma, and UCB, Consultant of: AbbVie, Aclaris, Amgen, Boehringer-Ingelheim, Bristol-Myers Squibb, Eli Lilly, Galapagos, Gilead, GSK, Inmagene, Janssen, Novartis, Pfizer, Sun Pharma, and UCB, Grant/research support from: AbbVie, Amgen, Bristol Myers Squibb, Eli Lilly, Galapagos, Gilead, Janssen, Novartis, Pfizer, Sun Pharma, and UCB.

BackgroundAlthough the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) is used to assess the activity of axial disease in patients (pts) with psoriatic arthritis (PsA), only one of its questions is specific to axial symptoms. Alternatively, the Ankylosing Spondylitis Disease Activity Score (ASDAS) excludes assessment of enthesitis, gives less weight to peripheral activity and is considered more objective than the BASDAI.ObjectivesThe current post hoc analysis aimed to compare the performance of BASDAI and ASDAS in evaluating symptoms of axial involvement in pts with axial PsA (axPsA).MethodsPts enrolled in the DISCOVER-1 (D1) and DISCOVER-2 (D2) studies were adults with active PsA despite standard therapies. D1 pts had ≥3 swollen and ≥3 tender joints (SJC; TJC) and C-reactive protein (CRP) ≥0.3 mg/dL; D2 pts had SJC ≥5, TJC ≥5 and CRP ≥0.6 mg/dL. 31% of D1 pts received 1-2 prior tumor necrosis factor inhibitors; D2 pts were biologic-naïve. Pts were randomized 1:1:1 to GUS 100 mg every 4 weeks (Q4W); GUS 100 mg at W0, W4, then Q8W; or placebo with crossover to GUS Q4W at W24. axPsA was defined by presence of sacroiliitis based on previous radiograph or magnetic resonance (MR) imaging confirmation. Data were pooled across all treatment groups. In addition to BASDAI and ASDAS, modified versions excluding the peripheral arthritis and enthesitis questions (mBASDAI) and the peripheral arthritis question (mASDAS) were calculated. Normalized (scale of 0-10) versions of ASDAS and mASDAS were calculated based on maximum scores of ≈7 and ≈6.3, respectively. The correlation of BASDAI/mBASDAI and ASDAS/mASDAS with SJC, TJC, enthesitis, Functional Assessment of Chronic Illness Therapy (FACIT)-fatigue, pt pain, pt global, and physician global was assessed with Pearson’s correlation coefficient. The cross-sectional and longitudinal (W52) effects of Leeds enthesitis index (LEI), SJC, and axPsA on BASDAI/mBASDAI and ASDAS/mASDAS were assessed with mixed models.Results436 pts with available baseline (BL) BASDAI information were included in the analysis. In pts with axPsA, BASDAI showed weak correlation with SJC, TJC, LEI, and physician global; moderate correlation with fatigue; and strong correlation with pt global and pt pain. Similar results were observed for ASDAS and modified versions. Among pts without axPsA, correlations of BASDAI and ASDAS with SJC, TJC, and LEI remained weak; correlations with pt global and pt pain remained strong. Longitudinally, among pts with and without BL enthesitis, respectively, LEI and SJC showed significant but not clinically important associations with either outcome. Presence of axial disease was associated with significantly greater BASDAI and ASDAS scores, at BL and longitudinally, without differences in the incremental effect on BASDAI, normalized ASDAS, or their modified versions.ConclusionIn pts with axPsA, the BASDAI and ASDAS performed similarly, with both demonstrating weak correlations with peripheral arthritis and moderate/strong correlations with pt fatigue and pain. The BASDAI and ASDAS also showed similar ability to discern changes in axial disease activity. These results suggest that both BASDAI and ASDAS are valid, and perform comparably, in assessing activity of axial disease in PsA pts.REFERENCES:NIL.Acknowledgements:NIL.Disclosure of InterestsXenofon Baraliakos Consultant of: AbbVie, Chugai, Eli Lilly, Galapagos, Janssen, MSD, Novartis, Pfizer, Roche, and UCB, Grant/research support from: AbbVie, MSD, and Novartis, Dafna D Gladman Consultant of: BMS, Galapagos, Gilead, and Novartis, Grant/research support from: AbbVie, Amgen, Eli Lilly, Janssen, Pfizer, UCB, Soumya D Chakravarty Employee of: Janssen Scientific Affairs, LLC and shareholder in Johnson & Johnson, of which Janssen Scientific Affairs, LLC is a wholly-owned subsidiary, Cinty Gong Employee of: Janssen Scientific Affairs, LLC and shareholder in Johnson & Johnson, of which Janssen Scientific Affairs, LLC is a wholly-owned subsidiary, May Shawi Shareholder of: Johnson & Johnson, Employee of: Janssen Pharmaceutical Companies, a wholly-owned subsidiary of Johnson & Johnson, Emmanouil Rampakakis Consultant of: Janssen, Employee of: JSS Medical Research, Mitsumasa Kishimoto Speakers bureau: AbbVie, Amgen, Asahi-Kasei Pharma, Astellas, Ayumi Pharma, BMS, Chugai, Daiichi-Sankyo, Eisai, Eli Lilly, Gilead, Janssen, Novartis, Pfizer, Tanabe-Mitsubishi, and UCB Pharma, Consultant of: AbbVie, Amgen, Asahi-Kasei Pharma, Astellas, Ayumi Pharma, BMS, Chugai, Daiichi-Sankyo, Eisai, Eli Lilly, Gilead, Janssen, Novartis, Pfizer, Tanabe-Mitsubishi, and UCB Pharma, Enrique Soriano Speakers bureau: AbbVie, Amgen, Bristol Myers Squibb, Eli Lilly, Janssen, Novartis, Pfizer, Roche, and UCB, Consultant of: AbbVie, Janssen, Novartis, and Roche, Grant/research support from: AbbVie, Janssen, Novartis, Pfizer, Roche, and UCB, Philip J Mease Speakers bureau: AbbVie, Amgen, Eli Lilly, Janssen, Novartis, Pfizer, Sun Pharma, and UCB, Consultant of: AbbVie, Aclaris, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Galapagos, Gilead, GlaxoSmithKline, Inmagene, Janssen, Novartis, Pfizer, Sun Pharma, and UCB, Grant/research support from: AbbVie, Amgen, Bristol Myers Squibb, Eli Lilly, Galapagos, Gilead, Janssen, Novartis, Pfizer, Sun Pharma, and UCB.

BackgroundThe IL-23p19-subunit inhibitor guselkumab (GUS) demonstrated clinically meaningful improvements in fatigue through one year of treatment[1]independent of its effects on American College of Rheumatology 20% (ACR20) improvement criteria and Minimal Disease Activity (MDA) achievement[2].ObjectivesIn this post-hoc analysis, the Functional Assessment of Chronic Illness Therapy – Fatigue (FACIT-F) scale was used to: (a) evaluate the long-term effect of GUS in maintaining or further improving fatigue between week (W) 52 and W100, and to (b) identify potential early (W8) predictors, in terms of fatigue, for improved long-term fatigue outcomes.MethodsDISCOVER-2 enrolled adult patients (pts) with active PsA (≥5 swollen and ≥5 tender joints and CRP ≥0.6 mg/dl) who were naïve to biologics/JAK inhibitors. Pts were randomized (1:1:1) and treated with GUS 100 mg every 4W (Q4W); GUS 100mg at W0, W4, then Q8W; or placebo (PBO→GUS Q4W; crossing over to GUS Q4W at W24). Pts with baseline (BL) fatigue levels lower than the normative value (FACIT-F score ≤43)[3]were included in these post hoc analyses (N=681). The proportions of pts with clinically meaningful improvement (≥4 points) from BL in FACIT-F and with normative FACIT-F levels between W52 and W100 were calculated using non-responder imputation (NRI) for missing data and compared over time within each treatment group with the McNemar test. Changes in FACIT-F over time were assessed with mixed models adjusting for time, treatment group, their interaction, and BL FACIT-F score. Receiver operating characteristics (ROC) analyses were conducted using Youden’s index to determine optimal cutoffs at W8 for predicting achievement of normative scores and clinically meaningful FACIT-F responses at W100.ResultsAt BL, the mean (SD) FACIT-F score was 28.3 (8.7) with similar levels across treatment groups. At W52, 66.1%, 69.6%, 68.0%, and 67.8% of pts in the PBO→GUS Q4W, GUS Q4W, GUS Q8W, and pooled GUS groups, respectively, achieved clinically meaningful improvements from BL in FACIT-F score; response rates were maintained through W100. Normative FACIT-F levels were achieved by 24.9%, 28.1%, 29.4% and 27.5% of pts in each treatment group, respectively, at W52, and by increasingly greater proportions of pts through W100. Significant improvements from BL in FACIT-F scores were observed at W52 (all nominal p<0.05), with further improvements seen from W52 to W100 across all GUS groups (Figure 1). ROC optimal cutoff in FACIT-F improvement from BL to W8 associated with a clinically meaningful improvement in FACIT-F at W100 was ≥2.0 (nominal p<0.0001); while for achieving normative FACIT-F levels at W100, the optimal cutoff in actual FACIT-F score at W8 was ≥39.5 (nominal p<0.0001).ConclusionThe clinically meaningful improvements in fatigue seen after 1 year of GUS treatment were further enhanced through 2 years, at which time nearly a third of GUS-treated pts reported normative FACIT-F levels. Early targets in FACIT-F levels achieved with GUS were identified to aid in guiding treatment decisions in routine clinical practice.References[1] Ritchlin CT et al. RMD Open. 2022 Mar;8(1);e002195.[2] Rahman P et al. Arthritis Res Ther. 2021 Jul 14;23(1):190.[3] Montan I et al. Value Health. 2018 Nov;21(11):1313-1321.Acknowledgements:NIL.Disclosure of InterestsDafna D Gladman Consultant of: AbbVie, Amgen, Eli Lilly, Janssen, Pfizer, UCB, BMS, Galapagos, Gilead, and Novartis, Grant/research support from: AbbVie, Amgen, Eli Lilly, Janssen, Pfizer, UCB, Michael Starr Speakers bureau: (Advisory boards or honorariums) AbbVie, Eli Lilly, Janssen, Novartis, Pfizer, and UCB, R Ranza Speakers bureau: AbbVie, Janssen, Novartis, Pfizer, Consultant of: AbbVie, Janssen, Novartis, Pfizer, Ana Maria Bravo Perdomo Shareholder of: Johnson & Johnson, Employee of: Janssen Latin America, Marcie Strauss Employee of: Medasource, May Shawi Shareholder of: Johnson & Johnson, Employee of: Janssen Pharmaceutical Companies of Johnson & Johnson, Chenglong Han Shareholder of: Johnson & Johnson, Employee of: Janssen Research & Development, LLC, Emmanouil Rampakakis Consultant of: Janssen, Employee of: JSS Medical Research, Andrew Andrew Östör Consultant of: AbbVie, BMS, Eli Lilly, Gilead, Janssen, Novartis, Paradigm, Pfizer, Roche, and UCB, Philip J Mease Speakers bureau: AbbVie, Amgen, Eli Lilly, Janssen, Novartis, Pfizer, Sun Pharma, and UCB, Consultant of: AbbVie, Aclaris, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Galapagos, Gilead, GlaxoSmithKline, Inmagene, Janssen, Novartis, Pfizer, Sun Pharma, and UCB, Grant/research support from: AbbVie, Amgen, Bristol Myers Squibb, Eli Lilly, Galapagos, Gilead, Janssen, Novartis, Pfizer, Sun Pharma, and UCB.

Background:Guselkumab (GUS), a human monoclonal antibody that specifically binds to the p19-subunit of interleukin (IL)-23, demonstrated efficacy in the Phase 3 VOYAGE 1&2 trials of patients (pts) with moderate to severe plaque psoriasis (PsO)1,2 and in the DISCOVER 1&2 trials of pts with active psoriatic arthritis (PsA).3,4 IL-17 inhibitors used to treat PsO and PsA have been associated with exacerbation or new onset of inflammatory bowel disease (IBD) (e.g., Crohn’s disease or ulcerative colitis).5Objectives:Evaluate the incidence of gastrointestinal (GI)-related and overall serious adverse events (SAEs) from pooled safety data through 1-year of GUS 100 mg treatment from the VOYAGE 1&2 and DISCOVER 1&2 trials.Methods:Using pooled safety data from the VOYAGE 1&2 PsO trials and DISCOVER 1&2 PsA trials, SAEs related to GI disorders were identified using the Medical Dictionary for Regulatory Activities (MedDRA) system-organ class “GI disorders”. Pts with a previous history of IBD were not excluded in these trials; medical history of IBD was collected at baseline in DISCOVER 1&2. Rates of overall SAEs and GI-related SAEs were calculated as the number of SAEs per 100 pt-years (PY) of follow-up (95% confidence intervals). Data are presented for the placebo (PBO)-controlled period (Weeks 0-16 for VOYAGE 1&2; Weeks 0-24 for DISCOVER 1&2) and through 1-year (defined as through Week 48 for VOYAGE 1&2; through Week 60 for DISCOVER 1, and through Week 52 for DISCOVER 2). Events of uveitis and opportunistic infections were also analyzed.Results:Through the PBO-controlled period, the overall rates of GI-related SAEs per 100 PY for pooled VOYAGE 1&2 were: PBO 0.78 (0.02, 4.34), GUS q8w 0; and for pooled DISCOVER 1&2: PBO 0.58 (0.01, 3.23), GUS q8w 0.58 (0.01, 3.21), GUS q4w 0. The GI-related SAEs included: gastrointestinal hemorrhage (PBO; n=1) for pooled VOYAGE 1&2; and inflammatory bowel disease (PBO; n=1) and mechanical ileus (GUS q8w; n=1) for pooled DISCOVER 1&2. Through 1-year, the overall rates of GI-related SAEs for pooled VOYAGE 1&2 were: Combined GUS group (GUS q8w and PBO→GUS groups) 0.51 (0.17, 1.20); and for pooled DISCOVER 1&2: GUS q8w 0.52 (0.06, 1.88), GUS q4w 0, Combined GUS group (GUS q8w, GUS q4w, and PBO→GUS groups) 0.21 (0.02, 0.74). The GI-related SAEs in the Combined GUS group for pooled VOYAGE 1&2 included: gastritis, hemorrhoids, inguinal hernia, pancreatitis, and umbilical hernia (0.10/100PY [0.00, 0.57]; n=1 for each); and in the Combined GUS group for pooled DISCOVER 1&2: mechanical ileus and pancreatitis chronic (0.10/100PY [0.00, 0.57]; n=1 for each). Overall, no cases of exacerbation or new onset of IBD were reported in GUS-treated pts, including 2 pts with a prior history of IBD in DISCOVER 1&2 (total PY of follow-up for the Combined GUS groups in VOYAGE and DISCOVER were 974 and 973, respectively). Through the PBO-controlled period, rates of overall SAEs for GUS-treated pts were comparable to PBO-pts and SAE rates remained low through 1-year of follow-up in the VOYAGE 1&2 and DISCOVER 1&2 trials. There were no reported cases of uveitis, opportunistic infections, or tuberculosis in GUS-treated pts through 1-year.Conclusion:Through 1-year of follow-up with GUS treatment in pooled VOYAGE 1&2 and DISCOVER 1&2, GI-related SAE rates were low. There were no reported cases of uveitis, opportunistic infections, or new onset/exacerbation of IBD in GUS-treated pts. No new safety concerns were identified through 1-year.References:[1]Blauvelt A., et al. J Am Acad Dermatol. 2017;76:405-17.[2]Reich K., et al. J Am Acad Dermatol. 2017;76:418-31.[3]Deodhar A., et al. Lancet. 2020;395:1115-25.[4]Mease P.J., et al. Lancet. 2020; 395:1126-36.[5]Hohenberger M., et al. J Dermatolog Treat. 2018;29:13-8.Disclosure of Interests:Philip J Mease Consultant of: AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Galapagos, Gilead, GlaxoSmithKline, Janssen, Novartis, Pfizer, SUN, and UCB, Grant/research support from: AbbVie, Amgen, Bristol Myers Squibb, Eli Lilly, Galapagos, Gilead, Janssen, Novartis, Pfizer, SUN, and UCB, Peter Foley Speakers bureau: AbbVie, Celgene, Janssen, Lilly, Merck, Novartis, Pfizer, Valeant, Galderma, GSK, Leo Pharma, and Roche, Consultant of: Janssen, Lilly, Novartis, Pfizer, Galderma, AbbVie, Amgen, AstraZeneca, Arcutis, Aslan, Boehringer Ingelheim, Celgene, Hexima, Merck, Sun Pharma, UCB Pharma, Valeant, BMS, Celtaxsys, CSL, Cutanea, Dermira, Genentech, GSK, Leo Pharma, Regeneron Pharmaceuticals Inc, Reistone, Roche, and Sanofi, Grant/research support from: AbbVie, Amgen, Celgene, Janssen, Leo Pharma, Lilly, Merck, Novartis, Pfizer, Sanofi, and Sun Pharma; travel grants from AbbVie, Janssen, Lilly, Merck, Novartis, Pfizer, Galderma, Leo Pharma, Roche, Sun Pharma, and Sanofi, Kristian Reich Consultant of: AbbVie, Amgen, Gilead, Janssen, Lilly, Novartis, Pfizer, and UCB Pharma, Grant/research support from: AbbVie, Amgen, and UCB Pharma, Jerry Bagel Speakers bureau: AbbVie, Celgene Corporation, Eli Lilly, Janssen Biotech, and Novartis, Consultant of: AbbVie, Amgen, Celgene Corporation, Eli Lilly and Company, Janssen Biotech, Leo Pharma, Novartis, Sun Pharmaceutical Industries Ltd, and Valeant Pharmaceuticals, Grant/research support from: AbbVie, Amgen, Arcutis Biotherapeutics, Boehringer Ingelheim, Bristol Myers Squibb, Celgene Corporation, Corrona, LLC, Dermavant Sciences, LTD, Dermira/UCB, Eli Lilly and Company, Glenmark Pharmaceuticals Ltd, Janssen Biotech, Kadmon Corporation, Leo Pharma, Lycera Corp, Menlo Therapeutics, Novartis, Pfizer, Regeneron Pharmaceuticals, Sun Pharma, Taro Pharmaceutical Industries Ltd, and Valeant Pharmaceuticals, Mark Lebwohl Consultant of: Aditum Bio, Allergan, Almirall, Arcutis, Inc., Avotres Therapeutics, BirchBioMed Inc., BMD skincare, Boehringer-Ingelheim, Bristol-Myers Squibb, Cara Therapeutics, Castle Biosciences, Corrona, Dermavant Sciences, Evelo, Evommune, Facilitate International Dermatologic Education, Foundation for Research and Education in Dermatology, Inozyme Pharma, Kyowa Kirin, LEO Pharma, Meiji Seika Pharma, Menlo, Mitsubishi, Neuroderm, Pfizer, Promius/Dr. Reddy’s Laboratories, Serono, Theravance, and Verrica, Grant/research support from: Abbvie, Amgen, Arcutis, Boehringer Ingelheim, Dermavant, Eli Lilly, Evommune, Incyte, Janssen, Leo Pharmaceutucals, Ortho Dermatologics, Pfizer, and UCB, Ya-Wen Yang Shareholder of: Johnson & Johnson, Employee of: Janssen Global Services, LLC, May Shawi Shareholder of: Johnson & Johnson, Employee of: Janssen Global Services, LLC, Megan Miller Shareholder of: Johnson & Johnson, Employee of: Janssen Research & Development, LLC, Alexa Kollmeier Shareholder of: Johnson & Johnson, Employee of: Janssen Research & Development, LLC, Elizabeth C Hsia Shareholder of: Johnson & Johnson, Employee of: Janssen Research & Development, LLC, Xie L Xu Shareholder of: Johnson & Johnson, Employee of: Janssen Research & Development, LLC, Miwa Izutsu Shareholder of: Johnson & Johnson, Employee of: Janssen Research & Development, LLC, Paraneedharan Ramachandran Shareholder of: Johnson & Johnson, Employee of: Janssen Research & Development, LLC, Shihong Sheng Shareholder of: Johnson & Johnson, Employee of: Janssen Research & Development, LLC, Yin You Shareholder of: Johnson & Johnson, Employee of: Janssen Research & Development, LLC, Philip Helliwell Consultant of: Galapagos, Janssen, Novartis, Grant/research support from: Abbvie, Janssen, Pfizer, Wolf-Henning Boehncke Speakers bureau: AbbVie, Almirall, Celgene, Janssen, Leo, Lilly, Novartis, and UCB Pharma, Consultant of: AbbVie, Almirall, Celgene, Janssen, Leo, Lilly, Novartis, and UCB Pharma, Grant/research support from: Pfizer

Background:In the DISCOVER-1 study, the interleukin-23 p19 subunit inhibitor guselkumab (GUS) demonstrated robust efficacy across joint and skin clinical manifestations of psoriatic arthritis (PsA).1 Patients (pts) with PsA also experience a broad range of symptoms that negatively impact health-related quality of life (eg, pain, fatigue, anxiety, depression, sleep disturbance, poor physical function).2Objectives:Assess the treatment effect of GUS on general health outcomes in pts with PsA in the DISCOVER-1 trial through Week (W) 52 using the Patient-Reported Outcomes Measurement Information System-29 (PROMIS-29) instrument.Methods:Pts with active PsA (≥3 swollen + ≥3 tender joints; C-reactive protein ≥0.3 mg/dL) and inadequate response to standard conventional therapies were randomized 1:1:1 to GUS 100 mg Q4W; GUS 100 mg at W0, W4, then Q8W; or placebo (PBO). PBO pts switched to GUS 100 mg Q4W at W24. PROMIS-29 contains 4 items for each of 7 domains (anxiety, depression, fatigue, pain interference, physical function, sleep disturbance, social participation) and 1 pain intensity item; 28 items are scored on a 5-point Likert-type scale, and pain intensity is rated from 0-10. The raw score of each domain is converted to a standardized T-score, with norms based on a general population mean score=50 and a standard deviation (SD)=10. Higher scores in anxiety, depression, fatigue, pain interference, and sleep disturbance indicate more severe symptoms; higher physical function and social participation scores indicate better health outcomes. Changes ≥5 points (1/2 SD of T-score) are considered clinically meaningful. Analyses were performed using both observed (mean scores/changes, effect sizes) and imputed (clinically meaningful response, whereby change from baseline was set to 0 at W24/52 for pts who had missing data or at W24 for pts who met treatment failure criteria prior to W24).Results:At baseline, mean PROMIS-29 T-scores for physical function, social participation, sleep disturbance, pain, and fatigue were worse in the 381 PsA pts enrolled in DISCOVER-1 than in the general US population. Across all 7 domains, observed mean PROMIS-29 T-scores showed improvements in GUS-treated pts from baseline to W24 and W52 (Figure 1). Observed mean changes from baseline to W24 and W52, with calculated effect size, are shown (Table 1). In all pts, including those with imputed data, significantly higher percentages of pts in both GUS treatment groups vs PBO had ≥5-point improvements in fatigue, pain interference, physical function, sleep disturbance, social participation, and pain intensity domains at W24 (all nominal p<0.05). Mean improvements in PROMIS-29 domains were maintained through W52.Conclusion:In pts with active PsA, PROMIS-29 results indicate that GUS treatment was associated with clinically meaningful reductions in fatigue and pain and improvement in physical function and social participation, which were maintained through 1 year.References:[1] Deodhar A et al. Lancet. 2020;395:1115-25.[2] Orbai A et al. Ann Rheum Dis. 2017;76:673-80.Table 1.Mean Change and Effect Size of Change From Baseline in PROMIS-29 Domain Scores at W24 and W52 (Observed)Mean Change From Baseline [Effect Size]GUS Q4WGUS Q8WPBOW0-24GUS Q4WW24-52W24W52W24W52W24W52Anxiety−3.1 [−0.3]−3.1 [−0.3]−3.7 [−0.4]−4.3 [−0.5]−1.5 [−0.2]−3.6 [−0.4]Depression−2.7 [−0.3]−3.0 [−0.4]−4.0 [−0.4]−4.0 [−0.4]−0.6 [−0.1]−2.5 [−0.3]Fatigue−4.8 [−0.5]−5.6 [−0.6]−4.8 [−0.5]−6.8 [−0.7]−2.1 [−0.2]−5.7 [−0.6]Pain interference−5.4 [−0.8]−6.2 [−1.0]−5.8 [−1.0]−7.0 [−1.1]−2.8 [−0.4]−6.3 [−1.0]Physical function5.0 [0.8]5.9 [0.9]4.1 [0.6]5.0 [0.7]1.7 [0.2]4.2 [0.6]Sleep disturbance−2.5 [−0.4]−3.9 [−0.6]−3.8 [−0.6]−4.4 [−0.6]−1.5 [−0.2]−3.3 [−0.5]Social participation4.2 [0.5]5.3 [0.7]5.3 [0.6]6.6 [0.8]1.7 [0.2]4.9 [0.6]Pain intensity*−2.3 [−1.2]−2.8 [−1.5]−2.1 [−1.1]−2.7 [−1.4]−0.7 [−0.4]−2.5 [−1.3]*Raw score; all other domains reported as T-score.Disclosure of Interests:Ana-Maria Orbai Consultant of: Eli Lilly, Janssen, Novartis, Pfizer, UCB, Grant/research support from: Abbvie, Eli Lilly and Company, Celgene, Novartis, Janssen, Horizon, Laura C Coates Consultant of: AbbVie, Amgen, Biogen, Bristol Myers Squibb, Boehringer Ingelehim, Celgene, Domain, Eli Lilly, Gilead, Janssen, Medac, Novartis, Pfizer and UCB, Grant/research support from: AbbVie, Amgen, Celgene, Eli Lilly, Gilead, Novartis, Pfizer, Atul Deodhar Speakers bureau: AbbVie, Eli Lilly, Janssen, Novartis, Pfizer, and UCB, Consultant of: AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Eli Lilly, Galapagos, GSK, Janssen, Novartis, Pfizer, and UCB, Grant/research support from: AbbVie, Eli Lilly, GSK, Novartis, Pfizer, and UCB, Philip Helliwell Consultant of: Galapagos, Janssen, and Novartis, Grant/research support from: Abbvie, Janssen, and Pfizer, Christopher T. Ritchlin Consultant of: AbbVie, Amgen, Gilead, Janssen, Lilly, Novartis, Pfizer, UCB Pharma, Grant/research support from: AbbVie, Amgen, UCB Pharma, Alexa Kollmeier Shareholder of: Johnson & Johnson, of which Janssen Research & Development, LLC is a wholly owned subsidiary, Employee of: Janssen Research & Development, LLC, Elizabeth C Hsia Shareholder of: Johnson & Johnson, of which Janssen Research & Development, LLC is a wholly owned subsidiary, Employee of: Janssen Research & Development, LLC, Xie L Xu Shareholder of: Johnson & Johnson, of which Janssen Research & Development is a wholly owned subsidiary, Employee of: Janssen Research & Development, LLC, Shihong Sheng Shareholder of: Johnson & Johnson, of which Janssen Research & Development, LLC is a wholly owned subsidiary, Employee of: Janssen Research & Development, LLC, Yusang Jiang Employee of: Cytel, Inc., providing statistical support (funded by Janssen), Yan Liu Shareholder of: Johnson & Johnson, of which Janssen Research & Development, LLC is a wholly owned subsidiary, Employee of: Janssen Research & Development, LLC, Chenglong Han Shareholder of: Johnson & Johnson, of which Janssen Research & Development, LLC is a wholly owned subsidiary, Employee of: Janssen Research & Development, LLC.

