Artigos de revistas sobre o tema "Myers, Kevin"

BackgroundDeucravacitinib is a first-in-class, oral, selective, allosteric tyrosine kinase 2 (TYK2) inhibitor approved in multiple countries for the treatment of adults with plaque psoriasis[1,2]. Deucravacitinib demonstrated efficacy across the primary endpoint and all key secondary endpoints in a phase 2 trial in patients with systemic lupus erythematosus (SLE)[3].ObjectivesHere, we describe 2 phase 3 trials currently underway to assess the efficacy and safety of deucravacitinib in patients with active SLE. These phase 3 trials have been designed to replicate the successful elements of the phase 2 trial, including its glucocorticoid-tapering strategy and rigorous management structure[3].MethodsIn these phase 3, randomized, double-blind, placebo-controlled, global trials (POETYK SLE-1 [NCT05617677], POETYK SLE-2 [NCT05620407]), adults (aged 18-75) with active SLE on background standard-of-care treatment will be randomized (1:1) to placebo or deucravacitinib for 52 weeks of double-blind treatment (Figure 1). Patients on glucocorticoids will be instructed to taper, unless significant disease activity is present, to a threshold dose level during the double-blind treatment period. At week 52, patients may choose to continue in a 104-week open-label extension phase, in which all patients receive deucravacitinib. Key eligibility criteria and study design are depicted below (Figure 1). The primary endpoint of SLE Responder Index (SRI[4]) and all secondary endpoints will be assessed at week 52 (Table 1). Safety and tolerability will be assessed throughout the trial.ResultsPlanned randomization in each trial includes 490 patients (245 per treatment group) in 27 countries across North and South America, Europe, and Asia-Pacific.ConclusionThe phase 3 POETYK SLE trials will further evaluate the efficacy and safety of deucravacitinib, an oral, selective, TYK2 inhibitor, in patients with active SLE.References[1]Armstrong A, et al.J Am Acad Dermatol.2022;S0190-9622(22)02256-3.[2]Strober B, et al.J Am Acad Dermatol.2022;S0190-9622(22)02643-3.[3]Morand E, et al.Arthritis Rheumatol.2022; Nov 11 (Epub ahead of print). doi: 10.1002/art.42391.Table 1.Primary and Secondary Endpoints Assessed at Week 52Primary Endpoint • Proportion of patients who achieve an SLE Responder Index (SRI[4]) responseSecondary Endpoints • Proportion of patients who achieve a British Isles Lupus Assessment Group-based Composite Lupus Assessment (BICLA) response • Proportion of patients with simultaneous achievement of SRI(4) and BICLA response (dual responders) • Proportion of patients who achieve a ≥ 50% reduction in Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI-50) among patients with CLASI activity score ≥ 10 at baseline • Proportion of patients who achieve Lupus Low Disease Activity State (LLDAS) • Proportion of patients maintaining ≤ 7.5 mg/day glucocorticoid dose from weeks 24 to 52 • Proportion of patients who achieve a ≥ 50% reduction in active joints (Joint-Count 50) among patients with ≥ 6 active joints at baseline • Change from baseline in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scoreAcknowledgementsThis study was sponsored by Bristol Myers Squibb.Disclosure of InterestsCristina Arriens Speakers bureau: AstraZeneca, Aurinia, Bristol Myers Squibb, GlaxoSmithKline, Kezar, AstraZeneca and Aurinia, Grant/research support from: AstraZeneca and Bristol Myers Squibb, Anca Askanase Consultant of: Abbvie, Amgen, AstraZeneca, Bristol Myers Squibb, Celgene, Eli Lilly, Genentech, GlaxoSmithKline, Idorsia, Janssen, Pfizer, and UCB, Richard Furie Consultant of: Bristol Myers Squibb, Grant/research support from: Bristol Myers Squibb, Eric F. Morand Consultant of: AstraZeneca, Biogen, Bristol Myers Squibb, Eli Lilly, EMD Serono, Genentech, Gilead, Novartis, and Servier, Grant/research support from: AbbVie, Amgen, AstraZeneca, Biogen, Bristol Myers Squibb, Eli Lilly, EMD Serono, Genentech, GlaxoSmithKline, Janssen, and UCB, Ronald van Vollenhoven Speakers bureau: AbbVie, Galapagos, Janssen, Pfizer, UCB, Consultant of: UCB, Pfizer, AstraZeneca, Biogen, Biotest, Celgene, Gilead, Servier, AbbVie, Galapagos, and Janssen, Grant/research support from: Bristol Myers Squibb, Eli Lilly, Pfizer, UCB, Roche, and GlaxoSmithKline, Kevin Connors Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Monica Davey Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Nikolay Delev Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Vaishali Shah Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Anna Stevens Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Thomas Wegman Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Coburn Hobar Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb.

BackgroundA previous real-world study has reported the characteristics, treatment patterns and clinical outcomes of patients with rheumatoid arthritis (RA) who received abatacept in UK clinical practice.1,2 However, many of the eligible population received abatacept monotherapy rather than as indicated. A subgroup analysis of patients treated with abatacept in combination with methotrexate (ABA + MTX) was therefore undertaken to explore the treatment effect in this specific patient population.ObjectivesPresent a subgroup analysis describing the clinical outcomes of patients with RA treated with ABA + MTX in UK real-world clinical practice.MethodsA multi-centre, retrospective observational study was undertaken in patients with RA treated with abatacept at any line of therapy between 1 January 2013 and 31 December 2017, across four UK centres. Data were collected from patient medical records from index date, defined as the date of first bDMARD initiation, to most recent RA clinic visit, death or end of study (31 December 2017). Clinical outcomes (disease activity and response to treatment) were measured using the 28-joint Disease Activity Score based on erythrocyte sedimentation rate (DAS28-ESR) and European League Against Rheumatism (EULAR) response criteria. Patients that received abatacept outside indication (i.e., without concomitant methotrexate) were retrospectively excluded from the analysis dataset. Statistical analyses for the ABA + MTX subgroup were repeated in line with the methodology previously reported.1,2ResultsThis subgroup analysis included 133 patients, of 213 patients included in the original study, with RA that received ABA + MTX (mean age 54.6 years, 77.4% female, 7.5 years mean duration of RA at index date). At index date, 64.8% of patients were positive for both anti-citrullinated protein antibodies (ACPA) and rheumatoid factor (RF), where data were available. In total, 77.8% of patients were categorised with high disease activity at index, with mean DAS28-ESR of 6.2 (SD 1.1).Irrespective of line of treatment (LOT), patients tended to have a more favourable distribution of good/moderate/no EULAR response when receiving ABA + MTX (31.8%/34.1%/34.1%; n=44) compared with receipt of other bDMARDs (12.7%/36.4%/50.9%; n=55) at 6 months. Similarly, a favourable distribution of good/moderate/no EULAR response in favour of those receiving ABA + MTX compared with other bDMARDs was observed at 12 months (30.6%/41.7%/27.8% versus 20.0%/35.0%/45.0%, respectively).Patients receiving ABA + MTX remained on treatment for significantly longer than patients in receipt of other bDMARDs as first LOT (median time on treatment 53.4 vs 18.1 months; p<0.01). A similar trend was observed at second LOT, although differences were not statistically significant (median time on treatment 40.1 vs 19.7 months; p =0.08).ConclusionPatients with RA who received treatment with any bDMARDs, including ABA + MTX, experienced reduced disease activity. However, those receiving ABA + MTX persisted with treatment significantly longer than when receiving other bDMARDs.References[1]Choy, E. et al. Outcomes in rheumatoid arthritis patients treated with abatacept: a UK multi-centre observational study. BMC Rheumatology5, 3, doi:10.1186/s41927-020-00173-0 (2021).[2]Henning, S. et al. AB0295 CHANGE IN DISEASE ACTIVITY AND TREATMENT RESPONSE AFTER ABATACEPT TREATMENT FOR RHEUMATOID ARTHRITIS: REAL-WORLD EVIDENCE FROM THE UK. Annals of the Rheumatic Diseases79, 1446-1447, doi:10.1136/annrheumdis-2020-eular.1069 (2020).AcknowledgementsThis analysis was supported by Bristol-Myers Squibb.Disclosure of InterestsErnest Choy Speakers bureau: Abbvie, Amgen, Bristol Myer Squibbs, Chugai Pharma, Eli Lilly, Galapagos, Gilead, Janssen, Novartis, Pfizer, Regeneron, Roche, Sanofi, and UCB, Consultant of: Abbvie, Amgen, Biogen, Biocon, Chugai Pharma, Eli Lilly, Gilead, Janssen, Merck Serono, Novartis, Pfizer, Regeneron, Roche, R-Pharm and Sanofi, Grant/research support from: Bio-Cancer, Biogen, Novartis, Pfizer, Roche, Sanofi and UCB, Sadie Henning Shareholder of: Bristol Myers Squibb, Employee of: Yes, Bristol Myers Squibb, Marie Brazil Shareholder of: Bristol Myers Squibb, Employee of: Currently an employee of Bristol Myers Squibb, Kevin Pollock Shareholder of: Yes - Bristol Myers Squibb, Speakers bureau: Yes - Merck Sharp & Dohme and Glaxo Smith Kline, Consultant of: Yes - Merck Sharp & Dohme, Employee of: Yes – currently employed by Bristol Myers Squibb, Lara Groves Grant/research support from: I am an employee of Health Economics and Outcomes Research Ltd., Cardiff, UK, who received fees from Bristol Myers Squibb in relation to this study, Daniel Sugrue Grant/research support from: I am an employee of Health Economics and Outcomes Research Ltd., Cardiff, UK, who received fees from Bristol Myers Squibb in relation to this study, John Houghton Grant/research support from: I am an employee of Health Economics and Outcomes Research Ltd., Cardiff, UK, who received fees from Bristol Myers Squibb in relation to this study

Background:Axial spondyloarthritis (axSpA) is a chronic inflammatory disease that affects the axial skeleton and sacroiliac joints, and can be classified as ankylosing spondylitis (AS) or non-radiographic (nr)-axSpA.1A 2016 analysis estimated the US diagnostic prevalence of axSpA to be 0.2% and AS to be 0.1%.2Previous studies use disparate populations and diagnostic definitions;3,4it is therefore unclear how AS prevalence has changed over time.Objectives:To investigate the annual diagnostic prevalence of AS in US healthcare insurance claims databases.Methods:A retrospective, observational cohort study was conducted using 2006–2014 data from US Medicare Fee-for-Service Claims (5% random sample of all enrolled patients [pts]) and Truven MarketScan®. Eligible pts were ≥20 years (yrs) and had ≥6 months of continuous medical and pharmacy enrolment prior to diagnosis. Diagnoses used relevant International Classification of Disease, 9thversion (ICD-9) diagnosis codes: ICD-9 720.x [x=any number] for “AS and other inflammatory spondylopathies [SpA]” or 720.0 for “AS”. Two diagnosis definitions were used: Definition 1, ≥1 relevant ICD-9 code from hospital discharge or ≥2 from rheumatologist visit; Definition 2, ≥1 relevant ICD-9 code from hospital discharge or rheumatologist visit. Annual diagnostic prevalence of SpA/AS was calculated as “number of enrolled pts who met the definition of SpA/AS within each calendar yr and had full insurance coverage (medical and pharmacy)”, divided by “total number of pts with full insurance coverage in the same yr”. A primary analysis of SpA prevalence rates used Definitions 1 and 2, followed by a sensitivity analysis for AS prevalence rates using only Definition 2. All prevalence rates are shown per 10,000 pts enrolled.Results:The annual diagnostic prevalence of SpA appeared to increase from 2006–2014 (Table). Similarly, the sensitivity analysis showed the annual diagnostic prevalence of AS appeared to increase during the period from 2006 (Medicare: 2.87/10,000 pts [n=501,031]; MarketScan: 1.37/10,000 pts [n=17,562,637]) to 2014 (Medicare: 4.77/10,000 pts [n=1,046,107]; MarketScan: 2.14/10,000 pts [n=34,553,135];Figure).Conclusion:The apparent increase in diagnostic prevalence of SpA and AS during the period from 2006–‍2014 may be a consequence of increased awareness and availability of effective treatments. Furthermore, the 2009 Assessment of SpondyloArthritis international Society development of the axSpA classification criteria to include pts with both established AS and nr-axSpA may have accelerated this increase.5References:[1]Strand V. Mayo Clin Proc 2017;92:555–64;[2]Curtis J. Perm J 2016;20:15–151;[3]Reveille J. Arthritis Care Res (Hoboken) 2012;64:905–10;[4]Danve A. Clin Rheumatol 2019;38:625–34;[5]Rudwaleit M. Ann Rheum Dis 2009;68:777–83.Table.Prevalence of SpA by calendar year and data sourceMedicare (5% random sample)MarketScanCalendar yrTotal number of eligible ptsPrevalence/10,000 ptsTotal number of eligible ptsPrevalence/10,000 ptsDefinition 1Definition 2Definition 1Definition 22006501,0314.397.6217,562,6371.332.172007816,9705.258.7219,518,0661.472.372008825,4454.898.7828,603,5251.582.532009830,9675.229.2131,757,0691.903.092010844,5285.499.9031,126,1721.963.172011879,9966.3010.7138,295,1211.943.112012921,9946.1710.8840,320,4371.913.0420131,032,8276.7410.8233,826,0412.003.1920141,046,1076.5210.8534,553,1352.213.51Medicare data included a 5% random sample of all enrolled pts age ≥20 yrs. pts: patients; SpA: ankylosing spondylitis and other inflammatory spondylopathies; yr: year.Acknowledgments:This study was funded by UCB Pharma. Editorial services were provided by Costello Medical.Disclosure of Interests:Jeffrey Curtis Grant/research support from: AbbVie, Amgen, Bristol-Myers Squibb, Corona, Crescendo, Genentech, Janssen, Pfizer, Roche and UCB Pharma, Consultant of: AbbVie, Amgen, Bristol-Myers Squibb, Corona, Crescendo, Genentech, Janssen, Pfizer, Roche and UCB Pharma, Kevin Winthrop Grant/research support from: Bristol-Myers Squibb, Consultant of: AbbVie, Bristol-Myers Squibb, Eli Lilly, Galapagos, Gilead, GSK, Pfizer Inc, Roche, UCB, Benjamin Chan: None declared, Sarah Siegel: None declared, Jeffrey Stark Employee of: UCB Pharma, Robert Suruki Employee of: UCB Pharma, Rhonda Bohn Consultant of: UCB Pharma, Fenglong Xie: None declared, Huifeng Yun Grant/research support from: Bristol-Myers Squibb and Pfizer, Lang Chen: None declared, 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