BackgroundPsoriatic arthritis (PsA) impacts patients’ (pts) work productivity (WP) and daily activity.1 DISCOVER-2 (D2), a Phase 3 trial of the selective interleukin-23 p19-subunit inhibitor guselkumab (GUS) in biologic-naïve pts with PsA,2 demonstrated significant improvements in pt-reported WP and daily activity following 1 year (Y) of GUS treatment.3ObjectivesAssess WP and daily activity impairment in D2 pts through 2Y. Estimate indirect savings associated with GUS treatment and assess changes in employment status.MethodsPts with active PsA received GUS 100 mg every 4 weeks (Q4W); GUS 100 mg at W0, W4, then Q8W; or placebo (PBO). At W24, PBO pts crossed over to GUS 100 mg Q4W. WPAI-PsA assesses PsA-related work time missed (absenteeism), impairment while working (presenteeism), and impaired overall WP (absenteeism + presenteeism) for pts employed at baseline (EBL) and daily activity for all pts, including those unemployed at baseline (UBL) during the previous week. Mean changes in WPAI-PsA domains were calculated for each multiple imputation (MI) dataset using an analysis of covariance (ANCOVA); the reported LS mean is the average of all MI datasets. Significance was defined as p<0.05. Among pts EBL, potential indirect savings from improved overall WP were estimated using 2020 European Union mean yearly wage estimate (all occupations) combined with LS mean change from BL in WPAI-PsA overall work impairment.4 A shift analysis evaluated proportions of pts employed vs unemployed by treatment group using observed data over time.ResultsPts EBL comprised 64% of the analysis cohort. Significant improvements in WP in pts EBL and in daily activity among all pts were observed with GUS Q4W/Q8W vs PBO at W24;3 mean improvements in WP and daily activity increased with continued GUS through 2Y (Table 1). Potential annual indirect savings from improved overall WP in pts EBL were €10,826 GUS Q4W, €12,712 GUS Q8W, and €10,948 PBO→ GUS Q4W at 2Y. Shift analysis showed relatively stable employment in pts EBL with GUS up to 2Y (>83% continued to work). Among pts UBL (36% of cohort), the proportion of pts employed increased by >20% through 2Y of GUS (Figure 1).Table 1.Model-Based Estimates of Change From BL in WPAI-PsA Domains1GUS 100mg Q4WGUS 100mg Q8WPBO (W0-24) → GUS 100 mg Q4W (W24-100)VisitW24W100W24W100W24W100Absenteeism, N145147147149162166 LS Mean (95% CI)-3.4 (-6.5, -0.3)-1.8 (-4.5, 0.9)-3.0 (-6.0, 0.1)-4.2 (-6.8,-1.5)-3.0 (-6.0, 0.04)-4.2 (-6.8,-1.6) Diff vs. PBO-0.4 (-4.6, 3.8)--0.01 (-4.2, 4.2)---Presenteeism, N145147147149162166 LS Mean (95% CI)-20.1 (-23.7, -16.6)-26.3 (-30.1,-22.5)-19.6 (-23.2, -16.1)-28.0 (-31.8, -24.2)-10.5 (-13.9, -7.0)-24.2 (-27.9, -20.5) Diff vs PBO-9.7* (-14.4, -5.0)--9.2* (-13.9, -4.5)---Work productivity, N145147147149162166 LS Mean (95% CI)-20.1 (-24.1, -16.1)-23.8 (-28.0, -19.6)-19.2 (-23.1, -15.2)-28.0 (-32.1, -23.8)-10.6 (-14.4, -6.8)-24.1 (-28.1, -20.1) Diff vs PBO-9.5* (-14.8, -4.2)--8.6* (-13.9, -3.3)---Daily Activity, N242242246246245245 LS Mean (95% CI)-20.5 (-23.3, -17.7)-29.2 (-32.2, -26.1)-21.2 (-23.9, -18.4)-28.0 (-31.0, -24.9)-9.9 (-12.6, -7.1)-26.6 (-29.6, -23.6) Diff vs PBO-10.6* (-14.4, -6.8)--11.3* (-15.1, -7.5)-1Mean changes in WPAI-PsA domains were calculated for each MI dataset using an ANCOVA; reported LS mean (95% confidence interval [CI]) = average of all MI datasets.*p<0.002ConclusionIn GUS-treated bio-naïve PsA pts, robust improvements in WP and daily activity seen at W24 were maintained and increased through 2Y of GUS. Long-term improvements in WP achieved may result in substantial indirect cost savings for GUS-treated pts. Rates of employment remained stable in pts employed and increased in those unemployed at BL.References[1]Tillett W et al. Rheumatol (Oxford). 2012;51:275–83.[2]Mease PJ, et al. Lancet. 2020;395:1126–36.[3]Curtis JR et al. EULAR, June 2–5, 2021. POS1026.[4]OECD (2020). Average wages (indicator). https://data.oecd.org/earnwage/average-wages.htmDisclosure of InterestsJeffrey Curtis Consultant of: AbbVie, Amgen, Bristol-Myers Squibb, CorEvitas, Eli Lilly and Company, Janssen, Myriad, Novartis, Pfizer, Sanofi, and UCB, Grant/research support from: AbbVie, Amgen, Bristol-Myers Squibb, CorEvitas, Eli Lilly and Company, Janssen, Myriad, Novartis, Pfizer, Sanofi, and UCB, Iain McInnes Shareholder of: Causeway Therapeutics, and Evelo Compugen, Consultant of: Astra Zeneca, AbbVie, Bristol-Myers Squibb, Amgen, Eli Lilly and Company, Cabaletta, Compugen, GSK, Gilead, Janssen, Novartis, Pfizer, Sanofi, Roche, and UCB, Grant/research support from: Astra Zeneca, Bristol-Myers Squibb, Amgen, Eli Lilly and Company, GSK, Janssen, Novartis, Roche, and UCB, Proton Rahman Consultant of: AbbVie, Amgen, Bristol Myers Squibb, Celgene, Eli Lilly, Janssen, Merck, Novartis, Pfizer, and UCB, Grant/research support from: Janssen and Novartis, Dafna D Gladman Consultant of: Abbvie, Amgen, BMS, Eli Lilly, Galapagos, Gilead, janssen, Novartis, Pfizer and UCB., Grant/research support from: Abbvie, Amgen, Eli Lilly, Janssen, Pfizer, UCB, Feifei Yang Shareholder of: Johnson & Johnson, Employee of: Janssen Global Services, LLC, Steve Peterson Shareholder of: Johnson & Johnson, Employee of: Janssen Global Services, LLC, Alexa Kollmeier Shareholder of: Johnson & Johnson, Employee of: Janssen Research & Development, LLC, Natalie Shiff Shareholder of: Johnson & Johnson, Abbvie, Gilead, Employee of: Janssen Scientific Affairs, LLC, Chenglong Han Shareholder of: Johnson & Johnson, Employee of: Janssen Research & Development, LLC, May Shawi Shareholder of: Johnson & Johnson, Employee of: Immunology Global Medical Affairs, Janssen Pharmaceutical Companies, William Tillett Speakers bureau: Abbvie, Amgen, Eli-Lilly, Janssen, MSD, Novartis, Pfizer, and UCB, Consultant of: Abbvie, Amgen, Eli-Lilly, Janssen, MSD, Novartis, Pfizer, and UCB, Grant/research support from: Abbvie, Amgen, Eli-Lilly, Janssen, and UCB, Philip J Mease Speakers bureau: AbbVie, Amgen, Eli Lilly, Janssen, Novartis, Pfizer, Sun Pharma, and UCB, Consultant of: AbbVie, Aclaris, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Galapagos, Gilead, GlaxoSmithKline, Inmagene, Janssen, Novartis, Pfizer, Sun Pharma, and UCB, Grant/research support from: AbbVie, Amgen, Bristol Myers Squibb, Eli Lilly, Galapagos, Gilead, Janssen, Novartis, Pfizer, Sun Pharma, and UCB

BackgroundDespite effective treatments, a minority of psoriatic arthritis (PsA) patients (pts) realize sustained minimal disease activity (MDA).1 Pt-driven domains of MDA are less frequently achieved, potentially arising from comorbid conditions.1ObjectivesIdentify domains contributing to and factors influencing MDA achievement in the 2-year Phase 3 DISCOVER-2 trial.MethodsRandomized and treated adults (N=739) had active PsA, were biologic/JAK inhibitor-naive, and had swollen and tender joint counts (SJC/TJC) each ≥5 and C-reactive protein ≥0.6 mg/dL. Pts with medical history of fibromyalgia (FM) were not excluded. Pts were randomized 1:1:1 to GUS 100 mg every 4 weeks (Q4W); GUS 100 mg at W0, W4, then every 8 weeks (Q8W); or placebo (PBO); PBO pts crossed over to GUS 100 mg Q4W at W24. MDA requires fulfillment of ≥5/7 criteria: TJC ≤1, SJC ≤1, Psoriasis Area and Severity Index (PASI) score ≤1, Pt Pain score ≤15, Pt global disease activity (PtGA) score ≤20, Health Assessment Questionnaire – Disability Index (HAQ-DI) score ≤0.5, and ≤1 tender entheses. A longitudinal trajectory of achieving each MDA criterion through W100 was derived (nonresponder imputation [NRI]). Time to achieve was estimated via Kaplan-Meier survival curve for scores deriving from native scales and those normalized to a 0-66 scale (corresponding to SJC). Multivariate regression models for time to achievement (cox proportional hazard) and achievement (logistic regression) of MDA at W100 identified predictors of response.ResultsAmong 492 GUS pts, continuous improvement across all MDA domains was shown through proportions of pts achieving criteria at W24 & W100 (NRI): SJC (45% & 65%), TJC (16% & 34%), PASI (71% & 72%), Pt Pain (23% & 37%), PtGA (29% & 45%), HAQ-DI (34% & 44%), entheseal points (75% & 80%). Times to achieve minimal SJC, PASI, and enthesitis with GUS were significantly faster than for PtGA, Pt Pain, TJC, and HAQ-DI for native-scale scores; when normalized, PtGA, Pt Pain, and HAQ-DI were achieved less often (Figure 1). Higher baseline (BL) Pt Pain score and lower BL Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue score (worse fatigue) were significant predictors of longer time; lower BMI was associated with shorter time to achieve Pt Pain ≤15. Results for achieving Pt Pain ≤15 at W100 were similar. Worse baseline fatigue and PtGA were significant predictors of longer time to PtGA ≤20; worse fatigue also predicted non-achievement of PtGA ≤20 at W100. For time to achieve HAQ-DI ≤0.5, significant BL negative predictors were higher age and BL HAQ-DI score, which were also significant predictors of HAQ-DI ≤0.5 non-achievement at W100. Although seen in only a small number of pts, a significant impact of FM history and suicidal ideation/behavior on Pt Pain ≤15 and HAQ-DI ≤0.5, respectively, was observed (Table 1).Table 1.Predictors of Time to Achievement and Achievement of Recalcitrant MDA Domains at Week 100 in GUS-randomized Pts (N=492)Time to achievementIndependent BL VariablesPt Pain ≤15PtGA ≤20HAQ-DI ≤0.5HR (95% CI)HR (95% CI)HR (95% CI)Age-0.98 (0.97-0.99)†HAQ-DI-0.26 (0.19-0.36)‡PtGA VAS-0.99 (0.98-1.00)*-Pain VAS0.99 (0.98-1.00)†-FACIT-Fatigue§1.02 (1.00-1.03)*1.02 (1.01-1.04)‡-BMI0.98 (0.96-1.00)*FM (N=8)0.70 (0.55-0.90)†--Achievement at W100OR (95% CL)∥OR (95% CL)∥OR (95% CL)∥Age--0.98 (0.96: 1.00)*HAQ-DI--0.13 (0.08: 0.20)‡Pain VAS0.98 (0.97: 1.00)†--FACIT-Fatigue§1.02 (1.00: 1.05)*1.05 (1.03: 1.07)‡-BMI0.97 (0.94: 1.00)*--Suicidal Ideation/Behaviour (N=9)--0.16 (0.03: 0.86)*FM (N=8)0.59 (0.40: 0.86)†--HR Hazard Ratio CI Confidence Interval OR Odds Ratio CL Confidence Limits*p <0.05; †p <0.01; ‡p ≤0.0001§Higher score indicates less fatigue∥Wald CLConclusionGUS provided continuous improvement in each MDA domain through W100. BL domain score, as well as age, fatigue, and BMI, were significant determinants of MDA achievement in recalcitrant pt-driven domains (Pt Pain, PtGA, HAQ-DI). The impact of FM and mental health status merits further evaluation.References[1]Rahman et al. BMJ Open 2017;7(8): e016619Disclosure of InterestsLaura Coates Speakers bureau: AbbVie, Amgen, Biogen, Celgene, Eli Lilly, Galapagos, Gilead, Janssen, Medac, Novartis, Pfizer and UCB, Consultant of: AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Eli Lilly, Gilead, Galapagos, Janssen, Novartis, Pfizer, and UCB, Grant/research support from: AbbVie, Amgen, Celgene, Eli Lilly, Janssen, Novartis, Pfizer, and UCB, Proton Rahman Consultant of: AbbVie, Amgen, Bristol Myers Squibb, Celgene, Eli Lilly, Janssen, Merck, Novartis, Pfizer, and UCB, Grant/research support from: Janssen and Novartis, Philip J Mease Speakers bureau: AbbVie, Amgen, Eli Lilly, Janssen, Novartis, Pfizer, Sun Pharma, and UCB, Consultant of: AbbVie, Aclaris, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Galapagos, Gilead, GSK, Inmagene, Janssen, Novartis, Pfizer, Sun Pharma, and UCB, Grant/research support from: AbbVie, Amgen, Bristol Myers Squibb, Eli Lilly, Galapagos, Gilead, Janssen, Novartis, Pfizer, Sun Pharma, and UCB, May Shawi Shareholder of: Johnson & Johnson, Employee of: Janssen Pharmaceutical Companies of Johnson & Johnson, Emmanouil Rampakakis Consultant of: Janssen, Employee of: JSS Medical Research, Alexa Kollmeier Shareholder of: Johnson & Johnson, Employee of: Janssen Research & Development, LLC, Xie L Xu Shareholder of: Johnson & Johnson, Employee of: Janssen Research & Development, LLC,, Soumya D Chakravarty Shareholder of: Johnson & Johnson, Employee of: Janssen Scientific Affairs, LLC, Iain McInnes Shareholder of: Causeway Therapeutics, and Evelo Compugen, Consultant of: Astra Zeneca, AbbVie, Bristol-Myers Squibb, Amgen, Eli Lilly and Company, Cabaletta, Compugen, GSK, Gilead, Janssen, Novartis, Pfizer, Sanofi, Roche, and UCB, Grant/research support from: Astra Zeneca, Bristol-Myers Squibb, Amgen, Eli Lilly and Company, GSK, Janssen, Novartis, Roche, and UCB, Lai-Shan Tam Consultant of: Janssen, Pfizer, Sanofi, AbbVie, Boehringer Ingelheim, and Lilly, Grant/research support from: Amgen, Boehringer Ingelheim, Janssen, GSK, Novartis and Pfizer

BackgroundGuselkumab (GUS) is associated with robust and sustained improvement in psoriatic arthritis (PsA) signs and symptoms in subgroups of patients (pts) pooled from the phase 3 DISCOVER-1 and DISCOVER-2 trials, across a variety of baseline (BL) pt characteristics through 1[1], and 2 years (DISCOVER-2 only)[2].ObjectivesThis post-hoc analysis using DISCOVER-2 data aimed to evaluate the efficacy of GUS in inducing long-term (Week [W]100) stringent disease control in Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA)-recommended domains across BL characteristics.MethodsDISCOVER-2 enrolled biologic-naïve adults with active PsA defined as ≥5 swollen and ≥5 tender joint counts (SJC; TJC) and C-reactive protein (CRP) ≥0.6 mg/dL. 739 pts were randomized (1:1:1) and treated with GUS 100 mg every 4 weeks (Q4W; n=245); GUS 100 mg at Week 0, Week 4, then every 8 weeks (Q8W; n=248); or placebo (n=246) with crossover to GUS 100 mg Q4W at W24. In this analysis, only GUS-randomized pts were included (n=493). Achievement of the following outcomes at W100 was assessed: minimal disease activity (MDA), American College of Rheumatology 50% improvement (ACR50), ACR70, Investigator’s Global Assessment score of 0 (clear skin) (IGA 0), Psoriatic Arthritis Disease Activity Score – low disease activity (PASDAS LDA), resolution of enthesitis and dactylitis, Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) response (≥4-point improvement), and Health Assessment Quality Disease Index (HAQ-DI) response (≥0.35-point improvement). BL characteristics of interest were pt sex, baseline body mass index (BMI), SJC, TJC, PsA duration, CRP, % body surface area (BSA) with psoriasis, and PASI score, and use of conventional synthetic (cs) DMARDs and methotrexate (MTX). Non-responder imputation was used for missing categorical response data.Results442 (90%) GUS-randomized pts completed study treatment through W100. With few exceptions, achievement of MDA response (Figure 1) at Week 100 was demonstrated across a variety of baseline pt characteristics, without consistent differences in proportion of responders across pt subgroups of adequate sample size or between GUS dosing regimens. Similar trends were observed for achievement of ACR50, ACR70, IGA 0, PASDAS LDA, enthesitis resolution, dactylitis resolution, FACIT-F response, and HAQ-DI response.ConclusionIrrespective of dosing regimen, treatment with GUS resulted in sustained achievement of several stringent endpoints spanning key GRAPPA-recommended domains through 2 years across a variety of BL demographic and disease characteristics. These results further support the long-term efficacy of GUS across the full spectrum of PsA disease domains and diverse PsA populations.References[1]Ritchlin CT. et al.RMD Open. 2022 Mar;8(1):e002195;[2]Ritchlin CT. et al. Abstract N°AB0526. EULAR 2021.Acknowledgements:NIL.Disclosure of InterestsChristopher T. Ritchlin Consultant of: AbbVie, Amgen, Eli Lilly, Gilead, Janssen, Novartis, Pfizer, and UCB, Grant/research support from: AbbVie, Amgen, and UCB, Philip J Mease Speakers bureau: AbbVie, Amgen, Eli Lilly, Janssen, Novartis, Pfizer, Sun Pharma, and UCB, Consultant of: AbbVie, Aclaris, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Galapagos, Gilead, GlaxoSmithKline, Inmagene, Janssen, Novartis, Pfizer, Sun Pharma, and UCB, Grant/research support from: AbbVie, Amgen, Bristol Myers Squibb, Eli Lilly, Galapagos, Gilead, Janssen, Novartis, Pfizer, Sun Pharma, and UCB, Wolf-Henning Boehncke Consultant of: AbbVie, Almirall, Eli Lilly, Janssen, Leo, Novartis, and UCB, John Tesser Speakers bureau: AbbVie, Amgen, Bristol Myers Squibb, Eli Lilly, Janssen and Pfizer, Consultant of: AbbVie, Eli Lilly, Janssen, Novartis, and Pfizer, advisory board fees from Bristol Myers Squibb, Eli Lilly, Gilead, Janssen, Novartis, and Pfizer, Grant/research support from: AbbVie, Amgen, Bristol Myers Squibb, Celgene, CorEvitas, Eli Lilly, Gilead, Janssen, Pfizer, and Sun Pharma, Soumya D Chakravarty Employee of: Janssen Scientific Affairs, LLC; shareholder in Johnson & Johnson, of which Janssen Scientific Affairs, LLC is a wholly-owned subsidiary, Emmanouil Rampakakis Consultant of: Janssen, Employee of: JSS Medical Research, May Shawi Employee of: Janssen Pharmaceutical Companies of Johnson & Johnson; shareholder of Johnson & Johnson, Elena Schiopu Consultant of: Janssen, Grant/research support from: Janssen, Joseph F. Merola Consultant of: AbbVie, Arena, Biogen, Bristol Myers Squibb, Dermavant, Eli Lilly, Janssen, Novartis, Pfizer, Sun Pharma, and UCB, Iain McInnes Shareholder of: Causeway Therapeutics, and Evelo Compugen; Non Exec Roles: NHS GGC Board Member, Evelo Board of Directors and Versus Arthritis Trustee Status, Consultant of: AbbVie, Amgen, Astra Zeneca, Bristol Myers Squibb, Cabaletta, Compugen, Eli Lilly, Gilead, GSK, Janssen, Novartis, Pfizer, Roche, Sanofi, and UCB, Grant/research support from: Astra Zeneca, Amgen, Bristol Myers Squibb, Eli Lilly, GSK, Janssen, Novartis, Roche, and UCB, Atul Deodhar Speakers bureau: AbbVie, Eli Lilly, Janssen, Novartis, Pfizer, and UCB, Consultant of: AbbVie, Amgen, Aurinia, Bristol Myers Squibb, Celgene, Eli Lilly, GSK, Janssen, MoonLake, Novartis, Pfizer, and UCB, Grant/research support from: AbbVie, Eli Lilly, GSK, Novartis, Pfizer, and UCB.

BackgroundGuselkumab (GUS), a fully human IL-23p19 subunit inhibitor, was shown to reduce mean changes in radiographic progression vs placebo (PBO) by week (W)24[1]and to be associated with low rates of radiographic progression through W100 among GUS-treated patients (pts) with PsA, irrespective of dosing regimen (every [Q] 4W or Q8W)[2]Furthermore, earlier clinical response predicted improved long-term radiographic outcome in GUS-treated pts with active PsA[3]. The recently developed 3 Visual Analogue Scale (VAS) and 4 VAS scores are the first short multidimensional composite measures specifically for use in PsA routine clinical care[4].ObjectivesDetermine whether early improvement in 3VAS/4VAS predicts radiographic change through W100.MethodsDISCOVER-2 included biologic-naïve pts with active PsA (≥5 swollen and ≥5 tender joint counts [SJC/TJC]; CRP ≥0.6 mg/dL) randomized (1:1:1) to GUS 100 mg Q4W; GUS 100 mg at W0, W4, then Q8W; or PBO with crossover to GUS 100 mg Q4W at W24. In the current analysis, only pts randomized to GUS were included (N=493), pooling Q4W and Q8W. Response at W8 was defined as achievement of low disease activity (LDA) in 3VAS (≤3.4), 4VAS (≤3.5), RAPID3 (≤6), DAPSA (≤14), and PASDAS (≤3.2). Association of W8 response with change from baseline (BL) to W100 in total PsA-modified van der Heijde-Sharp [vdH-S] score was assessed with the independent samples t-test and generalized linear models adjusting for known BL determinants of radiographic progression (vdH-S score, age, gender, and CRP). Pairwise correlations and agreement in LDA classification between the endpoints assessed were assessed with Pearson’s correlation coefficient and the kappa statistic, respectively.ResultsAmong GUS-treated pts not meeting the respective endpoints at BL, 32.9%, 31.6%, 12.4%, 17.8%, and 10.8% achieved LDA in 3VAS, 4VAS, RAPID3, DAPSA, and PASDAS, respectively, at W8. LDA achievement in 3VAS (0.86 vs. 2.15, p=0.03), RAPID3 LDA (0.74 vs. 1.80, p=0.049), DAPSA LDA (-0.05 vs. 2.08, p<0.001), and PASDAS LDA (0.58 vs. 1.87, p=0.006) at W8 were associated with significantly less radiographic progression through W100(Figure 1). For 4VAS, achievement of remission (≤2.1; 0.71 vs. 1.84, p=0.045), but not LDA (1.12 vs. 2.01, p=0.142), was also associated with improved radiographic outcome. In multivariate analyses, improved response to GUS treatment at W8 in all endpoints assessed was associated with numerically less radiographic progression through W100. 3VAS and 4VAS at W8 showed strong correlations with RAPID3 (r3VAS=0.787; r4VAS=0.877) and PASDAS (r3VAS=0.795; r4VAS=0.790) and moderate correlations with DAPSA (r3VAS=0.466; r4VAS=0.524), whereas fair to moderate agreement (kappa range: 0.325-0.545) in LDA classification was noted.ConclusionApproximately one-third of GUS-treated patients achieved early response (W8 LDA) in 3VAS/4VAS, which was associated with reduced rates of radiographic change, as was early response in the other outcomes assessed. These results suggest that, in addition to their usefulness in assessing disease activity in routine clinical care, 3VAS and 4VAS, the former being more sensitive, may predict long-term radiographic changes.References[1]Mease PJ, et al.Lancet.2020;395:1126–36[2]McInnes IB, et al.Arthritis Rheumatol.2022;74:475-85[3]Mease PJ, et al.Ann Rheum Dis. 2022;81:828-29[4]Tillett W, et al.J Rheumatol. 2021;jrheum.201675Acknowledgements:NIL.Disclosure of InterestsWilliam Tillett Speakers bureau: Abbvie, Amgen, Eli-Lilly, Janssen, MSD, Novartis, Pfizer, and UCB, Consultant of: Abbvie, Amgen, Eli-Lilly, Janssen, MSD, Novartis, Ono-Pharma, Pfizer, and UCB, Grant/research support from: Abbvie, Amgen, Eli-Lilly, Janssen, UCB and Pfizer, Laura Coates Speakers bureau: AbbVie, Amgen, Biogen, Celgene, Eli Lilly, Galapagos, Gilead, Janssen, Medac, Novartis, Pfizer, and UCB, Consultant of: AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Eli Lilly, Gilead, Galapagos, Janssen, Novartis, Pfizer, and UCB, Grant/research support from: AbbVie, Amgen, Celgene, Eli Lilly, Janssen, Novartis, Pfizer, and UCB. Funded by a National Institute for Health Research Clinician Scientist award. The research was supported by the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC). The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. We acknowledge the support of the National Institute for Health Research Clinical Research Network (NIHR CRN)., Marijn Vis Speakers bureau: Has received research grants, consulting or speaker fees from AbbVie, Amgen, Eli Lilly, Janssen, Novartis, Pfizer, UCB, and the Dutch Arthritis Foundation., Consultant of: Has received research grants, consulting or speaker fees from AbbVie, Amgen, Eli Lilly, Janssen, Novartis, Pfizer, UCB, and the Dutch Arthritis Foundation., Grant/research support from: Has received research grants, consulting or speaker fees from AbbVie, Amgen, Eli Lilly, Janssen, Novartis, Pfizer, UCB, and the Dutch Arthritis Foundation., Enrique Soriano Speakers bureau: AbbVie, Amgen, Bristol Myers Squibb, Eli Lilly, Janssen, Novartis, Pfizer, Roche and UCB, Consultant of: AbbVie, Janssen, Novartis, and Roche, Grant/research support from: AbbVie, Janssen, Novartis, Pfizer, Roche and UCB, Joseph F. Merola Consultant of: Is a consultant and/or investigator for Amgen, Bristol Myers Squibb, Abbvie, Dermavant, Eli Lilly, Incyte, Novartis, Janssen, UCB, Sanofi, Regeneron, Sun Pharma, Biogen, Pfizer and Leo Pharma. Payments received are considered honorarium, Miriam Zimmermann Shareholder of: Johnson & Johnson, Employee of: Janssen Research & Development, LLC, May Shawi Shareholder of: Johnson & Johnson, Employee of: Immunology Global Medical Affairs, Janssen Pharmaceutical Companies, a wholly owned subsidiary of Johnson & Johnson, Mohamed Sharaf Employee of: Janssen MEA, Dubai United Arab Emirates, Peter Nash Speakers bureau: Received grants for research and clinical trials and honoraria for advice and lectures on behalf of: UCB, Abbvie, Pfizer, Lilly, Novartis, GSK, MSD, Samsung, Janssen, Gilead/Galapagos, Boeringher-Ingelheim, Sun, Consultant of: Received grants for research and clinical trials and honoraria for advice and lectures on behalf of: UCB, Abbvie, Pfizer, Lilly, Novartis, GSK, MSD, Samsung, Janssen, Gilead/Galapagos, Boeringher-Ingelheim, Sun, Grant/research support from: Received grants for research and clinical trials and honoraria for advice and lectures on behalf of: UCB, Abbvie, Pfizer, Lilly, Novartis, GSK, MSD, Samsung, Janssen, Gilead/Galapagos, Boeringher-Ingelheim, Sun, Philip Helliwell Speakers bureau: Abbvie, Novartis, Janssen, Consultant of: Eli Lilly.

Abstract Extensive infiltration of tumor-associated macrophages (TAMs) into the solid tumor microenvironment (TME), where they promote angiogenesis, initiate metastasis, and tune immunosuppression, has long been proven to correlate with worse patient prognosis. Thus, much significance has been attached on either impeding TAM infiltration or reversing pro-tumoral TAMs back into phagocytic M1 phenotype. Nevertheless, while revealing underlying mechanisms of blocking TAM recruitment, widely adopted in vitro migration assays like Transwell, µ-slides fail to distinguish cell’s random migration from chemotaxis (biased migration) and introduce 3D extracellular matrix environment. Here we present data that monocytes, as major replenishment source of TAMs, massively boost their random migration via paracrine pathway to initiate early-stage infiltration using an advanced 3D multi-compartment organoid model. In addition, before re-educated into TAMs, monocytes in the TME are capable of inducing triple negative breast cancer cells’ hyper-proliferation by activating their MEK/ERK signaling pathway. This work provides evidence that TAM infiltration is driven by monocytes’ random/biased migration separately and identifies a potential combinational immunotherapy targeting at monocytes instead of TAMs. Citation Format: Wenxuan Du, Adrian Johnston, Praful Nair, Jingyi Zhu, Khin Sandar Win, Bryan Zhou, Jude Phillip, Pei-Hsun Wu, Denis Wirtz. Modulate TAM infiltration at cancer-immune interface by targeting at monocyte migration. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5949.

Abstract Background: Cancer Associated Fibroblasts (CAFs) are a significant component of tumor stroma, and have an important impact on immune infiltration in the tumor microenvironment (TME). Two major subtypes of CAFs have been previously identified by literature: myofibroblastic (myCAF) and inflammatory (iCAF). Our lab has identified subtype markers for each CAF phenotype and previously analyzed a sampling of 153 colorectal cancer (CRC) patients. Here, we validate these subtype markers and investigate CAF phenotypes in metastatic colorectal cancer patients. Methods: Dual immunofluorescence on formalin fixed paraffin embedded tissue sections was performed to analyze co-staining between combinations of myCAF markers, αSMA and TAGLN, and iCAF markers, PDPN and ICAM1. Slides were imaged using a fluorescent microscope. Also, tissue microarrays sampling 212 CRC patients spanning all stages of disease, 90 with matched metastatic cores, were stained via immunohistochemistry (IHC) for the CAF subtype markers then quantified on an intensity scale from 0-3+. iCAF and myCAF marker scores were averaged to get a composite score for each, then split into low (average score &lt;2) and high (average score ≥2) groups. CD8 IHC stains were quantified as the number of tumor infiltrating lymphocytes (TILs) per high power field (HPF) in the epithelial compartment. Results: Significant co-staining was observed between iCAF markers PDPN and ICAM1, as well as myCAF markers αSMA and TAGLN. Co-staining did not occur, or was minimal, between combinations of myCAF and iCAF markers. There is not significant different in abundance of iCAFs or myCAFs in primary site cores of patients with metastatic versus non-metastatic disease (p = 0.67 for iCAF, p = 0.57 for myCAF). Of matched primary and metastatic samples able to be scored, 43.3% of samples had a decrease in iCAF score from primary to metastatic site while only 18.8% increased. Overall, 34.4% of samples had a decrease in score of more than 1 and only 2.2% of samples had an increase of more than 1. However, the percentage of samples that had a decrease in myCAF score was 32.2% while 22.2% increased. In all primary cores of patients with metastatic disease, there was higher average CD8+ TILs in those with high iCAF scores compared to those with low iCAF scores (12.0 vs 5.5, p=0.03). There was not a significant difference in average CD8+ TILs in those with high myCAF scores compared to those with low myCAF scores (9.3 vs 7.1, p=0.7). Conclusions: Here, we validate the myCAF markers TAGLN and αSMA, as well as, iCAF markers ICAM1 and PDPN by demonstrating co-staining between CAFs of the same subtype and exclusion between different subtypes. These data indicate that that CAF phenotype correlates with CD8 T cell infiltration into the TME. iCAFs correlate with immune infiltration and myCAFs with immune exclusion. Citation Format: Anna L. Lippert, Katherine A. Johnson, Cheri A. Pasch, Sean G. Kraus, Philip B. Emmerich, Linda Clipson, Kristina A. Matkowskyj, Wei Zhang, Dustin A. Deming. Validation and analysis of cancer associated fibroblast subtype markers in metastatic colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3198.

Abstract HPV-positive (HPV+) head and neck squamous cell carcinoma (HNSCC) tumors typically have p53 loss due to the activity of the human papillomavirus (HPV)-encoded E6 protein and the E6-associated protein (HPVE6-AP) which mediate the degradation of wild-type (WT) p53 (p53α). The loss of p53 is thought to be a major contributor to the pathogenesis of HPV+ HNSCC, which comprise approximately 35% of all HNSCC. Currently, standard care for HPV+HNSCC includes radiation and chemotherapy. However long-term toxicity related to these treatments is a concern, and there is a need for newer therapeutic strategies. Previously, we reported that two alternatively spliced, functional truncated isoforms of p53 (p53β and p53γ, comprising of exons 1 to 9β or 9γ, respectively) are degraded by nonsense-mediated decay (NMD), a regulator of aberrant mRNA stability. Here, using HPV+HNSCC cell line models, we show that NMD inhibition rescues p53β/γ isoforms and activates p53 pathway. Furthermore, we show that p53β/γ isoforms are more stable compared to p53α in these cells, with reduced vulnerabililty to HPVE6-AP- mediated degradation, and that p53β/γ isoforms contribute to increased expression of p53 transcriptional targets p21 and PUMA following NMD inhibition. Consistent with p53 pathway activation, NMD inhibition enhanced radiosensitivity of HNSCC cells. NMD inhibition attenuated colony forming ability and disrupted cell cycle progression. To evaluate the therapeutic implications of NMD inhibition, we assessed the in vivo growth of HPV+ UMSCC47 tumors. Nude mice were injected with UMSCC47 cells either subcutaneously or orthotopically in the tongue and randomized to receive vehicle or with an NMD inhibitor. In both tumor models, we observed a significant reduction in tumor volume with NMD inhibition as compared to the vehicle-treated animals. To investigate whether NMD inhibition induced the expression of p53β/γ isoforms and activated the p53 pathway in vivo, we collected tumor tissues from animals and evaluated expression of p53 isoforms and transcriptional targets by RT-PCR. We observed increased expression of p53γ, p21, GADD45A and PUMA mRNAs in NMD inhibitor treated UMSCC47 tumors, compared to their respective vehicle treated controls. These results identify NMD inhibition as a novel therapeutic strategy for restoration of p53 function in major subgroups of p53-deficient HPV+ HNSCC tumors. Citation Format: Jayanthi Gudikote, Tina Cascone, Alissa Poteete, Piyada Sitthideatphaiboon, Sonia Patel, Yan Yang, Fahao Zhang, Lerong Li, Li Shen, Monique Nilsson, Phillip Jones, Jing Wang, Jean-Christophe Bourdon, Faye M. Johnson, John V. Heymach. Targeting nonsense-mediated decay restores p53 function in HPV-associated head and neck cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5733.