BackgroundTyrosine kinase 2 (TYK2) is an intracellular enzyme involved in IL-23 signaling that is important in the pathogenesis of immune-mediated diseases, including psoriasis, psoriatic arthritis, and systemic lupus erythematosus (SLE). Deucravacitinib is a first-in-class, oral, selective, allosteric TYK2 inhibitor approved in multiple countries for the treatment of adults with plaque psoriasis. Deucravacitinib uniquely binds to the TYK2 regulatory domain rather than the more conserved catalytic domain at which Janus kinase (JAK) 1/2/3 inhibitors bind. Deucravacitinib was efficacious compared with placebo in phase 2 trials in psoriatic arthritis and SLE.[1,2]Furthermore, deucravacitinib was significantly more efficacious than placebo or apremilast and was well tolerated in patients with moderate to severe plaque psoriasis, as observed in the phase 3 POETYK PSO-1 and PSO-2 trials.[3,4]Patients who completed the psoriasis trials could enroll in the ongoing open-label, 240-week long-term extension (LTE) trial.ObjectivesThis analysis examined whether changes occurred in blood laboratory parameters upon deucravacitinib treatment in the phase 3 POETYK PSO-1, PSO-2, and LTE trials and, if so, assessed how these compared with signature laboratory changes seen with JAK 1/2/3 inhibitors.MethodsPOETYK PSO-1 (NCT03624127) and PSO-2 (NCT03611751) were 52-week, double-blind trials that randomized patients with moderate to severe plaque psoriasis 2:1:1 to deucravacitinib 6 mg once daily, placebo, or apremilast 30 mg twice daily. Patients receiving placebo switched to deucravacitinib at Week 16, and patients receiving apremilast who failed to achieve ≥50% reduction from baseline in Psoriasis Area and Severity Index (PASI 50; PSO-1) or ≥75% reduction from baseline in PASI (PASI 75; PSO-2) at Week 24 switched to deucravacitinib. At Week 52, all eligible patients enrolled in the LTE trial (NCT04036435) and received open-label deucravacitinib 6 mg once daily. Changes from baseline in hematologic parameters (lymphocytes, neutrophils, platelets, hemoglobin) and lipid and chemistry parameters (cholesterol, creatinine, CPK, ALT) known to be impacted by JAK 1/2/3 inhibitors were assessed through Week 100 (LTE at Week 48). CTCAE grade ≥3 laboratory abnormalities and treatment discontinuations due to laboratory abnormalities were also evaluated.ResultsPatients (n=1519) received ≥1 dose of deucravacitinib in PSO-1, PSO-2, and/or the LTE through the cutoff date of 1 October 2021. In total, 1179 (77.6%) and 584 (38.4%) patients had ≥52 and ≥104 weeks, respectively, of continuous deucravacitinib exposure at the cutoff date, and the median duration of exposure was 682.0 days (97 weeks). No trends for clinically meaningful changes from baseline were observed in any laboratory parameters from Weeks 0–52 in PSO-1 or in the LTE. Grade 3 or 4 abnormalities over 100 weeks of deucravacitinib treatment were rare; incidence rates were comparable with placebo and apremilast through Week 52, and no increases were seen in the LTE. Two patients discontinued deucravacitinib treatment due to laboratory abnormalities (1 lymphopenia, 1 abnormal hepatic function).ConclusionNo trends for clinically meaningful changes from baseline were observed with deucravacitinib treatment in hematologic, lipid, or chemistry parameters, including signature laboratory changes associated with JAK 1/2/3 inhibitors, for up to 100 weeks. Treatment discontinuations and grade 3 or 4 laboratory abnormalities were rare, consistent with those in the parent studies, and comparable to the incidence rates seen with placebo and apremilast. These results suggest that laboratory monitoring in patients with plaque psoriasis is not warranted with deucravacitinib treatment.References[5]Mease PJ, et al.Ann Rheum Dis. 2022;81:815-822.[6] Morand E, et al.Arthritis Rheumatol. 2022 Nov 11. doi: 10.1002/art.42391. Epub ahead of print.[7] Armstrong AW, et al.J Am Acad Dermatol.2023;88:29-39.[8] Strober B, et al.J Am Acad Dermatol.2023;88:40-51.AcknowledgementsThese clinical trials were sponsored by Bristol Myers Squibb.Disclosure of InterestsNeil J Korman Speakers bureau: AbbVie, Eli Lilly, Janssen, Novartis, Regeneron, and Sanofi Genzyme, Consultant of: AbbVie, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Eli Lilly, Janssen, Leo Pharma, Novartis, Principia, Regeneron, Sanofi Genzyme, Sun Pharma, and UCB, Grant/research support from: AbbVie, Amgen, Argenx, Bristol Myers Squibb, Celgene, Chemocentryx, Eli Lilly, Galderma, Kyowa Hakko Kirin, Leo Pharma, Menlo, Principia, Prothena, Rhizen, Syntimmune, Trevi, and XBiotech, Thierry Passeron Consultant of: AbbVie, Almirall, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Eli Lilly, Galderma, Incyte, Janssen, Leo Pharma, Novartis, Pfizer, Sanofi Genzyme, Sun Pharma, and UCB, Kenneth B Gordon Consultant of: Almirall, Amgen, Dermira, Leo Pharma, Pfizer, and Sun Pharma, Grant/research support from: AbbVie, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Eli Lilly, Janssen, Novartis, and UCB, Yukari Okubo Speakers bureau: AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Eisai, Eli Lilly, Janssen Pharma, Jimro, Kyowa Kirin, Leo Pharma, Maruho, Novartis, Pfizer, Sanofi, Sun Pharma, Taiho, Tanabe-Mitsubishi, Torii, and UCB, Consultant of: AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Janssen, and Sun Pharma, Grant/research support from: Eisai, Maruho, Shiseido, and Torii. AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Eli Lilly, Janssen, Leo Pharma, Maruho, Pfizer, Sun Pharma, and UCB, Jerry Bagel Speakers bureau: AbbVie, Celgene, Eli Lilly, Janssen Biotech, and Novartis, Consultant of: AbbVie, Amgen, Celgene, Eli Lilly, Janssen Biotech, Novartis, Sun Pharma, and Valeant, Grant/research support from: AbbVie, Amgen, Arcutis, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, CorEvitas’ (Corrona) Psoriasis Registry, Dermavant, Dermira/UCB, Eli Lilly, Glenmark, Janssen Biotech, Kadmon, Leo Pharma, Lycera, Menlo Therapeutics, Novartis, Pfizer, Regeneron, Sun Pharma, Taro, and Valeant, Howard Sofen Grant/research support from: AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Janssen, Leo Pharma, Novartis, and Sun Pharma, Richard B. Warren Consultant of: AbbVie, Almirall, Amgen, Biogen, Boehringer Ingelheim, Celgene, DiCE Eli Lilly, Janssen, Leo Pharma, Novartis, Pfizer, Sanofi, UCB, and UNION, Grant/research support from: AbbVie, Almirall, Amgen, Celgene, Eli Lilly, Janssen, Leo Pharma, Novartis, Pfizer, and UCB, Neal Bhatia Consultant of: AbbVie, Almirall, Arcutis, Arena, Boehringer Ingelheim, Bristol Myers Squibb, Dermavant, InCyte, ISDIN, Johnson & Johnson, Leo Pharma, Lilly, Ortho, Pfizer, Regeneron, Sanofi, Stemline, and Sun Pharma, Grant/research support from: Arcutis, Biofrontera, Boehringer Ingelheim, Bristol Myers Squibb, Dermavant, Galderma, Leo Pharma, Lilly, and Ortho, Lynda Spelman Consultant of: AbbVie, Amgen, Anacor, Ascend, Astellas, AstraZeneca, Blaze Bioscience, Bristol Myers Squibb, Boehringer Ingelheim, Botanix, Celgene, Dermira, Eli Lilly, Galderma, Genentech, GlaxoSmithKline, Hexima, Janssen, Leo Pharma, Mayne, Medimmune, Merck, Merck-Serono, Novartis, Otsuka, Pfizer, Phosphagenics, Photon MD, Regeneron, Roche, Samumed, Sanofi Genzyme, SHR, Sun Pharma ANZ, Trius, UCB, and Zai Lab, Kevin Winthrop Consultant of: AbbVie, AstraZeneca, Bristol Myers Squibb, Eli Lilly, Galapagos, Gilead, GlaxoSmithKline, Novartis, Pfizer, Regeneron, Roche, Sanofi, and Union Chimique Belge (UCB), Grant/research support from: Bristol Myers Squibb and Pfizer, Lauren Hippeli Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Renata M Kisa Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Subhashis Banerjee Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Diamant Thaçi Speakers bureau: AbbVie, Almirall, Amgen, Biogen Idec, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Galapagos, Galderma, Janssen-Cilag, Leo Pharma, Novartis, Pfizer, Regeneron, Roche, Sandoz-Hexal, Sanofi, Target-Solution, and UCB, Consultant of: AbbVie, Almirall, Amgen, Biogen Idec, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Galapagos, Galderma, Janssen-Cilag, Leo Pharma, Novartis, Pfizer, Regeneron, Roche, Sandoz-Hexal, Sanofi, Target-Solution, and UCB, Grant/research support from: AbbVie, Almirall, Amgen, Biogen Idec, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Galapagos, Galderma, Janssen-Cilag, Leo Pharma, Novartis, Pfizer, Regeneron, Roche, Sandoz-Hexal, Sanofi, Target-Solution, and UCB.

Background:Comorbidities and extra-articular manifestations (EAMs) substantially increase disease burden and mortality risk in patients (pts) with ankylosing spondylitis (AS).1,2Tumour necrosis factor inhibitors (TNFi) are highly efficacious and effective in AS treatment (tx), and are used after inadequate response to non-steroidal anti-inflammatory drugs.3,4However, the impact of TNFi on the incidence of comorbidities and EAMs in pts with AS is unknown.5Objectives:To determine the incidence of comorbidities and EAMs in TNFi vs non-TNFi treated pts with AS in the US.Methods:This was a retrospective, observational cohort study using data from 3 healthcare insurance claims databases: Multi-Payer Claims Database (MPCD Optum Insight; 2007–2010), Truven MarketScan®(2010–2014) and US Medicare Fee-for-Service Claims database (2006–2014). Eligible pts: ≥20 years (yrs) for MarketScan/MPCD or ≥65 yrs for Medicare, had an AS diagnosis (≥2 International Classification of Disease, 9thversion [ICD-9] diagnosis codes of 720.0 from a rheumatologist) and ≥12 months’ continuous medical and pharmacy enrolment prior to AS diagnosis (AS index date). Pts with AS not receiving tx were excluded. Tx exposure was reported from the first date of a new prescription/administration of an AS tx (no prior exposure) after the AS index date. Crude incidence rates (IR; shown as cases/100 pt-yrs) were calculated for EAMs (uveitis, psoriasis [PSO], psoriatic arthritis [PsA], inflammatory bowel disease [IBD]), with follow-up until the earliest of: death, lost medical/pharmacy coverage, study period end, first outcome occurrence, tx switch/discontinuation. Hazard ratios (HRs) of comorbidities (hospitalised infection, solid cancers) and EAMs for propensity score (PS)-matched pt groups were calculated using Cox proportional hazard regression models. Pts with the specific comorbidity/EAM of interest prior to AS index date were excluded. PS analyses assessed probability of TNFi initiation vs non-TNFi tx and adjusted for factors including comorbidities and demographics. HRs with confidence intervals crossing 1 are not reported.Results:20,460 pts with AS were eligible (MPCD: 2,384; MarketScan: 9,032; Medicare: 9,044). In all databases, crude IR of EAMs were higher for TNFi vs non-TNFi treated pts (Figure 1). In the PS-matched cohort, incidences of hospitalised infections were lower in TNFi vs non-TNFi treated pts from the MarketScan and Medicare databases (Figure 2). Higher incidences of solid cancers and EAMs were observed in TNFi vs non-TNFi treated pts; Medicare data (Figure 2). A higher risk of PsA and PSO was seen in TNFi vs non-TNFi treated pts; MarketScan data (Figure 2). PS-matched cohort data from the MPCD database were non-significant.Conclusion:Despite strong efficacy in treating AS-related signs and symptoms, similar incidence of comorbidities and increased incidence of some EAMs (IBD, PSO/PsA, uveitis) was seen in TNFi vs non-TNFi treated pts in the PS-matched analyses. This may be due to channelling of pts with more severe AS to receive TNFi, despite the PS-matched analysis aiming to overcome this. Moreover, prior medical history of Medicare pts may not be captured in the database, as pts are typically older with longer disease durations. While these results confirm previous findings,6a prospective observational study is required to generalise to pts outside the US.References:[1]Stolwijk C. Ann Rheum Dis 2015;74:1373–8;[2]Bremander A. Arthritis Care Res 2011;63:550–6;[3]Braun J. Scand J Rheumatol 2005;34:178–90;[4]Ji X. Front Pharmacol 2019;10:1476;[5]Maxwell LJ. Cochrane Database Syst Rev 2015:CD005468;[6]Walsh J. J Pharm Health Serv Res 2018;9:115–21.Acknowledgments:This study was funded by UCB Pharma. Editorial services were provided by Costello Medical.Disclosure of Interests: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, Kevin Winthrop Grant/research support from: Bristol-Myers Squibb, Consultant of: AbbVie, Bristol-Myers Squibb, Eli Lilly, Galapagos, Gilead, GSK, Pfizer Inc, Roche, UCB, Rhonda Bohn Consultant of: UCB Pharma, Benjamin Chan: None declared, Robert Suruki Employee of: UCB Pharma, Jeffrey Stark Employee of: UCB Pharma, Huifeng Yun Grant/research support from: Bristol-Myers Squibb and Pfizer, Sarah Siegel: None declared, Lang Chen: None declared, Jeffrey Curtis Grant/research support from: AbbVie, Amgen, Bristol-Myers Squibb, Corona, Crescendo, Genentech, Janssen, Pfizer, Roche and UCB Pharma, Consultant of: AbbVie, Amgen, Bristol-Myers Squibb, Corona, Crescendo, Genentech, Janssen, Pfizer, Roche and UCB Pharma

Background:Upadacitinib (UPA) is an oral JAK inhibitor approved for the treatment of rheumatoid arthritis (RA). The background rate of herpes zoster (HZ) in patients (pts) with RA is around 0.98/100 person years (PY)1. Pts with RA receiving JAK inhibitors have been reported to have an increased risk of HZ.Objectives:To evaluate the incidence and risk factors for HZ in pts with RA receiving UPA relative to active comparators in the Phase 3 clinical trial program.Methods:The incidence rate of HZ was determined in pts receiving UPA (as monotherapy [mono] or combination therapy) in five randomized Phase 3 trials (SELECT-EARLY, SELECT-MONOTHERAPY, SELECT-NEXT, SELECT-COMPARE, and SELECT-BEYOND), of which 4 evaluated both the UPA 15 and 30 mg once-daily (QD) doses and 1 trial (SELECT-COMPARE) evaluated only the 15 mg QD dose. Incidence of HZ was also determined in pts receiving adalimumab (ADA) + methotrexate (MTX) in SELECT-COMPARE and MTX mono in SELECT-EARLY. Risk factors for HZ were assessed using univariate and multivariate Cox regression models. Data cut-off was 30 June 2019.Results:Overall, 2629 pts who received UPA 15 mg QD (4565.8 patient-years [PY]), 1204 pts who received UPA 30 mg QD (2309.7 PY), 579 pts who received ADA + MTX (768.6 PY), and 314 pts who received MTX mono (456.0 PY) were analyzed. Fewer than 5% of pts across the treatment groups reported prior HZ vaccination. HZ (n/100 PY [95% CI]) occurred in 142 pts (3.1 [2.6–3.7]) with UPA 15 mg, 126 pts (5.5 [4.5–6.5]) with UPA 30 mg, 8 pts (1.0 [0.4–2.1]) with ADA + MTX, and 5 pts (1.1 [0.4–2.6]) with MTX mono. Most of the HZ cases (~71%) with UPA (Table) and all cases with ADA + MTX and MTX mono involved a single dermatome. Ophthalmic involvement was seen in 6 (4.2%) and 3 (2.4%) cases in the UPA 15 and 30 mg groups, respectively, and unilateral involvement with multiple dermatomes was seen in 26 (18.3%) and 23 (18.3%) cases. There was a single case of HZ meningitis reported in a Japanese pt on UPA 30 mg. In multivariate analyses, prior history of HZ and Asian region were associated with an increased risk of HZ in both the UPA groups (p≤0.01;Figure). In addition, pts ≥65 years old had increased risk of HZ in the 15 mg group.Conclusion:HZ events in pts with RA receiving UPA were more common in the 30 mg vs 15 mg group, and in both UPA groups compared with the ADA + MTX and MTX groups.References:[1]Smitten AL, et al. Arthritis Rheum 2007;57:1431–8Table.Summary of extent of involvement in pts with HZCategories, n (%)aAny UPA 15 mg QD(N=2629)Any UPA 30 mg QD(N=1204)Total patients with ≥1 HZ event142 (5.4)126 (10.5)Single dermatome101 (71.1)89 (70.6)Ophthalmic involvement6 (4.2)3 (2.4)HZ Oticus (Ramsay Hunt Syndrome)2 (1.4)1 (0.8)Multidermatomal (unilateral)b26 (18.3)23 (18.3)Disseminated, cutaneous only (no CNS involvement)c7 (4.9)8 (6.3)Disseminated with CNS or visceral involvement01 (0.8)dMissing8 (5.6)5 (4.0)aPts may fall into >1 category;b≤2 adjacent dermatomes;c≥3 dermatomes, unilateral nonadjacent dermatomes, or bilateral dermatomes;dHZ meningitisFigure.Multivariable-adjusted risk factors for HZ in pts receiving UPADisclosure of Interests: :Kevin Winthrop Grant/research support from: Bristol-Myers Squibb, Consultant of: AbbVie, Bristol-Myers Squibb, Eli Lilly, Galapagos, Gilead, GSK, Pfizer Inc, Roche, UCB, Peter Nash Grant/research support from: AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly and Company, Gilead, Janssen, MSD, Novartis, Pfizer Inc, Roche, Sanofi, UCB, Consultant of: AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly, Gilead, Janssen, MSD, Novartis, Pfizer Inc, Roche, Sanofi, UCB, Speakers bureau: AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly, Gilead, Janssen, MSD, Novartis, Pfizer Inc, Roche, Sanofi, UCB, Kunihiro Yamaoka Speakers bureau: AbbVie GK, Astellas Pharma Inc., Bristol-Myers Squibb, Chugai Pharmaceutical Co. Ltd, Mitsubishi-Tanabe Pharma Corporation, Pfizer Japan Inc., and Takeda Pharmaceutical Company Ltd, Eduardo Mysler Grant/research support from: AbbVie, Lilly, Pfizer, Roche, BMS, Sandoz, Amgen, and Janssen., Consultant of: AbbVie, Lilly, Pfizer, Roche, BMS, Sandoz, Amgen, and Janssen., Leonard Calabrese Consultant of: AbbVie, GSK, Bristol-Myers Squibb, Genentech, Janssen, Novartis, Sanofi, Horizon, Crescendo, and Gilead, Speakers bureau: Sanofi, Horizon, Crescendo, Novartis, Genentech, Janssen, and AbbVie, Nasser Khan Shareholder of: AbbVie Inc., Employee of: AbbVie Inc., Jose Jeffrey Enejosa Shareholder of: AbbVie, Employee of: AbbVie, Yanna Song Shareholder of: AbbVie Inc., Employee of: AbbVie Inc., Jessica Suboticki Shareholder of: AbbVie Inc., Employee of: AbbVie Inc., Jeffrey R. Curtis Grant/research support from: Abbvie, Amgen, BMS, Corrona, Crescendo, Janssen, Pfizer, Regeneron/Sanofi, and UCB, Consultant of: AbbVie, Amgen, BMS, Corrona, Crescendo, Janssen, Pfizer, Sanofi/Regeneron, and UCB

BackgroundUpadacitinib (UPA) 15 mg once daily (QD) has demonstrated efficacy and safety in patients with psoriatic arthritis (PsA) for up to 56 weeks in the Phase 3 SELECT-PsA 1 and 2 trials.1,2ObjectivesThis post hoc analysis of these studies explored the association of baseline characteristics and short-term responses with achievement of minimal disease activity (MDA) and Disease Activity Index for Psoriatic Arthritis (DAPSA) low disease activity (LDA).MethodsData were pooled from patients with prior inadequate response or intolerance to ≥1 non-biologic (b) DMARDs (SELECT-PsA 1) or ≥1 bDMARDs (SELECT-PsA 2) originally randomized to UPA 15 mg QD. Logistic regression models were used to assess the association between baseline characteristics and short-term (Week 12) responses with achieving MDA or DAPSA LDA at 56 weeks, sustained MDA (MDA at Weeks 36 and 56), or sustained DAPSA LDA (DAPSA LDA at Weeks 36, 44, and 56). Each predictor was evaluated separately in an initial model that included effects for study and concurrent non-bDMARD use. Odds ratios and concordance (c-)statistics were used to determine the predictive accuracy. Statistically significant predictors were then evaluated simultaneously using stepwise logistic regression with the Akaike Information Criterion for model-building.ResultsOf 640 patients included in the analysis, 40% and 47% achieved MDA and DAPSA LDA, respectively, at 56 weeks. Evaluated separately, younger age, sex (male), geographic region, lower weight, lower body mass index, the presence of dactylitis or enthesitis, and lower scores of Patient’s Assessment of Pain (Pt-Pain), Patient’s Global Assessment (PtGA), tender joint count in 68 joints, and Health Assessment Questionnaire-Disability Index (HAQ-DI) were significant baseline predictors for achieving MDA and DAPSA LDA at Week 56. Lower Pt-Pain (Weeks 12–24) and PtGA (Weeks 16–24) scores were strongly predictive (c-statistics >0.8) of achieving MDA at Week 56, and both measures (from Week 8) were moderately predictive (c-statistics >0.7) of achieving DAPSA LDA. Evaluated simultaneously with several baseline characteristics, lower Pt-Pain and HAQ-DI scores at Week 12 were included in models strongly predictive of achieving MDA (c-statistic=0.850; Figure 1) and DAPSA LDA (c-statistic=0.840; Figure 2) at Week 56. For each 1-point increase in Pt-Pain or HAQ-DI scores at Week 12 (after adjusting for other effects in the model), patients were less likely to achieve MDA (by 32% or 56%, respectively) or DAPSA LDA (by 23% or 31%, respectively) at Week 56. Predictors for achieving sustained MDA and sustained DAPSA LDA were generally similar to those identified for achieving MDA and DAPSA LDA, respectively.ConclusionIn patients with PsA receiving UPA 15 mg, baseline characteristics and early responses strongly predicted achievement of MDA or DAPSA LDA at Week 56. This may guide considerations of treatment targets in clinical trials and encourage physicians to further optimize treatment of their patients in clinical practice.References[1]McInnes IB, et al. Ann Rheum Dis 2020;79:16–7.[2]Mease PJ, et al. Rheumatol Ther 2021 [Epub ahead of print].AcknowledgementsAbbVie funded this study and participated in the study design, research, analysis, data collection, interpretation of data, review, and approval of the abstract. No honoraria or payments were made for authorship. Medical writing support was provided by Hilary Wong, PhD, of 2 the Nth (Cheshire, UK), which was funded by AbbVie.Disclosure of InterestsDaniel Aletaha Consultant of: AbbVie, Grünenthal, Janssen, Medac, Merck, Mitsubishi/Tanabe, Pfizer, Roche, and UCB, Grant/research support from: AbbVie, Grünenthal, Janssen, Medac, Merck, Mitsubishi/Tanabe, Pfizer, Roche, and UCB, Philip J Mease Speakers bureau: AbbVie, Amgen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, Galapagos, Genentech, Gilead, and Janssen, Consultant of: AbbVie, Amgen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, Galapagos, Genentech, Gilead, and Janssen, Grant/research support from: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Eli Lilly, and Janssen, Ralph Lippe Shareholder of: AbbVie Inc., Employee of: AbbVie Inc., Frank Behrens Speakers bureau: AbbVie, Amgen, Boehringer Ingelheim, Celgene, Chugai, Eli Lilly, Janssen, Merck, Novartis, Pfizer, Roche, Sanofi, and UCB, Consultant of: AbbVie, Amgen, Boehringer Ingelheim, Celgene, Chugai, Eli Lilly, Janssen, Merck, Novartis, Pfizer, Roche, Sanofi, and UCB, Grant/research support from: Chugai, GlaxoSmithKline, Janssen, Pfizer, and Roche, Derek Haaland Speakers bureau: AbbVie, Amgen, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Janssen, Merck, Novartis, Pfizer, Roche, Sanofi, Takeda, and UCB, Consultant of: AbbVie, Amgen, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Janssen, Merck, Novartis, Pfizer, Roche, Sanofi, Takeda, and UCB, Grant/research support from: AbbVie, Adiga Life Sciences, Amgen, Bristol-Myers Squibb, Can-Fite BioPharma, Celgene, Eli Lilly, Gilead, GlaxoSmithKline, Janssen, Novartis, Pfizer, Regeneron, Sanofi, and UCB, Penelope Palominos Speakers bureau: AbbVie, Janssen, Novartis, Pfizer, and UCB, Consultant of: AbbVie, Janssen, Novartis, Pfizer, and UCB, Grant/research support from: AbbVie, Janssen, Novartis, Pfizer, and UCB, Apinya Lertratanakul Shareholder of: formerly of AbbVie, Employee of: former employee of AbbVie, Michael Lane Shareholder of: AbbVie Inc., Employee of: AbbVie Inc., Kevin Douglas Shareholder of: AbbVie Inc., Employee of: AbbVie Inc., Peter Nash Speakers bureau: AbbVie, Bristol-Myers Squibb, Eli Lilly, Janssen, Merck, Novartis, Pfizer, Roche, Sanofi, and UCB, Consultant of: AbbVie, Bristol-Myers Squibb, Eli Lilly, Janssen, Merck, Novartis, Pfizer, Roche, Sanofi, and UCB, Grant/research support from: AbbVie, Bristol-Myers Squibb, Eli Lilly, Janssen, Merck, Novartis, Pfizer, Roche, Sanofi, and UCB, Arthur Kavanaugh Speakers bureau: AbbVie, Amgen, Janssen, Novartis, Pfizer, and UCB, Consultant of: AbbVie, Amgen, Janssen, Novartis, Pfizer, and UCB, Grant/research support from: AbbVie, Amgen, Janssen, Novartis, Pfizer, and UCB

BackgroundPatients with PsA and axial involvement have higher disease activity and greater reductions in quality of life;1 however, there are no accepted criteria for identifying axial involvement in PsA.ObjectivesThe objective of this post-hoc analysis is to assess the efficacy of upadacitinib (UPA), a Janus kinase inhibitor, on axial symptoms in patients with active PsA and axial involvement defined by investigator assessment and PRO-based criteria from two phase 3 SELECT trials.2,3MethodsPatients with active PsA (≥3 swollen joints and ≥3 tender joints) and prior inadequate response or intolerance to ≥1 non-biologic (SELECT-PsA 1) or ≥1 biologic (SELECT-PsA 2) DMARD were randomly assigned to once daily oral UPA 15 mg or 30 mg, placebo (PBO), or every other week subcutaneous adalimumab (ADA) 40 mg (SELECT-PsA 1 only).2,3 At baseline, axial involvement in PsA was determined by investigator assessment based on the totality of clinical information, such as duration and character of back pain, age of onset, and previous imaging. In addition to investigator assessment, PRO-based criteria for axial involvement (BASDAI ≥4 and BASDAI Question 2 ≥4 at baseline) were applied for this analysis to identify patients with active disease. Efficacy in the sub-group of patients defined using both investigator assessment and PRO-based criteria was evaluated at week 24 for UPA 15 mg vs PBO and ADA (SELECT-PsA 1 only). Data were analyzed using mixed-effect model repeated measures (MMRM) or non-responder imputation (NRI), with nominal P-values shown.ResultsBased on investigator assessment alone, 31.3% (n=534/1704) of patients in SELECT-PsA 1 and 34.2% (n=219/641) in SELECT-PsA 2 were defined as having axial involvement. When both investigator assessment and PRO-based criteria were applied, 23.1% (n=393/1704) of patients in SELECT-PsA 1, or 73.6% (n=393/534) of those defined using investigator assessment alone, and 27.5% (n=176/641) in SELECT-PsA 2, or 80.4% (n=176/219) using investigator assessment alone, met the combined criteria for axial involvement. In both studies, UPA 15 mg showed significantly greater clinical responses vs PBO at week 24 across all endpoints assessed (Figure 1). In SELECT-PsA 1, UPA showed numerically greater responses than ADA at week 24 across all BASDAI and Ankylosing Spondylitis Disease Activity Score (ASDAS) endpoints. The proportion of patients achieving ASDAS clinically important improvement (CII) at week 24 was significantly greater with UPA vs ADA based on nominal P-value.ConclusionPatients with active PsA and axial involvement defined by both investigator assessment and PRO-based criteria demonstrated statistically greater clinical responses related to their axial involvement with UPA 15 mg compared to PBO, and consistently numerically higher responses compared to ADA, at week 24 in the SELECT-PsA trials. Findings from this post-hoc analysis are consistent with previous data based on investigator assessment alone.4References[1]Mease PJ et al. J Rheumatol. 2018; 45(10):1389-96[2]McInnes IB et al. N Engl J Med. 2021; 384(13):1227-39[3]Mease PJ et al. Ann Rheum Dis. 2020; 80(3):312-20[4]Deodhar A et al. Arthritis Rheumatol. 2020; 72(Suppl 10)AcknowledgementsAbbVie funded these studies and participated in the study design, research, analysis, data collection, interpretation of data, reviewing, and approval of the publication. No honoraria or payments were made for authorship. Medical writing support was provided by Monica R.P. Elmore, PhD of AbbVie.Disclosure of InterestsXenofon Baraliakos Speakers bureau: AbbVie, Bristol-Myers Squibb, Celgene, Chugai, Eli Lilly, Galapagos, Gilead, MSD, Novartis, Pfizer, and UCB, Consultant of: AbbVie, Bristol-Myers Squibb, Celgene, Chugai, Eli Lilly, Galapagos, Gilead, MSD, Novartis, Pfizer, and UCB, Grant/research support from: AbbVie, Bristol-Myers Squibb, Celgene, Chugai, Eli Lilly, Galapagos, Gilead, MSD, Novartis, Pfizer, and UCB, R Ranza Speakers bureau: AbbVie, Janssen, Novartis, and Pfizer, Consultant of: AbbVie, Janssen, Novartis, and Pfizer, Andrew Ostor Speakers bureau: AbbVie, Bristol-Myers Squibb, Eli Lilly, Gilead, MSD, Novartis, Pfizer, and Roche, Consultant of: AbbVie, Bristol-Myers Squibb, Eli Lilly, Gilead, MSD, Novartis, Pfizer, and Roche, francesco ciccia Consultant of: AbbVie, Bristol-Myers Squibb, Celgene, MSD, Novartis, Pfizer, Janssen, Sanofi, Sandoz, Galapagos, Sobi, and UCB, Grant/research support from: AbbVie, Celgene, Pfizer, Roche, and UCB, Laura Coates Speakers bureau: AbbVie, Bristol-Myers Squibb, Celgene, Novartis, Pfizer, and UCB, Consultant of: AbbVie, Bristol-Myers Squibb, Celgene, MSD, Novartis, Pfizer, Janssen, Sanofi, Sandoz, Galapagos, Sobi, and UCB, Grant/research support from: AbbVie, Celgene, Pfizer, Roche, and UCB, Simona Rednic Consultant of: AbbVie, Boehringer Ingelheim, Eli Lilly, MSD, Novartis, and Pfizer, Grant/research support from: AbbVie, Boehringer Ingelheim, Eli Lilly, MSD, Novartis, Pfizer, and UCB, Jessica A. Walsh Consultant of: AbbVie, Amgen, Eli Lilly, Merck, Novartis, Pfizer, and UCB, Grant/research support from: AbbVie, Amgen, Eli Lilly, Merck, Novartis, Pfizer, and UCB, Tianming Gao Shareholder of: AbbVie Inc., Employee of: AbbVie Inc., Apinya Lertratanakul Shareholder of: Formerly of AbbVie, Employee of: Former employee of AbbVie, In-Ho Song Shareholder of: AbbVie Inc., Employee of: AbbVie Inc., Fabiana Ganz Shareholder of: AbbVie Inc., Employee of: AbbVie Inc., Kevin Douglas Shareholder of: AbbVie Inc., Employee of: AbbVie Inc., Atul Deodhar Consultant of: AbbVie, Amgen, Aurinia, BMS, Boehringer Ingelheim, GSK, Janssen, Lilly, MoonLake, Novartis, Pfizer and UCB, Grant/research support from: AbbVie, GSK, Lilly, Novartis, Pfizer and UCB

The poet and novelist Francis Stuart’s sojourn in Germany during the Second World War and his broadcasting activities for the Nazis remain acnámh spairneamong historians and journalists alike. Assessments of his radio talks range from that of his biographer J.H. Natterstad, who described them as being of ‘a literary or semi-literary’ character, to that of Kevin Myers, who equated the broadcasts with ‘voluntary siding with the most bestial régime in the history of civilisation’. In October 1997 a television documentary during which Stuart was quoted as saying that ‘the Jew was always the worm that got into the rose and sickened it’ triggered off a long-running controversy in the letters pages of theIrish Times. Some prominent intellectuals rushed to Stuart’s defence, arguing, for example, that the worm metaphor was indeed a positive one, representing the ‘hidden, unheroic and critical’. On the other hand, leaving aside the question whether or not Stuart was an antisemite, two German emigrants to Ireland argued that anyone, including Stuart, ‘who lived in Germany at that time, any person working for the Ministry of Propaganda had to be an active Nazi sympathiser’. From a more scholarly perspective, David O’Donoghue has recorded that in his radio talks Stuart was neither anti-Jewish nor anti-Russian, while Dermot Keogh suggested that Stuart’s broadcasts from Germany in fact mirrored the content of antisemitic publications in Ireland at the time. Stuart himself denied ever having backed the Nazis, and rejected the charge of antisemitism in the R.T.É. interview broadcast in January 1998: ‘I never supported that régime.’

Background:Psoriatic arthritis (PsA) is a heterogeneous disease comprising musculoskeletal and dermatological manifestations, especially plaque psoriasis.1Secukinumab (SEC), an IL-17A inhibitor, provided significantly greater PASI 75/100 responses in a head-to-head trialversus (vs.) etanercept, a TNF inhibitor, in patients (pts) with moderate-to-severe plaque psoriasis.2The objective of the EXCEED study (NCT02745080) was to investigate whether SEC is superior to adalimumab (ADA), a TNF inhibitor, as monotherapy in biologic-naive active PsA pts with active plaque psoriasis (defined as having at least one psoriatic plaque of ≥2 cm diameter or nail changes consistent with psoriasis or documented history of plaque psoriasis).Objectives:To report the pre-specified skin outcomes from the EXCEED study in the subset of pts with at least 3% body surface area (BSA) affected with psoriasis at baseline.Methods:Head-to-head, phase-3b, randomised, double-blind, active-controlled, multicentre, parallel-group trial: pts were randomised to receive SEC 300 mg subcutaneous at baseline, Week 1-4, followed by dosing every 4 weeks (q4w) until Week 48 or ADA 40 mg subcutaneous at baseline followed by same dosing q2w until Week 50. The primary endpoint was superiority of SECvs.ADA on ACR20 response at Week 52. Pre-specified outcomes included the proportion of pts achieving a combined ACR50 and PASI 100 response, PASI 100 response, and absolute PASI score ≤3. Missing data was handled using multiple imputation.Results:853 pts were randomised to receive SEC (n=426) or ADA (n=427). At baseline, there were 215 and 202 pts having at least 3% BSA affected with psoriasis in the SEC and ADA groups, respectively. A higher proportion of patients achieved simultaneous improvement in ACR50 and PASI 100 response with SECvs.ADA (30·7%vs.19·2%; P=0·0087 [Figure]). Higher efficacy was demonstrated for SECvs.ADA for PASI 100 responses and for the proportion of pts achieving absolute PASI score ≤3 (Table).Conclusion:In this pre-specified analysis, SEC provided higher responses compared to ADA in achievement of simultaneous improvement of joint and skin disease (combined ACR50 and PASI 100 response) and in skin specific endpoints (PASI 100 and PASI score ≤3) at Week 52.References:[1]Coates LC and Helliwell PS.Clinical Med.2017;17:65–70.[2]Langley RG et al.N Engl J Med.2014;371:326–38.Figure.Combined ACR50 and PASI 100 Response through Week 52Table.Skin Specific Outcomes at Week 52Endpoints, data is presented as % responseSEC 300 mg(N = 215)ADA 40 mg(N = 202)P-value (unadjusted)PASI 10046·029·70·0007Absolute PASI score ≤379·265·00·0015P value vs. adalimumab; Unadjusted P values are presentedN, number of patients in psoriasis subsetMultiple imputation was used for handling missing dataADA, adalimumab; BSA, body surface area; PASI, psoriasis area severity index; SEC, secukinumabAcknowledgments:Suchita Dubey (Novartis) provided medical writing support.Disclosure of Interests: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., Frank Behrens Grant/research support from: Pfizer, Janssen, Chugai, Celgene, Lilly and Roche, Consultant of: Pfizer, AbbVie, Sanofi, Lilly, Novartis, Genzyme, Boehringer, Janssen, MSD, Celgene, Roche and Chugai, Peter Nash Grant/research support from: AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly and Company, Gilead, Janssen, MSD, Novartis, Pfizer Inc, Roche, Sanofi, UCB, Consultant of: AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly, Gilead, Janssen, MSD, Novartis, Pfizer Inc, Roche, Sanofi, UCB, Speakers bureau: AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly, Gilead, Janssen, MSD, Novartis, Pfizer Inc, Roche, Sanofi, UCB, 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, Kevin Ding Employee of: Novartis, Pascale Pellet Shareholder of: Novartis, Employee of: Novartis, Luminita Pricop Shareholder of: Novartis, Employee of: Novartis, 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