Background:Treatment effect on pain is a priority for patients (pts) with psoriatic arthritis (PsA) and physicians. As pain is multidimensional, there is growing interest to understand the mechanisms of pain relief during treatment. Tofacitinib is an oral Janus kinase inhibitor for the treatment of PsA. Previous analyses showed that the effect of tofacitinib on pain in pts with PsA was partially mediated through improvement of inflammation as assessed by C-reactive protein (CRP) and Swollen Joint Count (SJC). Additional potential inflammation-associated mediators that might contribute to tofacitinib’s effect on pain include enthesitis and skin disease.Objectives:To describe the interrelationship between pain, tofacitinib treatment and potential inflammatory-associated outcomes, using mediation modelling.Methods:Data from two Phase 3 studies (OPAL Broaden [NCT01877668]; OPAL Beyond [NCT01882439]) of pts with active PsA treated with tofacitinib 5 mg twice daily (BID) or placebo were used; pts were tumour necrosis factor inhibitor (TNFi)-naïve or had previous inadequate response to ≥1 TNFi. All pts were treated continuously with a single conventional synthetic DMARD. Analyses were completed using pooled and individual study data at Months 1 and 3 (using mean scores across visits). Mediation modelling seeks to explain mechanisms underlying observed relationships between independent and dependent variables via other variables (mediators). This initial model included: treatment as the independent (explanatory) binary variable (tofacitinib 5 mg BID vs placebo); pain, measured by Patient’s Assessment of Arthritis Pain (VAS, 0–100 mm), as the dependent (outcome) variable; mediators were: pt-reported Itch Severity Index (ISI); CRP; SJC; Psoriasis Area and Severity Index (PASI); and enthesitis, measured by Leeds Enthesitis Index (LEI) or Spondyloarthritis Research Consortium of Canada Enthesitis Index (SPARCC). The final model was revised based on results of the initial model.Results:The initial model (N=329; pooled data) showed that tofacitinib treatment affects pain mainly indirectly via ISI, CRP, SJC, PASI and enthesitis (LEI), with 16.0% (p=0.53) attributable to the direct effect. The indirect effect via SJC (<1%) was not significant (p=0.99); the indirect effect via PASI was contradictory (-14.4%, p=0.10). The final model (Figure 1) excluded SJC and PASI. Analysis of the final model (N=468; pooled data) revealed that 29.5% (p=0.0579) of tofacitinib treatment effect on pain was attributable to the direct effect, and 70.5% (p<0.0001) was attributable to the indirect effect. ISI, LEI and CRP mediated 37.4% (p=0.0002), 17.8% (p=0.0157) and 15.3% (p=0.0107) of the tofacitinib treatment effect on pain, respectively. Results for individual studies were consistent with pooled data, as were those when enthesitis was represented by SPARCC in the model.Conclusion:The majority of tofacitinib treatment effect on pain in pts with PsA is collectively mediated by itch, enthesitis and CRP, with itch being the main mediator of treatment effect (~37%), using mediation modelling analyses.Acknowledgments:Study sponsored by Pfizer Inc. Medical writing support was provided by Eric Comeau of CMC Connect and funded by Pfizer Inc.Disclosure of Interests:Peter C. Taylor Grant/research support from: Celgene, Eli Lilly and Company, Galapagos, and Gilead, Consultant of: AbbVie, Biogen, Eli Lilly and Company, Fresenius, Galapagos, Gilead, GlaxoSmithKline, Janssen, Nordic Pharma, Pfizer Roche, and UCB, Kurt de Vlam Grant/research support from: Celgene, Eli Lilly, Pfizer Inc, Consultant of: AbbVie, Eli Lilly, Galapagos, Johnson & Johnson, Novartis, Pfizer Inc, UCB, Andrew G Bushmakin Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Lara Fallon Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Joseph F. Merola Consultant of: Merck, AbbVie, Dermavant, Eli Lilly, Novartis, Janssen, UCB Pharma, Celgene, Sanofi, Regeneron, Arena, Sun Pharma, Biogen, Pfizer, EMD Sorono, Avotres and LEO Pharma, Joseph C Cappelleri Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Ming-Ann Hsu Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Philip J Mease Grant/research support from: Abbott, Amgen, Biogen Idec, BMS, Celgene Corporation, Eli Lilly, Novartis, Pfizer, Sun Pharmaceutical, UCB – grant/research support, Consultant of: Abbott, Amgen, Biogen Idec, BMS, Celgene Corporation, Eli Lilly, Novartis, Pfizer, Sun Pharmaceutical, UCB – consultant, Speakers bureau: Abbott, Amgen, Biogen Idec, BMS, Eli Lilly, Genentech, Janssen, Pfizer, UCB – speakers bureau

Abstract Background: Cancer-associated fibroblasts (CAFs) are major regulators of the immune microenvironment and therapeutic response in colorectal cancer (CRC). Neutralizing their role in modulating the immune landscape could be the key to enhancing immunotherapy success. Imatinib, dasatinib, and nilotinib are tyrosine kinase inhibitors with several kinase targets. Methods: Tissue microarrays spanning 153 patients were stained for αSMA, TAGLN, PDPN, ICAM1, and CD8. CD8 stains were quantified as number of tumor infiltrating lymphocytes per high powered field (TILs/HPF) in the epithelial compartment. All other stains were quantified by intensity on a 0-3+ scale. Scores for αSMA and TAGLN were combined into a myCAF score, and PDPN and ICAM1 into an iCAF score. myCAF gene expression signatures derived from a re-analysis of scRNA-seq data previously done by our lab were entered into the LINCS database to discover potential drugs to reverse the phenotype. Primary cancer associated fibroblasts were derived from patient tumor samples, then treated with clinically relevant concentrations of imatinib, dasatinib, or nilotinib for 96 hours. RNA was isolated and RT-qPCR was performed to quantify the myCAF genes ACTA2, COL11A1, and TAGLN, and the iCAF genes ICAM1, PDPN, IL1R1, CXCL1 and CXCL2. TGFB1 expression was also measured. Expression was normalized to untreated cells and GAPDH expression levels. Results: Cancers with high expression of myCAF markers but low expression of iCAF markers had the most CD8+ TILs (average 10.2; median 1.5; range 0-73), while cancers with low myCAF scores and high iCAF scores had the least (average 1.5; median 0; range 0-19; p &lt; 0.01). Reversing the myCAF signature relative to iCAFs in the LINCs database revealed nilotinib as a top hit. Treatment with imatinib did not significantly alter the expression of myCAF genes (control vs. max dose: p = 0.06 for ACTA2, COL11A1 p =0.2, TAGLN p = 1), while treatment with dasatinib significantly increased these genes (ACTA2 1.4x higher, p &lt; 0.001; COL11A1 2.6x higher, p &lt; 0.01; TAGLN 1.5x higher, p &lt; 0.001). Only treatment with nilotinib significantly decreased myCAF genes (ACTA2 2.2x lower, p &lt;0.001; COL11A1 1.3x lower, p =0.05; TAGLN 1.9x lower, p &lt; 0.01). All three drugs decreased iCAF gene CXCL1, and all but dasatinib decreased CXCL2. All three drugs significantly decreased TGFB1, a potential functional marker for altering myCAF phenotype (dasatinib 1.1x lower, p = 0.1; imatinib 1.6x lower, p &lt; 0.001; nilotinib 1.5x lower, p &lt; 0.05). Conclusions: myCAFs may be major actors in immune exclusion in the microenvironment, and the reversal of the myCAF phenotype may be a target for treatment with immunotherapy. Nilotinib, but not imatinib or dasatinib, is effective at decreasing expression of myCAF genes. Further research is warranted into the mechanisms of this drug on altering expression and whether these trends continue in vivo. Citation Format: Katherine Anne Johnson, Anna L. Lippert, Sean G. Kraus, Grace E. McGrath, Philip B. Emmerich, Cheri A. Pasch, Linda Clipson, Kristina A. Matkowskyj, Wei Zhang, Dustin A. Deming. Effects of tyrosine kinase inhibitors imatinib, dasatinib, and nilotinib on cancer-associated fibroblast phenotypes in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3533.

Abstract Background: WHIM syndrome (WHIMs; Warts, Hypogammaglobulinemia, Infections, Myelokathexis) is a rare autosomal dominant immunodeficiency disease attributable to mutations in CXCR4 . Most patients have severe neutropenia and lymphocytopenia with total white blood cell counts (WBC) &lt;1.0 x 109/L. In general, children have more frequent and more severe infections than adults. Adults are at risk of human papilloma virus (HPV)-associated malignancies. There are no treatments approved for WHIMs although immunoglobulin and G-CSF are used to treat clinical symptoms of the disease. CXCR4 antagonists are being evaluated as a treatment for patients with WHIMs. Methods: We have begun the phase 2, dose-titration portion of a phase 2/3 study of a novel, orally bioavailable, selective, CXCR4 antagonist, X4P-001, in adult patients with genetically confirmed WHIMs to evaluate safety and tolerability of X4P-001 and determine the dose for a phase 3 study. All patients were required to be off chronic immunoglobulin and/or G-CSF treatment while on study. Patients receive increasing doses of X4P-001 ranging from 50 mg to 300 mg orally once daily with periodic monitoring of serial blood counts and intra-patient dose escalation is based on 24-hour serial area-under-the-curve (AUC) measurements of absolute neutrophil counts (ANC) and absolute lymphocyte counts (ALC) with prespecified thresholds. Results: As of July 10, 2017, 4 patients (2 females, 2 males; age range 19 to 57 years; 3 with R334X and 1 with E343X mutation) have been enrolled. The study entry screening WBC was 0.775 x 109/L +/-0.16 (mean +/- SEM); ANC was 0.125 x 109/L +/- 0.027; and ALC was 0.588 x 109/L +/- 0.155. All patients had mild hypogammaglobulinemia; the mean levels were: Immunoglobulin G 766 +/- 130 (SEM), IgA 50 +/- 17, IgM 74 +/- 13. In the 6 months prior to study entry, these adult patients had up to 6 episodes of infections, primarily upper respiratory and skin infections. Patients 1 and 2 have escalated through 50 mg/day and 100 mg/day to 150 mg/day over a total exposure period of 169 days. Patients 3 and 4 have escalated from 100 mg/day to 200 mg/day with an exposure period of 62 and 54 days, respectively. All patients have demonstrated a dose-dependent increase in ANC and ALC from screening values, with ALC increasing in greater proportion than ANC. At the 100 mg dose level, the pre-dose WBC was 1.24 x 109/L +/- 0.469 (mean +/- SEM) with peak levels of 2.8 x 109/L +/- 0.721 (increase=2.3 fold), the pre-dose ANC was 0.385 x 109/L +/- 0.178) with peak levels of 0.58 x 109/L +/- 0.202 (increase=1.5 fold) and pre-dose ALC was 0.728 x 109/L +/- 0.276 with peak levels of 2.143 x 109/L +/-0.513 (increase=2.9 fold). The increases in the pre-dose levels of both neutrophils and lymphocytes above the study entry screening values after 1-3 months on treatment suggest a continuing effect of daily exposure to this drug. However, the ANC and ALC responses thus far are below the targeted AUC for ANC and ALC, so dose escalation continues. Thus far, X4P-001 has been well tolerated and the most common treatment-related adverse events are mild dyspepsia and dry eyes. Patients have not required antibiotic treatment for infections during the cumulative 15 months on X4P-001, except for Patient 1 who had an infection at the start of the study. Conclusion: Preliminary data suggests X4P-001 is a promising oral agent for treating WHIM syndrome. Disclosures Dale: Sanofi Aventis: Consultancy, Editor, Current Opinions in Hematology, Honoraria; Cellerant: Membership on an entity's Board of Directors or advisory committees; Genzyme (now owned by Sanofi-Aventis): Consultancy, Patents & Royalties, Research Funding; Genkyotex: Other: DSMB (work completed 6/2015); Hospira: Consultancy; Prolong: Consultancy; Boheringer-Ingelheim: Consultancy; Coherus: Consultancy; Omeros: Other: DSMB; Shire: Other: Independent Review Board; X4Pharma: Research Funding; Philips: Research Funding; Wolter Kluwer: Other: Editor, Current Opinions in Hematology; WedMD/Medscape: Membership on an entity's Board of Directors or advisory committees; National Institutes of Health: Research Funding; University of Washington: Employment, Research Funding; American College of Physicians: Other: Editor and author; GlaxoSmithKline: Equity Ownership; Johnson&Johnson: Equity Ownership; Amgen: Consultancy, Research Funding. Johnson: X4 Pharmaceuticals: Employment. Gan: X4 Pharmaceuticals: Employment, Equity Ownership. Parasuraman: X4 Pharmaceuticals: Employment, Equity Ownership.

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) is associated with poor prognosis, rising incidence and suffers from limited existing treatment options. Currently, salient features of PDAC are being investigated that can potentially predict immunotherapy outcomes, to identify small patient populations that can benefit from such strategies. Preliminary studies show that colony-stimulating factor-1 receptor (CSF1R), a surface receptor tyrosine kinase that drives survival, function, proliferation and differentiation of several myeloid lineage cell types can be a potentially interesting target for combination immunotherapy. Methods: PDAC patients from the TCGA PanCancer Atlas were stratified into CSF1Rhi and CSF1Rlo cohorts and clinically relevant characteristics were compared between the two. The mRNA expression of CSF1R and immunological markers of interest were evaluated and Gene Set Enrichment Analysis (GSEA) was run on the two groups to analyze differential expression of gene sets. Results: mRNA expression z-scores were used to classify 129 patient samples in the TCGA PanCancer Atlas dataset into CSF1Rhi (z-score&gt;1, n=20) and CSF1Rlo (z-score&lt;0, n=109) cohorts. Both have similar disease staging, MSI MANTIS scores, tumor mutation burden, median diagnosis age, sex and race distribution. However, the CSF1Rhi cohort has a distinct, non-conventional PDAC driver gene mutation profile (genomic alteration frequencies in CSF1Rhi vs CSF1Rlo cohorts respectively: a) KRAS: 30% vs 73% b) CDKN2A: 15% vs 57% and c) SMAD4: 5% vs 42%) (p-value&lt;0.01 for each). CSF1R correlates with markers of CD8+ T-cell function (R2 values: CD8A: 0.683, GZMB: 0.508, PRF1: 0.673), CD8+ T-cell infiltration (CXCL9: 0.596, CXCL10: 0.483, CCL5: 0.666) and expression of immune checkpoint genes (PDCD1: 0.602, CD274: 0.544, CTLA4: 0.613). CD8A, GZMB, PRF1, CXCL9, CXCL10, CCL5, PDCD1, CD274, CTLA4 are significantly upregulated in the CSF1Rhi group (log2Fold changes respectively: 2.07, 1.57, 1.48, 2.51, 1.71, 1.75, 1.63, 1.34, 1.80). GSEA against the hallmark gene set database shows that KRAS signaling, Inflammatory response, IL6 JAK STAT3 and Interferon-gamma signaling are significantly upregulated in the CSF1R high patient group (FDR q-value &lt;0.01 for each). Conclusion: Preliminary in silico analysis suggests that PDAC patients with higher levels of CSF1R may be more immune infiltrated. Future studies will evaluate the potential of CSF1R as a biomarker to identify an immune infiltrated subset of PDAC patients ex vivo and the mechanism of immune infiltration in CSF1Rhi PDACs in vivo. Citation Format: Somak Chaudhuri, Dustin A. Deming, Cheri A. Pasch, Katherine A. Johnson, Chelsie K. Sievers, Philip B. Emmerich. Colony-stimulating factor-1 receptor as a potential therapeutic target in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1581.

BackgroundDue to geographic isolation and border controls, Aotearoa New Zealand attained high levels of population coronavirus disease-19 (COVID-19) vaccination before widespread community transmission of Omicron variant COVID-19 in early 2022. This provides a unique opportunity to examine outcomes in people with rheumatic diseases immunologically naive to COVID-19.ObjectivesThis study aims to describe the outcomes of Omicron variant COVID-19 infection in people with rheumatic diseases in Aotearoa New Zealand.MethodsWe conducted an observational study of people with inflammatory rheumatic disease and COVID-19 infection from centers in Aotearoa New Zealand between 1 February to 30 April 2022. Data were collected via the Global Rheumatology Alliance Registry, including demographic and rheumatic disease characteristics and COVID-19 vaccination and outcomes. Multivariable logistic regression was used to explore associations of demographic and clinical factors with COVID-19 hospitalisation and death.ResultsA total of 1599 cases were included, with 98% from three hospitals that systematically identified all patients from rheumatology clinics who had COVID-19 infection. At the time of COVID-19 infection, 1513 cases (94.6%) had received at least two COVID-19 vaccinations. Hospitalisation occurred for 104 (6.5%) cases, and 10 (0.6%) patients died. A lower frequency of hospitalisation was seen in cases who had received at least two vaccinations (5.9%), compared to cases who were unvaccinated (20.6%) or who received a single vaccine dose (10.7%). In multivariable adjusted models, people with gout (OR 2.2 95% CI 1.02, 4.77) or connective tissue diseases (CTD) (OR 2.78 CI 1.61, 4.80) had increased risk of the combined outcome of hospitalisation and death, compared to people with inflammatory arthritis. Glucocorticoid and rituximab use were associated with 3 to 6 times higher odds of hospitalization and/or death. All cases who died had three or more co-morbidities associated with a known higher risk of poor outcomes or were over 60 years old.ConclusionIn this cohort of people with inflammatory rheumatic diseases with high vaccination rates, severe outcomes from Omicron variant COVID-19 were infrequent. The hospitalisation rate during COVID-19 infection was higher in people who had not completed the primary vaccination course, had gout or CTD, and used glucocorticoids. These findings suggest that outcomes of Omicron variant COVID-19 infection among people with rheumatic disease who are vaccinated but immunologically naive to prior COVID-19 variant infections were favorable.AcknowledgementsThere was no specific funding for data collection. Data analysis was funded by the COVID-19 Global Rheumatology Alliance. The Global Rheumatology Alliance registries are supported by the American College of Rheumatology and European Alliance of Associations of Rheumatology but the views expressed here are of the authors.We thank our colleagues who entered patients to the cohort who include Ms J Heslett, Dr S Bourke, Dr E Chan, Dr S Jordan, Dr K Lindsay, Dr R Murdoch and Dr S Stebbings,Disclosure of InterestsJonathon Brooks: None declared, Anna Montgomery: None declared, Nicola Dalbeth Consultant of: Personal fees from AstraZeneca, Dyve Biosciences, Horizon, Selecta, Arthrosi, JW Pharmaceutical Corporation, PK Med, LG Chem, JPI, PTC Therapeutics, Protalix, Unlocked Labs, Hikma, all outside this abstract, Mark Sapsford: None declared, Amy Cooper: None declared, Rachel Ngan Kee: None declared, Vicki Quincey: None declared, Jean Liew Grant/research support from: Pfizer, outside this abstract, Suleman Bhana Shareholder of: Owns restricted stock units with Pfizer as a Pfizer employee, Consultant of: Honoraria from AbbVie, Horizon, Novartis, Pfizer, has received travel support from Pfizer, Employee of: Pfizer Inc, Monique Gore-Massy Consultant of: Patient consultant for Aurinia Pharmaceuticals, Boehringer Ingelheim, Johnson & Johnson, Bristol-Myers Squibb, all unrelated to this abstract. Receives honoraria from Aurinia Pharmaceuticals, Boehringer Ingelheim, Bristol-Myers Squibb, all unrelated to this abstract, Jonathan Hausmann Consultant of: Consulting fees from Novartis, Pfizer, Sobi and Biogen, all unrelated to this manuscript, Pedro Machado Speakers bureau: PMM has received consulting/speaker’s fees from Abbvie, BMS, Celgene, Eli Lilly, Galapagos, Janssen, MSD, Novartis, Orphazyme, Pfizer, Roche and UCB, all unrelated to this manuscript, Paul Sufka: None declared, Emily Sirotich: None declared, Philip Robinson Speakers bureau: PR reports personal fees from Abbvie, Atom Biosciences, Eli Lilly, Gilead, GlaxoSmithKline, Janssen, Kukdong, Novartis, UCB, Roche, Pfizer;, Grant/research support from: Meeting attendance support from BMS, Pfizer and UCB and grant funding from Janssen, Novartis, Pfizer and UCB Pharma., Zachary Wallace Consultant of: Consulting fees from Zenas Biopharma, Horizon, Sanofi, Shionogi, Viela Bio, and MedPace, all outside this abstract., Grant/research support from: Research support from Bristol-Myers Squibb and Principia/Sanofi, all outside this abstract., Jinoos Yazdany Consultant of: Consulting fees from Astra Zeneca, Aurinia, Pfizer, all unrelated to this manuscript, Grant/research support from: Grants from Gilead, Astra Zeneca, BMS Foundation, all unrelated to this manuscript, Rebecca Grainger Speakers bureau: RG reports personal fees from AbbVie, Janssen, Cornerstones, Novartis; meeting attendance support from Pfizer.

Abstract Obesity is a worldwide epidemic associated with many cancer types due to persistent inflammation, hyperglycemia and hyperinsulinemia providing an abundance of nutrients and growth factors to cancer cells resulting in an ideal microenvironment. Maternal obesity often results in an increased risk of offspring developing obesity. Chronic inflammation and immunosuppression found in obese patients have been linked to ovarian cancer (OvCa). OvCa is the most lethal gynecological malignancy among women and approximately 12% of OvCa patients are obese. Poor survival rates are attributable to women presenting with advanced disease with disseminated intraperitoneal (i.p) metastasis at diagnosis. Metastatic tumor cells shed from the primary tumor and preferentially home to the mesothelium of the omentum and other peritoneal organs producing secondary lesions. Developmental programming suggests that perinatal nutritional influences can alter gene expression in offspring. A pre-clinical murine model of diet-induced obesity that included maternal cohorts of C57BL/6 mice (dam) with intact host immunity fed either a control diet (CD; 10% fat) or a high-fat diet (HFD; 40% fat) and the resulting offspring fed either diet was utilized to explore diet induced genetic and physical modifications. Body composition analysis revealed differences in weight and lean mass was dependent on offspring diet alone and fat mass was dam diet dependent among CD fed offspring. Second harmonic generation microscopy demonstrated a larger area of collagen mesh-work between fenestrations in the omentum of HFD fed mice as well as an increase in anisotropy. Additionally, a tumor study was performed using either CD or HFD fed offspring to quantify site-specific metastatic success to the adipose-rich tissues of the peritoneal cavity. Mice were injected i.p. with fluorescently tagged syngeneic ID8 murine OvCa cells and disease progression was tracked for 8 weeks. Abdominal organs were dissected, imaged, and organ-specific tumor burden quantified. Overall, offspring fed a HFD displayed an increase in organ-specific tumor burden relative to offspring fed a CD, regardless of dam diet. Furthermore, HFD offspring from HFD dams displayed higher omental tumor burden than HFD offspring from CD dams. In addition, HFD fed mice accumulated more ascites fluid than CD fed mice, however variances were independent of dam diet. Comparison of ascites cytokine expression revealed CXCL13, a dominant chemokine in adipocytes, was significantly increased in mice only exposed to a HFD suggesting an additive effect of both maternal and offspring obesity. Interestingly, increased CXCL13 expression has been reported in OvCa cell lines and in clinical samples. Together, the results suggest maternal obesity or subsequent exposure to a HFD can influence ovarian cancer metastasis. Citation Format: Tyvette Hilliard, Phillip Petrasko, Yueying Liu, Jing Yang, Marwa Asem, Jeff Johnson, Gifty Marfowaa, Brooke Kowalski, Elinor Schnautz, Morgan McCabe, M. Sharon Stack. The role of generational obesity on the ovarian metastatic niche [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2189.

Background:Bimekizumab (BKZ) is a humanised IgG1 monoclonal antibody, which selectively neutralises interleukin (IL)-17A and IL-17F. There is support for the BKZ mechanism of action as a novel therapeutic approach for psoriatic arthritis (PsA).1-3The phase 2b dose-ranging BE ACTIVE study assessed the efficacy and safety of BKZ in patients (pts) with PsA; data are reported elsewhere.4Patient-reported outcomes (PROs) are increasingly recognised as important endpoints in clinical trials.5The Psoriatic Arthritis Impact of Disease-9 (PsAID-9) questionnaire was specifically developed to assess health-related quality of life (QoL) in pts with PsA5and its validity in clinical practice has been demonstrated.5-6Objectives:To report the association between PsAID-9 score (a PRO) and disease activity response (very low disease activity [VLDA], minimal disease activity [MDA] or Disease Activity Index for Psoriatic Arthritis [DAPSA] remission) during 48 weeks’ (wks’) BKZ treatment.Methods:Details of the study design (NCT02969525) are reported elsewhere.4Here, we report the proportion of pts who achieved a PsAID-9 score ≤3, and the association between PsAID-9 score at Wk 48 (range 0–10, where 10 corresponds to worst QoL) and VLDA/MDA (binary states of disease control) or DAPSA (range 0–>28 where 0–4 is remission, 5–14 is low, 15–28 is moderate, and >28 is high disease activity) at Wk 12.Results:Across 206 randomised pts at baseline, 66.5% had psoriasis body surface area (BSA) ≥3%, 18.9% had prior tumour necrosis factor inhibitor (TNFi) exposure, and 63.6% received concomitant methotrexate. A substantial proportion of pts achieved MDA and/or DAPSA remission by Wk 12, which generally increased through to Wk 24 and 48 (Table 1). The 160 mg BKZ group saw the highest Wk 48 rates of MDA response (60.0%) and DAPSA remission (45.0%) (Table 1). The proportion of pts achieving a PsAID-9 score ≤3 was consistently high across all active treatment arms (Figure 1). PsAID-9 score was consistently lower (indicating better QoL) for pts with VLDA or MDA, and those in DAPSA remission (Figure 2), indicating that low disease activity was associated with improved PROs.Conclusion:In BKZ-treated pts, improvements in PsAID-9 were associated with achievement of VLDA/MDA response and DAPSA remission. These results suggest that pts achieving higher disease control have improved QoL.References:[1]Glatt S. Ann Rheum Dis 2018;77:523–32;2.Glatt S. Br J Clin Pharmacol 2017;83:991–1001;3.Papp KA. J Am Acad Dermatol 2018;79:277–86;4.Ritchlin CT. Ann Rheum Dis 2019;78:127–8;5.Gossec L. Ann Rheum Dis 2014;73:1012–19;6.Johnson K. Semin Arthritis Rheum 2019;49:241–45.Table 1.MDA and DAPSA responder ratesTreatment armMDA (%) [a]DAPSA remission (%) [b]Wk 12Wk 24Wk 48Wk 12Wk 24Wk 48BKZ 160 mg (n=40)47.550.060.020.035.045.0BKZ 160 mg LD (n=37) [c]43.259.554.129.748.637.8BKZ 320 mg (n=41)29.336.646.312.219.534.1[a] DBS, pts with missing data were counted as non-responders; [b] DBS, missing data are imputed using last observation carried forward; [c] 160 mg with 320 mg LD at baseline. BKZ: bimekizumab; DAPSA: Disease Activity Index for Psoriatic Arthritis; DBS: dose-blind set; LD: loading dose; MDA: minimal disease activity.Acknowledgments:This study was funded by UCB Pharma. Editorial services were provided by Costello Medical.Disclosure of Interests:Laure Gossec Grant/research support from: Lilly, Mylan, Pfizer, Sandoz, Consultant of: AbbVie, Amgen, Biogen, Celgene, Janssen, Lilly, Novartis, Pfizer, Sandoz, Sanofi-Aventis, UCB, Philip J Mease Grant/research support from: Abbott, Amgen, Biogen Idec, BMS, Celgene Corporation, Eli Lilly, Novartis, Pfizer, Sun Pharmaceutical, UCB – grant/research support, Consultant of: Abbott, Amgen, Biogen Idec, BMS, Celgene Corporation, Eli Lilly, Novartis, Pfizer, Sun Pharmaceutical, UCB – consultant, Speakers bureau: Abbott, Amgen, Biogen Idec, BMS, Eli Lilly, Genentech, Janssen, Pfizer, UCB – speakers bureau, Alice B Gottlieb Grant/research support from:: Research grants, consultation fees, or speaker honoraria for lectures from: Pfizer, AbbVie, BMS, Lilly, MSD, Novartis, Roche, Sanofi, Sandoz, Nordic, Celltrion and UCB., Consultant of:: Research grants, consultation fees, or speaker honoraria for lectures from: Pfizer, AbbVie, BMS, Lilly, MSD, Novartis, Roche, Sanofi, Sandoz, Nordic, Celltrion and UCB., Speakers bureau:: Research grants, consultation fees, or speaker honoraria for lectures from: Pfizer, AbbVie, BMS, Lilly, MSD, Novartis, Roche, Sanofi, Sandoz, Nordic, Celltrion and UCB., Alexis Ogdie Grant/research support from: Pfizer to Penn, Novartis to Penn, Amgen to Forward/NDB, Consultant of: Abbvie, Amgen, Bristol-Myers Squibb, Celgene, Corrona, Janssen, Eli Lilly, Novartis, Pfizer, Deepak Assudani Employee of: UCB Pharma, Jason Coarse Employee of: UCB Pharma, Barbara Ink Shareholder of: GlaxoSmithKline and UCB Pharma, Employee of: UCB Pharma, Laura C Coates: None declared

FAKTOR-FAKTOR YANG MEMPENGARUHI MORTALITAS PADA PASIEN DENGAN FRAKTUR COSTA: Literature Review Anna Tri Wahyuni1), Masfuri2), Liya Arista3)1,2,3 Fakultas Ilmu Keperawatan Universitas Indonesia ABSTRAK Cedera paling umum yang terjadi pada trauma tumpul adalah fraktur costa (patah tulang iga/rusuk) dimana mekanisme cedera berpotensi mengancam jiwa. Pasien fraktur costa yang menunjukkan tingkat keparahan trauma lebih dari 90% melibatkan kepala, perut dan ekstremitas. Nyeri yang dirasakan akibat dari fraktur costa berkontribusi pada gangguan pernafasan, peningkatan resiko pneumonia dan gagal nafas yang meningkatkan angka morbiditas dan mortalitas. Pedoman penanganan fraktur costa sangat dibutuhkan untuk terjadinya komplikasi. Studi literature ini bertujuan menganalisis faktor-faktor yang mempengaruhi mortalitas pada pasien fraktur costa. Metode penulisan artikel ini menggunakan literature review yang didapat melalui 5 online database yaitu Sage Publishing, Science Direct, SpringerLink, Pub Med dan Google Scholar. Kriteria inklusi jurnal terkait meliputi: free fulltext, berbahasa Indonesia atau Bahasa asing lainnya, metode penelitian prospective, retrospective, case-control, cohort dan terbit antara tahun 2004-2021. Kata kunci yang yang digunakan dalam pencarian adalah “Respiratory depression OR Respiratory failure AND fraktur ribs AND Mortality”. Dari pencarian artikel diperoleh hasil akhir sebanyak 7 artikel yang relevan dan dilakukan proses review. Artikel tersebut menunjukkan hasil bahwa angka mortalitas dipengaruhi oleh faktor usia, skor keparahan cedera, jumlah patah tulang rusuk, dan implementasi penanganan infeksi. Faktor usia, tingkat keparahan cedera dan jumlah tulang rusuk yang patah menentukan tinggi rendahnya angka mortalitas pasien fraktur costa. Penanganan yang tepat dan manajemen nyeri yang sesuai dapat mempengaruhi penurunan angka morbiditas dan mortalitas pasien dengan fraktur costa. Pengembangan intervensi perawatan pasien fraktur costa terkait manajemen nyeri dan kontrol infeksi menjadi penelitian menarik selanjutnya.Kata kunci : Depresi pernafasan, gagal nafas, fraktur iga, angka kematian, angka kesakitanABSTRACT The most common injury in blunt trauma is a rib fracture, where the mechanism of injury is potentially life-threatening. Patients with rib fracture whose severity of the injury is greater than 90% are associated with damage to the head, abdomen, and extremities. Pain from rib fractures contributes to respiratory failure, increasing the risk of pneumonia and respiratory failure, which increases morbidity and mortality. Recommendations are needed for the treatment of complicated rib fractures. This literature study aims to analyze the factors that influence mortality in rib fracture patients. The method of writing this article uses a literature review sourced from 5 online databases, namely Sage Publishing, Science Direct, SpringerLink, Pub Med, and Google Scholar. The inclusion criteria for related journals included: free full text, in Bahasa or another foreign language, prospective, retrospective, case-control, cohort study method, and published between 2004 and 2021. Keywords used in the search were: "respiratory depression OR respiratory failure AND rib fractures AND death." From the article search results, we obtained 7 relevant articles which are the final results and a review process is carried out. The article showed that mortality was influenced by age, injury severity score, number of rib fractures, and infection control practices. The mortality rate of patient with rib fracture is determined by Factors such as age, severity of injury, and number of rib fractures. Appropriate care and adequate pain management can help reduce morbidity and mortality in patients with rib fractures. Another interesting research is the development of interventions in the treatment of rib fracture patients related to pain management and infection control.Key words: respiratory depression; respiratory failure; rib fracture; mortality; morbidity. Alamat korespondensi: RSUD Dr.Kanujoso Djatiwibowo Jalan MT.Haryono No 656 Ringroad BalikpapanEmail: annazahra30@gmail.com PENDAHULUAN Fraktur costa adalah cedera pada dada karena trauma tumpul, tajam atau kondisi patologis angka morbiditas dan mortilitas. Berdasarkan Western Trauma Association (WTA) sekitar 10% kematian pada orang dewasa muda disebabkan oleh cedera patah tulang rusuk yang melibatkan kepala, perut dan ekstremitas. Sebaliknya, pasien lanjut usia dengan patah tulang rusuk memiliki setidaknya 20% kematian yang secara langsung menyebabkan gagal napas progresif dan pneumonia (Brasel et al., 2017). Risiko pneumonia meningkat sebesar 27%, dan kematian meningkat sebesar 19% untuk setiap fraktur costa lebih dari 2 pada kelompok lanjut usia (Wanek & Mayberry, 2004). Pasien dengan trauma dada atau fraktur costa harusnya dilakukan pemantauan ketat sejak masuk rumah sakit, 24 jam pertama merupakan identifikasi awal adanya komplikasi yang menyebabkan depresi pernafasan. Menurut penelitian Coary, et.al (2020) fraktur costa adalah cedera paling serius pada 55% pasien berusia di atas 60 tahun yang menyebabkan kematian karena 90% dari patah tulang rusuk menunjukkan cedera tambahan pada pemeriksaan sistemik. Trauma langsung dan hipoventilasi yang diinduksi nyeri menyebabkan komplikasi pernafasan sehingga menjadi beban morbiditas dan mortalitas. Komplikasi yang sering terjadi adalah pneumotoraks diikuti hemothoraks, kontusio paru dan flail chest.Nyeri adalah suatu pengalaman sensorik yang multidimensional dengan fenomena yang berbeda dalam intensitas (ringan,sedang, berat), kualitas (tumpul, seperti terbakar, tajam), durasi (transien, intermiten,persisten), dan penyebaran (superfisial atau dalam, terlokalisir atau difus) (Bahrudin, 2018). Induksi nyeri pada pasien dengan fraktur costa menyebabkan pasien kesulitan bernafas dimana keparahan memar paru yang mendasarinya signifikan dengan terjadinya hipoksemia atau gangguan pernafasan. Hal ini menyebabkan pasien cenderung membatasi pergerakan dan menjadi tirah baring lama. Kondisi tirah baring lama menyebabkan tubuh mengalami penurunan berbagai fungsi secara sistematis, yang disebut dengan sindroma dekondisi dan rentan terjadinya infeksi (Hashem, Nelliot, & Needham, 2016; Hunter, Johnson, & Coustasse, 2014; Phelan, Lin, Mitchell, & Chaboyer, 2018 dalam Ananta & Fitri, 2020).Fraktur costa atau patah tulang rusuk secara klinis penting disebabkan tiga hal yaitu: sebagai penanda penyakit serius cedera intrathoraks dan perut, sebagai sumber rasa sakit yang signifikan, dan sebagai prediktor untuk kerusakan paru, terutama pada pasien usia lanjut. Organ perut yang paling sering terluka adalah hati dan limpa. Pasien dengan patah tulang rusuk kanan, memiliki 19% hingga 56% kemungkinan cedera hati, sedangkan patah tulang sisi kiri memiliki 22% hingga 28% kemungkinan cedera limpa (Wanek & Mayberry, 2004). Kematian pada orang dewasa dan lansia cenderung terjadi kemudian (≥72 jam setelah masuk) dan biasanya sebagai akibat dari kegagalan multi-organ yang dipicu oleh insufisiensi pernapasan dan pneumonia sehingga tingkat kematian secara keseluruhan, tanpa memandang usia, diperkirakan antara 10 dan 12% (Wanek & Mayberry, 2004). Tingkat mortalitas untuk pasien trauma usia lanjut yang mengalami patah tulang rusuk lebih besar daripada mereka yang tidak mengalami cedera toraks (Coary, et.al, 2020). Penelitian yang dilakukan Marini, et.al, (2021) menyatakan indikator penyebab kematian pada pasien fraktur costa dengan atau tanpa trauma kepala dan cedera organ adalah usia, jenis kelamin, ISS (Injury Severe Score), dan GCS (Glasglow Coma Scale).Berdasarkan uraian diatas maka peneliti ingin menganalisis faktor-faktor yang mempengaruhi angka morbiditas dan mortalitas pada pasien dengan fraktur costa untuk meningkatkan pemahaman tentang penanganan fraktur costa serta mengidentifikasi dari beberapa artikel terkini dalam mengurangi mortalitas. METODE PENELITIAN Metode penulisan artikel ini menggunakan literature review yaitu studi yang berfokus pada hasil penulisan yang berkaitan dengan topik, tema atau variabel penulisan.dan dipakai untuk menghimpun data atau sebuah sintesa sumber-sumber yang berhubungan dengan topik penelitian (Nursalam, 2017). Didapatkan 5 database yang dilakukan melalui pencarian elektronik dari yaitu Sage Publishing, Science Direct, SpringerLink, Pub Med dan Google Scholar. Kriteria inklusi telaah jurnal ini adalah free fulltext, berbahasa Indonesia atau bahasa asing lainnya, dengan metode penelitian prospective, retrospective, case-control, cohort dan terbit tahun 2004-2021. Kata kunci yang yang digunakan dalam pencarian adalah “Respiratory depression OR Respiratory failure AND fraktur ribs AND Mortality”. HASIL DAN PEMBAHASAN Berdasarkan hasil studi literature terdapat banyak faktor yang mempengaruhi terjadinya depresi pernafasan pada pasien fraktur costa yang dapat menyebabkan kematian. Terdapat 17.500 artikel yang muncul setelah dilakukan telusur berdasarkan kata kunci dalam google scholar, 10.000 artikel tidak masuk kriteria inklusi, 350 artikel duplikat dengan database yang lain. Kemudian sisanya disaring kembali berdasarkan hasil abstrak, metode dan hasil temuan sesuai topik peneliti yang diinginkan dan diperoleh 7 artikel yang relevan dan tersedia dalam bentuk fulltext. Beberapa penelitian terkait pencegahan depresi pernafasan pada fraktur costa berfokus pada manajemen nyeri baik secara farmakologis maupun non farmakologis. Penanganan dan pemantauan yang ketat dapat mengurangi komplikasi yang menyebabkan terjadinya depresi pernafasan. Berikut faktor-faktor yang mempengaruhi angka morbiditas dan mortalitas pada fraktur costa menurut Coary, et.al (2020) yaitu: (1) Usia, pasien berusia > 65 tahun memiliki kematian 2-5 kali lebih tinggi dibandingkan usia dibawahnya pada kondisi fraktur costa lebih dari dua. Pasien dengan komorbid sering menjadi faktor penyulit ditambah dengan kondisi paru-paru yang buruk (misal: perokok). Faktor pemulihan menjadi terhambat disebabkan osteoporosis, sistem pernafasan yang buruk, gangguan pertukaran gas dan tergambar dari lama rawat inap. (2) Jumlah patah tulang, dari beberapa penelitian meta-analisis diperoleh hasil jumlah absolut fraktur tulang rusuk yang berjumlah >2 maka dua kali lebih mungkin meninggal dunia dibandingkan pasien dengan 1-2 patah tulang rusuk. (3) Posisi anatomi patah tulang, Fraktur costa bilateral memiliki resiko kematian lebih tinggi dimana segmen flail chest menghasilkan gerak paradox yang menyebabkan pergerakan dinding dada mengarah kedalam saat inspirasi sedangkan tulang rusuk yang sehat bergerak keluar sehingga ventilasi tidak adekuat dan terjadi depresi pernafasan dan kematian. Berbeda dengan penelitian yang dilakukan Brasel et al., (2006) faktor yang paling mempengaruhi kematian adalah faktor usia ditandai dengan Injury Severity Score (ISS) jika dikaitkan dengan peningkatan terjadinya pneumonia. Analisis yang menyatakan komorbiditas mempengaruhi kematian hal ini disertai dengan faktor usia bukan karena faktor komorbiditas murni. Komorbiditas yang biasanya menyertai fraktur costa menurut penelitian adalah komorbiditas yang spesifik seperti gagal jantung kongestif, aritmia, gagal ginjal, penyakit hati, kanker metastatik dan penyakit neurologis.Pada penelitian Bulger et al dalam Wanek & Mayberry, (2004), membandingkan pasien yang berusia minimal 65 tahun keatas dengan usia 18-64 tahun dengan metode cohort pada kasus fraktur costa pada kelompok >65 tahun memiliki dua kali mortalitas dan morbiditas yang tinggi. Risiko pneumonia meningkat sebesar 27%, dan kematian meningkat sebesar 19% untuk setiap fraktur tulang rusuk tambahan pada kelompok lanjut usia.Nyeri adalah keluhan yang paling dirasakan oleh pasien dengan fraktur costa. Oleh sebab itu penanganan manajemen nyeri untuk mengontrol nyeri terus-menerus dan mencegah depresi pernafasan harus diberikan terapi yang agresif dengan pendekatan multimodalitas. Penelitian yang dilakukan oleh Peek, et.al, (2019) dengan membandingkan pemberian analgesik dengan 4 metode yaitu analgesia epidural, analgesia intravena, blok paravertebral dan blok intercostal, diperoleh hasil berdasarkan systematic review dan meta-analysis analgesia epidural signifikan mengurangi rasa sakit dibandingkan intervensi yang lain. Intervensi keperawatan sendiri menekankan pada terapi non farmakologis untuk kontrol nyeri pada pasien fraktur. Terapi nonfarmakologis dengan guided imagery dapat mengurangi intensitas dan skala nyeri pada pasien fraktur. Guided imagery mempengaruhi hampir semua fisiologis sistem kontrol tubuh yaitu pernapasan, denyut jantung, tekanan darah, tingkat metabolisme dalam sel, mobilitas dan sekresi gastrointestinal, fungsi seksual, dan bahkan respon imun (Rossman, 2000). Intervensi ini juga dapat mempercepat penyembuhan pasien dan mengurangi hari rawat inap (Forward et.al, 2015) Gambar 1. Algorithma fraktur costa (Brasel K.J, et.al, 2016).Western Trauma Association (WTA) menyatakan algorithma penanganan fraktur costa sebagai suatu observasi atau pemantauan ketat pada fraktur costa lebih dari 2 patah tulang (Brasel et.al, 2017). Berdasarkan algoritma diatas maka pasien dengan patah tulang rusuk >2 dengan usia lebih dari 65 tahun jika pada observasi kurang dari 24 jam menunjukkan peningkatan pada depresi pernafasan maka segera pindahkan ke ICU dan pertimbangkan penggunaan ventilator dan operasi rib fixaxion. Penggunaan terapi analgesia epidural digunakan untuk kontrol nyeri dilanjutkan batuk efektif, tehnik relaksasi nafas dalam dan mobilisasi dini (Brasel et.al, 2017). Analisis terkait studi literatur untuk memperkuat hasil analisis terdapat pada masing-masing artikel dibawah ini. Tabel 1. Artikel terkait faktor-faktor yang mempengaruhi terjadinya depresi pernafasan pada pasien dengan fraktur costa.Study citationMetode penelitian Desain PenelitianSampel dan Jumlah sampelHasil temuanA multidisciplinary clinical pathway decreases rib fracture–associated infectious morbidity and mortality in high-risk trauma patientsTodd,et.al,(2006)prospective cohort study Non eksperimental150 pasien dari Februari 2002-Oktober 2004 dengan > 45 tahun dan>4 patah tulang rusuk.Diperoleh hasil usia, skor keparahan cedera, dan jumlah patah tulang rusuk, jalur klinis menurunkan mekanisme hari tergantung ventilator, lama rawat inap, morbiditas infeksi, dan mortalitas dengan (interval kepercayaan 95% [CI] P<0.01).Predicting outcome of patients with chest wall injuryPressley, et.al, (2012)retrospectively reviewedNon eksperimental649 pasien (Juni 2008 hingga Februari 2010) termasuk usia, jumlah patah tulang, cedera bilateral, adanya kontusio paru, klasifikasi memar, LOS, masuk ICU, ventilasi mekanikSebuah sistem penilaian sederhana memprediksi kemungkinan bahwa pasien akan memerlukan ventilasi mekanik dan perawatan yang berkepanjangan. Skor 7 atau 8 memprediksi peningkatan risiko kematian, penerimaanke ICU, dan intubasi. Skor 5 memprediksi lama tinggal yang lebih lama dan periode ventilasi yang lebih lama. Factors Affecting Pneumonia Occurring to Patients with Multiple Rib FracturesByun & Kim., (2013).retrospectively reviewedNon eksperimentalData rekam medis 327 pasien laki-laki rata-rata usia 53 tahun dengan fraktur costa akibat kecelakaan dari Januari 2002- Desember 2008.Faktor yang mempengaruhi pneumonia pada pasien dengan fraktur tulang rusuk multipel dalam analisis multivariat termasuk usia (p=0,004), ISS (p＜0,001), dan skor tulang rusuk(p=0,038). Penggunaan antibiotik tidak berhubungan dengan kejadian pneumonia (p=0,28).Determinants of Mortality in Chest Trauma PatientsEkpe & Eyo, (2014)Retrospective and prospective Non eksperimental149 pasien dengan trauma thoraks 121 laki-laki, 28 perempuan dari Januari 2007-Desember 2011Variabel bebas, umur, jenis kelamin dan jenis cedera dada tidak terbukti berkorelasi dengan mortalitas dengan nilai P >0,05. Namun adanya cedera organ ekstra toraks terkait, skor MEWS saat masuk tinggi> 9, cedera pada interval presentasi lebih dari 24 jam, dan cedera dada yang parah ditandai dengan keterlibatan dada bilateral yang berkorelasi positif dengan mortalitas dengan nilai P <0,05.The number of displaced rib fractures is more predictive for complications in chest trauma patientsChien et.al, (2017)retrospectively reviewedNon eksperimentalJanuari 2013 -Mei 2015 diperoleh data di rumah sakit dengan total pasien 3151. Pasien yang dirawat dengan trauma dada dan patah tulang rusuk, termasuk cedera otak, limpa, panggul atau hatiJumlah patah tulang rusuk yang bergeser bisa menjadi prediktor kuat untuk berkembangnya penyakit paru-paru komplikasi. Untuk pasien dengan kurang dari tiga patah tulang rusuk tanpa perpindahan tulang rusuk dan paru-paru awal atau cedera organ lainnya, manajemen rawat jalan bisa aman dan efisien.Is the number of rib fractures a risk factor for delayed complications? Flores-Funes, et.al, (2020)Retrospective case–control studyNon eksperimentalPasien yang dirawat dengan diagnosis patah tulang rusuk antara 2010 dan 2014, diperoleh 141 pasien.Tidak ada perbedaan dalam karakteristik dasar pasien (usia, jenis kelamin dan Indeks Komorbiditas Charlson) antara kedua kelompok. Perbedaan ditemukan pada jumlah fraktur pada kelompok tanpa komplikasi p>0,05 (tidak signifikan) pada kelompok dengan komplikasi, (p=0,05) dan pada penurunan kadar hemoglobin (p=0,01). Hari rawat inap bervariasi pada setiap kelompok tetapi tanpa signifikansi statistik (p=0,11). Kesimpulan: Jumlah fraktur iga yang paling baik memprediksi munculnya komplikasi (delayed pleuro-pulmonary) dan perdarahan yang lebih besar) adalah patah tulang rusuk 3 atau lebihPredictors of mortality in patients with rib fracturesMarini, et.al, (2021) Retrospective review Non eksperimental1188 pasien patah tulang rusuk dan cedera tambahan yang dirawat selama Januari 2013-Desember 2014; 800 laki-laki dan 388 perempuan Usia, GCS, jenis kelamin laki-laki, dan Injury Severity Score (ISS) tetapi tidak jumlah patah tulang rusuk dan/atau Pulmonary contusion merupakan prediksi kematian. Peningkatan mortalitas pada pasien patah tulang rusuk dimulai pada usia 65-80 tahun tanpa peningkatan lebih lanjut. Jumlah patah tulang rusuk bukan faktor independen peningkatan mortalitas terlepas dari usia. Severe traumatic brain injury adalah penyebab kematian paling umum pada pasien usia 16-65 tahun, dibandingkan dengan komplikasi pernapasan pada pasien berusia 80 tahun atau lebih. Banyak penelitian yang telah dilakukan untuk menentukan faktor prediktor kematian pada pasien fraktur costa. Dari 7 artikel di atas terdapat berbagai bukti yang mempengaruhi kematian akibat fraktur costa dengan metode penelitian yang berbeda.Penelitian Chien, et.al, (2017) dan Flores-Funes, et.al, (2020) menunjukkan hasil yang hampir sama dimana jumlah fraktur costa yang >2 akan meningkatkan angka morbiditas dan mortalitas dikarenakan faktor komplikasi pada paru. Berbeda dengan penelitian yang dilakukan Marini, et.al, (2021) yang menyatakan jumlah dari fraktur costa tidak memprediksi peningkatan mortalitas terlepas dari usia. Menurut peneliti faktor usia menjadi prediktor utama dalam menentukan angka mortalitas pada pasien dengan fraktur costa, dimana peningkatan mortalitas pada pasien patah tulang rusuk dimulai pada usia 65-80 tahun ke atas.Penelitian yang dilakukan Todd et.al,(2006) menghasilkan hipotesa bahwa usia, skor keparahan cedera, dan jumlah patah tulang rusuk, dan implementasi jalur klinis signifikan dengan penurunan lama perawatan di unit perawatan intensif, lama rawat inap di rumah sakit, infeksi pneumonia, dan mortalitas. Maka semakin lanjut usia, tingkat keparahan yang tinggi dan jumlah patah tulang rusuk bilateral atau >2 dapat meningkatkan angka morbiditas dan mortalitas pasien dengan fraktur costa.Penelitian Pressley et.al, (2012) dilakukan dengan melakukan analisis dengan menggunakan trauma dada scoring system dimana skor >7 memprediksi peningkatan risiko kematian, penerimaan ke ICU, dan intubasi. Penilaian scoring system ini dapat digunakan untuk memprediksi kemungkinan pasien akan memerlukan ventilasi mekanik dan perawatan yang berkepanjangan sehingga dapat memperparah penyakit, menimbulkan infeksi oportunistik dan menyebabkan resiko mortalitas.Penelitian Ekpe & Eyo, (2014) menggunakan system MEWS (modified early warning signs) untuk menganalis faktor prognosis pada pasien dengan trauma dada. Sebagai variabel bebas, umur, jenis kelamin dan jenis cedera dada tidak terbukti berkorelasi dengan mortalitas dengan nilai P >0,05. Namun adanya cedera organ ekstra toraks terkait, skor MEWS saat masuk tinggi> 9, dimana interval presentasi lebih dari 24 jam dengan cedera dada yang parah ditandai dengan keterlibatan dada bilateral, berkorelasi positif pada mortalitas. Berbeda dengan penelitian sebelumnya Byun & Kim., (2013) dimana faktor umur berpengaruh pada terjadinya infeksi pneumonia dan meningkatkan angka mortilitas dengan atau tanpa diikuti tingkat keparahan pada trauma dada.Berdasarkan analisis diatas terdapat persamaan hasil penelitian dimana rata-rata metode penelitian yang dilakukan dengan menggunakan retrospective review non eksperimental. Peneliti mengamati data rekam medis dari beberapa rentang waktu dengan kriteria inklusi menderita patah tulang rusuk lebih dari dua. Namun, terdapat kriteria yang berbeda-beda pula dimana peneliti memasukkan trauma tambahan seperti brain injury dan cedera pada organ yang lain. Jumlah sampel antara penelitian satu dengan yang lain juga berbeda dari ratusan hingga ribuan data yang dianalisis. Hal ini menyebabkan hasil penelitian yang diperoleh sedikit berbeda antara satu dengan yang lain.Manajemen fraktur costa berfokus pada manajemen nyeri yang adekuat, batuk efektif, relaksasi nafas dalam dan mobilisasi dini (Brasel et al., 2017). Berdasarkan beberapa penelitian manajemen nyeri pada pasien orthopedic terutama pasca operasi adalah dengan guided imagery. The American Holistic Nurses Association menyatakan guided imagery adalah modalitas holistik yang membantu klien dalam menghubungkan pengetahuan batin mereka pada pemikiran, perasaan, dan tingkat penginderaan, mempromosikan penyembuhan bawaan mereka dengan kemampuan bersama-sama memandu klien mengatasi stres; resolusi konflik; masalah pemberdayaan diri; dan persiapan medis-bedah (Integrative & Review, 2016). Oleh sebab itu, guided imagery tepat jika digunakan pada managemen nyeri non farmakologis yang diterapkan dalam intervensi keperawatan.Dalam teori keperawatan Jean Watson tentang Transpersonal Caring mendefinisikan hubungan manusia yang bersifat caring, bersatu dengan orang lain dengan menghargai klien seutuhnya termasuk keberadaannya di dunia (Alligood, 2014). Watson menyatakan kepedulian transpersonal caring adalah dasar dari teori kepedulian manusia dimana fokus dari kepedulian transpersonal adalah pada peduli, penyembuhan, dan keutuhan, bukan pada penyakit, sakit dan patologi yang mencakup 10 faktor karatif dalam konsep utamanya (Integrative & Review, 2016). Sesuai dengan teori Watson, Guided Imagery (GI) menggabungkan kedua sains (melalui praktik berbasis bukti) dan seni (melalui aplikasi untuk berlatih) untuk mengobati rasa sakit pasien menggunakan imaginasi terbimbing dan teknik relaksasi nafas dalam. Kombinasi dengan terapi obat, GI menyediakan rezim pengobatan holistik untuk manajemen nyeri untuk menenangkan pikiran dan merilekskan tubuh mereka, memberikan kesempatan bagi klien untuk menciptakan lingkungan penyembuhan internalnya sendiri (Integrative & Review, 2016).Intervensi keperawatan untuk batuk efektif dan mobilisasi dini termasuk poin penting dalam manajemen perawatan pasien fraktur costa. Batuk efektif adalah suatu metode batuk dengan benar dan pasien dapat mengeluarkan dahak secara maksimal untuk mengeluarkan sekret dari saluran pernapasan bawah (Potter dan Perry, 2006). Mobilisasi sendiri dapat menghasilkan outcome yang baik bagi pasien seperti meningkatkan pertukaran gas, mengurangi angka Ventilator Associated Pneumoia (VAP), mengurangi durasi penggunaan ventilator, dan meningkatkan kemampuan fungsional jangka panjang (Green, Marzano, Leditschke, Mitchell, & Bissett, 2016 dalam Ananta & Fitri, 2020). Oleh sebab itu, kedua intervensi ini perlu diteliti lebih lanjut guna mengembangkan riset terkait manajemen pasien fraktur costa. SIMPULAN Pasien dengan usia lanjut dengan patah tulang rusuk atau fraktur costa biasanya menunjukkan tingkat kelemahan, multi-morbiditas, dan kompleksitas medis yang tinggi (Coary, et.al, 2020). Hal ini tentu menjadi penghambat dalam faktor penyembuhan tulang dan dapat meningkatkan angka mortalitas. Pemaparan hasil analisis menggambarkan faktor usia, cedera tulang rusuk atau costa bilateral lebih dari 2, terjadinya komplikasi dan cedera pada organ lain menyebabkan pasien harus dirawat di ruang ICU lebih lama karena resiko infeksi dan komplikasi yang dapat meningkatkan angka morbiditas dan mortalitas.Terlepas dari faktor usia, tingkat keparahan cedera dan jumlah tulang rusuk yang patah menentukan haluaran pasien yang lebih baik. Penanganan fraktur costa yang tepat yang berfokus pada kontrol kerusakan, manajemen nyeri, fiksasi seleksi, dan kualitas hidup mempengaruhi penurunan angka morbiditas dan mortalitas pasien dengan fraktur costa. Kedudukan dan peran perawat spesialis dalam tugas mengatur asuhan klien dengan kompleksitas tinggi menjadi sangat penting (Masfuri, et.all, 2019) SARAN Penelitian klinis terkait implementasi keperawatan berbasis kasus masih jarang dilakukan. Implementasi keperawatan pada pasien dengan fraktur costa terkait manajemen nyeri dan kontrol infeksi menjadi penelitian yang menarik untuk dilakukan karena hal ini menjadi indikator faktor yang mempengaruhi angka mortalitas pasien dengan fraktur costa. DAFTAR PUSTAKA Alligood Raile Martha,2014, Nursing Theorits and their Work, 8th edition, by Mosby, an imprint of Elsevier IncAnanta Tanujiarso, B., & Fitri Ayu Lestari, D. (2020). Mobilisasi Dini Pada Pasien Kritis Di Intensive Care Unit (Icu): Case Study. 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T., Blaney, G. N., Huang, T. S., & Chen, K. F. (2017). The number of displaced rib fractures is more predictive for complications in chest trauma patients. Scandinavian Journal of Trauma, Resuscitation and Emergency Medicine, 25(1), 19. https://doi.org/10.1186/s13049-017-0368-yCoary, R., Skerritt, C., Carey, A., Rudd, S., & Shipway, D. (2020). New horizons in rib fracture management in the older adult. Age and Ageing, 49(2), 161–167. https://doi.org/10.1093/ageing/afz157Ekpe, E. E., & Eyo, C. (2014). Determinants of mortality in chest trauma patients. Nigerian Journal of Surgery : Official Publication of the Nigerian Surgical Research Society, 20(1), 30–304. https://doi.org/10.4103/1117-6806.127107Forward, J. B., Greuter, N. E., Crisall, S. J., & Lester, H. F. (2015). Effect of Structured Touch and Guided Imagery for Pain and Anxiety in Elective Joint Replacement Patients--A Randomized Controlled Trial: M-TIJRP. The Permanente Journal, 19(4), 18–28. https://doi.org/10.7812/TPP/14-236Flores-Funes, D., Lluna-Llorens, A. D., Jiménez-Ballester, M. Á., Valero-Navarro, G., Carrillo-Alcaráz, A., Campillo-Soto, Á., & Aguayo-Albasini, J. L. (2020). Is the number of rib fractures a risk factor for delayed complications? A case–control study. European Journal of Trauma and Emergency Surgery, 46(2), 435–440. https://doi.org/10.1007/s00068-018-1012-xIntegrative, A., & Review, L. (2016). jhn. 1–10.Marini, C. P., Petrone, P., Soto-Sánchez, A., García-Santos, E., Stoller, C., & Verde, J. (2021). Predictors of mortality in patients with rib fractures. European Journal of Trauma and Emergency Surgery, 47(5), 1527–1534. https://doi.org/10.1007/s00068-019-01183-5Masfuri Masfuri, Agung Waluyo, Yati Afiyanti, Achir Yani S. Hamid (2019) Educational background and clinical nursing tasks performed by nurses in Indonesian hospitals. Enfermería Clínica. 29 (2), 418-423. https://doi.org/10.1016/j.enfcli.2019.04.061.Nursalam. (2017). Metodologi Penelitian Ilmu Keperawatan: Pendekatan Praktis. (P. P. Lestari, Ed.) (4th ed.). Jakarta: Salemba Medika.Peek, J., Smeeing, D. P. J., Hietbrink, F., Houwert, R. M., Marsman, M., & de Jong, M. B. (2019). Comparison of analgesic interventions for traumatic rib fractures: a systematic review and meta-analysis. European Journal of Trauma and Emergency Surgery, 45(4), 597–622. https://doi.org/10.1007/s00068-018-0918-7Potter&Perry. (2006). Buku ajar Fundamental Keperawatan Konsep, Proses, dan Praktik. Jakarta: Penerbit Buku Kedokteran, EGC.Pressley, C. M., Fry, W. R., Philp, A. S., Berry, S. D., & Smith, R. S. (2012). Predicting outcome of patients with chest wall injury. American Journal of Surgery, 204(6), 910–914. https://doi.org/10.1016/j.amjsurg.2012.05.015Rossman, M. L. (2000). G uided I magery and I nteractive G uided I magery. M. L. Guided Imagery for Self Healing: An Essential for Anyone Seeking Wellness, 930.Simon, B. J., Cushman, J., Barraco, R., Lane, V., Luchette, F. A., Miglietta, M., Roccaforte, D. J., & Spector, R. (2005). Pain management guidelines for blunt thoracic trauma. Journal of Trauma - Injury, Infection and Critical Care, 59(5), 1256–1267. https://doi.org/10.1097/01.ta.0000178063.77946.f5Todd, S. R., McNally, M. M., Holcomb, J. B., Kozar, R. A., Kao, L. S., Gonzalez, E. A., Cocanour, C. S., Vercruysse, G. A., Lygas, M. H., Brasseaux, B. K., & Moore, F. A. (2006). A multidisciplinary clinical pathway decreases rib fracture-associated infectious morbidity and mortality in high-risk trauma patients. American Journal of Surgery, 192(6), 806–811. https://doi.org/10.1016/j.amjsurg.2006.08.048Wanek, S., & Mayberry, J. C. (2004). Blunt thoracic trauma: Flail chest, pulmonary contusion, and blast injury. Critical Care Clinics, 20(1), 71–81. https://doi.org/10.1016/S0749-0704(03)00098-8