Background:Psoriatic arthritis (PsA) is a chronic inflammatory arthritis characterized by joint and entheseal inflammation seen in 30% patients with psoriasis (Pso). In 90% of patients, Pso precedes PsA. Inhibitors of tumor necrosis factor (TNFi) are efficacious treatment options for both, though whether they prevent development of incident PsA in Pso patients is unknown.Objectives:To determine if the use of TNFi reduces the risk of developing psoriatic arthritis in Pso patients compared to those treated with methotrexate alone.Methods:Records on all Pso patients seen at dermatology clinic at our University from January 2006 - June 2019 were reviewed. Patients with any musculoskeletal symptoms were referred to rheumatology and were considered to have PsA if they were diagnosed by a rheumatologist. We used Student’s t-test to compare continuous covariates and Pearson’s chi-squared test or Fisher’s exact test to compare categorical covariates. Variables that were found to be significantly associated with PsA diagnosis were included as potential confounders in the multivariate model. We used Cox proportional hazards models to compare the risk of incident PsA diagnosis for those who initiated TNFi compared to those who initiated methotrexate. A propensity score of TNFi therapy compared to methotrexate therapy was calculated using variables associated with treatment choice and adjusted for in the model. Variables that were associated with both treatment choice and PsA risk were not included in the propensity score. We used backwards stepwise variable selection to build the final model.Results:Out of 154 Pso patients who did not have PsA at baseline, and were started exclusively on a TNFi or methotrexate during the study period,, 85 (55.2%) initiated methotrexate and 69 (44.8%) initiated a TNFi. Mean duration of therapy for those on TNFi was 3.95 (standard error: 0.50) years while mean duration of therapy for those on methotrexate was 1.93 years (standard error: 0.28). Mean follow-up time for those on TNFi was 5.18 years (standard error: 0.49) and for those on methotrexate was 2.71 years (standard error: 0.37) Seventy nine (51.3%) of the cohort were women. Thirty five (22.7%) of subjects developed PsA over the course of the study. After adjusting for propensity score, nail pitting, body surface area (BSA) involved in psoriasis, and depression, TNFi did not significantly reduce the risk of PsA as compared to methotrexate (HR: 0.68 [95% CI: 0.32, 1.41]).Conclusion:Use ofTNFi was not associated with a statistically significant decreased risk of incident PsA compared to methotrexate in this study, but a larger cohort with longer follow up will have better power to estimate the true association.Table 1.Characteristics of the psoriasis cohort starting exclusively TNFi or methotrexateIncident PsAn = 35PsA negativen = 119p-valueTreatment [n (%)]0.37TNFi18 (51.4)51 (42.9)Methotrexate17 (48.6)68 (57.1)Sex [n (%)]0.24Female21 (60.0)58 (48.7)Male14 (40.0)61 (51.3)Age [median (IQR)]47.0 (39.4, 59.7)48.9 (35.3, 61.7)0.71Pso manifestations [n (%)]Nail pitting27 (77.1)51 (42.9)<0.01Scalp psoriasis31 (88.6)105 (89.0)0.95Inverse psoriasis14 (40.0)37 (31.09)0.33BSA [median (IQR)]6 (3, 15)12 (5, 22)0.06BMI [median (IQR)]31.7 (25.9, 40.4)29.1 (26.3, 34.7)0.30Therapy duration (years)TNFi [median (IQR)]4.38 (1.34, 8.13)2.26 (0.76, 5.82)0.29Methotrexate [median (IQR)]2.44 (0.06, 3.44)0.94 (0.27, 2.39)0.43Disclosure of Interests:Noah Lininger: None declared, Sarah Siegel: None declared, Sonam Kiwalkar: None declared, Kevin Winthrop Grant/research support from: Bristol-Myers Squibb, Consultant of: AbbVie, Bristol-Myers Squibb, Eli Lilly, Galapagos, Gilead, GSK, Pfizer Inc, Roche, UCB, Alex Ortega Loayza Consultant of: Adviser board for Janssen, 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

Turnage, Richard H., John L. LaNoue, Kevin M. Kadesky, Yan Meng, and Stuart I. Myers. Thromboxane A2 mediates increased pulmonary microvascular permeability after intestinal reperfusion. J. Appl. Physiol. 82(2): 592–598, 1997.—This study examines the hypothesis that intestinal reperfusion (IR)-induced pulmonary thromboxane A2(TxA2) release increases local microvascular permeability and induces pulmonary vasoconstriction. Sprague-Dawley rats underwent 120 min of intestinal ischemia and 60 min of IR. Sham-operated animals (Sham) served as controls. After IR or Sham, the pulmonary vessels were cannulated, and the lungs were perfused in vitro with Krebs buffer. Microvascular permeability was quantitated by determining the filtration coefficient ( K f), and pulmonary arterial (Ppa), venous (Ppv), and capillary (Ppc) pressures were measured to calculate vascular resistance (Rt). After baseline measurements, imidazole (TxA2 synthase inhibitor) or SQ-29,548 (TxA2-receptor antagonist) was added to the perfusate; then K f, Ppa, Ppv, and Ppc were again measured. The K fof lungs from IR animals was four times greater than that of Sham ( P = 0.001), and Rt was 63% greater in the injured group ( P = 0.01). Pc of IR lungs was twice that of controls (5.4 ± 1.0 vs. 2.83 ± 0.3 mmHg, IR vs. Sham, respectively; P < 0.05). Imidazole or SQ-29,548 returned K fto baseline measurements ( P < 0.05) and reduced Rt by 23 and 17%, respectively ( P < 0.05). IR-induced increases in Pc were only slightly reduced by 500 μg/ml imidazole (14%; P = 0.05) but unaffected by lower doses of imidazole (5 or 50 μg/ml) or SQ-29,548. These data suggest that IR-induced pulmonary edema is caused by both increased microvascular permeability and increased hydrostatic pressure and that these changes are due, at least in part, to the ongoing release of TxA2.

Abstract APOBEC-catalyzed deamination of cytosine bases is the largest enzymatic and second largest overall source of mutation in cancer. One member from the APOBEC family of enzymes, APOBEC3B (A3B) is overexpressed and dysregulated in many different cancer types. In addition to hallmark C-to-T transitions and C-to-G transversions, APOBEC-catalyzed uracil lesions can be processed into single- and double-strand DNA breaks. Therefore, A3B-positive tumors are under continual stress to repair DNA breaks and may be vulnerable to DNA repair inhibition. Previous results from the Harris lab have identified UNG2, DNA uracil glycosylase 2 (UNG2), initiator of the base excision repair pathway, as synthetic lethal pair with A3B. The genetic disruption of UNG2 combined with high expression of A3B, causes cell death. This provides the rational to hypothesize that also other DNA repair proteins could be putative synthetic lethal pairs with A3B, when its expression and activity are high. To test this hypothesis, CRISPR guide RNA library targeting 237 DNA damage repair and response genes was used in doxycycline-inducible TREX-293-A3Bi-eGFP cell line. Cells expressing or not A3B were harvested for DNA extraction and sequencing at different time points. Comparison of guide RNA abundance between doxycycline and H2O treated cells revealed the dropout guides that disrupt genes and create putative synthetic lethal combinations with A3B. The screen design and overall results will be presented Citation Format: Bojana Stefanovska, Kevin Lin, Benjamin Troness, Chad Myers, Reuben Harris. Targeted CRISPR screen to identify synthetic lethal combinations between APOBEC3B and DNA repair [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-17-01.

Background:Secukinumab (SEC), an interleukin-17A inhibitor, has demonstrated improvements on multiple domains of psoriatic arthritis (PsA).1Adalimumab (ADA), a TNF inhibitor, is widely used as a first–line biologic in PsA.Objectives:To report efficacy and safety outcomes from the head-to-head EXCEED trial (NCT02745080) that compares SECvs.ADA as first–line biologic monotherapy through 52-weeks (wks), with a musculoskeletal primary endpoint in pts with active PsA.Methods:Head-to-head, phase-3b, randomised, double-blind trial: biologic naïve active PsA pts were randomised to receive SEC 300mg subcutaneous at baseline, Wk1-4, and then every 4wks (q4w) until Wk48 or ADA 40mg subcutaneous at baseline and then q2w until Wk50. The primary endpoint was superiority of SECvs.ADA on ACR20 response at Wk52. Binary and continuous variables were analysed using logistic-regression model and MMRM, respectively. Safety analysis included patients who received ≥1 dose of study-drug.Results:853 pts were randomised to receive SEC (n=426) or ADA (n=427). Baseline demographics and disease characteristics were comparable between treatment-groups except higher proportion of female pts and pts without enthesitis in the SEC group. ACR20 response at Wk52 for SECvs.ADA were 67·4%vs.61·5%, respectively (p=0·0719) (Figure). Higher clinical responses were observed with SECvs.ADA for a range of musculoskeletal, skin, and higher-hurdle outcomes (Table). A higher retention rate was observed for SEC (85.7%)vs.ADA (76.3%). Safety profiles of SEC and ADA were consistent with previous reports.2,3Conclusion:Results suggest that SEC is at least as efficacious as ADA on musculoskeletal endpoints whilst providing higher responses on skin endpoints, and is associated with a higher retention rate. No new safety signals were reported.References:[1]van der Heijde, et al. Rheumatol. (Oxford).2019; DOI10.1093/rheumatology/kez420.[2]Deodhar A, et al. Arthritis Res Ther. 2019;21:111.[3]Burmester GR, et al. Ann Rheum Dis.2013; 72:517-24.Figure.ACR20 Response through Wk 52Table.Efficacy Outcomes at Wk 52Endpoints, % response unless specified otherwiseSEC 300 mg(N=426)ADA 40 mg(N=427)P-value (unadjusted)*ACR2067·461·50·0719aACR2066·959·50·0239Key SecondarybPASI 9065·443·2<0·0001ACR5049·044·80·2251HAQ-DI mean change from baseline ± SE-0·58 ± 0.03-0·56 ± 0.030·5465cResolution of enthesitis (based on LEI)60·554·20·1498ExploratoryMDA43·037·90·1498VLDA18·116·60·6107DAPSA LDA+Remission61·753·10·0178PASDAS LDA+Remission51·144·10·0557*Unadjusted P-valuesvsADABinary variables were analysed using logistic regression. Pts who discontinued study treatment prematurely or took csDMARDs after week-36 were considered non-responders. Multiple imputation was used for all other missing data. HAQ-DI mean change from baseline was analysed using mixed-effect model repeated measuresaNon-responder imputation was used for pre-specified sensitivity analysisbN=215 in SEC and N=202 in ADA in psoriasis subsetcN=234 in SEC and N=264 in ADA in enthesitis subsetDisclosure of Interests: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, Frank Behrens Grant/research support from: Pfizer, Janssen, Chugai, Celgene, Lilly and Roche, Consultant of: Pfizer, AbbVie, Sanofi, Lilly, Novartis, Genzyme, Boehringer, Janssen, MSD, Celgene, Roche and Chugai, 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, Arthur Kavanaugh Grant/research support from: Abbott, Amgen, AstraZeneca, BMS, Celgene Corporation, Centocor-Janssen, Pfizer, Roche, UCB – grant/research support, Christopher T. Ritchlin Grant/research support from: UCB Pharma, AbbVie, Amgen, Consultant of: UCB Pharma, Amgen, AbbVie, Lilly, Pfizer, Novartis, Gilead, Janssen, Peter Nash Grant/research support from: AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly and Company, Gilead, Janssen, MSD, Novartis, Pfizer Inc, Roche, Sanofi, UCB, Consultant of: AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly, Gilead, Janssen, MSD, Novartis, Pfizer Inc, Roche, Sanofi, UCB, Speakers bureau: AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly, Gilead, Janssen, MSD, Novartis, Pfizer Inc, Roche, Sanofi, UCB, Jordi Gratacos-Masmitja Grant/research support from: a grant from Pfizzer to study implementation of multidisciplinary units to manage PSA in SPAIN, Consultant of: Pfizzer, MSD, ABBVIE, Janssen, Amgen, BMS, Novartis, Lilly, Speakers bureau: Pfizzer, MSD, ABBVIE, Janssen, Amgen, BMS, Novartis, Lilly, Philippe Goupille Grant/research support from: AbbVie, Amgen, Biogen, BMS, Celgene, Chugai, Lilly, Janssen, Medac, MSD France, Nordic Pharma, Novartis, Pfizer, Sanofi and UCB, Consultant of: AbbVie, Amgen, Biogen, BMS, Celgene, Chugai, Lilly, Janssen, Medac, MSD France, Nordic Pharma, Novartis, Pfizer, Sanofi and UCB, Speakers bureau: AbbVie, Amgen, Biogen, BMS, Celgene, Chugai, Lilly, Janssen, Medac, MSD France, Nordic Pharma, Novartis, Pfizer, Sanofi and UCB, Tatiana Korotaeva Grant/research support from: Pfizer, Consultant of: Abbvie, BIOCAD, Bristol-Myers Squibb, Celgene, Eli Lilly, Janssen, Merck Sharp & Dohme, Novartis, Novartis-Sandoz, Pfizer, UCB, Speakers bureau: Abbvie, BIOCAD, Bristol-Myers Squibb, Celgene, Eli Lilly, Janssen, Merck Sharp & Dohme, Novartis, Novartis-Sandoz, Pfizer, UCB, 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., Ruvie Martin Shareholder of: Novartis, Employee of: Novartis, Kevin Ding Employee of: Novartis, Pascale Pellet Shareholder of: Novartis, Employee of: Novartis, Shephard Mpofu Shareholder of: Novartis, Employee of: Novartis, Luminita Pricop Shareholder of: Novartis, Employee of: Novartis

Background:Filgotinib (FIL), an oral, potent, selective JAK-1 inhibitor, provided statistically significant and clinically meaningful improvement in rheumatoid arthritis (RA) signs and symptoms, physical function, radiographic progression, and quality of life in a comprehensive clinical program of 4 phase 3 (FINCH 1–4;NCT02889796,NCT02873936,NCT02886728,NCT03025308) and 3 phase 2 (DARWIN 1–3;NCT01668641,NCT01894516,NCT02065700) trials in patients (pts) with early and biologic-refractory RA.1–3Objectives:To assess long-term safety of FIL.Methods:Treatment-emergent adverse events (TEAEs) from the FIL clinical program were integrated and presented for pts receiving FIL 200 mg or FIL 100 mg QD (including pts who transitioned to FIL from placebo [PBO], methotrexate [MTX], adalimumab [ADA], or another dose of FIL) as well as pts receiving PBO, MTX, and ADA across all 7 studies. Exposure-adjusted incidence rates (EAIRs) per 100 patient-years (PY) were calculated for adverse events (AEs) of interest per treatment. Incidence was total number of pts with events, and PY exposure was time between first and last doses. Major adverse cardiovascular events (MACE) and venous thromboembolism (VTE) were centrally adjudicated by an independent committee.Results:Across the 7 trials, 4057 pts with RA (2227 pts FIL 200 mg; 1600 pts FIL 100 mg) received >1 dose of treatment for 5493 total PY of exposure (3079.2 PY FIL 200 mg; 1465.3 PY FIL 100 mg) (Table). EAIRs of serious AEs and TEAEs leading to death in pts receiving FIL were comparable to those for PBO, ADA, or MTX, with no dose-dependent effect (Figure 1). EAIR for herpes zoster (HZ), serious, and opportunistic infections are shown in Figure 2. EAIR for HZ were low overall, but numerically slightly higher for FIL relative to PBO, ADA, and similar to MTX. Serious infection EAIRs were comparable between pts receiving FIL 100 mg and ADA, and numerically slightly lower for FIL 200 mg and MTX. Rates of opportunistic infections (including active tuberculosis) were low overall; EAIR for FIL doses were comparable to placebo and numerically lower than ADA or MTX. Rates of MACE and VTE were numerically lower for FIL relative to PBO (Figure 1). Malignancies, including nonmelanoma skin cancer, were rare overall, and rates were low in pts receiving FIL (Figure 1).Table.Total exposure to study treatments pooled from 7 studiesNumber of patientsPatient-years of exposureFIL 200 mg22273079.2FIL 100 mg16001465.3ADA325290.1MTX416356.2PBO781302.4Patients could contribute to >1 treatment group.ADA, adalimumab; FIL, filgotinib; MTX, methotrexate; PBO, placebo.Conclusion:In this integrated analysis, FIL was well-tolerated, and no new safety concerns were identified. No clinically meaningful dose-dependent safety effects were observed. MACE and VTE were uncommon. Serious infections rates were low; HZ reactivation was infrequent. Safety results were consistent with selective JAK-1 inhibition and highlight the favourable safety and tolerability of FIL in patients with RA.References:[1]Genovese, et al.JAMA2019;322(4):315–25.[2]Westhovens, et al.Ann Rheum Dis2017;76:998–1008.[3]Kavanaugh, et al.Ann Rheum Dis2017;76:1009–19.Disclosure of Interests:Mark C. Genovese Grant/research support from: Abbvie, Eli Lilly and Company, EMD Merck Serono, Galapagos, Genentech/Roche, Gilead Sciences, Inc., GSK, Novartis, Pfizer Inc., RPharm, Sanofi Genzyme, Consultant of: Abbvie, Eli Lilly and Company, EMD Merck Serono, Genentech/Roche, Gilead Sciences, Inc., GSK, Novartis, RPharm, Sanofi Genzyme, Kevin Winthrop Grant/research support from: Bristol-Myers Squibb, Consultant of: AbbVie, Bristol-Myers Squibb, Eli Lilly, Galapagos, Gilead, GSK, Pfizer Inc, Roche, UCB, Yoshiya Tanaka Grant/research support from: Asahi-kasei, Astellas, Mitsubishi-Tanabe, Chugai, Takeda, Sanofi, Bristol-Myers, UCB, Daiichi-Sankyo, Eisai, Pfizer, and Ono, Consultant of: Abbvie, Astellas, Bristol-Myers Squibb, Eli Lilly, Pfizer, Speakers bureau: Daiichi-Sankyo, Astellas, Chugai, Eli Lilly, Pfizer, AbbVie, YL Biologics, Bristol-Myers, Takeda, Mitsubishi-Tanabe, Novartis, Eisai, Janssen, Sanofi, UCB, and Teijin, Tsutomu Takeuchi Grant/research support from: Eisai Co., Ltd, Astellas Pharma Inc., AbbVie GK, Asahi Kasei Pharma Corporation, Nippon Kayaku Co., Ltd, Takeda Pharmaceutical Company Ltd, UCB Pharma, Shionogi & Co., Ltd., Mitsubishi-Tanabe Pharma Corp., Daiichi Sankyo Co., Ltd., Chugai Pharmaceutical Co. Ltd., Consultant of: Chugai Pharmaceutical Co Ltd, Astellas Pharma Inc., Eli Lilly Japan KK, Speakers bureau: AbbVie GK, Eisai Co., Ltd, Mitsubishi-Tanabe Pharma Corporation, Chugai Pharmaceutical Co Ltd, Bristol-Myers Squibb Company, AYUMI Pharmaceutical Corp., Eisai Co., Ltd, Daiichi Sankyo Co., Ltd., Gilead Sciences, Inc., Novartis Pharma K.K., Pfizer Japan Inc., Sanofi K.K., Dainippon Sumitomo Co., Ltd., Alan Kivitz Shareholder of: AbbVie, Amgen, Gilead, GSK, Pfizer Inc, Sanofi, Consultant of: AbbVie, Boehringer Ingelheim,,Flexion, Genzyme, Gilead, Janssen, Novartis, Pfizer Inc, Regeneron, Sanofi, SUN Pharma Advanced Research, UCB, Paid instructor for: Celgene, Genzyme, Horizon, Merck, Novartis, Pfizer, Regeneron, Sanofi, Speakers bureau: AbbVie, Celgene, Flexion, Genzyme, Horizon, Merck, Novartis, Pfizer Inc, Regeneron, Sanofi, Franziska Matzkies Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Lei Ye Shareholder of: Gilead Sciences Inc., Employee of: Gilead Sciences Inc., Deyuan Jiang Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Ying Guo Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Beatrix Bartok Shareholder of: Gilead Sciences Inc., Employee of: Gilead Sciences Inc., Robin Besuyen Shareholder of: Galapagos, Employee of: Galapagos, Gerd Rüdiger Burmester Consultant of: AbbVie Inc, Eli Lilly, Gilead, Janssen, Merck, Roche, Pfizer, and UCB Pharma, Speakers bureau: AbbVie Inc, Eli Lilly, Gilead, Janssen, Merck, Roche, Pfizer, and UCB Pharma, Jacques-Eric Gottenberg Grant/research support from: BMS, Pfizer, Consultant of: BMS, Sanofi-Genzyme, UCB, Speakers bureau: Abbvie, Eli Lilly and Co., Roche, Sanofi-Genzyme, UCB

Background:Durability over time varies according to the safety, tolerability and efficacy of a drug.1However, durability may vary between patient (pt) subgroups,1,2and physicians should consider pt characteristics when making treatment decisions. Certolizumab pegol (CZP) is an anti-tumour necrosis factor (anti-TNF) agent approved for the treatment of chronic inflammatory diseases, including rheumatoid arthritis (RA) and plaque psoriasis (PSO).3However, little is known about the impact of pt baseline characteristics on long-term CZP durability.Objectives:To investigate the durability of CZP and reasons for discontinuation over 3 years (yrs) in subgroups of pts with RA or PSO using pooled clinical trial data.Methods:27 RA and 3 PSO clinical trials were pooled for indication-specific analyses. Kaplan-Meier curves were calculated to estimate CZP durability for pt subgroups by age, gender, disease duration, prior anti-TNF use and geographic region. Reasons for CZP discontinuation were investigated.Results:6927 RA and 1112 PSO pts were included; mean ages were 53.0 yrs (standard deviation [SD]: 12.2 yrs) and 45.4 (13.0) yrs, respectively. 79.3% RA pts were female (of all patients, 19.4% were women of childbearing age [18–<45 yrs; WoCBA]) compared with 33.5% (15.2% WoCBA) in PSO. Mean disease durations were 6.4 (6.9) yrs for RA and 18.4 (12.3) yrs for PSO. 18.5% RA and 13.3% PSO pts had prior anti-TNF use. Maximum CZP exposure was ~8 yrs for RA and ~3 yrs for PSO. At 1 yr, 63.4% of RA pts remained on CZP vs 80.3% PSO pts, decreasing to 49.2% RA pts and 70.1% PSO pts at 3 yrs (Table 1). Reasons for discontinuation, at any time during the trials, included lack of efficacy (RA 13.5%; PSO 1.8%), adverse events (RA 11.9%; PSO 8.1%), consent withdrawn (RA 6.7%; PSO 6.7%), lost to follow-up (RA 1.8%; PSO 4.3%), protocol violation (RA 1.7%; PSO 0.3%) and other (RA 9.2%; PSO 8.7%). In RA pts, CZP durability was lower in the elderly and in pts with disease duration <1 yr. In PSO, durability was lower in pts with disease duration <1 yr or prior anti-TNF use. Durability was lower in WoCBA pts than male pts aged 18–<45 yrs for both indications. CZP durability was lower in Western Europe and North America compared to other regions.Table 1.CZP durability at 3 years,[a] by patient subgroup% patientsRAPSOAll49.270.1Age, yrs 18–<4552.166.3 45–<6549.468.3 ≥6543.369.4Gender Female49.364.1 Male48.269.2 WoCBA51.162.0 Male aged 18–<45 yrs56.568.3Prior anti-TNF use Yes49.360.1 No49.668.5Disease duration, yrs <143.239.6 1–<552.663.6 5–<1051.464.4 ≥1048.769.7Region Asia-Pacific58.5 Central Europe61.578.8 Eastern Europe54.2 Latin America57.1 N America36.653.9 W Europe33.867.7 Rest of the world66.3[a] For PSO, the 3 year analysis was calculated with Week 144 data. CZP: certolizumab pegol; N: North; PSO: psoriasis; RA: rheumatoid arthritis; TNF: tumour necrosis factor; W: Western; yrs: years.Conclusion:Overall, CZP durability was similar to that reported for other anti-TNFs with some differences between indication and subgroups.1Factors influencing durability included age, disease duration and geographic region. Gender differences were observed in the 18–45 yrs age group, however, both male and female CZP durability was higher than in older RA pts.References:[1]Neovius M. Ann Rheum Dis 2015;74:354–60;2.Lie E. Ann Rheum Dis 2015;74:970–8;3.EMA. CIMZIA SmPC 2019. Available at:https://www.ema.europa.eu[Last accessed 09/01/20].Acknowledgments:This study was funded by UCB Pharma. Editorial services were provided by Costello Medical.Disclosure of Interests:Vivian Bykerk: None declared, 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., Kristian Reich Grant/research support from: Affibody; Almirall; Amgen; Biogen; Boehringer Ingelheim; Celgene; Centocor; Covagen; Eli Lilly; Forward Pharma; Fresenius Medical Care; GlaxoSmithKline; Janssen; Kyowa Kirin; LEO Pharma; Medac; Merck; Novartis; Miltenyi Biotec; Ocean Pharma; Pfizer; Regeneron; Samsung Bioepis; Sanofi Genzyme; Takeda; UCB; Valeant and Xenoport., Consultant of: Affibody; Almirall; Amgen; Biogen; Boehringer Ingelheim; Celgene; Centocor; Covagen; Eli Lilly; Forward Pharma; Fresenius Medical Care; GlaxoSmithKline; Janssen; Kyowa Kirin; LEO Pharma; Medac; Merck; Novartis; Miltenyi Biotec; Ocean Pharma; Pfizer; Regeneron; Samsung Bioepis; Sanofi Genzyme; Takeda; UCB; Valeant and Xenoport., Speakers bureau: Affibody; Almirall; Amgen; Biogen; Boehringer Ingelheim; Celgene; Centocor; Covagen; Eli Lilly; Forward Pharma; Fresenius Medical Care; GlaxoSmithKline; Janssen; Kyowa Kirin; LEO Pharma; Medac; Merck; Novartis; Miltenyi Biotec; Ocean Pharma; Pfizer; Regeneron; Samsung Bioepis; Sanofi Genzyme; Takeda; UCB; Valeant and Xenoport., Yoshiya Tanaka Grant/research support from: Asahi-kasei, Astellas, Mitsubishi-Tanabe, Chugai, Takeda, Sanofi, Bristol-Myers, UCB, Daiichi-Sankyo, Eisai, Pfizer, and Ono, Consultant of: Abbvie, Astellas, Bristol-Myers Squibb, Eli Lilly, Pfizer, Speakers bureau: Daiichi-Sankyo, Astellas, Chugai, Eli Lilly, Pfizer, AbbVie, YL Biologics, Bristol-Myers, Takeda, Mitsubishi-Tanabe, Novartis, Eisai, Janssen, Sanofi, UCB, and Teijin, Kevin Winthrop Grant/research support from: Bristol-Myers Squibb, Consultant of: AbbVie, Bristol-Myers Squibb, Eli Lilly, Galapagos, Gilead, GSK, Pfizer Inc, Roche, UCB, Christina Popova Employee of: UCB Pharma, Nicola Tilt Employee of: UCB Pharma, Andrew Blauvelt Consultant of: AbbVie, Aclaris, Almirall, Arena, Athenex, Boehringer Ingelheim, Bristol-Myers Squibb, Dermavant, Dermira, Eli Lilly, FLX Bio, Forte, Galderma, Janssen, Leo, Novartis, Ortho, Pfizer, Regeneron, Sandoz, Sanofi Genzyme, Sun Pharma, and UCB Pharma, Speakers bureau: AbbVie

-William Roseberry, Michel-Rolph Trouillot, Peasants and capital: Dominica in the world economy. Baltimore and London: The Johns Hopkins University Press. Johns Hopkins Studies in Atlantic History and Culture, 1988. xiv + 344 pp.-Michel-Rolph Trouillot, Robert A. Myers, Dominica. Oxford, Santa Barbara, Denver: Clio Press, World Bibliographic Series, volume 82. xxv + 190 pp.-Michel-Rolph Trouillot, Robert A. Myers, A resource guide to Dominica, 1493-1986. New Haven: Human Area Files, HRA Flex Books, Bibliography Series, 1987. 3 volumes. xxxv + 649.-Stephen D. Glazier, Colin G. Clarke, East Indians in a West Indian town: San Fernando, Trinidad, 1930-1970. London: Allen and Unwin, 1986 xiv + 193 pp.-Kevin A. Yelvington, M.G. Smith, Culture, race and class in the Commonwealth Caribbean. Foreword by Rex Nettleford. Mona: Department of Extra-Mural Studies, University of the West Indies, 1984. xiv + 163 pp.-Aart G. Broek, T.F. Smeulders, Papiamentu en onderwijs: veranderingen in beeld en betekenis van de volkstaal op Curacoa. (Utrecht Dissertation), 1987. 328 p. Privately published.-John Holm, Peter A. Roberts, West Indians and their language. Cambridge: Cambridge University Press, 1988 vii + 215 pp.-Kean Gibson, Francis Byrne, Grammatical relations in a radical Creole: verb complementation in Saramaccan. Amsterdam and Philadelphia: John Benjamins Publishing Company, Creole Language Library, vol. 3, 1987. xiv + 294 pp.-Peter L. Patrick, Pieter Muysken ,Substrata versus universals in Creole genesis. Amsterdam and Philadelphia: John Benjamins Publishing Company, Creol Language Library - vol 1, 1986. 315 pp., Norval Smith (eds)-Jeffrey P. Williams, Glenn G. Gilbert, Pidgin and Creole languages: essays in memory of John E. Reinecke. Honolulu: University of Hawaii, 1987. x + 502 pp.-Samuel M. Wilson, C.N. Dubelaar, The petroglyphs in the Guianas and adjacent areas of Brazil and Venezuela: an inventory. With a comprehensive biography of South American and Antillean petroglyphs. Los Angeles: The Institute of Archaeology of the University of California, Los Angeles. Monumenta Archeologica 12, 1986. xi + 326 pp.-Gary Brana-Shute, Henk E. Chin ,Surinam: politics, economics, and society. London and New York: Francis Pinter, 1987. xvii, 192 pp., Hans Buddingh (eds)-Lester D. Langley, Howard J. Wiarda ,The communist challenge in the Caribbean and Central America. With E. Evans, J. Valenta and V. Valenta. Lanham, MD: American Enterprise Institute for Public Policy Research. xiv + 249 pp., Mark Falcoff (eds)-Forrest D. Colburn, Michael Kaufman, Jamaica under Manley: dilemmas of socialism and democracy. London, Toronto, Westport: Zed Books, Between the Lines and Lawrence Hill, 1985. xvi 282 pp.-Dale Tomich, Robert Miles, Capitalism and unfree labour: anomaly or necessity? London. New York: Tavistock Publications. 1987. 250 pp.-Robert Forster, Mederic-Louis-Elie Moreau de Saint-Mery, A civilization that perished: the last years of white colonial rule in Haiti. Translated, abridged and edited by Ivor D. Spencer. Lanham, New York, London: University Press of America, 1985. xviii + 295 pp.-Carolyn E. Fick, Robert Louis Stein, Léger Félicité Sonthonax: the lost sentinel of the Republic. Rutherford, Madison: Fairleigh Dickinson University Press; London and Toronto: Associated University Press, 1985. 234 pp.

Background:For patients (pts) with PsA, several disease activity measures are available including very low/minimal disease activity (VLDA/MDA), cutoffs based on the Disease Activity in PsA (DAPSA) score, and on the Psoriatic Arthritis Disease Activity Score (PASDAS) score.Objectives:To assess the rates of pts achieving these remission or low disease activity (LDA) criteria at Wk 24 using data from the SELECT-PsA 1 and SELECT-PsA 2 phase 3 studies;1,2 Additionally, we assessed the distribution of individual MDA components among pts who did or did not achieve MDA criteria at Wk 24.Methods:In SELECT-PsA 1 and SELECT-PsA 2, pts with PsA and prior inadequate response (IR) or intolerance to ≥1 non-biologic DMARD (N=1705) or ≥1 biologic DMARD (N=642), respectively, were randomized to once daily upadacitinib (UPA) 15mg, UPA 30mg, adalimumab (ADA) 40mg every other week (SELECT-PsA 1 only), or placebo (PBO). Remission and LDA were assessed using VLDA/MDA, DAPSA scores of ≤4/≤14, and PASDAS scores of ≤1.9/≤3.2, at Wk 24 (Table 1). Non-responder imputation (NRI) was used for handling missing data; pts rescued at Wk 16 were considered non-responders. Pairwise comparisons between UPA doses and PBO or ADA were conducted using the Cochran-Mantel-Haenszel test.Results:Overall, 2345 pts were analyzed; mean age 51 years, 53% female. In both studies, higher rates of remission and LDA were observed with both UPA doses vs PBO at Wk 24 (nominal P-values <0.05 for both time points; Table 1). Generally, higher rates of remission and LDA were also observed with UPA30 vs ADA in non-biologic DMARD-IR pts (nominal P-values <0.05). Greater rates of MDA/VLDA were observed at Wk 24 with UPA15 and UPA30 vs PBO in both studies and with UPA30 vs ADA in non-biologic DMARD-IR pts (nominal P-values <0.05 for all comparisons). The proportion of responder or non-responder pts receiving UPA15 or UPA30 was similar for each of the MDA components in both studies. At Wk 24, more responder and non-responder pts in both studies achieved Swollen Joint Count (SJC) 66 ≤1, Psoriasis Area and Severity Index (PASI) ≤1 or Body Surface Area-Psoriasis (BSA-Ps) ≤3%, and Leeds Enthesitis Index (LEI) ≤1 (Figure 1). Conversely, the proportion of pts Achieving Tender Joint Count (TJC) 68 ≤1 and Pt’s Global Assessment of Pain ≤1.5 tended to be lower.Conclusion:Regardless of previous biologic DMARD failure, pts treated with UPA15 or UPA30 achieved a higher rate of remission or LDA measured by various disease activity measures vs PBO at Wk 24; higher rates of response were observed in most of the remission and LDA measures with UPA30 vs ADA in non-biologic DMARD-IR pts. Among pts who did or did not achieve MDA criteria at Wk 24, a greater proportion of UPA-treated pts achieved physician derived measures such as SJC ≤1, PASI ≤1 or BSA-Ps ≤3%, and LEI ≤1.References:[1]McInnes IB, et al. Ann Rheum Dis, 2020; 79:12.[2]Genovese MC, et al. Ann Rheum Dis, 2020; 79:139.Table 1.Proportion of Patients Achieving Remission and LDA Measures at Week 24Endpoint, n (%)SELECT-PsA 1SELECT-PsA 2PBON=423ADA 40mg EOWN=429UPA 15mg QDN=429UPA 30mg QDN=423PBON=212UPA 15mg QDN=211UPA 30mg QDN=218MDA52 (12.3)143 (33.3)157 (36.6) *, #192(45.4) *, †, #6 (2.8)53 (25.1) *, #63 (28.9) *, #≥6 VLDA components25 (5.9)90 (21.0)105 (24.5) *134 (31.7) *, †3 (1.4)26 (12.3) *44 (20.2) *VLDA11 (2.6)62 (14.5)55 (12.8) *72 (17.0) *3 (1.4)16 (7.6) *21(9.6) *DAPSA REM9 (2.1)43 (10.0)47 (11.0) *79 (18.7) *, †1 (0.5)15 (7.1) *28 (12.8) *DAPSA LDA70 (16.5)198 (46.2)204 (47.6) *235(55.6) *, †14 (6.6)73 (34.6) *91 (41.7) *PASDAS REM12 (2.8)51 (11.9)60 (14.0) *91 (21.5) *, †4 (1.9)20 (9.5) *31 (14.2) *PASDAS LDA63 (14.9)168 (39.2)195 (45.5) *211 (49.9) *, †9 (4.2)69 (32.7) *82 (37.6) **P ≤ 0.05 for UPA15 and UPA30 vs PBO; †P ≤ 0.05 for UPA30 vs ADA; #Statistically significant in the multiplicity-controlled analysis.MDA (5/7) and VLDA (7/7): TJC ≤ 1; SJC ≤ 1; PASI ≤ 1 or BSA-Psoriasis ≤ 3%; Patient’s Assessment of Pain NRS ≤ 1.5; PtGA-Disease Activity NRS ≤ 2.0; HAQ-DI score ≤ 0.5; and tender entheseal points ≤ 1.DAPSA REM ≤ 4; DAPSA LDA ≤ 14.PASDAS REM ≤ 1.9; PASDAS LDA ≤ 3.2.Figure 1Acknowledgements:AbbVie and the authors thank the patients, study sites, and investigators who participated in this clinical trial. AbbVie, Inc was the study sponsor, contributed to study design, data collection, analysis & interpretation, and to writing, reviewing, and approval of final version. No honoraria or payments were made for authorship. Medical writing support was provided by Ramona Vladea, PhD of AbbVie Inc.Disclosure of Interests:Philip J Mease Speakers bureau: AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers, Celgene, Galapagos, Gilead, GlaxoSmithKline, Janssen, Lilly, Merck, Novartis, Pfizer, Sun Pharma, and UCB., Consultant of: AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers, Celgene, Galapagos, Gilead, GlaxoSmithKline, Janssen, Lilly, Merck, Novartis, Pfizer, Sun Pharma, and UCB., Grant/research support from: AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers, Celgene, Galapagos, Gilead, GlaxoSmithKline, Janssen, Lilly, Merck, Novartis, Pfizer, Sun Pharma, and UCB., Arthur Kavanaugh Consultant of: AbbVie Inc., Amgen, Astra-Zeneca, BMS, Celgene, Centocor-Janssen, Pfizer, Roche, and UCB, Grant/research support from: AbbVie Inc., Amgen, Astra-Zeneca, BMS, Celgene, Centocor-Janssen, Pfizer, Roche, and UCB, Dafna D Gladman Grant/research support from: AbbVie, Amgen, Bristol-Myers Squibb, Celgene Corporation, Eli Lilly, Galapagos, Gilead, Janssen, Novartis, Pfizer Inc, and UCB, Oliver FitzGerald Speakers bureau: AbbVie, Amgen, BMS, Celgene, Janssen, Lilly, Novartis, Pfizer and UCB, Consultant of: AbbVie, Amgen, BMS, Celgene, Janssen, Lilly, Novartis, Pfizer and UCB, Grant/research support from: AbbVie, Amgen, BMS, Celgene, Janssen, Lilly, Novartis, Pfizer and UCB, Enrique Soriano Speakers bureau: AbbVie, Amgen, Bristol Myers, Celgene, Janssen, Lilly, Novartis, Pfizer, Roche, Sanofi, and UCB, Consultant of: AbbVie, Amgen, Bristol Myers, Celgene, Janssen, Lilly, Novartis, Pfizer, Roche, Sanofi, and UCB, Grant/research support from: AbbVie, Amgen, Bristol Myers, Celgene, Janssen, Lilly, Novartis, Pfizer, Roche, Sanofi, and UCB, Peter Nash Speakers bureau: AbbVie, BMS, Roche, Pfizer, Janssen, Amgen, Sanofi-Aventis, UCB, Eli Lilly, Novartis, and Celgene, Consultant of: AbbVie, BMS, Roche, Pfizer, Janssen, Amgen, Sanofi-Aventis, UCB, Eli Lilly, Novartis, and Celgene, Grant/research support from: AbbVie, BMS, Roche, Pfizer, Janssen, Amgen, Sanofi-Aventis, UCB, Eli Lilly, Novartis, and Celgene, Dai Feng Shareholder of: AbbVie, Employee of: AbbVie, Apinya Lertratanakul Shareholder of: AbbVie, Employee of: AbbVie, Kevin Douglas Shareholder of: AbbVie, Employee of: AbbVie, Ralph Lippe Shareholder of: AbbVie, Employee of: AbbVie, Laure Gossec Consultant of: AbbVie,Amgen, Biogen, Celgene, Janssen, Lilly, Novartis, Pfizer, Samsung, Sanofi, UCB, Grant/research support from: Lilly, Pfizer, and Sandoz.