Introduction: We explored findings associated with the risk of DKA in pts with T2D, with and without dapagliflozin (DAPA). Methods: DECLARE-TIMI 58 was a CV outcomes trial of 17160 pts with T2D randomized to DAPA vs placebo (PBO) with a median follow-up of 4.2 yrs. Pts with known T1D were excluded. DKA events adjudicated as definite or probable were analyzed. Results: DKA occurred in 27/8574 pts (0.31%) in DAPA vs 12/8569 (0.14%) in PBO arm (HR 2.18 [1.10-4.30]). Pts who developed DKA were more likely to be insulin users (82.1% vs 40.8%) and had a longer duration of T2D (14 vs 11 yrs), higher HbA1c (9.0% vs 8.0%), lower fasting C-peptide (C-pep; 0.2 vs 1.0 nmol/L) and HOMA2-B (20.7 vs 58.0; P&lt;0.02 for all). 63% of DKA events occurred in pts with fasting C-pep &lt;0.4 nmol/L and no DKA occurred in pts with C-pep &gt;0.97 nmol/L (Fig A). The 4-yr KM rate of DKA in pts with C-pep &lt;0.4 vs ≥0.4 nmol/L was 1.4% vs 0.09% (aHR 15.7 [7.7-32.2]). The absolute risk difference between DAPA and PBO was 1.84% vs 0.07% in pts with C-pep &lt;0.4 vs ≥0.4 nmol/L (Fig B). Conclusion: In DECLARE-TIMI 58, DKA was rare, and occurred mostly in pts with impaired insulin secretion. In pts with C-pep ≥0.4 nmol/L, the excess in DKA with DAPA was less than 1/1000pts/yr. Further research is needed to determine the utility of prospective C-peptide testing when initiating SGLT2i in pts suspected to have insulin deficiency. Disclosure Y. Kang: None. A. Cahn: Advisory Panel; Novo Nordisk. Speaker's Bureau; Novo Nordisk, AstraZeneca, Eli Lilly and Company, Bayer Inc. Advisory Panel; Eli Lilly and Company. I. Raz: Consultant; AstraZeneca, Eli Lilly and Company, Novo Nordisk, Johnson & Johnson Medical Devices Companies, Bayer Inc. F. Moura: Consultant; Janssen Pharmaceuticals, Inc. D.L. Bhatt: Advisory Panel; Angiowave, Bayer, Boehringer Ingelheim, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, High Enroll, Janssen, Level Ex, McKinsey, Medscape Cardiology, Merck, MyoKardia, NirvaMed,. Board Member; American Heart Association New York City, Angiowave (stock options), Bristol Myers Squibb (stock), DRS.LINQ (stock options), High Enroll (stock);. Consultant; Broadview Ventures, GlaxoSmithKline, Hims, SFJ, Youngene. Other Relationship; Acesion Pharma, Assistance Publique-Hôpitaux de Paris, Baim Institute, Boston Scientific, Cleveland Clinic, Contego Medical, Duke Clinical Research Institute, Mayo Clinic, Mount Sinai, Novartis, Popul, ACC, Arnold and Porter Law Firm, Baim Institute, Belvoir Publications, CSL Behring, Cowen and Company, Duke Clinical Research Institute, HMP Global, Journal of the ACC, K2P, Level Ex, Medtelligence/Re, Population Health Research Institute, Wiley, Clinical Cardiology, Lexicon Pharmaceuticals, Inc. Research Support; Abbott, Acesion Pharma, Afimmune, Aker Biomarine, Alnylam, Amarin, Amgen, AstraZeneca, Bayer, Beren, Boehringer Ingelheim, Boston Scientific, Bristol-Myers Squibb, Cardax, CellProthera, Cereno Scienti, Ethicon, Faraday Pharmaceuticals, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Garmin, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Janssen, Javelin, Lexicon, Lilly, Medtronic, Merck, Mode, Otsuka, Owkin, Pfizer, PhaseBio, PLx Pharma, Recardio, Regeneron, Reid Hoffman Foundation, Roche, Sanofi, Stasys, Synaptic, The Medicines Company, Youngene, 89Bio. Other Relationship; Elsevier (Editor, Braunwald’s Heart Disease), Abbott, Biotronik, Boston Scientific, CSI, Endotronix, St. Jude Medical (now Abbott), Philips, SpectraWAVE, Svelte, Vascular Solutions, American College of Cardiology, FlowCo. Stock/Shareholder; Angiowave (stock options), Bristol Myers Squibb (stock), DRS.LINQ (stock options), High Enroll (stock). S.E. Inzucchi: Consultant; AstraZeneca, Boehringer-Ingelheim, Merck & Co., Inc., Pfizer Inc., Novo Nordisk, Bayer Inc. L.A. Leiter: Advisory Panel; Abbott. Other Relationship; Amarin Corporation, Amgen Inc., Applied Therapeutics Inc. Advisory Panel; AstraZeneca. Other Relationship; Bayer Inc. Advisory Panel; Boehringer-Ingelheim. Other Relationship; CRISPR Therapeutics Other, Eli Lilly and Company. Speaker's Bureau; EOCI Pharmacomm. Research Support; ESPERION Therapeutics, Inc. Other Relationship; HLS Therapeutics Inc. Research Support; Kowa Company, Ltd., Lexicon Pharmaceuticals, Inc. Advisory Panel; Merck & Co., Inc. Speaker's Bureau; Novartis AG. Advisory Panel; Novo Nordisk. Other Relationship; Novo Nordisk Canada Inc. Speaker's Bureau; Pfizer Inc. Advisory Panel; Sanofi. Speaker's Bureau; Toronto Knowledge Translation Working Group. Other Relationship; Up-To-Date. D.K. McGuire: Other Relationship; Merck & Co., Inc., Eli Lilly and Company, Boehringer-Ingelheim, Novo Nordisk, Pfizer Inc., AstraZeneca. Consultant; Bayer Inc., Lexicon Pharmaceuticals, Inc., Altimmune Inc., Intercept Pharmaceuticals, Inc., Applied Therapeutics. J. Wilding: Speaker's Bureau; Boehringer-Ingelheim. Consultant; Eli Lilly and Company, Napp Pharmaceuticals Limited, Novo Nordisk. Advisory Panel; AstraZeneca. Consultant; Alnylam Pharmaceuticals, Inc., Rhythm Pharmaceuticals, Inc. Speaker's Bureau; Sanofi. Consultant; A. Menarini Diagnostics. I.A. Gause-Nilsson: Employee; AstraZeneca. J. Oscarsson: Employee; AstraZeneca. Stock/Shareholder; AstraZeneca. N. Marston: Research Support; Ionis Pharmaceuticals, Amgen Inc., Pfizer Inc. C.T. Ruff: Research Support; Anthos, AstraZeneca, Daiichi Sankyo, Janssen Pharmaceuticals, Inc., Novartis AG. Other Relationship; Altimmune Inc. Advisory Panel; Bayer Inc., Merck & Co., Inc., Anthos, Janssen Pharmaceuticals, Inc. M.S. Sabatine: Research Support; Abbott, Amgen Inc. Consultant; Amgen Inc. Research Support; Anthos. Consultant; Anthos. Research Support; AstraZeneca. Consultant; AstraZeneca, Beren Therapeutics. Research Support; Boehringer-Ingelheim. Consultant; Boehringer-Ingelheim. Research Support; Daiichi Sankyo. Consultant; Dr. Reddy's Laboratories. Research Support; Ionis Pharmaceuticals, Merck & Co., Inc. Consultant; Merck & Co., Inc., Moderna, Inc. Research Support; Novartis AG. Consultant; Novo Nordisk. Research Support; Pfizer Inc. Consultant; Precision Biosciences. Research Support; Saghmos Therapeutics. Consultant; Silence Therapeutics. Research Support; Verve Therapeutics. S.D. Wiviott: Consultant; Novo Nordisk, Varian, Icon. Research Support; Amgen Inc., Merck & Co., Inc., AstraZeneca, Pfizer Inc. Other Relationship; Vertex Pharmaceuticals Incorporated, Flagship Pioneering. Funding National Institutes of Health (5T32DK007529)

Introduction: We aimed to study the association of T1D polygenic score (PS) & C-peptide (C-pep) with the risk of DKA in DECLARE-TIMI 58. Methods: DECLARE-TIMI 58 was a CV outcomes trial of dapagliflozin (DAPA) vs. placebo (PBO) in pts clinically diagnosed with T2D. T1D PS consists of scores based on HLA and non-HLA allele composition. High T1D PS was defined as having both HLA and non-HLA PS within the top tertile. Fasting C-pep &lt;0.4 nmol/L was considered low. Pts were divided into 4 groups based on the presence/absence of high T1D PS and low C-pep. Results: Among 10,956 pts with genetic data, 27 (2.5%; 21 in DAPA and 6 in PBO) had DKA over 4.2 yrs. Of all pts, 1,272 (11.6%) had high T1D PS and their risk of DKA was 4-fold higher vs the rest (HR 3.90, 95% CI 1.75-8.70). 9.3% of all pts had low C-pep, and 1.6% had both high T1D PS and low C-pep. The 4-yr KM rate for DKA in pts with no risk factors was 0.06%, followed by 0.21% in pts with high T1D PS only, 1.38% in pts with low C-pep only, and 4.28% in pts with both (Fig A). Absolute differences in rates between DAPA and PBO tended to be greater in the higher-risk groups (P-trend &lt;0.001: Fig B). Conclusion: Although rare overall, DKA was more common in DAPA arm, and it was largely confined to high-risk pts defined by T1D PS and C-peptide. These tools can help identify pts at increased risk of DKA associated with SGTL2i. The clinical implications of these findings require further investigation. Disclosure Y. Kang: None. A. Cahn: Advisory Panel; Novo Nordisk. Speaker's Bureau; Novo Nordisk, AstraZeneca, Eli Lilly and Company, Bayer Inc. Advisory Panel; Eli Lilly and Company. I. Raz: Consultant; AstraZeneca, Eli Lilly and Company, Novo Nordisk, Johnson & Johnson Medical Devices Companies, Bayer Inc. F. Moura: Consultant; Janssen Pharmaceuticals, Inc. D.L. Bhatt: Advisory Panel; Angiowave, Bayer, Boehringer Ingelheim, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, High Enroll, Janssen, Level Ex, McKinsey, Medscape Cardiology, Merck, MyoKardia, NirvaMed,. Board Member; American Heart Association New York City, Angiowave (stock options), Bristol Myers Squibb (stock), DRS.LINQ (stock options), High Enroll (stock);. Consultant; Broadview Ventures, GlaxoSmithKline, Hims, SFJ, Youngene. Other Relationship; Acesion Pharma, Assistance Publique-Hôpitaux de Paris, Baim Institute, Boston Scientific, Cleveland Clinic, Contego Medical, Duke Clinical Research Institute, Mayo Clinic, Mount Sinai, Novartis, Popul, ACC, Arnold and Porter Law Firm, Baim Institute, Belvoir Publications, CSL Behring, Cowen and Company, Duke Clinical Research Institute, HMP Global, Journal of the ACC, K2P, Level Ex, Medtelligence/Re, Population Health Research Institute, Wiley, Clinical Cardiology, Lexicon Pharmaceuticals, Inc. Research Support; Abbott, Acesion Pharma, Afimmune, Aker Biomarine, Alnylam, Amarin, Amgen, AstraZeneca, Bayer, Beren, Boehringer Ingelheim, Boston Scientific, Bristol-Myers Squibb, Cardax, CellProthera, Cereno Scienti, Ethicon, Faraday Pharmaceuticals, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Garmin, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Janssen, Javelin, Lexicon, Lilly, Medtronic, Merck, Mode, Otsuka, Owkin, Pfizer, PhaseBio, PLx Pharma, Recardio, Regeneron, Reid Hoffman Foundation, Roche, Sanofi, Stasys, Synaptic, The Medicines Company, Youngene, 89Bio. Other Relationship; Elsevier (Editor, Braunwald’s Heart Disease), Abbott, Biotronik, Boston Scientific, CSI, Endotronix, St. Jude Medical (now Abbott), Philips, SpectraWAVE, Svelte, Vascular Solutions, American College of Cardiology, FlowCo. Stock/Shareholder; Angiowave (stock options), Bristol Myers Squibb (stock), DRS.LINQ (stock options), High Enroll (stock). S.E. Inzucchi: Consultant; AstraZeneca, Boehringer-Ingelheim, Merck & Co., Inc., Pfizer Inc., Novo Nordisk, Bayer Inc. L.A. Leiter: Advisory Panel; Abbott. Other Relationship; Amarin Corporation, Amgen Inc., Applied Therapeutics Inc. Advisory Panel; AstraZeneca. Other Relationship; Bayer Inc. Advisory Panel; Boehringer-Ingelheim. Other Relationship; CRISPR Therapeutics Other, Eli Lilly and Company. Speaker's Bureau; EOCI Pharmacomm. Research Support; ESPERION Therapeutics, Inc. Other Relationship; HLS Therapeutics Inc. Research Support; Kowa Company, Ltd., Lexicon Pharmaceuticals, Inc. Advisory Panel; Merck & Co., Inc. Speaker's Bureau; Novartis AG. Advisory Panel; Novo Nordisk. Other Relationship; Novo Nordisk Canada Inc. Speaker's Bureau; Pfizer Inc. Advisory Panel; Sanofi. Speaker's Bureau; Toronto Knowledge Translation Working Group. Other Relationship; Up-To-Date. D.K. McGuire: Other Relationship; Merck & Co., Inc., Eli Lilly and Company, Boehringer-Ingelheim, Novo Nordisk, Pfizer Inc., AstraZeneca. Consultant; Bayer Inc., Lexicon Pharmaceuticals, Inc., Altimmune Inc., Intercept Pharmaceuticals, Inc., Applied Therapeutics. J. Wilding: Speaker's Bureau; Boehringer-Ingelheim. Consultant; Eli Lilly and Company, Napp Pharmaceuticals Limited, Novo Nordisk. Advisory Panel; AstraZeneca. Consultant; Alnylam Pharmaceuticals, Inc., Rhythm Pharmaceuticals, Inc. Speaker's Bureau; Sanofi. Consultant; A. Menarini Diagnostics. I.A. Gause-Nilsson: Employee; AstraZeneca. J. Oscarsson: Employee; AstraZeneca. Stock/Shareholder; AstraZeneca. N. Marston: Research Support; Ionis Pharmaceuticals, Amgen Inc., Pfizer Inc. C.T. Ruff: Research Support; Anthos, AstraZeneca, Daiichi Sankyo, Janssen Pharmaceuticals, Inc., Novartis AG. Other Relationship; Altimmune Inc. Advisory Panel; Bayer Inc., Merck & Co., Inc., Anthos, Janssen Pharmaceuticals, Inc. M.S. Sabatine: Research Support; Abbott, Amgen Inc. Consultant; Amgen Inc. Research Support; Anthos. Consultant; Anthos. Research Support; AstraZeneca. Consultant; AstraZeneca, Beren Therapeutics. Research Support; Boehringer-Ingelheim. Consultant; Boehringer-Ingelheim. Research Support; Daiichi Sankyo. Consultant; Dr. Reddy's Laboratories. Research Support; Ionis Pharmaceuticals, Merck & Co., Inc. Consultant; Merck & Co., Inc., Moderna, Inc. Research Support; Novartis AG. Consultant; Novo Nordisk. Research Support; Pfizer Inc. Consultant; Precision Biosciences. Research Support; Saghmos Therapeutics. Consultant; Silence Therapeutics. Research Support; Verve Therapeutics. S.D. Wiviott: Consultant; Novo Nordisk, Varian, Icon. Research Support; Amgen Inc., Merck & Co., Inc., AstraZeneca, Pfizer Inc. Other Relationship; Vertex Pharmaceuticals Incorporated, Flagship Pioneering. Funding National Institutes of Health (5T32DK007529)