BackgroundConnective tissue disease-associated interstitial lung disease (CTD-ILD) is a serious complication and an important prognostic factor of various autoimmune diseases. Many cell types and both innate and adaptive immune systems are implicated in the pathogenesis of fibrotic lung injury. The presentation and clinical course of CTD-ILD are diverse, and the heterogeneity reflects differences in underlying pathogenic mechanisms.ObjectivesThe objective of this study is to reveal the different characteristics of immune cells among diseases.MethodsWe collected bronchoalveolar lavage fluid (BALF) and peripheral blood from patients who newly complicated interstitial lung disease and agreed to participate in this study; 5 patients with Sjögren syndrome (SS), 8 patients with dermatomyositis (DM), 6 patients with rheumatoid arthritis (RA), 7 patients with systemic sclerosis (SSc), 4 patients with ANCA-associated vasculitis (AAV), and 12 patients with idiopathic interstitial pneumonia (IIP) included. We applied Seq-Well, a portable platform of single-cell RNA sequencing[1], to analyze gene expressions in immune cells in BALF and blood. We compared the distribution of immune cells and differential gene expressions in BALF and blood among diseases.ResultsWe compared immune cell numbers in BALF among diseases. We found more T cells in patients with DM and SS, more B cells in patients with SS, more neutrophils in patients with RA, and more alveolar macrophages (AMs) in patients with AAV or SSc. We further performed gene ontology enrichment analysis of each immune cells in BALF. In patients with DM, the gene expression pathways related to the response to virus was increased in T cells. On the other hand, in patients with SS, the gene expression pathways involved in innate immunity and antigen presentation were enhanced in B cells. In addition, the gene expression associated with T cell activation was enhanced in T cells. In neutrophils from patients with RA, the gene expression involved in inflammation was increased. We next performed gene ontology enrichment analysis of blood. In monocytes and neutrophils, patients with DM had increased gene expression pathways associated with viruses, while patients with SS had increased gene expression of both innate immune pathways and acquired immunity. These results suggested that the common pathways were enhanced in BALF lymphocytes and in blood monocytes and neutrophils in patients with DM and SS.ConclusionOur comprehensive single-cell analysis of BALF and blood from CTD-ILD patients has revealed that the phenotypes and states of immune cells differ among diseases (Figure 1). We found that the common pathways were enhanced in BALF and blood, i.e., pathways associated with response to virus were enhanced in DM while innate immunity and antigen presentation pathways were enhanced in SS, suggesting the relationship between systemic immune abnormality and ILD. These results may lead to the optimal diagnosis and the precision medicine for patients with CTD-ILDs.Reference[1]Gierahn TM et al, Seq-Well: portable, low-cost RNA sequencing of single cells at high throughput. Nat Methods 2017;14(4):395-398.Figure 1.Acknowledgements:NIL.Disclosure of InterestsAiko Hirano Speakers bureau: Sanofi K.K., Wataru Fujii Speakers bureau: Boehringer Ingelheim Japan, Inc., Mitsubishi Tanabe Pharma Corporation, Grant/research support from: Boehringer Ingelheim Japan, Inc., GlaxoSmithKline K.K., Takeda Pharmaceutical Co.,Ltd., Aki Sakashita: None declared, Kevin Baßler: None declared, Masatoshi Kadoya: None declared, Atsushi Omoto Speakers bureau: AbbVie GK, Chugai Pharmaceutical Co. Ltd., Ono Pharmaceutical Co., Ltd., Daiichi-Sankyo Inc., Astellas Pharma Inc., Mitsubishi Tanabe Pharma Co., Pfizer Japan Inc., Asahi Kasei Pharma Corp, Novartis Pharma KK, Gilead Sciences Inc., Janssen Pharmaceutical K.K., GlaxoSmithKline K.K, Eli Lilly Japan K.K, Wataru Fukuda Speakers bureau: Chugai Pharmaceutical Co., Eisai Co., Ltd., Eli Lilly Japan K.K., AbbVie GK, Ono Pharmaceutical Co. Ltd., Astellas Pharma Inc., UCB Japan Co. Ltd., Pfizer Japan Inc., Giread Science K.K., Asahikasei Pharma Co., Daiichi-Sankyo Inc., Takahiro Seno Speakers bureau: Asahi Kasei Pharma, Janssen Pharmaceutical K.K., Boehringer Ingelheim Japan, Inc, Makoto Wada Speakers bureau: AbbVie GK, Astellas Pharma Inc., Bristol Myers Squibb Co., Chugai Pharmaceutical Co. Ltd., Eisai Co. Ltd., Eli Lilly Japan K.K, Janssen Pharmaceutical K.K., Mitsubishi Tanabe Pharma Co., Pfizer Japan Inc., Sanofi Japan K.K., Masataka Kohno Speakers bureau: AbbVie GK, Astellas Pharma Inc., Bristol Myers Squibb Co., Chugai Pharmaceutical Co. Ltd., Daiichi Sankyo Co., Eli Lilly Japan K.K, Janssen Pharmaceutical K.K., Mitsubishi Tanabe Pharma Co., Asahikasei Pharma Co., Pfizer Japan Inc., Sanofi Japan K.K., Boehringer Ingelheim Co. Ltd., UCB Japan Co. Ltd., Eisai Co. Ltd., GlaxoSmithKline K.K., Yutaka Kawahito Speakers bureau: AbbVie GK, Asahi Kasei Pharma Corp, Astellas Pharma Inc., Ayumi Pharmaceutical Corp., Boehringer Ingelheim Japan Inc., Bristol Myers Squibb Co., Chugai Pharmaceutical Co. Ltd., Daiichi Sankyo Co., Eisai Co. Ltd., Mitsubishi Tanabe Pharma Co., Pfizer Japan Inc., Takeda Pharmaceutical Co. Ltd., Teijin Pharma Ltd., UCB Japan Co. Ltd., GlaxoSmithKline K.K., Eli Lilly Japan K.K, Janssen Pharmaceutical K.K., Sanofi Japan K.K., Gilead Sciences Inc., Mylan EPD, Grant/research support from: AbbVie GK, Asahi Kasei Pharma Corp, Astellas Pharma Inc., Ayumi Pharmaceutical Corp., Boehringer Ingelheim Japan Inc., Bristol Myers Squibb Co., Chugai Pharmaceutical Co. Ltd., Daiichi Sankyo Co., Eisai Co. Ltd., Mitsubishi Tanabe Pharma Co., Pfizer Japan Inc., Takeda Pharmaceutical Co. Ltd., Teijin Pharma Ltd., GlaxoSmithKline K.K., Gilead Sciences Inc.

Background:The efficacy and safety of upadacitinib (UPA) in patients (pts) with active psoriatic arthritis (PsA) was demonstrated in the phase 3 SELECT-PsA 1 and SELECT-PsA 2 clinical trials.1,2Objectives:To explore the relationship between achievement of low disease activity (LDA) or remission (REM) and pt-reported outcomes (PROs) in SELECT-PsA 1 and 2.Methods:The SELECT-PsA program enrolled pts with prior inadequate response or intolerance to ≥1 non-biologic disease-modifying antirheumatic drug (DMARD; SELECT-PsA 1) or ≥1 biologic DMARD (SELECT-PsA 2). Pts were randomized to 56 weeks (wks) of blinded treatment with UPA 15 or 30 mg once daily (QD), placebo switched to UPA 15 or 30 mg QD at Wk 24, or adalimumab (SELECT-PsA 1 only) 40 mg every other wk. LDA and REM were evaluated using the minimal disease activity (MDA; fulfillment of 5 out of 7) criteria and the Disease Activity index for Psoriatic Arthritis (DAPSA; cutoff ≤4), respectively. PROs assessed included Health Assessment Questionnaire-Disability Index (HAQ-DI), 36-Item Short-Form Survey physical component summary (SF-36 PCS), 5-Level EuroQol 5-Dimension (EQ-5D-5L) Index, and EQ-5D-5L Visual Analog Scale (VAS). Integrated data through Wk 56 from SELECT-PsA 1 and 2 from the full analysis set with both continuous UPA 15 mg and 30 mg groups were analyzed by responder status at Wks 24 and 56. Changes from baseline (BL) in PROs were analyzed using mixed effects repeated measures models (fixed effects for study, current use of non-biologic DMARDs, treatment group, visit, responder status, and continuous BL PROs). As-observed data were used in the models.Results:A total of 1281 pts were included in the analysis (UPA 15 mg, n=640; UPA 30 mg, n=641). MDA was achieved by 33% (UPA 15 mg) and 40% (UPA 30 mg) of patients atWk 24, and 40% (UPA 15 mg) and 43% (UPA 30 mg) at Wk 56; and DAPSA-REM by 10% (UPA 15 mg) and 17% (UPA 30 mg) at Wk 24, and 16% (UPA 15 mg) and 18% (UPA 30 mg) at Wk 56. Pts who achieved MDA or DAPSA-REM (responders) at Wk 56 achieved larger reductions in HAQ-DI and larger increases in SF-36 PCS, EQ-5D-5L Index and EQ-5D-5L VAS compared with non-responders (Table 1) (all p<0.0001; statistical significance was exploratory in nature). MDA or DAPSA-REM response at Wk 24 was also associated with greater PRO improvements at Wk 56 (Figure 1). Consistent with the results presented for MDA and DAPSA-REM, patients who achieved Very Low Disease Activity or DAPSA-LDA also experienced greater improvements in PROs than those who did not.Table 1.Change from BL in PROs at Wk 56 by MDA and DAPSA-REM responder status at Wk 56UPA 15 mg QD(n=640)UPA 30 mg QD(n=641)Least squares mean change from BL(95% CI), unless stated otherwiseNon-responderResponderNon-responderResponderMDA, na386254368273HAQ-DI−0.26 (−0.30, −0.22)−0.61* (−0.66, −0.56)−0.27 (−0.31, −0.23)−0.69* (−0.74, −0.64)SF-36 PCS5.25 (4.60, 5.90)12.63* (11.84, 13.41)5.09 (4.42, 5.75)13.84* (13.08,14.59)EQ-5D-5L Index0.11 (0.09, 0.12)0.25* (0.23, 0.26)0.10 (0.09, 0.12)0.27* (0.25, 0.28)EQ-5D-5L VAS9.3 (7.8, 10.9)23.3* (21.4, 25.1)9.0 (7.4, 10.5)26.1* (24.4, 27.9)DAPSA-REM, na539101526115HAQ-DI−0.36 (−0.39, −0.32)−0.63* (−0.71, −0.55)−0.39 (−0.43, −0.35)−0.71* (−0.78, −0.63)SF-36 PCS6.99 (6.39, 7.59)14.54* (13.22, 15.86)7.43 (6.82, 8.03)15.16* (13.91, 16.40)EQ-5D-5L Index0.14 (0.13, 0.15)0.27* (0.24, 0.30)0.15 (0.14, 0.16)0.29* (0.26, 0.31)EQ-5D-5L VAS12.7 (11.3, 14.0)26.7* (23.7, 29.8)13.3 (11.9, 14.7)30.0* (27.1, 32.8)*p<0.0001 vs non-responder (statistical significance was exploratory in nature)an may vary by PRO assessedConclusion:Among UPA-treated pts with PsA, improvements in quality of life and physical function were greater in pts who achieved MDA or DAPSA-REM than in those who did not. Despite DAPSA-REM being a more stringent measure (achieved by a smaller proportion of patients), these improvements were similar between MDA and DAPSA-REM responders.References:[1]McInnes I, et al. Ann Rheum Dis 2020;79(Suppl 1):16–7; 2. Mease PJ, et al. Ann Rheum Dis 2020Figure 1.Acknowledgements:AbbVie funded this study; contributed to its design; participated in data collection, analysis, and interpretation of the data; and participated in the writing, review, and approval of the abstract. No honoraria or payments were made for authorship. Medical writing support was provided by Laura Chalmers, PhD, of 2 the Nth (Cheshire, UK), and was funded by AbbVie.Disclosure of Interests:Arthur Kavanaugh Grant/research support from: Research grants and/or personal fees from AbbVie, Amgen, Bristol-Myers Squibb, Eli Lilly, Janssen, Novartis, and Pfizer, Philip J Mease Grant/research support from: Research grants and personal fees from AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Eli Lilly, and Janssen; and personal fees from Boehringer Ingelheim, Galapagos, Genentech, and Gilead, Kevin Douglas Employee of: Employee of AbbVie and may own stock or options, Frank Behrens Grant/research support from: Research grants from Celgene, Chugai, Janssen, Pfizer, and Roche; personal fees from AbbVie, Boehringer Ingelheim, Celgene, Chugai, Eli Lilly, Genzyme, Janssen, MSD, Novartis, Pfizer, Roche, and Sanofi; and investigator fees from Eli Lilly, Derek Haaland Speakers bureau: Advisory board/speaker bureau membership for AbbVie, Amgen, AstraZeneca, Bristol-Myers Squibb, GSK, Janssen, Novartis, Pfizer, Roche, Sanofi, and Takeda, Consultant of: Honoraria or other fees from AbbVie, Amgen, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, GSK, Janssen, MSD, Novartis, Pfizer, Roche, Sanofi, Takeda, and UCB, Grant/research support from: Research grants from AbbVie, Adiga Life Sciences, Amgen, Bristol-Myers Squibb, Can-Fite Biopharma, Celgene, Eli Lilly, Gilead, GSK, Janssen, Novartis, Pfizer, Regeneron, Sanofi Genzyme, and UCB, Penelope Palominos Speakers bureau: Advisory board/speaker bureau membership for Janssen and Novartis, Consultant of: Personal fees from AbbVie, Grant/research support from: Research support from Novartis, Pfizer, and Roche, Apinya Lertratanakul Employee of: Employee of AbbVie and may own stock or options, Michael Lane Employee of: Employee of AbbVie and may own stock or options, Ralph Lippe Employee of: Employee of AbbVie and may own stock or options, Daniel Aletaha Consultant of: AbbVie, Grünenthal, Janssen, Medac, Mitsubishi Tanabe, MSD, Pfizer, Roche, and UCB, Grant/research support from: AbbVie, Grünenthal, Janssen, Medac, Mitsubishi Tanabe, MSD, Pfizer, Roche, and UCB, Peter Nash Grant/research support from: Received honoraria and research support from AbbVie, Bristol-Myers Squibb, Boehringer Ingelheim, Eli Lilly, Gilead/Galapagos, Janssen, MSD, Novartis, Pfizer, Roche, Samsung, Sanofi, and UCB.

BackgroundRisankizumab (RZB) is a monoclonal antibody that specifically inhibits interleukin 23.ObjectivesTo evaluate the achievement of Minimal Disease Activity (MDA), its components, and achievement of Disease Activity in PsA Low Disease Activity and Remission (DAPSA LDA+REM, [DAPSA score ≤14]) in patients receiving RZB or placebo (PBO) in the KEEPsAKE 1 and 2 clinical trials.MethodsKEEPsAKE-1 and -2, double-blind, phase 3 trials, evaluated the efficacy of RZB versus PBO for the treatment of adult patients with active psoriatic arthritis (PsA). Patients were randomized (1:1) to receive subcutaneous RZB 150 mg or PBO at weeks 0, 4, and 16. The open label extension began at Week 24 with all patients receiving RZB 150 mg every 12 weeks thereafter. Achievement of MDA, its components, and achievement of DAPSA LDA+REM are reported using non-responder imputation.ResultsMDA achievement at Week 52 in KEEPsAKE-1 was 37.9% for patients originally randomized to RZB and 27.4% for patients originally randomized to PBO. In KEEPsAKE-2, MDA achievement was 27.2% and 33.8% for patients originally randomized to RZB and PBO, respectively. Achievement of MDA and its components are presented in Figure 1. In KEEPsAKE-1, at Week 52 59.2% of patients originally randomized to RZB and 51.4% of patients originally randomized to PBO achieved DAPSA LDA+REM. At Week 52 in KEEPsAKE-2, DAPSA LDA+REM was achieved by 44.6% of patients originally randomized to RZB and 46.6% of patients originally randomized to PBO (Figure 1).ConclusionPatients treated with RZB demonstrate achievement of MDA, its components, and DAPSA LDA+REM at Weeks 24 and 52.AcknowledgementsAbbVie Inc, participated in the study design; study research; collection, analysis and interpretation of data; and writing, reviewing, and approving of this abstract for submission. AbbVie funded the research for this study and provided writing support for this abstract. Medical writing assistance was provided by Trisha Rettig, Ph.D. of AbbVieDisclosure of InterestsJoseph F. Merola Consultant of: Amgen, Bristol-Myers Squibb, Abbvie, Dermavant, Eli Lilly, Novartis, Janssen, UCB, Sanofi, Regeneron, Sun Pharma, Biogen, Pfizer and Leo Pharma, Iain McInnes Consultant of: AbbVie, Amgen, Astra Zeneca, Compugen, Cabaletta, Evelo, Janssen, Lilly, Novartis, Pfizer, Sanofi, and UCB, Grant/research support from: AbbVie, Amgen, Astra Zeneca, Janssen, Lilly, Novartis, Pfizer, UCB, Arthur Kavanaugh Consultant of: AbbVie Inc., Amgen, Astra-Zeneca, BMS, Celgene, Centocor-Janssen, Pfizer, Roche, and UCB, Grant/research support from: AbbVie Inc., Amgen, Astra-Zeneca, BMS, Celgene, Centocor-Janssen, Pfizer, Roche, and UCB, Peter Nash Speakers bureau: Abbvie, Amgen, Janssen, Lilly, Novartis, Pfizer, UCB, BMS, Rocje, Sanofi, Gilead/Galapagos, MSD, Samsung, Celgene, Amgen, Boehringer, Consultant of: Abbvie, Amgen, Janssen, Lilly, Novartis, Pfizer, UCB, BMS, Rocje, Sanofi, Gilead/Galapagos, MSD, Samsung, Celgene, Amgen, Boehringer, Grant/research support from: Abbvie, Amgen, Janssen, Lilly, Novartis, Pfizer, UCB, BMS, Rocje, Sanofi, Gilead/Galapagos, MSD, Samsung, Celgene, Amgen, Boehringer, Zhenyi Xue Shareholder of: AbbVie Inc., Employee of: AbbVie Inc., Vassilis Stakias Shareholder of: AbbVie Inc., Employee of: AbbVie Inc., Ann Eldred Shareholder of: AbbVie Inc., Employee of: AbbVie Inc., Sandra Ciecinski Shareholder of: AbbVie Inc., Employee of: AbbVie Inc., Kevin Douglas Shareholder of: AbbVie Inc., Employee of: AbbVie Inc., 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 and Pfizer

BackgroundBelimumab, which targets the B Cell activator and survival factor BLyS, is an approved treatment for systemic lupus (SLE) and has demonstrated efficacy in multiple clinical trials around the world. Nevertheless, like other SLE treatments, belimumab can have disappointing results in a significant proportion of this heterogenous population, a problem further complicated by the unpredictable impact of various combination treatments used with belimumab in trials and clinical practice.ObjectivesExamination of gene expression variables in SLE patients prior to belimumab treatment with limited background medications in order to distinguish those who subsequently respond from those who do not.MethodsA prospective open-label study of belimumab was conducted in 24 SLE patients with active but non-organ threatening disease, who were required to withdraw other immune suppressants (only antimalarials or low dose steroids allowed). At baseline, patients were given optional steroid injections for temporary relief, then followed for six months on intravenous belimumab (10 mg/kg). The primary endpoint was time to treatment failure compared to historical controls from the BOLD study which followed the same protocol but without treatment after initial steroids[1]. Response was also evaluated at six months by the SLE Responder Index (SRI-4) or the BILAG-based Combined Lupus Assessment (BICLA). Before and during treatment, Pax Gene tubes were collected, and RNA sequenced, using the same methods for healthy control samples. To maximally discriminate clinical responders from non-responders by baseline gene expression patterns in a small, heterogenous population, principal component analysis was conducted with modules (metagenes) comprised of differentially expressed genes (DEGs).ResultsOf 24 patients entering the study, 20 completed 6 months of treatment. The mean survival time without flare, treatment change, or study withdrawal was 18.4 weeks (CI 15.3-21.5) compared to the 41 BOLD participants with mean survival 9.829 weeks (CI 0.999-7.871) (p<0.001 by log rank test). At 6 months, 14 patients who received belimumab (58%) and 1 from the BOLD study (2.4%) remained free of flare. The SRI-4 was met by 7 patients in this study (29.2%), the BICLA by 9 (37.5%). SRI-4 response was used as the basis for modeling two metagenes comprised of the 25 most upregulated and 25 most downregulated genes at baseline in belimumab responders as compared to non-responders. There was no overlap between metagene scores of responders’ vs non-responders (Figure 1). After 3 months of treatment with belimumab all metagene scores corrected towards levels in healthy controls. The most discriminatory DEGs included protein transcription factors and long non-coding RNA (transcription regulators).ConclusionWhen background immune suppressants are excluded, belimumab still achieves SRI 4 or BICLA response for some patients, and most do not flare for at least six months. A composite metagene model has been identified as a potential predictor of belimumab response. Confirmation studies should be prospectively conducted.Reference[1]Merrill, Arth Rheum 2017 69:1257Acknowledgements:NIL.Disclosure of InterestsJoan T Merrill: None declared, Miles Smith: None declared, Kevin Thomas: None declared, Carla Guthridge: None declared, Nicolas Dominguez: None declared, Susan Macwana: None declared, Wade DeJager: None declared, Stan Kamp: None declared, Cristina Arriens Speakers bureau: AstraZeneca and Aurinia, Consultant of: Advisor or review panel: AstraZeneca, Aurinia, Bristol Myers Squibb, GlaxoSmithKline, and Kezar, Grant/research support from: AstraZeneca and Bristol Myers Squibb, Bridget Parrish: None declared, Judith A. James: None declared.

BackgroundConnective tissue disease-associated interstitial lung disease (CTD-ILD) is a severe complication of rheumatic and musculoskeletal diseases, e.g. rheumatoid arthritis (RA), dermatomyositis (DM), systemic sclerosis (SSc) and so on. CTD-ILD is a heterogeneous syndrome driven by different diseases and cell types. This complexity provides a challenging field for elucidating the mechanism of the disease. Although some patients with CTD-ILD develop progressive fibrosing interstitial lung disease (PF-ILD) like as other ILD despite immunosuppressive treatment, it is difficult to predict which patients develop PF-ILD before treatment.ObjectivesThe objective of this study is to find characteristics of immune cells and predictive biomarkers of PF-ILD in CTD-ILD patients.MethodsWe collected BALF and blood from 30 CTD-ILD and 12 idiopathic interstitial pneumonia (IIP) patients before treatment. Twelve out of 42 patients fulfilled PF-ILD criteria[1]in 1 year period. PF-ILD patients included 3 RA, 2 DM, 2 Sjögren syndrome, 1 ANCA-associated vasculitis, and 4 IIP patients. We applied Seq-Well, a portable platform of single-cell RNA sequencing[2], to analyze gene expressions in immune cells in BALF and blood. We compared the distribution of immune cells and differential gene expressions in BALF and blood between PF-ILD patients and patients without PF-ILD in CTD-ILD and IIP patients.ResultsWe found that alveolar macrophages are the most abundant cell types in BALF of PF-ILD patients. We further classified alveolar macrophages and neutrophils into more detailed subsets based on their gene expression patterns and compared them between PF-ILD and patients without PF-ILD. In PF-ILD patients, we found increased CXCL10+, CXCL8+alveolar macrophages and complement activation associated genes were upregulated in BALF. Moreover, we found increased interferon-induced proteins with tetratricopeptide repeats (IFIT)+, MMP-9+and immature neutrophils, which were reported to be associated with severe COVID-19 pneumonia[3], in the blood of PF-ILD patients. Differentially expressed gene analysis revealed high levels of high mobility group box (HMGB)-2, IL-1β, and complement activation associated genes in alveolar macrophages in PF-ILD patients.ConclusionAlveolar macrophage phenotypes were changed in BALF while neutrophil phenotypes were changed in the blood of PF-ILD in CTD-ILD and IIP patients, which are consistent with the characteristics of severe COVID-19 pneumonia patients, suggesting common pathological pathways of lung fibrosis. We propose the hypothesis that alveolar macrophage phenotypic changes lead to complement and cytokine/chemokine mediated neutrophil activation and progression of PF-ILD (Figure 1). These cell subpopulations and up-regulated genes would be potential biomarkers or therapeutic target of PF-ILD in CTD-ILD patients.References[1]Flaherty KR et al, Nintedanib in Progressive fibrosing interstitial lung diseases. New Engl J Med 2019; 381(18):1718-1727.[2]Gierahn TM et al, Seq-Well: portable, low-cost RNA sequencing of single cells at high throughput. Nat Methods 2017;14(4):395-398.[3]Schulte-Schrepping J et al, Severe COVID-19 is marked by a dysregulated myeloid cell compartment. Cell 2020; 182(6): 1419-1440.Figure 1.Acknowledgements:NIL.Disclosure of InterestsWataru Fujii Speakers bureau: Boehringer Ingelheim Japan, Inc., Mitsubishi Tanabe Pharma Corporation, Grant/research support from: Boehringer Ingelheim Japan, Inc., GlaxoSmithKline K.K., Takeda Pharmaceutical Co.,Ltd., Aki Sakashita: None declared, Aiko Hirano Speakers bureau: Sanofi K.K., Kevin Baßler: None declared, Masatoshi Kadoya: None declared, Atsushi Omoto Speakers bureau: AbbVie GK, Chugai Pharmaceutical Co. Ltd., Ono Pharmaceutical Co., Ltd., Daiichi-Sankyo Inc., Astellas Pharma Inc., Mitsubishi Tanabe Pharma Co., Pfizer Japan Inc., Asahi Kasei Pharma Corp, Novartis Pharma KK, Gilead Sciences Inc., Janssen Pharmaceutical K.K., GlaxoSmithKline K.K, Eli Lilly Japan K.K, Wataru Fukuda Speakers bureau: Chugai Pharmaceutical Co., Eisai Co., Ltd., Eli Lilly Japan K.K., AbbVie GK, Ono Pharmaceutical Co. Ltd., Astellas Pharma Inc., UCB Japan Co. Ltd., Pfizer Japan Inc., Giread Science K.K., Asahikasei Pharma Co., Daiichi-Sankyo Inc., Takahiro Seno Speakers bureau: Asahi Kasei Pharma, Janssen Pharmaceutical K.K., Boehringer Ingelheim Japan, Inc, Makoto Wada Speakers bureau: AbbVie GK, Astellas Pharma Inc., Bristol Myers Squibb Co., Chugai Pharmaceutical Co. Ltd., Eisai Co. Ltd., Eli Lilly Japan K.K, Janssen Pharmaceutical K.K., Mitsubishi Tanabe Pharma Co., Pfizer Japan Inc., Sanofi Japan K.K., Masataka Kohno Speakers bureau: AbbVie GK, Astellas Pharma Inc., Bristol Myers Squibb Co., Chugai Pharmaceutical Co. Ltd., Daiichi Sankyo Co., Eli Lilly Japan K.K, Janssen Pharmaceutical K.K., Mitsubishi Tanabe Pharma Co., Asahikasei Pharma Co., Pfizer Japan Inc., Sanofi Japan K.K., Boehringer Ingelheim Co. Ltd., UCB Japan Co. Ltd., Eisai Co. Ltd., GlaxoSmithKline K.K., Yutaka Kawahito Speakers bureau: AbbVie GK, Asahi Kasei Pharma Corp, Astellas Pharma Inc., Ayumi Pharmaceutical Corp., Boehringer Ingelheim Japan Inc., Bristol Myers Squibb Co., Chugai Pharmaceutical Co. Ltd., Daiichi Sankyo Co., Eisai Co. Ltd., Mitsubishi Tanabe Pharma Co., Pfizer Japan Inc., Takeda Pharmaceutical Co. Ltd., Teijin Pharma Ltd., UCB Japan Co. Ltd., GlaxoSmithKline K.K., Eli Lilly Japan K.K, Janssen Pharmaceutical K.K., Sanofi Japan K.K., Gilead Sciences Inc., Mylan EPD, Grant/research support from: AbbVie GK, Asahi Kasei Pharma Corp, Astellas Pharma Inc., Ayumi Pharmaceutical Corp., Boehringer Ingelheim Japan Inc., Bristol Myers Squibb Co., Chugai Pharmaceutical Co. Ltd., Daiichi Sankyo Co., Eisai Co. Ltd., Mitsubishi Tanabe Pharma Co., Pfizer Japan Inc., Takeda Pharmaceutical Co. Ltd., Teijin Pharma Ltd., GlaxoSmithKline K.K., Gilead Sciences Inc.

Background:The Janus kinase (JAK)-1 preferential inhibitor filgotinib (FIL) improved rheumatoid arthritis (RA) signs and symptoms in 3 phase (P)3 trials.1–3 Like other RA therapies, JAK inhibition is associated with increased infection rates.4Objectives:To assess long-term safety across the FIL program regarding infections, including serious infections (SI).Methods:Patients (pts) meeting 2010 ACR/EULAR RA criteria in pooled analysis of P2 DARWIN 1–2 (D1–2), P3 FINCH 1–3 (F1–3), and long-term extension studies (DARWIN 3, FINCH 4) were included. The placebo (PBO)-controlled as-randomised data set included pts receiving FIL 100 mg (FIL100), FIL 200 mg (FIL200), or PBO up to week (W)12 (D1–2, F1–2). The active-controlled as-randomised data set included pts receiving FIL100, FIL200, adalimumab (ADA), or methotrexate (MTX) up to W52 (F1, F3). The long-term as-treated data set included pts in all 7 studies receiving FIL100 or FIL200; data after rerandomisation were included and contributed to treatment received.Exposure-adjusted incidence rates (EAIRs) per 100 patient-years exposure (PYE) and differences with 95% confidence intervals (CIs) were calculated using Poisson regression; EAIRs for tuberculosis (TB) in active controlled sets were calculated using an Exact Poisson method. Kaplan-Meier (KM) event probabilities with 95% CIs were provided for SI. If pts had multiple events within the same treatment period, only the first event was counted in EAIR calculation; PYE were calculated up to the last follow-up time or day before next treatment, including after first event. For KM analysis, time to event was calculated until the first event.Results:Of 2267/1647 pts in as-treated set receiving FIL200/FIL100, 1697 had treatment-emergent infection; 118 were SI. Baseline potential risk factors for pts with SI are in Table.Table 1.Baseline characteristics of pts with/without treatment emergent SIaParameter, n (%)SIN = 92No SIN = 2491Medical history Chronic lung disease13 (14.1)125 (5.0) Chronic renal disease3 (3.3)23 (0.9) Infections and infestations29 (31.5)499 (20.0)Baseline body mass index, kg/m2 <3064 (69.6)1749 (70.2) ≥3028 (30.4)742 (29.8)Age, years <6567 (72.8)2006 (80.5) ≥6525 (27.2)485 (19.5)Former/current smoker30 (32.6)677 (27.2)Oral corticosteroids, mg <7.528 (56.0)731 (66.1) ≥7.522 (44.0)375 (33.9) Missing data421385aPhase 3 (FINCH 1-4) studies, as randomised.SI, serious infection.In 12W PBO-controlled period, infection rates were 17.9%/15.6%/13.3% for FIL200/FIL100/PBO. In 52W ADA-controlled period, infection EAIRs (95% CIs)/100 PYE were 46.9 (40.9, 53.7)/43.7 (38.0, 50.4)/43.4 (36.5, 51.5), FIL200/FIL100/ADA; and 38.5 (33.8, 43.9)/39.0 (31.1, 48.8)/42.2 (36.1, 49.3), FIL200/FIL100/MTX in 52W MTX-controlled period; 24.8 (23.1, 26.5)/34.4 (30.4, 38.8), FIL200/FIL100 in long-term analysis. In 12W PBO-controlled period, there was no active TB for FIL200/FIL100/PBO. In 52W ADA-controlled period, active TB EAIRs (95% CIs)/100 PYE were: 0 (0.0, 0.8)/0 (0.0, 0.8)/0.3 (0.0, 1.9), FIL200/FIL100/ADA and 0 (0.0, 0.6)/0 (0.0, 1.9)/0 (0.0, 1.0), FIL200/FIL100/MTX in 52W MTX-controlled period; 0/0.1 (0.0, 0.5), FIL200/FIL100 in long-term analysis.SI rate or EAIRs are in Figure. Most common infections were upper respiratory tract infection and nasopharyngitis; majority were low grade. Pneumonia was most common SI (<1%). In long-term population, event probability (95% CI) of SI was 2.2% (1.6, 2.9)/2.5% (1.8, 3.4) for FIL200/FIL100 at 52W. In F1–3 (excluding data after rerandomisation), there were no significant changes in mean neutrophil and lymphocyte counts; values remained within normal limits up to W52 for all arms.Conclusion:EAIRs of infections and SI for FIL were similar to PBO, ADA, and MTX. At 52W, incidence rates of SI were comparable for FIL100 and FIL200. Long-term SI EAIR for FIL100 was slightly higher than for FIL200.References:[1]Genovese et al. JAMA. 2019;322:315–25.[2]Westhovens et al. Ann Rheum Dis. 2021; online first.[3]Combe et al. Ann Rheum Dis. 2021; online first.[4]Strand et al. Arthritis Res Ther. 2015;17:362.Disclosure of Interests:James Galloway Speakers bureau: Pfizer, Bristol-Myers Squibb, UCB and Celgene, Maya H Buch Consultant of: Pfizer; AbbVie; Eli Lilly; Gilead Sciences, Inc.; Merck-Serono; Sandoz; and Sanofi, Grant/research support from: Pfizer, Roche, and UCB, Kunihiro Yamaoka Speakers bureau: AbbVie, Actelion Pharmaceuticals Japan, Asahikasei Pharma Corp, Astellas Pharma, AYUMI Pharma Co, Boehringer Ingelheim Japan, Bristol-Myers Squibb, Chugai Pharma, Daiichi Sankyo, Eisai Pharma, Eli Lilly, GlaxoSmithKline, Gilead G.K., Hisamitsu Pharma Co., Janssen Pharma, Mitsubishi-Tanabe Pharma, MSD, Nippon Kayaku, Nippon Shinyaku, Ono Pharma, Otsuka Pharma, Pfizer, Sanofi, and Takeda Industrial Pharma, Consultant of: Asahikasei Pharma Corp., AbbVie, Gilead G.K., Pfizer, Astellas Pharma Inc, Eli Lilly Japan K.K., and Japan Tobacco Inc., Grant/research support from: Takeda Industrial Pharma, Pfizer, Astellas Pharma, Daiichi Sankyo, Eli Lilly, Eisai Pharma, Teijin Pharma, MSD, Shionogi, Chugai Pharma, Nippon Kayaku, Mitsubishi-Tanabe Pharma, and AbbVie, Cianna Leatherwood Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Alena Pechonkina Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Iyabode Tiamiyu Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Deyuan Jiang Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Lei Ye Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Robin Besuyen Shareholder of: Galapagos BV, Employee of: Galapagos BV, Daniel Aletaha Speakers bureau: AbbVie, Celgene, Lilly, Merck, Novartis, Pfizer, Sanofi Genzyme, UCB, Consultant of: AbbVie, Amgen, Celgene, Lilly, Medac, Merck, Novartis, Pfizer, Roche, Sandoz, Sanofi Genzyme, Grant/research support from: AbbVie, Novartis, Roche, Kevin Winthrop Consultant of: AbbVie, Bristol-Myers Squibb, Eli Lilly and Co., Galapagos NV, Gilead Sciences, GlaxoSmithKline, Pfizer, Roche, and UCB, Grant/research support from: AbbVie, Bristol-Myers Squibb, and Pfizer