Introduction Daffodil Day, usually held in spring, raises funds for cancer awareness and research using this symbol of hope. On that day, people who donate money to this good cause are usually given a yellow daffodil pin to wear. When I lived in Auckland, New Zealand, on the last Friday in August most people walking around the city centre proudly wore a cheerful yellow flower. So many people generously participated in this initiative that one almost felt obliged to join the cause in order to wear the ‘uniform’ – the daffodil pin – as everyone else did on that day. To donate and to wear a daffodil is the social expectation, and operating in social environment people often endeavour to meet the expectation by doing the ‘appropriate things’ defined by societies or communities. After all, who does not like to receive a beam of acceptance and appreciation from a fellow daffodil bearer in Auckland’s Queen Street? States in international society are no different. In some ways, states wear ‘uniforms’ while executing domestic and foreign affairs just as human beings do within their social groups. States develop the understandings of desirable behaviour from the international community with which they interact and identify. They are ‘socialised’ to act in line with the expectations of international community. These expectations are expressed in the form of international norms, a prescriptive set of ideas about the ‘appropriate behaviour for actors with a given identity’ (Finnemore and Sikkink 891). Motivated by this logic of appropriateness, states that comply with certain international norms in world politics justify and undertake actions that are considered appropriate for their identities. This essay starts with examining how international norms can be spread to different countries through the process of ‘state socialisation’ (how the countries are ‘talked into’ wearing the ‘uniform’). Second, the essay investigates the idea of ‘cultural match’: how domestic actors comply with an international norm by interpreting and manipulating it according to their local political and legal practices (how the countries wear the ‘uniform’ differently). Lastly, the essay probes the current international normative community and the liberal values embedded in major international norms (whether states would continue wearing the ‘uniform’). International Norms and State Socialisation: Why Do States Wear the ‘Uniforms’? Norm diffusion is related to the efforts of ‘norm entrepreneurs’ using various platforms to convince a critical mass of states to embrace new norms (Finnemore and Sikkink 895-896). Early studies of norm diffusion tend to emphasise nongovernmental organisations (NGOs) as norm entrepreneurs and advocates, such as Oxfam and its goal of reducing poverty and hunger worldwide (Capie 638). In other empirical research, intergovernmental organisations (IGOs) were shown to serve as ‘norm teachers,’ such as UNESCO educating developing countries the value of science policy organisations (Finnemore 581-586). Additionally, states and other international actors can also play important roles in norm diffusion. Powerful states with more communication resources sometimes enjoy advantages in creating and promoting new norms (Florini 375). For example, the United States and Western European countries have often been considered as the major proponents of free trade. Norm emergence and state socialisation in a normative community often occurs during critical historical periods, such as wars and major economic downturns, when international changes and domestic crises often coincide with each other (Ikenberry and Kupchan 292). For instance, the norm entrepreneurs of ‘responsible power/state’ can be traced back to the great powers (mainly the United States, Great Britain, and the Soviet Union) and their management of international order at the end of WWII (see Bull). With their negotiations and series of international agreements at the Cairo, Tehran, Yalta, and Potsdam Conference in the 1940s, these great powers established a post-World War international society based on the key liberal values of international peace and security, free trade, human rights, and democracy. Human beings are not born to know what appropriate behaviour is; we learn social norms from parents, schools, peers, and other community members. International norms are collective expectations and understanding of how state governments should approach their domestic and foreign affairs. States ‘learn’ international norms while socialising with a normative community. From a sociological perspective, socialisation summarises ‘how and to what extent diverse individuals are meshed with the requirement of collective life’ at the societal level (Long and Hadden 39). It mainly consists of the process of training and shaping newcomers by the group members and the social adjustment of novices to the normative framework and the logic of appropriateness (Long and Hadden 39). Similarly, social psychology defines socialisation as the process in which ‘social organisations influence the action and experience of individuals’ (Gold and Douvan 145). Inspired by sociology and psychology, political scientists consider socialisation to be the mechanism through which norm entrepreneurs persuade other actors (usually a norm novice) to adhere to a particular prescriptive standard (Johnston, “Social State” 16). Norm entrepreneurs can change novices’ behaviour by the methods of persuasion and social influence (Johnston, “Treating International Institutions” 496-506). Socialisation sometimes demands that individual actors should comply with organisational norms by changing their interests or preferences (persuasion). Norm entrepreneurs often attempt to construct an appealing cognitive frame in order to persuade the novices (either individuals or states) to change their normative preferences or adopt new norms. They tend to use language that can ‘name, interpret and dramatise’ the issues related to the emerging norm (Finnemore and Sikkink 987). As a main persuasive device, ‘framing’ can provide a singular interpretation and appropriate behavioural response for a particular situation (Payne 39). Cognitive consistency theory found in psychology has suggested the mechanism of ‘analogy’, which indicates that actors are more likely to accept new ideas that share some similarities to the extant belief or ideas that they have already accepted (see Hybel, ch. 2). Based on this understanding, norm entrepreneurs usually frame issues in a way that can associate and resonate with the shared value of the targeted novices (Payne 43). For example, Finnemore’s research shows that when it promoted the creation of state science bureaucracies in the 1960s, UNESCO associated professional science policy-making with the appropriate role of a modern state, which was well received by the post-war developing countries in Latin America, the Middle East, and Southeast Asia (Finnemore 565-597). Socialisation can also emanate actors’ pro-norm behaviour through a cost-benefit calculation made with social rewards and punishments (social influence). A normative community can use the mechanism of back-patting and opprobrium to distribute social reward and punishment. Back-patting – ‘recognition, praise and normative support’ – is offered for a novice’s or member’s cooperative and pro-norm behaviour (Johnston, “Treating International Institutions” 503). In contrast, opprobrium associated with status denial and identity rejection can create social and psychological costs (Johnston 504). Both the reward and punishment grow in intensity with the number of co-operators (Johnston 504). A larger community can often create more criticism towards rule-breakers, and thus greatly increase the cost of disobedience. For instance, the lack of full commitment from major powers, such as China, the United States, and some other OECD countries, has arguably made global collective action towards mitigating climate change more difficult, as the cost of non-compliance is relatively low. While being in a normative environment, novice or emerging states that have not yet been socialised into the international community can respond to persuasion and social influence through the processes of identification and mimicking. Social psychology indicates that when one actor accepts persuasion or social influence based on its desire to build or maintain a ‘satisfying self-defining relationship’ to another actor, the mechanism of identification starts to work (Kelman 53). Identification among a social group can generate ‘obligatory’ behaviour, where individual states make decisions by attempting to match their perceptions of ‘who they are’ (national identity) with the expectation of the normative community (Glodgeier and Tetlock 82). After identifying with the normative community, a novice state would then mimic peer states’ pro-norm behaviour in order to be considered as a qualified member of the social group. For example, when the Chinese government was deliberating over its ratification of the Cartagena Protocol on Biosafety in 2003, a Ministry of Environmental Protection brief noted that China should ratify the Protocol as soon as possible because China had always been a country ‘keeping its word’ in international society, and non-ratification would largely ‘undermine China’s international image and reputation’ (Ministry of Environmental Protection of PRC). Despite the domestic industry’s disagreement with entering into the Protocol, the Chinese government’s self-identification as a ‘responsible state’ that performs its international promises and duties played an important role in China’s adoption of the international norm of biosafety. Domestic Salience of International Norms: How Do States Wear the ‘Uniforms’ Differently? Individual states do not accept international norms passively; instead, state governments often negotiate and interact with domestic actors, such as major industries and interest groups, whose actions and understandings in turn impact on how the norm is understood and implemented. This in turn feeds back to the larger normative community and creates variations of those norms. There are three main factors that can contribute to the domestic salience of an international norm. First, as the norm-takers, domestic actors can decide whether and to what extent an international norm can enter the domestic agenda and how it will be implemented in policy-making. These actors tend to favour an international norm that can justify their political and social programs and promote their interests in domestic policy debates (Cortell and Davis, “How Do International Institutions Matter?” 453). By advocating the existence and adoption of an international norm, domestic actors attempt to enhance the legitimacy and authority of their current policy or institution (Acharya, “How Ideas Spread” 248). Political elites can strengthen state legitimacy by complying with an international norm in their policy-making, and consequently obtain international approval with reputation, trust, and credibility as social benefits in the international community (Finnemore and Sikkink 903). For example, when the UN General Assembly adopted the Declaration on the Rights of Indigenous Peoples (UNDRIP), only four states – Australia, Canada, New Zealand, and the United States – voted against the Declaration. They argued that their constitutional and national policies were sufficiently responsive to the type of Indigenous self-determination envisioned by UNDRIP. Nevertheless, given the opprobrium directed against these states by the international community, and their well-organised Indigenous populations, the four state leaders recognised the value of supporting UNDRIP. Subsequently all four states adopted the Declaration, but in each instance state leaders observed UNDRIP’s ‘aspirational’ rather than legal status; UNDRIP was a statement of values that these states’ policies should seek to incorporate into their domestic Indigenous law. Second, the various cultural, political, and institutional strategies of domestic actors can influence the effectiveness of norm empowerment. Political rhetoric and political institutions are usually created and used to promote a norm domestically. Both state and societal leaders can make the performative speech act of an international norm work and raise its importance in a national context by repeated declarations on the legitimacy and obligations brought by the norm (Cortell and Davis, “Understanding the Domestic Impact” 76). Moreover, domestic actors can also develop or modify political institutions to incorporate an international norm into the domestic bureaucratic or legal system (Cortell and Davis, “Understanding the Domestic Impact” 76). These institutions provide rules for domestic actors and articulate their rights and obligations, which transforms the international norm’s legitimacy and authority into local practices. For example, the New Zealand Government adopted a non-nuclear policy in the 1980s. This policy arose from the non-nuclear movement that was leading the development of the Raratonga Treaty (South Pacific Nuclear Free Zone) and peace and Green party movements across Europe who sought to de-nuclearise the European continent. The Lange Labour Government’s 1984 adoption of an NZ anti-nuclear policy gained impetus because of these larger norm movements, and these movements in turn recognised the normative importance of a smaller power in international relations. Third, the characteristics of the international norm can also impact on the likelihood that the norm will be accepted by domestic actors. A ‘cultural match’ between international norm and local values can facilitate norm diffusion to domestic level. Sociologists suggest that norm diffusion is more likely to be successful if the norm is congruent with the prior values and practices of the norm-taker (Acharya, “Asian Regional Institutions” 14). Norm diffusion tends to be more efficient when there is a high degree of cultural match such that the global norm resonates with the target country’s domestic values, beliefs or understandings, which in turn can be reflected in national discourse, as well as the legal and bureaucratic system (Checkel 87; Cortell and Davis, “Understanding the Domestic Impact” 73). With such cultural consistency, domestic actors are more likely to accept an international norm and treat it as a given or as ‘matter-of-fact’ (Cortell and Davis, “Understanding the Domestic Impact” 74). Cultural match in norm localisation explains why identical or similar international socialisation processes can lead to quite different local developments and variations of international norms. The debate between universal human rights and the ‘Asian values’ of human rights is an example where some Asian states, such as Singapore and China, prioritise citizen’s economic rights over social and political rights and embrace collective rights instead of individual rights. Cultural match can also explain why one country may easily accept a certain international norm, or some aspect of one particular norm, while rejecting others. For example, when Taiwanese and Japanese governments adapted the United Nations Declaration on the Rights of Indigenous Peoples into their local political and legal practice, various cultural aspects of Indigenous rights have been more thoroughly implemented compared to indigenous economic and political rights (Gao et al. 60-65). In some extreme cases, the norm entrepreneurs even attempt to change the local culture of norm recipients to create a better cultural match for norm localisation. For example, when it tried to socialise India into its colonial system in the early nineteenth century, Britain successfully shaped the evolution of Indian political culture by adding British values and practices into India’s social, political, and judicial system (Ikenberry and Kupchan 307-309). The International Normative Community: Would States Continue Wearing ‘Uniforms’? International norms evolve. Not every international norm can survive and sustain. For example, while imperialism and colonial expansion, where various European states explored, conquered, settled, and exploited other parts of the world, was a widely accepted idea and practice in the nineteenth century, state sovereignty, equality, and individual rights have replaced imperialism and become the prevailing norms in international society today. The meanings of the same international norm can evolve as well. The Great Powers first established the post-war international norms of ‘state responsibility’ based on the idea of sovereign equality and non-intervention of domestic affairs. However, the 1980s saw the emergence of many international organisations, which built new standards and offered new meanings for a responsible state in international society: a responsible state must actively participate in international organisations and comply with international regimes. In the post-Cold War era, international society has paid more attention to states’ responsibility to offer global common goods and to promote the values of human rights and democracy. This shift of focus has changed the international expectation of state responsibility again to embrace collective goods and global values (Foot, “Chinese Power” 3-11). In addition to the nature and evolution of international norms, the unity and strength of the normative community can also affect states’ compliance with the norms. The growing size of the community group or the number of other cooperatives can amplify the effect of socialisation (Johnston, “Treating International Institutions” 503-506). In other words, individual states are often more concerned about their national image, reputation and identity regarding norm compliance when a critical mass of states have already subscribed into the international norm. How much could this critical mass be? Finnemore and Sikkink suggest that international norms reach the threshold global acceptance when the norm entrepreneurs have persuaded at least one third of all states to adopt the new norm (901). The veto record of the United Nation Security Council (UNSC) shows this impact. China, for example, has cast a UNSC veto vote 17 times as of 2022, but it has rarely excised its veto power alone (Security Council Report). For instance, though being sceptical of the notion of ‘Responsibility to Protect’, which prioritises human right over state sovereignty, China did not veto Resolution 1973 (2011) regarding the Libyan civil war. The Resolution allowed the international society to take ‘all necessary measure to protect civilians’ from a failed state government, and it received wide support among UNSC members (no negative votes from the other 14 members). Moreover, states are not entirely equal in terms of their ‘normative weight’. When Great Powers act as norm entrepreneurs, they can usually utilise their wealth and influence to better socialise other norm novice states. In the history of promoting biological diversity norms which are embedded in the Convention on Biological Diversity (CBD), the OECD countries, especially France, UK, Germany, and Japan, have been regarded as normative leaders. French and Japanese political leaders employed normative language (such as ‘need’ and ‘must’) in various international forums to promote the norms and to highlight their normative commitment (see e.g. Chirac; Kan). Additionally, both governments provided financial assistance for developing countries to adopt the biodiversity norms. In the 2011 annual review of CBD, Japan reaffirmed its US$12 million contribution to assisting developing countries (Secretariat of the Convention on Biological Diversity 9). France joined Japan’s commitment by announcing a financial contribution of €1 million along, with some additional funding from Norway and Switzerland (Secretariat of the Convention on Biological Diversity 9). Today, biological diversity has been one of the most widely accepted international environmental norms, which 196 states/nations have ratified (United Nations). While Great Powers can make more substantial contributions to norm diffusion compared to many smaller powers with limited state capacity, Great Powers’ non-compliance with the normative ‘uniform’ can also significantly undermine the international norms’ validity and the normative community’s unity and reputation. The current normative community of climate change is hardly a unified one, as it is characterised by a low degree of consensus. Major industrial countries, such as the United States, Canada, and Australia, have not yet reached an agreement concerning their individual responsibilities for reducing greenhouse emissions. This lack of agreement, which includes the amount of cuts, the feasibility and usefulness of such cuts, and the relative sharing of cuts across various states, is complicated by the fact that large developing countries, such as China, Brazil, and India, also hold different opinions towards climate change regimes (see Vidal et al.). Experts heavily criticised the major global powers, such as the European Union and the United States, for their lack of ambition in phasing out fossil fuels during the 2022 climate summit in Egypt (COP27; Ehsan et al.). In international trade, both China and the United States are among the leading powers because of their large trade volume, capacity, and transnational network; however, both countries have recently undermined the world trade system and norms. China took punitive measures against Australian export products after Australia’s Covid-19 inquiry request at the World Health Organisation. The United States, particularly under the Trump Administration, invoked the WTO national security exception in Article XXI of the General Agreement on Tariffs and Trade (GATT) to justify its tariffs on steel and aluminium. Lastly, norm diffusion and socialisation can be a ‘two-way path,’ especially when the norm novice state is a powerful and influential state in the international system. In this case, the novices are not merely assimilated into the group, but can also successfully exert some influence on other group members and affect intra-group relations (Moreland 1174). As such, the novices can be both targets of socialisation and active agents who can shape the content and outcome of socialisation processes (Pu 344). The influence from the novices can create normative contestation and thus influence the norm evolution (Thies 547). In other words, novice states can influence international society and shape the international norm during the socialisation process. For example, the ‘ASEAN Way’ is a set of norms that regulate member states’ relationships within the Association of Southeast Asian Nations (ASEAN). It establishes a diplomatic and security culture characterised by informality, consultation, and dialogue, and consensus-building in decision-making processes (Caballero-Anthony). From its interaction with ASEAN, China has been socialised into the ‘ASEAN Way’ (Ba 157-159). Nevertheless, China’s relations with the ASEAN Regional Forum (ARF) also suggest that there exists a ‘feedback’ process between China and ARF which resulted in institutional changes in ARF to accommodate China’s response (Johnston, “The Myth of the ASEAN Way?” 291). For another example, while the Western powers generally promote the norm of ‘shared responsibility’ in global environment regimes, the emerging economies, such as the BRICS countries (Brazil, Russia, India, China, and South Africa), have responded to the normative engagement and proposed a ‘Common but Differentiated Responsibilities’ regime where the developing countries shoulder less international obligations. Similarly, the Western-led norm of ‘Responsibility to Protect’, which justifies international humanitarian intervention, has received much resistance from the countries that only adhere to the conventional international rules regarding state sovereignty rights and non-intervention to domestic affairs. Conclusion International norms are shared expectations about what constitutes appropriate state behaviour. They are the ‘uniforms’ for individual states to wear when operating at the international level. States comply with international norms in order to affirm their preferred national identities as well as to gain social acceptance and reputation in the normative community. When the normative community is united and sizable, states tend to receive more social pressure to consistently wear these normative uniforms – be they the Geneva Conventions or nuclear non-proliferation. Nevertheless, in the post-pandemic world where liberal values, such as individual rights and rule of law, face significant challenges and democracies are in decline, the future success of the global normative community may be at risk. Great Powers are especially responsible for the survival and sustainability of international norms. The United States under President Trump adopted a nationalist ‘America First’ security agenda: alienating traditional allies, befriending authoritarian regimes previously shunned, and rejecting multilateralism as the foundation of the post-war global order. While the West has been criticised of failing to live up to its declared values, and has suffered its own loss of confidence in the liberal model, the rising powers have offered their alternative version of the world system. Instead of merely adapting to the Western-led global norms, China has created new institutions, such as the Belt and Road Initiatives, to promote its own preferred values, and has reshaped the global order where it deems the norms undesirable (Foot, “Chinese Power in a Changing World Order” 7). Great Power participation has reshaped the landscape of global normative community, and sadly not always in positive ways. Umberto Eco lamented the disappearance of the beauty of the past in his novel The Name of the Rose: ‘stat rosa pristina nomine, nomina nuda tenemus’ ('yesterday’s rose endures in its name, we hold empty names'; Eco 538). If the international community does not want to witness an era where global norms and universal values are reduced to nominalist symbols, it must renew and reinvigorate its commitment to global values, such as human rights and democracy. It must consider wearing these uniforms again, properly. 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When we think of disability today in the Western world, Christopher Reeve most likely comes to mind. A film star who captured people’s imagination as Superman, Reeve was already a celebrity before he took the fall that would lead to his new position in the fame game: the role of super-crip. As a person with acquired quadriplegia, Christopher Reeve has become both the epitome of disability in Western culture — the powerful cultural myth of disability as tragedy and catastrophe — and, in an intimately related way, the icon for the high-technology quest for cure. The case of Reeve is fascinating, yet critical discussion of Christopher Reeve in terms of fame, celebrity and his performance of disability is conspicuously lacking (for a rare exception see McRuer). To some extent this reflects the comparative lack of engagement of media and cultural studies with disability (Goggin). To redress this lacuna, we draw upon theories of celebrity (Dyer; Marshall; Turner, Bonner, & Marshall; Turner) to explore the production of Reeve as celebrity, as well as bringing accounts of celebrity into dialogue with critical disability studies. Reeve is a cultural icon, not just because of the economy, industrial processes, semiotics, and contemporary consumption of celebrity, outlined in Turner’s 2004 framework. Fame and celebrity are crucial systems in the construction of disability; and the circulation of Reeve-as-celebrity only makes sense if we understand the centrality of disability to culture and media. Reeve plays an enormously important (if ambiguous) function in the social relations of disability, at the heart of the discursive underpinning of the otherness of disability and the construction of normal sexed and gendered bodies (the normate) in everyday life. What is distinctive and especially powerful about this instance of fame and disability is how authenticity plays through the body of the celebrity Reeve; how his saintly numinosity is received by fans and admirers with passion, pathos, pleasure; and how this process places people with disabilities in an oppressive social system, so making them subject(s). An Accidental Star Born September 25, 1952, Christopher Reeve became famous for his roles in the 1978 movie Superman, and the subsequent three sequels (Superman II, III, IV), as well as his role in other films such as Monsignor. As well as becoming a well-known actor, Reeve gained a profile for his activism on human rights, solidarity, environmental, and other issues. In May 1995 Reeve acquired a disability in a riding accident. In the ensuing months, Reeve’s situation attracted a great deal of international attention. He spent six months in the Kessler Rehabilitation Institute in New Jersey, and there gave a high-rating interview on US television personality Barbara Walters’ 20/20 program. In 1996, Reeve appeared at the Academy Awards, was a host at the 1996 Paralympic Games, and was invited to speak at the Democratic National Convention. In the same year Reeve narrated a film about the lives of people living with disabilities (Mierendorf). In 1998 his memoir Still Me was published, followed in 2002 by another book Nothing Is Impossible. Reeve’s active fashioning of an image and ‘new life’ (to use his phrase) stands in stark contrast with most people with disabilities, who find it difficult to enter into the industry and system of celebrity, because they are most often taken to be the opposite of glamorous or important. They are objects of pity, or freaks to be stared at (Mitchell & Synder; Thomson), rather than assuming other attributes of stars. Reeve became famous for his disability, indeed very early on he was acclaimed as the pre-eminent American with disability — as in the phrase ‘President of Disability’, an appellation he attracted. Reeve was quickly positioned in the celebrity industry, not least because his example, image, and texts were avidly consumed by viewers and readers. For millions of people — as evident in the letters compiled in the 1999 book Care Packages by his wife, Dana Reeve — Christopher Reeve is a hero, renowned for his courage in doing battle with his disability and his quest for a cure. Part of the creation of Reeve as celebrity has been a conscious fashioning of his life as an instructive fable. A number of biographies have now been published (Havill; Hughes; Oleksy; Wren). Variations on a theme, these tend to the hagiographic: Christopher Reeve: Triumph over Tragedy (Alter). Those interested in Reeve’s life and work can turn also to fan websites. Most tellingly perhaps is the number of books, fables really, aimed at children, again, on a characteristic theme: Learning about Courage from the Life of Christopher Reeve (Kosek; see also Abraham; Howard). The construction, but especially the consumption, of Reeve as disabled celebrity, is consonant with powerful cultural myths and tropes of disability. In many Western cultures, disability is predominantly understood a tragedy, something that comes from the defects and lack of our bodies, whether through accidents of birth or life. Those ‘suffering’ with disability, according to this cultural myth, need to come to terms with this bitter tragedy, and show courage in heroically overcoming their lot while they bide their time for the cure that will come. The protagonist for this this script is typically the ‘brave’ person with disability; or, as this figure is colloquially known in critical disability studies and the disability movement — the super-crip. This discourse of disability exerts a strong force today, and is known as the ‘medical’ model. It interacts with a prior, but still active charity discourse of disability (Fulcher). There is a deep cultural history of disability being seen as something that needs to be dealt with by charity. In late modernity, charity is very big business indeed, and celebrities play an important role in representing the good works bestowed on people with disabilities by rich donors. Those managing celebrities often suggest that the star finds a charity to gain favourable publicity, a routine for which people with disabilities are generally the pathetic but handy extras. Charity dinners and events do not just reinforce the tragedy of disability, but they also leave unexamined the structural nature of disability, and its associated disadvantage. Those critiquing the medical and charitable discourses of disability, and the oppressive power relations of disability that it represents, point to the social and cultural shaping of disability, most famously in the British ‘social’ model of disability — but also from a range of other perspectives (Corker and Thomas). Those formulating these critiques point to the crucial function that the trope of the super-crip plays in the policing of people with disabilities in contemporary culture and society. Indeed how the figure of the super-crip is also very much bound up with the construction of the ‘normal’ body, a general economy of representation that affects everyone. Superman Flies Again The celebrity of Christopher Reeve and what it reveals for an understanding of fame and disability can be seen with great clarity in his 2002 visit to Australia. In 2002 there had been a heated national debate on the ethics of use of embryonic stem cells for research. In an analysis of three months of the print media coverage of these debates, we have suggested that disability was repeatedly, almost obsessively, invoked in these debates (‘Uniting the Nation’). Yet the dominant representation of disability here was the cultural myth of disability as tragedy, requiring cure at all cost, and that this trope was central to the way that biotechnology was constructed as requiring an urgent, united national response. Significantly, in these debates, people with disabilities were often talked about but very rarely licensed to speak. Only one person with disability was, and remains, a central figure in these Australian stem cell and biotechnology policy conversations: Christopher Reeve. As an outspoken advocate of research on embryonic stem-cells in the quest for a cure for spinal injuries, as well as other diseases, Reeve’s support was enlisted by various protagonists. The current affairs show Sixty Minutes (modelled after its American counterpart) presented Reeve in debate with Australian critics: PRESENTER: Stem cell research is leading to perhaps the greatest medical breakthroughs of all time… Imagine a world where paraplegics could walk or the blind could see … But it’s a breakthrough some passionately oppose. A breakthrough that’s caused a fierce personal debate between those like actor Christopher Reeve, who sees this technology as a miracle, and those who regard it as murder. (‘Miracle or Murder?’) Sixty Minutes starkly portrays the debate in Manichean terms: lunatics standing in the way of technological progress versus Christopher Reeve flying again tomorrow. Christopher presents the debate in utilitarian terms: CHRISTOPHER REEVE: The purpose of government, really in a free society, is to do the greatest good for the greatest number of people. And that question should always be in the forefront of legislators’ minds. (‘Miracle or Murder?’) No criticism of Reeve’s position was offered, despite the fierce debate over the implications of such utilitarian rhetoric for minorities such as people with disabilities (including himself!). Yet this utilitarian stance on disability has been elaborated by philosopher Peter Singer, and trenchantly critiqued by the international disability rights movement. Later in 2002, the Premier of New South Wales, Bob Carr, invited Reeve to visit Australia to participate in the New South Wales Spinal Cord Forum. A journalist by training, and skilled media practitioner, Carr had been the most outspoken Australian state premier urging the Federal government to permit the use of embryonic stem cells for research. Carr’s reasons were as much as industrial as benevolent, boosting the stocks of biotechnology as a clean, green, boom industry. Carr cleverly and repeated enlisted stereotypes of disability in the service of his cause. Christopher Reeve was flown into Australia on a specially modified Boeing 747, free of charge courtesy of an Australian airline, and was paid a hefty appearance fee. Not only did Reeve’s fee hugely contrast with meagre disability support pensions many Australians with disabilities live on, he was literally the only voice and image of disability given any publicity. Consuming Celebrity, Contesting Crips As our analysis of Reeve’s antipodean career suggests, if disability were a republic, and Reeve its leader, its polity would look more plutocracy than democracy; as befits modern celebrity with its constitutive tensions between the demotic and democratic (Turner). For his part, Reeve has criticised the treatment of people with disabilities, and how they are stereotyped, not least the narrow concept of the ‘normal’ in mainstream films. This is something that has directly effected his career, which has become limited to narration or certain types of television and film work. Reeve’s reprise on his culture’s notion of disability comes with his starring role in an ironic, high-tech 1998 remake of Alfred Hitchcock’s Rear Window (Bleckner), a movie that in the original featured a photojournalist injured and temporarily using a wheelchair. Reeve has also been a strong advocate, lobbyist, and force in the politics of disability. His activism, however, has been far more strongly focussed on finding a cure for people with spinal injuries — rather than seeking to redress inequality and discrimination of all people with disabilities. Yet Reeve’s success in the notoriously fickle star system that allows disability to be understood and mapped in popular culture is mostly an unexplored paradox. As we note above, the construction of Reeve as celebrity, celebrating his individual resilience and resourcefulness, and his authenticity, functions precisely to sustain the ‘truth’ and the power relations of disability. Reeve’s celebrity plays an ideological role, knitting together a set of discourses: individualism; consumerism; democratic capitalism; and the primacy of the able body (Marshall; Turner). The nature of this cultural function of Reeve’s celebrity is revealed in the largely unpublicised contests over his fame. At the same time Reeve was gaining fame with his traditional approach to disability and reinforcement of the continuing catastrophe of his life, he was attracting an infamy within certain sections of the international disability rights movement. In a 1996 US debate disability scholar David T Mitchell put it this way: ‘He’s [Reeve] the good guy — the supercrip, the Superman, and those of us who can live with who we are with our disabilities, but who cannot live with, and in fact, protest and retaliate against the oppression we confront every second of our lives are the bad guys’ (Mitchell, quoted in Brown). Many feel, like Mitchell, that Reeve’s focus on a cure ignores the unmet needs of people with disabilities for daily access to support services and for the ending of their brutal, dehumanising, daily experience as other (Goggin & Newell, Disability in Australia). In her book Make Them Go Away Mary Johnson points to the conservative forces that Christopher Reeve is associated with and the way in which these forces have been working to oppose the acceptance of disability rights. Johnson documents the way in which fame can work in a variety of ways to claw back the rights of Americans with disabilities granted in the Americans with Disabilities Act, documenting the association of Reeve and, in a different fashion, Clint Eastwood as stars who have actively worked to limit the applicability of civil rights legislation to people with disabilities. Like other successful celebrities, Reeve has been assiduous in managing his image, through the use of celebrity professionals including public relations professionals. In his Australian encounters, for example, Reeve gave a variety of media interviews to Australian journalists and yet the editor of the Australian disability rights magazine Link was unable to obtain an interview. Despite this, critiques of the super-crip celebrity function of Reeve by people with disabilities did circulate at the margins of mainstream media during his Australian visit, not least in disability media and the Internet (Leipoldt, Newell, and Corcoran, 2003). Infamous Disability Like the lives of saints, it is deeply offensive to many to criticise Christopher Reeve. So deeply engrained are the cultural myths of the catastrophe of disability and the creation of Reeve as icon that any critique runs the risk of being received as sacrilege, as one rare iconoclastic website provocatively prefigures (Maddox). In this highly charged context, we wish to acknowledge his contribution in highlighting some aspects of contemporary disability, and emphasise our desire not to play Reeve the person — rather to explore the cultural and media dimensions of fame and disability. In Christopher Reeve we find a remarkable exception as someone with disability who is celebrated in our culture. We welcome a wider debate over what is at stake in this celebrity and how Reeve’s renown differs from other disabled stars, as, for example, in Robert McRuer reflection that: ... at the beginning of the last century the most famous person with disabilities in the world, despite her participation in an ‘overcoming’ narrative, was a socialist who understood that disability disproportionately impacted workers and the power[less]; Helen Keller knew that blindness and deafness, for instance, often resulted from industrial accidents. At the beginning of this century, the most famous person with disabilities in the world is allowing his image to be used in commercials … (McRuer 230) For our part, we think Reeve’s celebrity plays an important contemporary role because it binds together a constellation of economic, political, and social institutions and discourses — namely science, biotechnology, and national competitiveness. In the second half of 2004, the stem cell debate is once again prominent in American debates as a presidential election issue. Reeve figures disability in national culture in his own country and internationally, as the case of the currency of his celebrity in Australia demonstrates. In this light, we have only just begun to register, let alone explore and debate, what is entailed for us all in the production of this disabled fame and infamy. Epilogue to “Fame and Disability” Christopher Reeve died on Sunday 10 October 2004, shortly after this article was accepted for publication. His death occasioned an outpouring of condolences, mourning, and reflection. We share that sense of loss. How Reeve will be remembered is still unfolding. The early weeks of public mourning have emphasised his celebrity as the very embodiment and exemplar of disabled identity: ‘The death of Christopher Reeve leaves embryonic-stem-cell activism without one of its star generals’ (Newsweek); ‘He Never Gave Up: What actor and activist Christopher Reeve taught scientists about the treatment of spinal-cord injury’ (Time); ‘Incredible Journey: Facing tragedy, Christopher Reeve inspired the world with hope and a lesson in courage’ (People); ‘Superman’s Legacy’ (The Express); ‘Reeve, the Real Superman’ (Hindustani Times). In his tribute New South Wales Premier Bob Carr called Reeve the ‘most impressive person I have ever met’, and lamented ‘Humankind has lost an advocate and friend’ (Carr). The figure of Reeve remains central to how disability is represented. In our culture, death is often closely entwined with disability (as in the saying ‘better dead than disabled’), something Reeve reflected upon himself often. How Reeve’s ‘global mourning’ partakes and shapes in this dense knots of associations, and how it transforms his celebrity, is something that requires further work (Ang et. al.). The political and analytical engagement with Reeve’s celebrity and mourning at this time serves to underscore our exploration of fame and disability in this article. Already there is his posthumous enlistment in the United States Presidential elections, where disability is both central and yet marginal, people with disability talked about rather than listened to. The ethics of stem cell research was an election issue before Reeve’s untimely passing, with Democratic presidential contender John Kerry sharply marking his difference on this issue with President Bush. After Reeve’s death his widow Dana joined the podium on the Kerry campaign in Columbus, Ohio, to put the case herself; for his part, Kerry compared Bush’s opposition to stem cell research as akin to favouring the candle lobby over electricity. As we write, the US polls are a week away, but the cultural representation of disability — and the intensely political role celebrity plays in it — appears even more palpably implicated in the government of society itself. References Abraham, Philip. Christopher Reeve. New York: Children’s Press, 2002. Alter, Judy. Christopher Reeve: Triumph over Tragedy. Danbury, Conn.: Franklin Watts, 2000. Ang, Ien, Ruth Barcan, Helen Grace, Elaine Lally, Justine Lloyd, and Zoe Sofoulis (eds.) Planet Diana: Cultural Studies and Global Mourning. Sydney: Research Centre in Intercommunal Studies, University of Western Sydney, Nepean, 1997. Bleckner, Jeff, dir. Rear Window. 1998. Brown, Steven E. “Super Duper? The (Unfortunate) Ascendancy of Christopher Reeve.” Mainstream: Magazine of the Able-Disabled, October 1996. Repr. 10 Aug. 2004 http://www.independentliving.org/docs3/brown96c.html>. Carr, Bob. “A Class Act of Grace and Courage.” Sydney Morning Herald. 12 Oct. 2004: 14. Corker, Mairian and Carol Thomas. “A Journey around the Social Model.” Disability/Postmodernity: Embodying Disability Theory. Ed. Mairian Corker and Tom Shakespeare. London and New York: Continuum, 2000. Donner, Richard, dir. Superman. 1978. Dyer, Richard. Heavenly Bodies: Film Stars and Society. London: BFI Macmillan, 1986. Fulcher, Gillian. Disabling Policies? London: Falmer Press, 1989. Furie, Sidney J., dir. Superman IV: The Quest for Peace. 1987. Finn, Margaret L. Christopher Reeve. Philadelphia: Chelsea House Publishers, 1997. Gilmer, Tim. “The Missionary Reeve.” New Mobility. November 2002. 13 Aug. 2004 http://www.newmobility.com/>. Goggin, Gerard. “Media Studies’ Disability.” Media International Australia 108 (Aug. 2003): 157-68. Goggin, Gerard, and Christopher Newell. Disability in Australia: Exposing a Social Apartheid. Sydney: UNSW Press, 2005. —. “Uniting the Nation?: Disability, Stem Cells, and the Australian Media.” Disability & Society 19 (2004): 47-60. Havill, Adrian. Man of Steel: The Career and Courage of Christopher Reeve. New York, N.Y.: Signet, 1996. Howard, Megan. Christopher Reeve. Minneapolis: Lerner Publications, 1999. Hughes, Libby. Christopher Reeve. Parsippany, NJ.: Dillon Press, 1998. Johnson, Mary. Make Them Go Away: Clint Eastwood, Christopher Reeve and the Case Against Disability Rights. Louisville : Advocado Press, 2003. Kosek, Jane Kelly. Learning about Courage from the Life of Christopher Reeve. 1st ed. New York : PowerKids Press, 1999. Leipoldt, Erik, Christopher Newell, and Maurice Corcoran. “Christopher Reeve and Bob Carr Dehumanise Disability — Stem Cell Research Not the Best Solution.” Online Opinion 27 Jan. 2003. http://www.onlineopinion.com.au/view.asp?article=510>. Lester, Richard (dir.) Superman II. 1980. —. Superman III. 1983. Maddox. “Christopher Reeve Is an Asshole.” 12 Aug. 2004 http://maddox.xmission.com/c.cgi?u=creeve>. Marshall, P. David. Celebrity and Power: Fame in Contemporary Culture. Minneapolis and London: U of Minnesota P, 1997. Mierendorf, Michael, dir. Without Pity: A Film about Abilities. Narr. Christopher Reeve. 1996. “Miracle or Murder?” Sixty Minutes. Channel 9, Australia. March 17, 2002. 15 June 2002 http://news.ninemsn.com.au/sixtyminutes/stories/2002_03_17/story_532.asp>. Mitchell, David, and Synder, Sharon, eds. The Body and Physical Difference. Ann Arbor, U of Michigan, 1997. McRuer, Robert. “Critical Investments: AIDS, Christopher Reeve, and Queer/Disability Studies.” Journal of Medical Humanities 23 (2002): 221-37. Oleksy, Walter G. Christopher Reeve. San Diego, CA: Lucent, 2000. Reeve, Christopher. Nothing Is Impossible: Reflections on a New Life. 1st ed. New York: Random House, 2002. —. Still Me. 1st ed. New York: Random House, 1998. Reeve, Dana, comp. Care Packages: Letters to Christopher Reeve from Strangers and Other Friends. 1st ed. New York: Random House, 1999. Reeve, Matthew (dir.) Christopher Reeve: Courageous Steps. Television documentary, 2002. Thomson, Rosemary Garland, ed. Freakery: Cultural Spectacles of the Extraordinary Body. New York: New York UP, 1996. Turner, Graeme. Understanding Celebrity. Thousands Oak, CA: Sage, 2004. Turner, Graeme, Frances Bonner, and David P Marshall. Fame Games: The Production of Celebrity in Australia. Melbourne: Cambridge UP, 2000. Wren, Laura Lee. Christopher Reeve: Hollywood’s Man of Courage. Berkeley Heights, NJ : Enslow, 1999. Younis, Steve. “Christopher Reeve Homepage.” 12 Aug. 2004 http://www.fortunecity.com/lavender/greatsleep/1023/main.html>. Citation reference for this article MLA Style Goggin, Gerard & Newell, Christopher. "Fame and Disability: Christopher Reeve, Super Crips, and Infamous Celebrity." M/C Journal 7.5 (2004). echo date('d M. Y'); ?> <http://journal.media-culture.org.au/0411/02-goggin.php>. APA Style Goggin, G. & Newell, C. (Nov. 2004) "Fame and Disability: Christopher Reeve, Super Crips, and Infamous Celebrity," M/C Journal, 7(5). Retrieved echo date('d M. Y'); ?> from <http://journal.media-culture.org.au/0411/02-goggin.php>.

When historian Graeme Davison famously declared that “Australia was born urban and quickly grew suburban” (98), he was clearly referring to Melbourne or Sydney, but certainly not Brisbane. Although the Brisbane of 2011 might resemble a contemporary, thriving metropolis, its genealogy is not an urban one. For most of its history, as Gillian Whitlock has noted, Brisbane was “a place where urban industrial society is kept at bay” (80). What distinguishes Brisbane from Australia’s larger southern capital cities is its rapid morphology into a city from a provincial, suburban, town. Indeed it is Brisbane’s distinctive regionalism, with its sub-tropical climate, offering a steamy, fecund backdrop to narratives of the city that has produced a plethora of writing in literary accounts of the city, from author David Malouf through to contemporary writers such as Andrew McGahan, John Birmingham, Venero Armanno, Susan Johnson, and Nick Earls. Brisbane’s lack of urban tradition makes its transformation unique among Australian cities. Its rapid population growth and urban development have changed the way that many people now live in the city. Unlike the larger cities of Sydney or Melbourne, whose inner cities were established on the Victorian model of terrace-row housing on small lots, Brisbane’s early planners eschewed this approach. So, one of the features that gives the city its distinction is the languorous suburban quality of its inner-city areas, where many house blocks are the size of the suburban quarter-acre block, all within coo-ee of the city centre. Other allotments are medium to small in size, and, until recently, housed single dwellings of varying sizes and grandeur. Add to this a sub-tropical climate in which ‘green and growth’ is abundant and the pretty but flimsy timber vernacular housing, and it’s easy to imagine that you might be many kilometres from a major metropolitan centre as you walk around Brisbane’s inner city areas. It is partly this feature that prompted demographer Bernard Salt to declare Brisbane “Australia’s most suburban city” (Salt 5). Prior to urban renewal in the early 1990s, Brisbane was a low-density town with very few apartment blocks; most people lived in standalone houses.From the inception of the first Urban Renewal program in 1992, a joint initiative of the Federal government’s Building Better Cities Program and managed by the Brisbane City Council (BCC), Brisbane’s urban development has undergone significant change. In particular, the city’s Central Business District (CBD) and inner city have experienced intense development and densification with a sharp rise in medium- to high-density apartment dwellings to accommodate the city’s swelling population. Population growth has added to the demand for increased density, and from the period 1995–2006 Brisbane was Australia’s fastest growing city (ABS).Today, parts of Brisbane’s inner city resembles the density of the larger cities of Melbourne and Sydney. Apartment blocks have mushroomed along the riverfront and throughout inner and middle ring suburbs. Brisbane’s population has enthusiastically embraced apartment living, with “empty nesters” leaving their suburban family homes for the city, and apartments have become the affordable option for renters and first home purchasers. A significant increase in urban amenities such as large-scale parklands and river side boardwalks, and a growth in service industries such as cafes, restaurants and bars—a feature of cities the world over—have contributed to the appeal of the city and the changing way that people live in Brisbane.Urbanism demands specific techniques of living—life is different in medium- to high-density dwellings, in populous places, where people live in close proximity to one another. In many ways it’s the antithesis to suburban life, a way of living that, as Davison notes, was established around an ethos of privacy, health, and seclusion and is exemplified in the gated communities seen in the suburbs today. The suburbs are characterised by generosity of space and land, and developed as a refuge and escape from the city, a legacy of the nineteenth-century industrial city’s connection with overcrowding, disease, and disorder. Suburban living flourished in Australia from the eighteenth century and Davison notes how, when Governor Phillip drew up the first town plan for Sydney in 1789, it embodied the aspirations of “decency, good order, health and domestic privacy,” which lie at the heart of suburban ideals (100).The health and moral impetus underpinning the establishment of suburban life—that is, to remove people from overcrowding and the unhygienic conditions of slums—for Davison meant that the suburban ethos was based on a “logic of avoidance” (110). Attempting to banish anything deemed dangerous and offensive, the suburbs were seen to offer a more natural, orderly, and healthy environment. A virtuous and happy life required plenty of room—thus, a garden and the expectation of privacy was paramount.The suburbs as a site of lived experience and cultural meaning is significant for understanding the shift from suburban living to the adoption of medium- to high-density inner-city living in Brisbane. I suggest that the ways in which this shift is captured discursively, particularly in promotional material, are indicative of the suburbs' stronghold on the collective imagination. Reinforcing this perception of Brisbane as a suburban city is a history of literary narratives that have cast Brisbane in ways that set it apart from other Australian cities, and that are to do with its non-urban characteristics. Imaginative and symbolic discourses of place have real and material consequences (Lefebvre), as advertisers are only too well aware. Discursively, city life has been imagined oppositionally from life in the suburbs: the two sites embody different cultural meanings and values. In Australia, the suburbs are frequently a site of derision and satire, characterized as bastions of conformity and materialism (Horne), offering little of value in contrast to the city’s many enchantments and diverse pleasures. In the well-established tradition of satire, “suburban bashing is replete in literature, film and popular culture” (Felton et al xx). From Barry Humphries’s characterisation of Dame Edna Everage, housewife superstar, who first appeared in the 1960s, to the recent television comedy series Kath and Kim, suburbia and its inhabitants are represented as dull-witted, obsessed with trivia, and unworldly. This article does not intend to rehearse the tradition of suburban lampooning; rather, it seeks to illustrate how ideas about suburban living are hard held and how the suburban ethos maintains its grip, particularly in relation to notions of privacy and peace, despite the celebratory discourse around the emerging forms of urbanism in Brisbane.As Brisbane morphed rapidly from a provincial, suburban town to a metropolis throughout the 1990s and early 2000s, a set of metropolitan discourses developed in the local media that presented new ways of inhabiting and imagining the city and offered new affiliations and identifications with the city. In establishing Brisbane’s distinction as a city, marketing material relied heavily on the opposition between the city and the suburbs, implying that urban vitality and diversity rules triumphant over the suburbs’ apparent dullness and homogeneity. In a billboard advertisement for apartments in the urban renewal area of Newstead (2004), images of architectural renderings of the apartments were anchored by the words—“Urban living NOT suburban”—leaving little room for doubt. It is not the design qualities of the apartments or the building itself being promoted here, but a way of life that alludes to utopian ideas of urban life, of enchantment with the city, and implies, with the heavy emphasis of “NOT suburban,” the inferiority of suburban living.The cultural commodification of the late twentieth- and twenty-first-century city has been well documented (Evans; Dear; Zukin; Harvey) and its symbolic value as a commodity is expressed in marketing literature via familiar metropolitan tropes that are frequently amorphous and international. The malleability of such images makes them easily transportable and transposable, and they provided a useful stockpile for promoting a city such as Brisbane that lacked its own urban resources with which to construct a new identity. In the early days of urban renewal, the iconic images and references to powerhouse cities such as New York, London, and even Venice were heavily relied upon. In the latter example, an advertisement promoting Brisbane appeared in the Sydney Morning Herald colour magazine (May 2005). This advertisement represented Brisbane as an antipodean Venice, showing a large reach of the Brisbane river replete with gondolas flanked by the city’s only nineteenth-century riverside building, the Custom’s House. The allusion to traditional European culture is a departure from the usual tropes of “fun and sun” associated with promotions of Queensland, including Brisbane, while the new approach to promoting Brisbane is cognizant of the value of culture in the symbolic and economic hierarchy of the contemporary city. Perhaps equally, the advertisement could be read as ironic, a postmodern self-parodying statement about the city in general. In a nod to the centrality of the spectacle, the advertisement might be a salute to idea of the city as theme park, a pleasure playground and a collective fantasy of escape. Nonetheless, either interpretation presents Brisbane as somewhere else.In other promotional literature for apartment dwellings, suburban living maintains its imaginative grip, evident in a brochure advertising Petrie Point apartments in Brisbane’s urban renewal area of inner-city New Farm (2000). In the brochure, the promise of peace and calm—ideals that have their basis in suburban living—are imposed and promoted as a feature of inner-city living. Paradoxically, while suggesting that a wholesale evacuation and rejection of suburban life is occurring presumably because it is dull, the brochure simultaneously upholds the values of suburbia:Discerning baby boomers and generation X’ers who prefer lounging over latte rather than mowing the quarter acre block, are abandoning suburban living in droves. Instead, hankering after a more cosmopolitan lifestyle without the mind numbing drive to work, they are retreating to the residential mecca, the inner city, for chic shops and a lively dining, arts and theatre culture. (my italics)In the above extract, the rhetoric used to promote and uphold the virtues of a cosmopolitan inner-city life is sabotaged by a language that in many respects capitulates to the ideals of suburban living, and evokes the health and retreat ethos of suburbia. “Lounging” over lattes and “retreating to a residential mecca”[i] allude to precisely the type of suburban living the brochure purports to eschew. Privacy, relaxation, and health is a discourse and, more importantly, a way of living that is in many ways anathema to life in the city. It is a dream-wish that those features most valued about suburban life, can and should somehow be transplanted to the city. In its promotion of urban amenity, the brochure draws upon a somewhat bourgeois collection of cultural amenities and activities such as a (presumably traditional) arts and theatre culture, “lively dining,” and “chic” shops. The appeal to “discerning baby boomers and generation X’ers” has more than a whiff of status and class, an appeal that disavows the contemporary city’s attention to diversity and inclusivity, and frequently the source of promotion of many international cities. In contrast to the suburban sub-text of exclusivity and seclusion in the Petrie Point Apartment’s brochure, is a promotion of Sydney’s inner-city Newtown as a tourist site and spectacle, which makes an appeal to suburban antipathy clear from the outset. The brochure, distributed by NSW Tourism (2000) displays a strong emphasis on Newtown’s cultural and ethnic diversity, and the various forms of cultural consumption on offer. The inner-city suburb’s appeal is based on its re-framing as a site of tourist consumption of diversity and difference in which diversity is central to its performance as a tourist site. It relies on the distinction between “ordinary” suburbs and “cosmopolitan” places:Some cities are cursed with suburbs, but Sydney’s blessed with Newtown — a cosmopolitan neighbourhood of more than 600 stores, 70 restaurants, 42 cafes, theatres, pubs, and entertainment venues, all trading in two streets whose origins lie in the nineteenth century … Newtown is the Catwalk for those with more style than money … a parade where Yves St Laurent meets Saint Vincent de Paul, where Milano meets post-punk bohemia, where Max Mara meets Doc Marten, a stage where a petticoat is more likely to be your grandma’s than a Colette Dinnigan designer original (From Sydney Marketing brochure)Its opening oppositional gambit—“some cities are cursed with suburbs”—conveniently elides the fact that like all Australian cities, Sydney is largely suburban and many of Sydney’s suburbs are more ethnically diverse than its inner-city areas. Cabramatta, Fairfield, and most other suburbs have characteristically high numbers of ethnic groups such as Vietnamese, Korean, Lebanese, and so forth. Recent events, however, have helped to reframe these places as problem areas, rather than epicentres of diversity.The mingling of social groups invites the tourist-flâneur to a performance of difference, “a parade where Yves St Laurent meets Saint Vincent de Paul (my italics), where Milano meets post-punk bohemia,” and where “the upwardly mobile and down at heel” appear in what is presented as something of a theatrical extravaganza. Newtown is a product, its diversity a commodity. Consumed visually and corporeally via its divergent sights, sounds, smells and tastes (the brochure goes on to state that 70 restaurants offer cuisine from all over the globe), Newtown is a “successful neighbourhood experiment in the new globalism.” The area’s social inequities—which are implicit in the text, referred to as the “down at heel”—are vanquished and celebrated, incorporated into the rhetoric of difference.Brisbane’s lack of urban tradition and culture, as well as its lack of diversity in comparison to Sydney, reveals itself in the first brochure while the Newtown brochure appeals to the idea of a consumer-based cosmopolitanism. As a sociological concept, cosmopolitanism refers to a set of "subjective attitudes, outlooks and practices" broadly characterized as “disposition of openness towards others, people, things and experiences whose origin is non local” (Skrbis and Woodward 1). Clearly cosmopolitan attitudes do not have to be geographically located, but frequently the city is promoted as the site of these values, with the suburbs, apparently, forever looking inward.In the realm of marketing, appeals to the imagination are ubiquitous, but discursive practices can become embedded in everyday life. Despite the growth of urbanism, the increasing take up of metropolitan life and the enduring disdain among some for the suburbs, the hard-held suburban values of peace and privacy have pragmatic implications for the ways in which those values are embedded in people’s expectations of life in the inner city.The exponential growth in apartment living in Brisbane offers different ways of living to the suburban house. For a sub-tropical city where "life on the verandah" is a significant feature of the Queenslander house with its front and exterior verandahs, in the suburbs, a reasonable degree of privacy is assured. Much of Brisbane’s vernacular and contemporary housing is sensitive to this indoor-outdoor style of living, a distinct feature and appeal of everyday life in many suburbs. When "life on the verandah" is adapted to inner-city apartment buildings, expectations that indoor-outdoor living can be maintained in the same way can be problematic. In the inner city, life on the verandah may challenge expectations about privacy, noise and visual elements. While the Brisbane City Plan 2000 attempts to deal with privacy issues by mandating privacy screenings on verandahs, and the side screening of windows to prevent overlooking neighbours, there is ample evidence that attitudinal change is difficult. The exchange of a suburban lifestyle for an urban one, with the exposure to urbanity’s complexity, potential chaos and noise, can be confronting. In the Urban Renewal area and entertainment precinct of Fortitude Valley, during the late 1990s, several newly arrived residents mounted a vigorous campaign to the Brisbane City Council (BCC) and State government to have noise levels reduced from local nightclubs and bars. Fortitude Valley—the Valley, as it is known locally—had long been Brisbane’s main area for nightclubs, bars and brothels. A small precinct bounded by two major one-way roads, it was the locus of the infamous ABC 4 Corners “Moonlight State” report, which exposed the lines of corruption between politicians, police, and the judiciary of the former Bjelke-Petersen government (1974–1987) and who met in the Valley’s bars and brothels. The Valley was notorious for Brisbanites as the only place in a provincial, suburban town that resembled the seedy side of life associated with big cities. The BCC’s Urban Renewal Task Force and associated developers initially had a tough task convincing people that the area had been transformed. But as more amenity was established, and old buildings were converted to warehouse-style living in the pattern of gentrification the world over, people started moving in to the area from the suburbs and interstate (Felton). One of the resident campaigners against noise had purchased an apartment in the Sun Building, a former newspaper house and in which one of the apartment walls directly abutted the adjoining and popular nightclub, The Press Club. The Valley’s location as a music venue was supported by the BCC, who initially responded to residents’ noise complaints with its “loud and proud” campaign (Valley Metro). The focus of the campaign was to alert people moving into the newly converted apartments in the Valley to the existing use of the neighbourhood by musicians and music clubs. In another iteration of this campaign, the BCC worked with owners of music venues to ensure the area remains a viable music precinct while implementing restrictions on noise levels. Residents who objected to nightclub noise clearly failed to consider the impact of moving into an area that was already well known, even a decade ago, as the city’s premier precinct for music and entertainment venues. Since that time, the Valley has become Australia’s only regulated and promoted music precinct.The shift from suburban to urban living requires people to live in very different ways. Thrust into close proximity with strangers amongst a diverse population, residents can be confronted with a myriad of sensory inputs—to a cacophony of noise, sights, smells (Allon and Anderson). Expectations of order, retreat, and privacy inevitably come into conflict with urbanism’s inherent messiness. The contested nature of urban space is expressed in neighbour disputes, complaints about noise and visual amenity, and sometimes in eruptions of street violence. There is no shortage of examples in the Brisbane’s Urban Renewal areas such as Fortitude Valley, where acts of homophobia, racism, and other less destructive conflicts continue to be a frequent occurrence. While the refashioned discursive Brisbane is re-presented as cool, cultured, and creative, the tensions of urbanism and tests to civility remain in a process of constant negotiation. This is the way the city’s past disrupts and resists its cool new surface.[i] The use of the word mecca in the brochure occurred prior to 11 September 2001.ReferencesAllon, Fiona, and Kay Anderson. "Sentient Sydney." In Passionate City: An International Symposium. Melbourne: RMIT, School of Media Communication, 2004. 89–97.Australian Bureau of Statistics (ABS). Regional Population Growth, Australia, 1996-2006.Birmingham, John. "The Lost City of Vegas: David Malouf’s Old Brisbane." Hot Iron Corrugated Sky. Ed. R. Sheahan-Bright and S. Glover. St Lucia: U of Queensland P, 2002. xx–xx.Davison, Graeme. "The Past and Future of the Australian Suburb." Suburban Dreaming: An Interdisciplinary Approach to Australian Cities. Ed. L. Johnson. Geelong: Deakin University Press, 1994. xx–xx.Dear, Michael. The Postmodern Urban Condition. Oxford: Blackwell, 2000.Evans, Graeme. “Hard-Branding the Cultural City—From Prado to Prada.” International Journal of Urban and Regional Research 27.2 (2003): 417–40.Evans, Raymond, and Carole Ferrier, eds. Radical Brisbane. Melbourne: The Vulgar Press, 2004.Felton, Emma, Christy Collis, and Phil Graham. “Making Connections: Creative Industries Networks in Outer Urban Locations.” Australian Geographer 14.1 (Mar. 2010): 57–70.Felton, Emma. Emerging Urbanism: A Social and Cultural Study of Urban Change in Brisbane. PhD thesis. Brisbane: Griffith University, 2007.Glover, Stuart, and Stuart Cunningham. "The New Brisbane." Artlink 23.2 (2003): 16–23. Harvey, David. The Condition of Postmodernity: An Enquiry into the Origins of Cultural Change. Cambridge, MA: Blackwell, 1990. Horne, Donald. The Lucky Country: Australia in the Sixties. Ringwood: Penguin, 1964.Lefebvre, Henri. The Production of Space. Oxford: Basil Blackwell, 1991.Malouf, David. Johnno. St Lucia: University of Queensland Press, 1975. ---. 12 Edmondstone Street. London: Penguin, 1986.NSW Tourism. Sydney City 2000. Sydney, 2000.Salt, Bernard. Cinderella City: A Vision of Brisbane’s Rise to Prominence. Sydney: Austcorp, 2005.Skrbis, Zlatko, and Ian Woodward. “The Ambivalence of Ordinary Cosmopolitanism: Investigating the Limits of Cosmopolitanism Openness.” Sociological Review (2007): 1-14.Valley Metro. 1 May 2011 < http://www.valleymetro.com.au/the_valley.aspx >.Whitlock, Gillian. “Queensland: The State of the Art on the 'Last Frontier.’" Westerly 29.2 (1984): 85–90.Zukin, Sharon. The Culture of Cities. Cambridge, MA: Basil Blackwell, 1995.

This paper will compare the metaphoric structuring of the ecological concept of resilience—with its roots in Holling's 1973 paper; with psychological concepts of resilience which followed from research—such as Werner, Bierman, and French and Garmezy and Streitman) published in the early 1970s. This metaphoric analysis will expose the difference between complex adaptive systems models of resilience in ecology and studies related to resilience in relation to climate change; compared with the individualism of linear equilibrium models of resilience which have dominated discussions of resilience in psychology and economics. By examining the ontological commitments of these competing metaphors, I will show that the individualistic concept of resilience which dominates psychological discussions of resilience is incompatible with the ontological commitments of ecological concepts of resilience. Because the ontological commitments of the concepts of ecological resilience on the one hand, and psychological resilience on the other, are so at odds with one another, it is important to be clear which concept of resilience is being evaluated for its adequacy as a concept. Having clearly distinguished these competing metaphors and their ontological commitments, this paper will show that it is the complex adaptive systems model of resilience from ecology, not the individualist concept of psychological resilience, that has been utilised by both the academic discussions of adaptation to climate change, and the operationalisation of the concept of resilience by social movements like the permaculture, ecovillage, and Transition Towns movements. Ontological Metaphors My analysis of ontological metaphors draws on insights from Kuhn's (114) account of gestalt perception in scientific paradigm shifts; the centrality of the role of concrete analogies in scientific reasoning (Masterman 77); and the theorisation of ontological metaphors in cognitive linguistics (Gärdenfors). Figure 1: Object Ontological commitments reflect the shared beliefs within a community about the sorts of things that exist. Our beliefs about what exists are shaped by our sensory and motor interactions with objects in the physical world. Physical objects have boundaries and surfaces that separate the object from not-the-object. Objects have insides and outsides, and can be described in terms of more-or-less fixed and stable “objective” properties. A prototypical example of an “object” is a “container”, like the example shown in Figure 1. Ontological metaphors allow us to conceive of “things” which are not objects as if they were objects by picking “out parts of our experience and treat them as [if they were] discrete entities or substances of a uniform kind” (Lakoff and Johnson 25). We use ontological metaphors when we imagine a boundary around a collection of things, such as the members of a team or trees in a forest, and conceive of them as being in a container (Langacker 191–97). We can then think of “things” like a team or forest as if they were a single entity. We can also understand processes and activities as if they were things with boundaries. Whether or not we characterise some aspect of our experience as a noun (a bounded entity) or as a verb (a process that occurs over time) is not determined by the nature of things in themselves, but by our understanding and interpretation of our experience (Langacker 233). In this paper I employ a technique that involves examining the details of “concrete images” from the source domains for metaphors employed in the social sciences to expose for analysis their ontological commitments (Harrison, “Politics” 215; Harrison, “Economics” 7). By examining the ontological metaphors that structure the resilience literature I will show how different conceptions of resilience reflect different beliefs and commitments about the sorts of “things” there are in the world, and hence how we can study and understand these “things.” Engineering Metaphors In his discussion of engineering resilience, Holling (“Engineering Vs. Ecological” 33) argues that this conception is the “foundation for economic theory”, and defined in terms of “resistance to disturbance and the speed of return to the equilibrium” or steady state of the system. Whereas Holling takes his original example of the use of the engineering concept of resilience from economics, Pendall, Foster, & Cowell (72), and Martin-Breen and Anderies (6) identify it as the concept of resilience that dominates the field of psychology. They take the stress loading of bridges to be the engineering source for the metaphor. Figure 2: Pogo stick animation (Source: Blacklemon 67, CC http://en.wikipedia.org/wiki/File:Pogoanim.gif). In order to understand this metaphor, we need to examine the characteristics of the source domain for the metaphor. A bridge can be “under tension, compression or both forces at the same time [and] experiences what engineers define as stress” (Matthews 3). In order to resist these forces, bridges need to be constructed of material which “behave much like a spring” that “strains elastically (deforms temporarily and returns to its original shape after a load has been removed) under a given stress” (Gordon 52; cited in Matthews). The pogostick shown in Figure 2 illustrates how a spring returns to its original size and configuration once the load or stress is removed. WGBH Educational Foundation provides links to simple diagrams that illustrate the different stresses the three main designs of bridges are subject to, and if you compare Computers & Engineering's with Gibbs and Bourne's harmonic spring animation you can see how both a bridge under live load and the pogostick in Figure 2 oscillate just like an harmonic spring. Subject to the elastic limits of the material, the deformation of a spring is proportional to the stress or load applied. According to the “modern theory of elasticity [...] it [is] possible to deduce the relation between strain and stress for complex objects in terms of intrinsic properties of the materials it is made of” (“Hooke’s Law”). When psychological resilience is characterised in terms of “properties of individuals [that] are identified in isolation” (Martin-Breen and Anderies 12); and in terms of “behaviours and attributes [of individuals] that allow people to get along with one another and to succeed socially” (Pendall, Foster, and Cowell 72), they are reflecting this engineering focus on the properties of materials. Martin-Breen and Anderies (42) argue that “the Engineering Resilience framework” has been informed by ontological metaphors which treat “an ecosystem, person, city, government, bridge, [or] society” as if it were an object—“a unified whole”. Because this concept of resilience treats individuals as “objects,” it leads researchers to look for the properties or characteristics of the “materials” which individuals are “made of”, which are either elastic and allow them to “bounce” or “spring” back after stress; or are fragile and brittle and break under load. Similarly, the Designers Institute (DINZ), in its conference on “Our brittle society,” shows it is following the engineering resilience approach when it conceives of a city or society as an object which is made of materials which are either “strong and flexible” or “brittle and fragile”. While Holling characterises economic theory in terms of this engineering metaphor, it is in fact chemistry and the kinetic theory of gases that provides the source domain for the ontological metaphor which structures both static and dynamic equilibrium models within neo-classical economics (Smith and Foley; Mirowski). However, while springs are usually made out of metals, they can be made out of any “material [that] has the required combination of rigidity and elasticity,” such as plastic, and even wood (in a bow) (“Spring (device)”). Gas under pressure turns out to behave the same as other springs or elastic materials do under load. Because both the economic metaphor based on equilibrium theory of gases and the engineering analysis of bridges under load can both be subsumed under spring theory, we can treat both the economic (gas) metaphor and the engineering (bridge) metaphor as minor variations of a single overarching (spring) metaphor. Complex Systems Metaphors Holling (“Resilience & Stability” 13–15) critiques equilibrium models, arguing that non-deterministic, complex, non-equilibrium and multi-equilibrium ecological systems do not satisfy the conditions for application of equilibrium models. Holling argues that unlike the single equilibrium modelled by engineering resilience, complex adaptive systems (CAS) may have multi or no equilibrium states, and be non-linear and non-deterministic. Walker and Salt follow Holling by calling for recognition of the “dynamic complexity of the real world” (8), and that “these [real world] systems are complex adaptive systems” (11). Martin-Breen and Anderies (7) identify the key difference between “systems” and “complex adaptive systems” resilience as adaptive capacity, which like Walker and Salt (xiii), they define as the capacity to maintain function, even if system structures change or fail. The “engineering” concept of resilience focuses on the (elastic) properties of materials and uses language associated with elastic springs. This “spring” metaphor emphasises the property of individual components. In contrast, ecological concepts of resilience examine interactions between elements, and the state of the system in a multi-dimensional phase space. This systems approach shows that the complex behaviour of a system depends at least as much on the relationships between elements. These relationships can lead to “emergent” properties which cannot be reduced to the properties of the parts of the system. To explain these relationships and connections, ecologists and climate scientists use language and images associated with landscapes such as 2-D cross-sections and 3-D topology (Holling, “Resilience & Stability” 20; Pendall, Foster, and Cowell 74). Figure 3 is based on an image used by Walker, Holling, Carpenter and Kinzig (fig. 1b) to represent possible states of ecological systems. The “basins” in the image rely on our understanding of gravitational forces operating in a 3-D space to model “equilibrium” states in which the system, like the “ball” in the “basin”, will tend to settle. Figure 3: (based on Langston; in Walker et al. fig. 1b) – Tipping Point Bifurcation Wasdell (“Feedback” fig. 4) adapted this image to represent possible climate states and explain the concept of “tipping points” in complex systems. I have added the red balls (a, b, and c to replace the one black ball (b) in the original which represented the state of the system), the red lines which indicate the path of the ball/system, and the black x-y axis, in order to discuss the image. Wasdell (“Feedback Dynamics” slide 22) takes the left basin to represents “the variable, near-equilibrium, but contained dynamics of the [current] glacial/interglacial period”. As a result of rising GHG levels, the climate system absorbs more energy (mostly as heat). This energy can force the system into a different, hotter, state, less amenable to life as we know it. This is shown in Figure 3 by the system (represented as the red ball a) rising up the left basin (point b). From the perspective of the gravitational representation in Figure 3, the extra energy in the basin operates like the rotation in a Gravitron amusement ride, where centrifugal force pushes riders up the sides of the ride. If there is enough energy added to the climate system it could rise up and jump over the ridge/tipping point separating the current climate state into the “hot earth” basin shown on the right. Once the system falls into the right basin, it may be stuck near point c, and due to reinforcing feedbacks have difficulty escaping this new “equilibrium” state. Figure 4 represents a 2-D cross-section of the 3-D landscape shown in Figure 3. This cross-section shows how rising temperature and greenhouse gas (GHG) concentrations in a multi-equilibrium climate topology can lead to the climate crossing a tipping point and shifting from state a to state c. Figure 4: Topographic cross-section of possible climate states (derived from Wasdell, “Feedback” 26 CC). As Holling (“Resilience & Stability”) warns, a less “desirable” state, such as population collapse or extinction, may be more “resilient”, in the engineering sense, than a more desirable state. Wasdell (“Feedback Dynamics” slide 22) warns that the climate forcing as a result of human induced GHG emissions is in fact pushing the system “far away from equilibrium, passed the tipping point, and into the hot-earth scenario”. In previous episodes of extreme radiative forcing in the past, this “disturbance has then been amplified by powerful feedback dynamics not active in the near-equilibrium state [… and] have typically resulted in the loss of about 90% of life on earth.” An essential element of system dynamics is the existence of (delayed) reinforcing and balancing causal feedback loops, such as the ones illustrated in Figure 5. Figure 5: Pre/Predator model (Bellinger CC-BY-SA) In the case of Figure 5, the feedback loops illustrate the relationship between rabbit population increasing, then foxes feeding on the rabbits, keeping the rabbit population within the carrying capacity of the ecosystem. Fox predation prevents rabbit over-population and consequent starvation of rabbits. The reciprocal interaction of the elements of a system leads to unpredictable nonlinearity in “even seemingly simple systems” (“System Dynamics”). The climate system is subject to both positive and negative feedback loops. If the area of ice cover increases, more heat is reflected back into space, creating a positive feedback loop, reinforcing cooling. Whereas, as the arctic ice melts, as it is doing at present (Barber), heat previously reflected back into space is absorbed by now exposed water, increasing the rate of warming. Where negative feedback (system damping) dominates, the cup-shaped equilibrium is stable and system behaviour returns to base when subject to disturbance. [...]The impact of extreme events, however, indicates limits to the stable equilibrium. At one point cooling feedback loops overwhelmed the homeostasis, precipitating the "snowball earth" effect. […] Massive release of CO2 as a result of major volcanic activity […] set off positive feedback loops, precipitating runaway global warming and eliminating most life forms at the end of the Permian period. (Wasdell, “Topological”) Martin-Breen and Anderies (53–54), following Walker and Salt, identify four key factors for systems (ecological) resilience in nonlinear, non-deterministic (complex adaptive) systems: regulatory (balancing) feedback mechanisms, where increase in one element is kept in check by another element; modularity, where failure in one part of the system will not cascade into total systems failure; functional redundancy, where more than one element performs every essential function; and, self-organising capacity, rather than central control ensures the system continues without the need for “leadership”. Transition Towns as a Resilience Movement The Transition Town (TT) movement draws on systems modelling of both climate change and of Limits to Growth (Meadows et al.). TT takes seriously Limits to Growth modelling that showed that without constraints in population and consumption the world faces systems collapse by the middle of this century. It recommends community action to build as much capacity as possible to “maintain existence of function”—Holling's (“Engineering vs. Ecological” 33) definition of ecological resilience—in the face of failing economic, political and environmental systems. The Transition Network provides a template for communities to follow to “rebuild resilience and reduce CO2 emissions”. Rob Hopkins, the movements founder, explicitly identifies ecological resilience as its central concept (Transition Handbook 6). The idea for the movement grew out of a project by (2nd year students) completed for Hopkins at the Kinsale Further Education College. According to Hopkins (“Kinsale”), this project was inspired by Holmgren’s Permaculture principles and Heinberg's book on adapting to life after peak oil. Permaculture (permanent agriculture) is a design system for creating agricultural systems modelled on the diversity, stability, and resilience of natural ecosystems (Mollison ix; Holmgren xix). Permaculture draws its scientific foundations from systems ecology (Holmgren xxv). Following CAS theory, Mollison (33) defines stability as “self-regulation”, rather than “climax” or a single equilibrium state, and recommends “diversity of beneficial functional connections” (32) rather than diversity of isolated elements. Permaculture understands resilience in the ecological, rather than the engineering sense. The Transition Handbook (17) “explores the issues of peak oil and climate change, and how when looked at together, we need to be focusing on the rebuilding of resilience as well as cutting carbon emissions. It argues that the focus of our lives will become increasingly local and small scale as we come to terms with the real implications of the energy crisis we are heading into.” The Transition Towns movement incorporate each of the four systems resilience factors, listed at the end of the previous section, into its template for building resilient communities (Hopkins, Transition Handbook 55–6). Many of its recommendations build “modularity” and “self-organising”, such as encouraging communities to build “local food systems, [and] local investment models”. Hopkins argues that in a “more localised system” feedback loops are tighter, and the “results of our actions are more obvious”. TT training exercises include awareness raising for sensitivity to networks of (actual or potential) ecological, social and economic relationships (Hopkins, Transition Handbook 60–1). TT promotes diversity of local production and economic activities in order to increase “diversity of functions” and “diversity of responses to challenges.” Heinberg (8) wrote the forward to the 2008 edition of the Transition Handbook, after speaking at a TotnesTransition Town meeting. Heinberg is now a senior fellow at the Post Carbon Institute (PCI), which was established in 2003 to “provide […] the resources needed to understand and respond to the interrelated economic, energy, environmental, and equity crises that define the 21st century [… in] a world of resilient communities and re-localized economies that thrive within ecological bounds” (PCI, “About”), of the sort envisioned by the Limits to Growth model discussed in the previous section. Given the overlapping goals of PCI and Transition Towns, it is not surprising that Rob Hopkins is now a Fellow of PCI and regular contributor to Resilience, and there are close ties between the two organisations. Resilience, which until 2012 was published as the Energy Bulletin, is run by the Post Carbon Institute (PCI). Like Transition Towns, Resilience aims to build “community resilience in a world of multiple emerging challenges: the decline of cheap energy, the depletion of critical resources like water, complex environmental crises like climate change and biodiversity loss, and the social and economic issues which are linked to these. […] It has [its] roots in systems theory” (PCI, “About Resilience”). Resilience.org says it follows the interpretation of Resilience Alliance (RA) Program Director Brian Walker and science writer David Salt's (xiii) ecological definition of resilience as “the capacity of a system to absorb disturbance and still retain its basic function and structure.“ Conclusion This paper has analysed the ontological metaphors structuring competing conceptions of resilience. The engineering resilience metaphor dominates in psychological resilience research, but is not adequate for understanding resilience in complex adaptive systems. Ecological resilience, on the other hand, dominates in environmental and climate change research, and is the model of resilience that has been incorporated into the global permaculture and Transition Towns movements. References 2nd year students. Kinsale 2021: An Energy Descent Action Plan. Kinsale, Cork, Ireland: Kinsale Further Education College, 2005. 16 Aug. 2013 ‹http://transitionculture.org/wp-content/uploads/KinsaleEnergyDescentActionPlan.pdf>. Barber, Elizabeth. “Arctic Ice Continues to Thin, and Thin, European Satellite Reveals.” Christian Science Monitor 11 Sep. 2013. 25 Sep. 2013 ‹http://www.csmonitor.com/Environment/2013/0911/Arctic-ice-continues-to-thin-and-thin-European-satellite-reveals>. 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IntroductionThe walking tour is an enduring feature of cities. Fuelled by a desire to learn more about the hidden and unknown spaces of the city, the walking tour has moved beyond its historical role as tourist attraction to play a key role in the transformation of urban space through gentrification. Conversely, the walking tour has a counter-history as part of a critical urban praxis. This article reflects on historical examples, as well as our own experience of conducting Field Trip, a critical geographical walking tour through an industrial precinct in Marrickville, a suburb of Sydney that is set to undergo rapid change as a result of high-rise residential apartment construction (Gibson et al.). This precinct, known as Carrington Road, is located on the unceded land of the Cadigal and Wangal people of the Eora nation who call the area Bulanaming.Drawing on a long history of philosophical walking, many contemporary writers (Solnit; Gros; Bendiner-Viani) have described walking as a practice that can open different ways of thinking, observing and being in the world. Some have focused on the value of walking to the study of place (Hall; Philips; Heddon), and have underscored its relationship to established research methods, such as sensory ethnography (Springgay and Truman). The work of Michel de Certeau pays particular attention to the relationship between walking and the city. In particular, the concepts of tactics and strategy have been applied in a variety of ways across cultural studies, cultural geography, and urban studies (Morris). In line with de Certeau’s thinking, we view walking as an example of a tactic – a routine and often unconscious practice that can become a form of creative resistance.In this sense, walking can be a way to engage in and design the city by opposing its structures, or strategies. For example, walking in a city such as Sydney that is designed for cars requires choosing alternative paths, redirecting flows of people and traffic, and creating custom shortcuts. Choosing pedestrianism in Sydney can certainly feel like a form of resistance, and we make the argument that Field Trip – and walking tours more generally – can be a way of doing this collectively, firstly by moving in opposite directions, and secondly, at incongruent speeds to those for whom the scale and style of strategic urban development is inevitable. How such tactical walking relates to the design of cities, however, is less clear. Walking is a generally described in the literature as an individual act, while the design of cities is, at its best participatory, and always involving multiple stakeholders. This reveals a tension between the practice of walking as a détournement or appropriation of urban space, and its relationship to existing built form. Field Trip, as an example of collective walking, is one such appropriation of urban space – one designed to lead to more democratic decision making around the planning and design of cities. Given the anti-democratic, “post-political” nature of contemporary “consultation” processes, this is a seemingly huge task (Legacy et al.; Ruming). We make the argument that Field Trip – and walking tours more generally – can be a form of collective resistance to top-down urban planning.By using an open-source wiki in combination with the Internet Archive, Field Trip also seeks to collectively document and make public the local knowledge generated by walking at the frontier of gentrification. We discuss these digital choices as oppositional practice, and consider the idea of tactical media (Lovink and Garcia; Raley) in order to connect knowledge sharing with the practice of walking.This article is structured in four parts. Firstly, we provide a historical introduction to the relationship between walking tours and gentrification of global cities. Secondly, we examine the significance of walking tours in Sydney and then specifically within Marrickville. Thirdly, we discuss the Field Trip project as a citizen-led walking tour and, finally, elaborate on its role as tactical media project and offer some conclusions.The Walking Tour and Gentrification From the outset, people have been walking the city in their own ways and creating their own systems of navigation, often in spite of the plans of officialdom. The rapid expansion of cities following the Industrial Revolution led to the emergence of “imaginative geographies”, where mediated representations of different urban conditions became a stand-in for lived experience (Steinbrink 219). The urban walking tour as mediated political tactic was utilised as far back as Victorian England, for reasons including the celebration of public works like the sewer system (Garrett), and the “othering” of the working class through upper- and middle-class “slum tourism” in London’s East End (Steinbrink 220). The influence of the Situationist theory of dérive has been immense upon those interested in walking the city, and we borrow from the dérive a desire to report on the under-reported spaces of the city, and to articulate alternative voices within the city in this project. It should be noted, however, that as Field Trip was developed for general public participation, and was organised with institutional support, some aspects of the dérive – particularly its disregard for formal structure – were unable to be incorporated into the project. Our responsibility to the participants of Field Trip, moreover, required the imposition of structure and timetable upon the walk. However, our individual and collective preparation for Field Trip, as well as our collective understanding of the area to be examined, has been heavily informed by psychogeographic methods that focus on quotidian and informal urban practices (Crosby and Searle; Iveson et al).In post-war American cities, walking tours were utilised in the service of gentrification. Many tours were organised by real estate agents with the express purpose of selling devalorised inner-city real estate to urban “pioneers” for renovation, including in Boston’s South End (Tissot) and Brooklyn’s Park Slope, among others (Lees et al 25). These tours focused on a symbolic revalorisation of “slum neighbourhoods” through a focus on “high culture”, with architectural and design heritage featuring prominently. At the same time, urban socio-economic and cultural issues – poverty, homelessness, income disparity, displacement – were downplayed or overlooked. These tours contributed to a climate in which property speculation and displacement through gentrification practices were normalised. To this day, “ghetto tours” operate in minority neighbourhoods in Brooklyn, serving as a beachhead for gentrification.Elsewhere in the world, walking tours are often voyeuristic, featuring “locals” guiding well-meaning tourists through the neighbourhoods of some of the world’s most impoverished communities. Examples include the long runningKlong Toei Private Tour, through “Bangkok’s oldest and largest slum”, or the now-ceased Jakarta Hidden Tours, which took tourists to the riverbanks of Jakarta to see the city’s poorest before they were displaced by gentrification.More recently, all over the world activists have engaged in walking tours to provide their own perspective on urban change, attempting to direct the gentrifier’s gaze inward. Whilst the most confrontational of these might be the Yuppie Gazing Tour of Vancouver’s historically marginalised Downtown Eastside, other tours have highlighted the deleterious effects of gentrification in Williamsburg, San Francisco, Oakland, and Surabaya, among others. In smaller towns, walking tours have been utilised to highlight the erasure of marginalised scenes and subcultures, including underground creative spaces, migrant enclaves, alternative and queer spaces. Walking Sydney, Walking Marrickville In many cities, there are now both walking tours that intend to scaffold urban renewal, and those that resist gentrification with alternative narratives. There are also some that unwittingly do both simultaneously. Marrickville is a historically working-class and migrant suburb with sizeable populations of Greek and Vietnamese migrants (Graham and Connell), as well as a strong history of manufacturing (Castles et al.), which has been undergoing gentrification for some time, with the arts playing an often contradictory role in its transformation (Gibson and Homan). More recently, as the suburb experiences rampant, financialised property development driven by global flows of capital, property developers have organised their own self-guided walking tours, deployed to facilitate the familiarisation of potential purchasers of dwellings with local amenities and ‘character’ in precincts where redevelopment is set to occur. Mirvac, Marrickville’s most active developer, has designed its own self-guided walking tour Hit the Marrickville Pavement to “explore what’s on offer” and “chat to locals”: just 7km from the CBD, Marrickville is fast becoming one of Sydney’s most iconic suburbs – a melting pot of cuisines, creative arts and characters founded on a rich multicultural heritage.The perfect introduction, this self-guided walking tour explores Marrickville’s historical architecture at a leisurely pace, finishing up at the pub.So, strap on your walking shoes; you're in for a treat.Other walking tours in the area seek to highlight political, ecological, and architectural dimension of Marrickville. For example, Marrickville Maps: Tropical Imaginaries of Abundance provides a series of plant-led walks in the suburb; The Warren Walk is a tour organised by local Australian Labor Party MP Anthony Albanese highlighting “the influence of early settlers such as the Schwebel family on the area’s history” whilst presenting a “political snapshot” of ALP history in the area. The Australian Ugliness, in contrast, was a walking tour organised by Thomas Lee in 2016 that offered an insight into the relationships between the visual amenity of the streetscape, aesthetic judgments of an ambiguous nature, and the discursive and archival potentialities afforded by camera-equipped smartphones and photo-sharing services like Instagram. Figure 1: Thomas Lee points out canals under the street of Marrickville during The Australian Ugliness, 2016.Sydney is a city adept at erasing its past through poorly designed mega-projects like freeways and office towers, and memorialisation of lost landscapes has tended towards the literary (Berry; Mudie). Resistance to redevelopment, however, has often taken the form of spectacular public intervention, in which public knowledge sharing was a key goal. The Green Bans of the 1970s were partially spurred by redevelopment plans for places like the Rocks and Woolloomooloo (Cook; Iveson), while the remaking of Sydney around the 2000 Olympics led to anti-gentrification actions such as SquatSpace and the Tour of Beauty, an “aesthetic activist” tour of sites in the suburbs of Redfern and Waterloo threatened with “revitalisation.” Figure 2: "Tour of Beauty", Redfern-Waterloo 2016. What marks the Tour of Beauty as significant in this context is the participatory nature of knowledge production: participants in the tours were addressed by representatives of the local community – the Aboriginal Housing Company, the local Indigenous Women’s Centre, REDWatch activist group, architects, designers and more. Each speaker presented their perspective on the rapidly gentrifying suburb, demonstrating how urban space is made an remade through processes of contestation. This differentiation is particularly relevant when considering the basis for Sydney-centric walking tours. Mirvac’s self-guided tour focuses on the easy-to-see historical “high culture” of Marrickville, and encourages participants to “chat to locals” at the pub. It is a highly filtered approach that does not consider broader relations of class, race and gender that constitute Marrickville. A more intense exploration of the social fabric of the city – providing a glimpse of the hidden or unknown spaces – uncovers the layers of social, cultural, and economic history that produce urban space, and fosters a deeper engagement with questions of urban socio-spatial justice.Solnit argues that walking can allow us to encounter “new thoughts and possibilities.” To walk, she writes, is to take a “subversive detour… the scenic route through a half-abandoned landscape of ideas and experiences” (13). In this way, tactical activist walking tours aim to make visible what cannot be seen, in a way that considers the polysemic nature of place, and in doing so, they make visible the hidden relations of power that produce the contemporary city. In contrast, developer-led walking tours are singularly focussed, seeking to attract inflows of capital to neighbourhoods undergoing “renewal.” These tours encourage participants to adopt the position of urban voyeur, whilst activist-led walking tours encourage collaboration and participation in urban struggles to protect and preserve the contested spaces of the city. It is in this context that we sought to devise our own walking tour – Field Trip – to encourage active participation in issues of urban renewal.In organising this walking tour, however, we acknowledge our own entanglements within processes of gentrification. As designers, musicians, writers, academics, researchers, venue managers, artists, and activists, in organising Field Trip, we could easily be identified as “creatives”, implicated in Marrickville’s ongoing transformation. All of us have ongoing and deep-rooted connections to various Sydney subcultures – the same subcultures so routinely splashed across developer advertising material. This project was borne out of Frontyard – a community not-just-art space, and has been supported by the local Inner West Council. As such, Field Trip cannot be divorced from the highly contentious processes of redevelopment and gentrification that are always simmering in the background of discussions about Marrickville. We hope, however, that in this project we have started to highlight alternative voices in those redevelopment processes – and that this may contribute towards a “method of equality” for an ongoing democratisation of those processes (Davidson and Iveson).Field Trip: Urban Geographical Enquiry as Activism Given this context, Field Trip was designed as a public knowledge project that would connect local residents, workers, researchers, and decision-makers to share their experiences living and working in various parts of Sydney that are undergoing rapid change. The site of our project – Carrington Road, Marrickville in Sydney’s inner-west – has been earmarked for major redevelopment in coming years and is quickly becoming a flashpoint for the debates that permeate throughout the whole of Sydney: housing affordability, employment accessibility, gentrification and displacement. To date, public engagement and consultation regarding proposed development at Carrington Road has been limited. A major landholder in the area has engaged a consultancy firm to establish a community reference group (CRG) the help guide the project. The CRG arose after public outcry at an original $1.3 billion proposal to build 2,616 units in twenty towers of up to 105m in height (up to thirty-five storeys) in a predominantly low-rise residential suburb. Save Marrickville, a community group created in response to the proposal, has representatives on this reference group, and has endeavoured to make this process public. Ruming (181) has described these forms of consultation as “post-political,” stating thatin a universe of consensual decision-making among diverse interests, spaces for democratic contest and antagonistic politics are downplayed and technocratic policy development is deployed to support market and development outcomes.Given the notable deficit of spaces for democratic contest, Field Trip was devised as a way to reframe the debate outside of State- and developer-led consultation regimes that guide participants towards accepting the supposed inevitability of redevelopment. We invited a number of people affected by the proposed plans to speak during the walking tour at a location of their choosing, to discuss the work they do, the effect that redevelopment would have on their work, and their hopes and plans for the future. The walking tour was advertised publicly and the talks were recorded, edited and released as freely available podcasts. The proposed redevelopment of Carrington Road provided us with a unique opportunity to develop and operate our own walking tour. The linear street created an obvious “circuit” to the tour – up one side of the road, and down the other. We selected speakers based on pre-existing relationships, some formed during prior rounds of research (Gibson et al.). Speakers included a local Aboriginal elder, a representative from the Marrickville Historical Society, two workers (who also gave tours of their workplaces), the Lead Heritage Adviser at Sydney Water, who gave us a tour of the Carrington Road pumping station, and a representative from the Save Marrickville residents’ group. Whilst this provided a number of perspectives on the day, regrettably some groups were unrepresented, most notably the perspective of migrant groups who have a long-standing association with industrial precincts in Marrickville. It is hoped that further community input and collaboration in future iterations of Field Trip will address these issues of representation in community-led walking tours.A number of new understandings became apparent during the walking tour. For instance, the heritage-listed Carrington Road sewage pumping station, which is of “historic and aesthetic significance”, is unable to cope with the proposed level of residential development. According to Philip Bennett, Lead Heritage Adviser at Sydney Water, the best way to maintain this piece of heritage infrastructure is to keep it running. While this issue had been discussed in private meetings between Sydney Water and the developer, there is no formal mechanism to make this expert knowledge public or accessible. Similarly, through the Acknowledgement of Country for Field Trip, undertaken by Donna Ingram, Cultural Representative and a member of the Metropolitan Local Aboriginal Land Council, it became clear that the local Indigenous community had not been consulted in the development proposals for Carrington Road. This information, while not necessary secret, had also not been made public. Finally, the inclusion of knowledgeable local workers whose businesses are located on Carrington Road provided an insight into the “everyday.” They talked of community and collaboration, of site-specificity, the importance of clustering within their niche industries, and their fears for of displacement should redevelopment proceed.Via a community-led, participatory walking tour like Field Trip, threads of knowledge and new information are uncovered. These help create new spatial stories and readings of the landscape, broadening the scope of possibility for democratic participation in cities. Figure 3: Donna Ingram at Field Trip 2018.Tactical Walking, Tactical Media Stories connected to walking provide an opportunity for people to read the landscape differently (Mitchell). One of the goals of Field Trip was to begin a public knowledge exchange about Carrington Road so that spatial stories could be shared, and new readings of urban development could spread beyond the confines of the self-contained tour. Once shared, this knowledge becomes a story, and once remixed into existing stories and integrated into the way we understand the neighbourhood, a collective spatial practice is generated. “Every story is a travel story – a spatial practice”, says de Certeau in “Spatial Stories”. “In reality, they organise walks” (72). As well as taking a tactical approach to walking, we took a tactical approach to the mediation of the knowledge, by recording and broadcasting the voices on the walk and feeding information to a publicly accessible wiki. The term “tactical media” is an extension of de Certeau’s concept of tactics. David Garcia and Geert Lovink applied de Certeau’s concept of tactics to the field of media activism in their manifesto of tactical media, identifying a class of producers who amplify temporary reversals in the flow of power by exploiting the spaces, channels and platforms necessary for their practices. Tactical media has been used since the late nineties to help explain a range of open-source practices that appropriate technological tools for political purposes. While pointing out the many material distinctions between different types of tactical media projects within the arts, Rita Raley describes them as “forms of critical intervention, dissent and resistance” (6). The term has also been adopted by media activists engaged in a range of practices all over the world, including the Tactical Technology Collective. For Field Trip, tactical media is a way of creating representations that help navigate neighbourhoods as well as alternative political processes that shape them. In this sense, tactical representations do not “offer the omniscient point of view we associate with Cartesian cartographic practice” (Raley 2). Rather these representations are politically subjective systems of navigation that make visible hidden information and connect people to the decisions affecting their lives. Conclusion We have shown that the walking tour can be a tourist attraction, a catalyst to the transformation of urban space through gentrification, and an activist intervention into processes of urban renewal that exclude people and alternative ways of being in the city. This article presents practice-led research through the design of Field Trip. By walking collectively, we have focused on tactical ways of opening up participation in the future of neighbourhoods, and more broadly in designing the city. 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Rib Fractures are a common injury in trauma patients and affect 10% of all injured patients who require admission to the hospital. Currently, there is no consensus on the most efficacious treatment for rib fractures with the debate comparing non-surgical versus surgical management. Medical management of rib fractures often requires admission to the intensive care unit with a focus on pain control to allow good pulmonary hygiene. Pain control involved a multimodal approach with current techniques including epidural anesthesia and paravertebral blocks. Although many patients recover with medical management alone, some patients may benefit from surgical stabilization of rib fractures as a means of augmenting pain control. Flail chest is the most evidence-based indication for surgical stabilization of rib fractures SSRF with many studies showing decreased days on mechanical ventilation, risk of pneumonia, intensive care unit length of stay, and hospital length of stay. Additionally, in patients with non-flail chest and ventilator dependent respiratory failure, surgical stabilization of rib fractures may provide an advantage over medical management for pain control. There are relatively few contraindications and complications associated with surgical stabilization of rib fractures. Therefore, with proper patient selection, surgical stabilization of rib fractures can improve outcomes in patients with rib fractures. Medical management with or without surgical intervention requires a multidisciplinary approach to prevent adverse clinical outcomes. Keywords: Surgical stabilization of rib fractures, rib plating, rib fracture, flail chest, non-flail chest Article Details How to Cite RAFFA, Taylor et al. Surgical Stabilization of Rib Fractures: A Review of the Indications, Technique, and Outcomes. Medical Research Archives, [S.l.], v. 11, n. 11, nov. 2023. ISSN 2375-1924. Available at: <https://esmed.org/MRA/mra/article/view/4694>. 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An update on regional analgesia for rib fractures. Current opinion in anaesthesiology. 2018;31(5):601-607. https://www.ncbi.nlm.nih.gov/pubmed/30020155. doi: 10.1097/ACO.0000000000000637. 27. Galvagno J, Samuel Michael, Smith CE, Varon AJ, et al. Pain management for blunt thoracic trauma: A joint practice management guideline from the eastern association for the surgery of trauma and trauma anesthesiology society. The journal of trauma and acute care surgery. 2016;81(5):936-951. https://www.ncbi.nlm.nih.gov/pubmed/27533913. doi: 10.1097/TA.0000000000001209. 28. Witt CE, Bulger EM. Comprehensive approach to the management of the patient with multiple rib fractures: A review and introduction of a bundled rib fracture management protocol. Trauma Surgery & Acute Care Open. 2017;2(1):e000064. http://dx.doi.org.proxygw.wrlc.org/10.1136/tsaco-2016-000064. doi: 10.1136/tsaco-2016-000064. 29. Malekpour M, Hashmi A, Dove J, Torres D, Wild J. 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Prospective randomized controlled trial of operative rib fixation in traumatic flail chest. Journal of the American College of Surgeons. 2013;216(5):924-932. https://www-clinicalkey-es.proxygw.wrlc.org/playcontent/1-s2.0-S1072751512014299. doi: 10.1016/j.jamcollsurg.2012.12.024. 45. Doben AR, MD, Eriksson, Evert A., MD, FACS, FCCP, Denlinger CE, MD, et al. Surgical rib fixation for flail chest deformity improves liberation from mechanical ventilation. Journal of critical care. 2014;29(1):139-143. https://www-clinicalkey-es.proxygw.wrlc.org/playcontent/1-s2.0-S0883944113002888. doi: 10.1016/j.jcrc.2013.08.003. 46. Khandelwal G, Mathur RK, Shukla S, Maheshwari A. A prospective single center study to assess the impact of surgical stabilization in patients with rib fracture. International Journal of Surgery. 2011;9(6):478-481._https://www-clinicalkey-es.proxygw.wrlc.org/playcontent/1-s2.0-S1743919111001051. doi: 10.1016/j.ijsu.2011.06.003. 47. Prins J, van Lieshout E, Ali-Osman F, et al. Outcome after surgical stabilization of rib fractures versus nonoperative treatment in patients with multiple rib fractures and moderate to severe traumatic brain injury (CWIS-TBI). The journal of trauma and acute care surgery. 2021;90(3):492-500. https://www.narcis.nl/publication/RecordID/oai:pure.eur.nl:publications%2F1484a1fe-ee48-495e-828e-7732a85dc6bd. doi: 10.1097/TA.0000000000002994. 48. Lardinois D, Krueger T, Dusmet M, Ghisletta N, Gugger M, Ris H-. Pulmonary function testing after operative stabilisation of the chest wall for flail chest. Eur J Cardiothorac Surg. 2001;20(3):496-501. http://ejcts.ctsnetjournals.org/cgi/content/abstract/20/3/496. doi: 10.1016/S1010-7940(01)00818-1. 49. Craxford S, Owyang D, Marson B, et al. Surgical management of rib fractures after blunt trauma: A systematic review and meta-analysis of randomised controlled trials. Annals of the Royal College of Surgeons of England. 2022;104(4):249-256. https://www.ncbi.nlm.nih.gov/pubmed/34928718. doi: 10.1308/rcsann.2021.0148. 50. Apampa AA, Ali A, Kadir B, Ahmed Z. Safety and effectiveness of surgical fixation versus non-surgical methods for the treatment of flail chest in adult populations: A systematic review and meta-analysis. Eur J Trauma Emerg Surg. 2022;48(2):1025-1034. https://link.springer.com/article/10.1007/s00068-021-01606-2. doi: 10.1007/s00068-021-01606-2. 51. Swart E, Laratta J, Slobogean G, Mehta S. Operative treatment of rib fractures in flail chest injuries: A meta-analysis and cost-effectiveness analysis. Journal of orthopaedic trauma. 2017;31(2):64-70. https://www.ncbi.nlm.nih.gov/pubmed/27984449. doi: 10.1097/BOT.0000000000000750. 52. Schulte K, Whitaker D, Attia R. In patients with acute flail chest does surgical rib fixation improve outcomes in terms of morbidity and mortality? Interactive cardiovascular and thoracic surgery. 2016;23(2):314-319. https://www.ncbi.nlm.nih.gov/pubmed/27073261. doi: 10.1093/icvts/ivw092. 53. Choi J, Gomez GI, Kaghazchi A, Borghi JA, Spain DA, Forrester JD. Surgical stabilization of rib fracture to mitigate pulmonary complication and mortality: A systematic review and bayesian meta-analysis. Journal of the American College of Surgeons. 2021;232(2):211-219.e2. https://dx.doi.org/10.1016/j.jamcollsurg.2020.10.022. doi: 10.1016/j.jamcollsurg.2020.10.022. 54. Slobogean, Gerard P., MD, MPH, FRCSC, MacPherson, Cailan Alexander, MD, MHSc, Sun T, BSc, Pelletier M, MD, Hameed, S. Morad, MD, MPH, FRCSC, FACS. Surgical fixation vs nonoperative management of flail chest: A meta-analysis. Journal of the American College of Surgeons. 2013;216(2):302-311.e1. https://www.clinicalkey.es/playcontent/1-s2.0-S1072751512012768. doi: 10.1016/j.jamcollsurg.2012.10.010. 55. Farquhar J, MD, Almahrabi Y, MD, Slobogean, Gerard, MD, MPH, et al. 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This article investigates the possibilities for understanding waste as a resource, with a particular focus on understanding food waste as a food resource. It considers the popular yeast spread Vegemite within this frame. The spread’s origins in waste product, and how it has achieved and sustained its status as a popular symbol of Australia despite half a century of Australian gastro-multiculturalism and a marked public resistance to other recycling and reuse of food products, have not yet been a focus of study. The process of producing Vegemite from waste would seem to align with contemporary moves towards recycling food waste, and ensuring environmental sustainability and food security, yet even during times of austerity and environmental concern this has not provided the company with a viable marketing strategy. Instead, advertising copywriting and a recurrent cycle of product memorialisation have created a superbrand through focusing on Vegemite’s nutrient and nostalgic value.John Scanlan notes that producing waste is a core feature of modern life, and what we dispose of as surplus to our requirements—whether this comprises material objects or more abstract products such as knowledge—reveals much about our society. In observing this, Scanlan asks us to consider the quite radical idea that waste is central to everything of significance to us: the “possibility that the surprising core of all we value results from (and creates even more) garbage (both the material and the metaphorical)” (9). Others have noted the ambivalent relationship we have with the waste we produce. C. T. Anderson notes that we are both creator and agent of its disposal. It is our ambivalence towards waste, coupled with its ubiquity, that allows waste materials to be described so variously: negatively as garbage, trash and rubbish, or more positively as by-products, leftovers, offcuts, trimmings, and recycled.This ambivalence is also crucial to understanding the affectionate relationship the Australian public have with Vegemite, a relationship that appears to exist in spite of the product’s unpalatable origins in waste. A study of Vegemite reveals that consumers can be comfortable with waste, even to the point of eating recycled waste, as long as that fact remains hidden and unmentioned. In Vegemite’s case not only has the product’s connection to waste been rendered invisible, it has been largely kept out of sight despite considerable media and other attention focusing on the product. Recycling Food Waste into Food ProductRecent work such as Elizabeth Royte’s Garbage Land and Tristram Stuart’s Waste make waste uncomfortably visible, outlining how much waste, and food waste in particular, the Western world generates and how profligately this is disposed of. Their aim is clear: a call to less extravagant and more sustainable practices. The relatively recent interest in reducing our food waste has, of course, introduced more complexity into a simple linear movement from the creation of a food product, to its acquisition or purchase, and then to its consumption and/or its disposal. Moreover, the recycling, reuse and repurposing of what has previously been discarded as waste is reconfiguring the whole idea of what waste is, as well as what value it has. The initiatives that seem to offer the most promise are those that reconfigure the way waste is understood. However, it is not only the process of transforming waste from an abject nuisance into a valued product that is central here. It is also necessary to reconfigure people’s acculturated perceptions of, and reactions to waste. Food waste is generated during all stages of the food cycle: while the raw materials are being grown; while these are being processed; when the resulting food products are being sold; when they are prepared in the home or other kitchen; and when they are only partly consumed. Until recently, the food industry in the West almost universally produced large volumes of solid and liquid waste that not only posed problems of disposal and pollution for the companies involved, but also represented a reckless squandering of total food resources in terms of both nutrient content and valuable biomass for society at large. While this is currently changing, albeit slowly, the by-products of food processing were, and often are, dumped (Stuart). In best-case scenarios, various gardening, farming and industrial processes gather household and commercial food waste for use as animal feed or as components in fertilisers (Delgado et al; Wang et al). This might, on the surface, appear a responsible application of waste, yet the reality is that such food waste often includes perfectly good fruit and vegetables that are not quite the required size, shape or colour, meat trimmings and products (such as offal) that are completely edible but extraneous to processing need, and other high grade product that does not meet certain specifications—such as the mountains of bread crusts sandwich producers discard (Hickman), or food that is still edible but past its ‘sell by date.’ In the last few years, however, mounting public awareness over the issues of world hunger, resource conservation, and the environmental and economic costs associated with food waste has accelerated efforts to make sustainable use of available food supplies and to more efficiently recycle, recover and utilise such needlessly wasted food product. This has fed into and led to multiple new policies, instances of research into, and resultant methods for waste handling and treatment (Laufenberg et al). Most straightforwardly, this involves the use or sale of offcuts, trimmings and unwanted ingredients that are “often of prime quality and are only rejected from the production line as a result of standardisation requirements or retailer specification” from one process for use in another, in such processed foods as soups, baby food or fast food products (Henningsson et al. 505). At a higher level, such recycling seeks to reclaim any reusable substances of significant food value from what could otherwise be thought of as a non-usable waste product. Enacting this is largely dependent on two elements: an available technology and being able to obtain a price or other value for the resultant product that makes the process worthwhile for the recycler to engage in it (Laufenberg et al). An example of the latter is the use of dehydrated restaurant food waste as a feedstuff for finishing pigs, a reuse process with added value for all involved as this process produces both a nutritious food substance as well as a viable way of disposing of restaurant waste (Myer et al). In Japan, laws regarding food waste recycling, which are separate from those governing other organic waste, are ensuring that at least some of food waste is being converted into animal feed, especially for the pigs who are destined for human tables (Stuart). Other recycling/reuse is more complex and involves more lateral thinking, with the by-products from some food processing able to be utilised, for instance, in the production of dyes, toiletries and cosmetics (Henningsson et al), although many argue for the privileging of food production in the recycling of foodstuffs.Brewing is one such process that has been in the reuse spotlight recently as large companies seek to minimise their waste product so as to be able to market their processes as sustainable. In 2009, for example, the giant Foster’s Group (with over 150 brands of beer, wine, spirits and ciders) proudly claimed that it recycled or reused some 91.23% of 171,000 tonnes of operational waste, with only 8.77% of this going to landfill (Foster’s Group). The treatment and recycling of the massive amounts of water used for brewing, rinsing and cooling purposes (Braeken et al.; Fillaudeaua et al.) is of significant interest, and is leading to research into areas as diverse as the development microbial fuel cells—where added bacteria consume the water-soluble brewing wastes, thereby cleaning the water as well as releasing chemical energy that is then converted into electricity (Lagan)—to using nutrient-rich wastewater as the carbon source for creating bioplastics (Yu et al.).In order for the waste-recycling-reuse loop to be closed in the best way for securing food supplies, any new product salvaged and created from food waste has to be both usable, and used, as food (Stuart)—and preferably as a food source for people to consume. There is, however, considerable consumer resistance to such reuse. Resistance to reusing recycled water in Australia has been documented by the CSIRO, which identified negative consumer perception as one of the two primary impediments to water reuse, the other being the fundamental economics of the process (MacDonald & Dyack). This consumer aversion operates even in times of severe water shortages, and despite proof of the cleanliness and safety of the resulting treated water. There was higher consumer acceptance levels for using stormwater rather than recycled water, despite the treated stormwater being shown to have higher concentrations of contaminants (MacDonald & Dyack). This reveals the extent of public resistance to the potential consumption of recycled waste product when it is labelled as such, even when this consumption appears to benefit that public. Vegemite: From Waste Product to Australian IconIn this context, the savoury yeast spread Vegemite provides an example of how food processing waste can be repurposed into a new food product that can gain a high level of consumer acceptability. It has been able to retain this status despite half a century of Australian gastronomic multiculturalism and the wide embrace of a much broader range of foodstuffs. Indeed, Vegemite is so ubiquitous in Australian foodways that it is recognised as an international superbrand, a standing it has been able to maintain despite most consumers from outside Australasia finding it unpalatable (Rozin & Siegal). However, Vegemite’s long product history is one in which its origin as recycled waste has been omitted, or at the very least, consistently marginalised.Vegemite’s history as a consumer product is narrated in a number of accounts, including one on the Kraft website, where the apocryphal and actual blend. What all these narratives agree on is that in the early 1920s Fred Walker—of Fred Walker and Company, Melbourne, canners of meat for export and Australian manufacturers of Bonox branded beef stock beverage—asked his company chemist to emulate Marmite yeast extract (Farrer). The imitation product was based, as was Marmite, on the residue from spent brewer’s yeast. This waste was initially sourced from Melbourne-based Carlton & United Breweries, and flavoured with vegetables, spices and salt (Creswell & Trenoweth). Today, the yeast left after Foster Group’s Australian commercial beer making processes is collected, put through a sieve to remove hop resins, washed to remove any bitterness, then mixed with warm water. The yeast dies from the lack of nutrients in this environment, and enzymes then break down the yeast proteins with the effect that vitamins and minerals are released into the resulting solution. Using centrifugal force, the yeast cell walls are removed, leaving behind a nutrient-rich brown liquid, which is then concentrated into a dark, thick paste using a vacuum process. This is seasoned with significant amounts of salt—although less today than before—and flavoured with vegetable extracts (Richardson).Given its popularity—Vegemite was found in 2009 to be the third most popular brand in Australia (Brand Asset Consulting)—it is unsurprising to find that the product has a significant history as an object of study in popular culture (Fiske et al; White), as a marker of national identity (Ivory; Renne; Rozin & Siegal; Richardson; Harper & White) and as an iconic Australian food, brand and product (Cozzolino; Luck; Khamis; Symons). Jars, packaging and product advertising are collected by Australian institutions such as Sydney’s Powerhouse Museum and the National Museum of Australia in Canberra, and are regularly included in permanent and travelling exhibitions profiling Australian brands and investigating how a sense of national identity is expressed through identification with these brands. All of this significant study largely focuses on how, when and by whom the product has been taken up, and how it has been consumed, rather than its links to waste, and what this circumstance could add to current thinking about recycling of food waste into other food products.It is worth noting that Vegemite was not an initial success in the Australian marketplace, but this does not seem due to an adverse public perception to waste. Indeed, when it was first produced it was in imitation of an already popular product well-known to be made from brewery by-products, hence this origin was not an issue. It was also introduced during a time when consumer relationships to waste were quite unlike today, and thrifty re-use of was a common feature of household behaviour. Despite a national competition mounted to name the product (Richardson), Marmite continued to attract more purchasers after Vegemite’s launch in 1923, so much so that in 1928, in an attempt to differentiate itself from Marmite, Vegemite was renamed “Parwill—the all Australian product” (punning on the idea that “Ma-might” but “Pa-will”) (White 16). When this campaign was unsuccessful, the original, consumer-suggested name was reinstated, but sales still lagged behind its UK-owned prototype. It was only after remaining in production for more than a decade, and after two successful marketing campaigns in the second half of the 1930s that the Vegemite brand gained some market traction. The first of these was in 1935 and 1936, when a free jar of Vegemite was offered with every sale of an item from the relatively extensive Kraft-Walker product list (after Walker’s company merged with Kraft) (White). The second was an attention-grabbing contest held in 1937, which invited consumers to compose Vegemite-inspired limericks. However, it was not the nature of the product itself or even the task set by the competition which captured mass attention, but the prize of a desirable, exotic and valuable imported Pontiac car (Richardson 61; Superbrands).Since that time, multinational media company, J Walter Thompson (now rebranded as JWT) has continued to manage Vegemite’s marketing. JWT’s marketing has never looked to Vegemite’s status as a thrifty recycler of waste as a viable marketing strategy, even in periods of austerity (such as the Depression years and the Second World War) or in more recent times of environmental concern. Instead, advertising copywriting and a recurrent cycle of cultural/media memorialisation have created a superbrand by focusing on two factors: its nutrient value and, as the brand became more established, its status as national icon. Throughout the regular noting and celebration of anniversaries of its initial invention and launch, with various commemorative events and products marking each of these product ‘birthdays,’ Vegemite’s status as recycled waste product has never been more than mentioned. Even when its 60th anniversary was marked in 1983 with the laying of a permanent plaque in Kerferd Road, South Melbourne, opposite Walker’s original factory, there was only the most passing reference to how, and from what, the product manufactured at the site was made. This remained the case when the site itself was prioritised for heritage listing almost twenty years later in 2001 (City of Port Phillip).Shying away from the reality of this successful example of recycling food waste into food was still the case in 1990, when Kraft Foods held a nationwide public campaign to recover past styles of Vegemite containers and packaging, and then donated their collection to Powerhouse Museum. The Powerhouse then held an exhibition of the receptacles and the historical promotional material in 1991, tracing the development of the product’s presentation (Powerhouse Museum), an occasion that dovetailed with other nostalgic commemorative activities around the product’s 70th birthday. Although the production process was noted in the exhibition, it is noteworthy that the possibilities for recycling a number of the styles of jars, as either containers with reusable lids or as drinking glasses, were given considerably more notice than the product’s origins as a recycled product. By this time, it seems, Vegemite had become so incorporated into Australian popular memory as a product in its own right, and with such a rich nostalgic history, that its origins were no longer of any significant interest or relevance.This disregard continued in the commemorative volume, The Vegemite Cookbook. With some ninety recipes and recipe ideas, the collection contains an almost unimaginably wide range of ways to use Vegemite as an ingredient. There are recipes on how to make the definitive Vegemite toast soldiers and Vegemite crumpets, as well as adaptations of foreign cuisines including pastas and risottos, stroganoffs, tacos, chilli con carne, frijole dip, marinated beef “souvlaki style,” “Indian-style” chicken wings, curries, Asian stir-fries, Indonesian gado-gado and a number of Chinese inspired dishes. Although the cookbook includes a timeline of product history illustrated with images from the major advertising campaigns that runs across 30 pages of the book, this timeline history emphasises the technological achievement of Vegemite’s creation, as opposed to the matter from which it orginated: “In a Spartan room in Albert Park Melbourne, 20 year-old food technologist Cyril P. Callister employed by Fred Walker, conducted initial experiments with yeast. His workplace was neither kitchen nor laboratory. … It was not long before this rather ordinary room yielded an extra-ordinary substance” (2). The Big Vegemite Party Book, described on its cover as “a great book for the Vegemite fan … with lots of old advertisements from magazines and newspapers,” is even more openly nostalgic, but similarly includes very little regarding Vegemite’s obviously potentially unpalatable genesis in waste.Such commemorations have continued into the new century, each one becoming more self-referential and more obviously a marketing strategy. In 2003, Vegemite celebrated its 80th birthday with the launch of the “Spread the Smile” campaign, seeking to record the childhood reminisces of adults who loved Vegemite. After this, the commemorative anniversaries broke free from even the date of its original invention and launch, and began to celebrate other major dates in the product’s life. In this way, Kraft made major news headlines when it announced that it was trying to locate the children who featured in the 1954 “Happy little Vegemites” campaign as part of the company’s celebrations of the 50th anniversary of the television advertisement. In October 2006, these once child actors joined a number of past and current Kraft employees to celebrate the supposed production of the one-billionth jar of Vegemite (Rood, "Vegemite Spreads" & "Vegemite Toasts") but, once again, little about the actual production process was discussed. In 2007, the then iconic marching band image was resituated into a contemporary setting—presumably to mobilise both the original messages (nutritious wholesomeness in an Australian domestic context) as well as its heritage appeal. Despite the real interest at this time in recycling and waste reduction, the silence over Vegemite’s status as recycled, repurposed food waste product continued.Concluding Remarks: Towards Considering Waste as a ResourceIn most parts of the Western world, including Australia, food waste is formally (in policy) and informally (by consumers) classified, disposed of, or otherwise treated alongside garden waste and other organic materials. Disposal by individuals, industry or local governments includes a range of options, from dumping to composting or breaking down in anaerobic digestion systems into materials for fertiliser, with food waste given no special status or priority. Despite current concerns regarding the security of food supplies in the West and decades of recognising that there are sections of all societies where people do not have enough to eat, it seems that recycling food waste into food that people can consume remains one of the last and least palatable solutions to these problems. This brief study of Vegemite has attempted to show how, despite the growing interest in recycling and sustainability, the focus in both the marketing of, and public interest in, this iconic and popular product appears to remain rooted in Vegemite’s nutrient and nostalgic value and its status as a brand, and firmly away from any suggestion of innovative and prudent reuse of waste product. 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