Background:Pneumococcal vaccinations are recommended for patients with rheumatoid arthritis (RA). There is evidence that pneumococcal vaccinations are less effective when administered after starting conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs). Vaccination guidelines have changed over time, since 1992 UK guidelines recommend pneumococcal vaccination for the immunocompromised, and in 2003 was expanded to all individual’s age ≥65 years. Guidelines from British Society of Rheumatology (2011) and EULAR (2019) advise to vaccinate prior to starting csDMARDs where possible. There is little evidence about whether these guidelines are being followed.Objectives:The aims of this study were to explore the timing of pneumococcal vaccination in patients with RA in relation to starting csDMARDs and examine whether this has changed over time.Methods:This was a cross-sectional study using UK electronic health records from primary care between 1st January 2000 and 31st December 2018. To be included in the study patients needed to 1) have a diagnosis of RA, 2) be prescribed csDMARDs up to 3 months prior to, or after RA diagnosis date and 3) have received a pneumococcal vaccination. Index date was considered the start of csDMARDs and vaccinations were required to be up to 5 years prior to the index date or after index date until leaving the practice, death or the end of the study period. For each patient it was determined if the first vaccination was prior to starting csDMARDs. For those vaccinated up to 3 years prior to, or up to 3 years after starting csDMARDs, the time between vaccination and starting csDMARDs in months was determined and this distribution was plotted in a bar chart. To explore how timing of vaccination has changed over time the proportion (with 95% confidence intervals (CI)) of people vaccinated prior to starting csDMARDs was plotted by year.Results:Of 21461 people with RA identified who were prescribed their first csDMARD on or after 1st January 2000, there were 8205 (38.2%) patients vaccinated and eligible to be included in the study. The cohort had a mean age 62 years, 66.4% were female. There were 2997 (36.5%) patients vaccinated prior to starting csDMARDs. Those vaccinated prior to starting csDMARDs were older, with 72% (n=2168) being aged 65 years or over vs 28% (n=1465) in those vaccinated after starting csDMARDs. 5358 (65.3%) were vaccinated up to 3 years prior to, or up to 3 years after starting csDMARDs. The distribution showed that the most frequent time of vaccination was in the 3 months after starting csDMARDs and the frequency was higher in the months after starting csDMARDs than in the months preceding (Figure 1). Of those vaccinated outside these times, 1000 (12.2%) were vaccinated >3 years prior and 1844 (22.5%) were vaccinated >3 years after starting csDMARDs. The proportion vaccinated prior to starting csDMARDs has increased over time from a minimum of 17.2% in 2001 to a maximum of 55.6% in 2016. The greatest increases were seen between 2003 and 2007 (Figure 2).Figure 1.Time between starting csDMARDs and pneumococcal vaccinationFigure 2.Proportion and 95% confidence interval of those vaccinated prior to starting csDMARDs by year.Conclusion:This study shows that timing of pneumococcal vaccination is improving with a trend towards increasing vaccination prior to starting csDMARDs and a high proportion of patients were vaccinated around the time of csDMARD initiation. However, just over a fifth (22.5%) were vaccinated more than 3 years after starting csDMARDs. Rheumatologists need to continue to work to raise awareness of the importance of vaccinations through better communications to patients and primary care physicians, to ensure best practice is being followed.Disclosure of Interests:Ruth E Costello: None declared, Jenny Humphreys: None declared, Kevin Winthrop Grant/research support from: Bristol-Myers Squibb, Consultant of: AbbVie, Bristol-Myers Squibb, Eli Lilly, Galapagos, Gilead, GSK, Pfizer Inc, Roche, UCB, William Dixon Consultant of: Bayer and Google

Background:Baricitinib (bari) is an oral selective inhibitor of Janus kinase (JAK) 1 and 2, approved for the treatment of moderately to severely active rheumatoid arthritis (RA) in adults.Objectives:Here we update the drug’s safety profile with data up to 8.4 years of treatment.Methods:Long-term safety of bari was assessed from 9 completed randomized trials (5 Ph3, 3 Ph2, 1 Ph 1b) and 1 ongoing long-term extension (LTE) study. Incidence rates (IR) per 100 patient-years (PY) were calculated for all patients with RA treated with ≥1 dose of bari through 1-Sep-2019 (All-Bari-RA analysis set). IRs for deep vein thrombosis (DVT), pulmonary embolism (PE), and DVT and/or PE (DVT/PE) were also calculated for groups of patients while receiving bari 2mg or bari 4mg within All-Bari-RA. Major adverse cardiovascular events (MACE) were adjudicated in 5 phase 3 studies and the LTE.Results:3770 pts received bari for 13,148 PY, with a median and maximum exposure of 4.2 and 8.4 years, respectively. Overall IRs per 100 PY were: for any treatment-emergent adverse event (AE)(25.8); serious AE (including death)(7.2); temporary interruption due to AE (9.5); permanent discontinuation due to AE (4.8); death (0.52); serious infection (2.7); opportunistic infection (0.44) (excluding tuberculosis [TB], including multidermatomal herpes zoster [HZ]); TB (0.15); HZ (3.0); MACE (0.50); DVT (0.31); PE (0.24); DVT/PE (0.45); malignancies excluding non-melanoma skin cancer (NMSC) (0.90); NMSC (0.33); lymphoma (0.06); and gastrointestinal perforation (0.04). Incidence rates (IR)[95% confidence intervals] for patients while receiving bari 2mg (N=1077) and bari 4mg (N=3400) were DVT 2mg (0.38) [0.18, 0.73] and 4mg (0.30) [0.21, 0.43]; PE 2mg (0.26) [0.09, 0.56] and 4mg (0.25) [0.16, 0.36]; and DVT/PE 2mg (0.47) [0.23, 0.84] and 4mg (0.46) [0.34, 0.61]. IRs for death tended to increase in later time intervals (beyond 192 weeks). No particular cause of death contributed to this increase. For all other safety topics of interest, across 48-week treatment intervals, IRs remained stable over time. Across safety topics, IRs were consistent with previous analyses1,2.Conclusion:In this update with 3,021 additional PY of exposure, bari maintained a safety profile similar to that previously reported,1,2with no increase of IRs across safety topics through exposures up to 8.4 years.References:[1]Smolen JS et al. J Rheumatol. 2019 Jan;46(1):7-18[2]Genovese MC et al. Ann Rheum Dis. 2019 78(supp. 2):A308Table.n/NARIRTreatment emergent AE3391/377025.8Serious AE (including death)940/37707.2Temporary d/c due to AE1241/36479.5Permanent d/c due to AE644/37704.8Death69/37700.52Serious infection344/37702.7Opportunistic infection (excluding tuberculosis, including multidermatomal herpes zoster)59/37700.44Herpes zoster384/37703.0Tuberculosis20/37700.15Major adverse cardiovascular events*63/32510.50DVT41/37700.31PE32/37700.24DVT and/or PE60/37700.45Malignancies excluding NMSC120/37700.90NMSC44/37700.33Lymphoma8/37700.06Gastrointestinal perforation6/37700.04*studies with positive adjudication. AE=adverse event; D/C= discontinuation; DVT=deep vein thrombosis; IR=incidence rate; NAR=number of patients at risk; NMSC=non-melanoma skin cancer; PE=pulmonary embolismDisclosure of Interests:Mark C. Genovese Grant/research support from: Abbvie, Eli Lilly and Company, EMD Merck Serono, Galapagos, Genentech/Roche, Gilead Sciences, Inc., GSK, Novartis, Pfizer Inc., RPharm, Sanofi Genzyme, Consultant of: Abbvie, Eli Lilly and Company, EMD Merck Serono, Genentech/Roche, Gilead Sciences, Inc., GSK, Novartis, RPharm, Sanofi Genzyme, Josef S. Smolen Grant/research support from: AbbVie, AstraZeneca, Celgene, Celltrion, Chugai, Eli Lilly, Gilead, ILTOO, Janssen, Novartis-Sandoz, Pfizer Inc, Samsung, Sanofi, Consultant of: AbbVie, AstraZeneca, Celgene, Celltrion, Chugai, Eli Lilly, Gilead, ILTOO, Janssen, Novartis-Sandoz, Pfizer Inc, Samsung, Sanofi, Tsutomu Takeuchi Grant/research support from: Eisai Co., Ltd, Astellas Pharma Inc., AbbVie GK, Asahi Kasei Pharma Corporation, Nippon Kayaku Co., Ltd, Takeda Pharmaceutical Company Ltd, UCB Pharma, Shionogi & Co., Ltd., Mitsubishi-Tanabe Pharma Corp., Daiichi Sankyo Co., Ltd., Chugai Pharmaceutical Co. Ltd., Consultant of: Chugai Pharmaceutical Co Ltd, Astellas Pharma Inc., Eli Lilly Japan KK, Speakers bureau: AbbVie GK, Eisai Co., Ltd, Mitsubishi-Tanabe Pharma Corporation, Chugai Pharmaceutical Co Ltd, Bristol-Myers Squibb Company, AYUMI Pharmaceutical Corp., Eisai Co., Ltd, Daiichi Sankyo Co., Ltd., Gilead Sciences, Inc., Novartis Pharma K.K., Pfizer Japan Inc., Sanofi K.K., Dainippon Sumitomo Co., Ltd., Gerd Rüdiger Burmester Consultant of: AbbVie Inc, Eli Lilly, Gilead, Janssen, Merck, Roche, Pfizer, and UCB Pharma, Speakers bureau: AbbVie Inc, Eli Lilly, Gilead, Janssen, Merck, Roche, Pfizer, and UCB Pharma, Walter Deberdt Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Douglas Schlichting Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Hongsuk Song Employee of: Syneos Health under contract to Eli Lilly and Company, Daojun Mo Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Chad Walls Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Kevin Winthrop Grant/research support from: Bristol-Myers Squibb, Consultant of: AbbVie, Bristol-Myers Squibb, Eli Lilly, Galapagos, Gilead, GSK, Pfizer Inc, Roche, UCB

Abstract Genome-wide association studies (GWAS) have identified 13 renal cell carcinoma (RCC) risk regions, as well as 7 regions with nominal significance, but detailed investigation of how these regions function is required to reveal the underlying biological bases of disease susceptibility. While detailed study of four loci have implicated critical pathways in RCC, causal genes and pathways for most loci remain unidentified. To identify such causative variants and target genes, we evaluated a set of variants based on Massively Parallel Reporter Assays (MPRA), eQTL analysis, capture Hi-C, and an arrayed CRISPR inhibition (CRISPRi) screen. The MPRA identified 196 variants across 19 regions with significant allele-specific effects, indicating cis-regulatory activity. Of these, 39 variants across 10 RCC loci displayed chromatin loops allowing physical interaction with the promoter of 24 nearby putative gene targets, as well as a significant cis-eQTL with the same gene. To confirm the presence of a cis-regulatory relationship between these 39 candidate variants and 24 putative target genes, we performed an arrayed CRISPRi screen in ACHN (RCC) and HEK293T (embryonic renal) cells covering each of the 10 nominated regions. Cells were stably transduced with inactive Cas9 fused to the ZIM3 transcriptional repressor domain and cis-regulatory relationships were assessed by TaqMan qPCR for the target genes. The screen identified multiple novel relevant target genes of RCC predisposition variants, including UCK2 at 1q24, ABL2 and TDRD5 at 1q25, GTDC1 at 2q22, GPR37 at 7q31, AGBL3 and CALD1 at 7q33, and MAP2K1 at 15q22. At some regions, evidence indicates cis-regulatory relationships occur between a target gene and all variants predicted to be ‘causative’ at the region (e.g., UCK2 at 1q24 and ABL2 at 1q25). For other regions, cis-regulatory relationships occur between a gene and only one variant tested (e.g., GPR37 at 7q31 and TDRD5 at 1q25).Previously, target genes of only four RCC susceptibility regions had been identified and published. This study identifies eight novel target genes across six additional RCC susceptibility regions, representing a significant advance in understanding of the underlying biology of RCC susceptibility variants. Furthermore, ongoing screening using the orthologous method, CRISPR activation (CRISPRa), and integration of both normoxic and hypoxic conditions continues to provide further insight into the underlying biology at these regions. Citation Format: Timothy Winter, Timothy Myers, Leandro Colli, Lea Jessop, Jiyeon Choi, Mitchell J. Machiela, Mark P. Purdue, Kevin Brown, Stephen Chanock. Targeted CRISPRi screen identifies functional variants and novel target genes at multiple renal cell carcinoma (RCC) susceptibility loci [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 6154.

Background:Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). A recent ad hoc safety analysis (as of August 2019; may be subject to change) from an ongoing, open-label, randomised, post-authorisation safety study, Study A3921133 (NCT02092467), conducted in RA patients (pts) aged ≥50 years with ≥1 cardiovascular risk factor has shown that incidence rates (IRs) of serious infection events (SIEs) were higher with tofacitinib 10 mg BID vs tumour necrosis factor inhibitors (TNFi; adalimumab [ADA] and etanercept) and this difference was more pronounced in pts aged ≥65 years (Pfizer Inc; data on file).Objectives:To assess the IRs of overall infection events and SIEs in pts from Phase (P)2, P3 and P3b/4 tofacitinib RA trials which had a TNFi (ADA) active control or comparator arm.Methods:This is a post hoc analysis of Month 0–12 data pooled from P2 (A3921035;NCT00550446[first 12-week randomised parallel treatment period only]), P3 (ORAL Standard;NCT00853385) and P3b/4 (ORAL Strategy;NCT02187055) studies. Pts randomised to receive tofacitinib 5 mg BID, tofacitinib 10 mg BID, ADA 40 mg subcutaneously every other week and placebo (PBO) were included and assessed overall and by age (<65 or ≥65 years). SIEs were defined as infections requiring hospitalisation or parenteral antimicrobial therapy, or meeting other criteria for a serious adverse event. IRs (pts with events/100 pt-years of exposure [PY]) and 95% confidence intervals (CIs) were calculated for all infection events and SIEs; only the first infection events that occurred up to 28 days after the last dose or to the data cut-off date were considered.Results:Of 2180 pts included in the pooled studies (tofacitinib 5 mg BID: N=1064 [943.4 PY]; tofacitinib 10 mg BID: N=306 [236.6 PY]; ADA: N=643 [554.3 PY]; PBO: N=167 [108.1 PY]), 1841 (84.4%) were aged <65 years and 339 (15.6%) were aged ≥65 years. In general, the IRs for all infection events and SIEs were higher with tofacitinib 5 mg BID, tofacitinib 10 mg BID and ADA in pts aged ≥65 years compared with pts aged <65 years. Overall and when stratified by age, IRs for all infection events were similar across the active treatment groups (Figure 1); IRs with PBO were lower vs the active treatment groups overall and in pts aged <65 years, and numerically lower vs the active treatment groups in pts aged ≥65 years. IRs for SIEs were comparable across active treatment groups in pts aged <65 years, while among pts aged ≥65 years, IRs were numerically higher for tofacitinib 10 mg BID vs ADA, and appeared to be similar for tofacitinib 5 mg BID and ADA (Figure 2).Conclusion:In this analysis of data pooled from P2, P3 and P3b/4 tofacitinib RA studies which included a TNFi arm (ADA), the risk of SIEs or infections overall was similar for tofacitinib and ADA with the exception of a numerically higher rate of SIEs with tofacitinib 10 mg BID vs ADA in pts aged ≥65 years. In most countries, tofacitinib 10 mg BID is not an approved dose for the treatment of RA. This post hoc comparison is limited by variation in sample size and PY of exposure between treatment and age groups, and a small number of cases of SIEs in the ≥65-year age group resulting in wide 95% CIs; interpretation of results should be made with caution. The findings in the present analysis are consistent with increasing age being a known risk factor for infections.Acknowledgments:Study sponsored by Pfizer Inc. Medical writing support was provided by Christina Viegelmann of CMC Connect and funded by Pfizer Inc.Disclosure of Interests: :Kevin Winthrop Grant/research support from: Bristol-Myers Squibb, Consultant of: AbbVie, Bristol-Myers Squibb, Eli Lilly, Galapagos, Gilead, GSK, Pfizer Inc, Roche, UCB, David Gold Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Dan Henrohn Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Lisy Wang Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Andrea Shapiro Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Harry Shi Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Gustavo Citera Grant/research support from: AbbVie, Amgen, Eli Lilly, Gema, Genzyme, Novartis and Pfizer Inc, Consultant of: AbbVie, Amgen, Eli Lilly, Gema, Genzyme, Novartis and Pfizer Inc, Hendrik Schulze-Koops Grant/research support from: Pfizer Inc

Abstract Many GWAS loci occur in non-coding regions and often overlap with gene regulatory elements such as distant enhancers, making functional interpretation and target gene discovery challenging. The 3D chromatin organization brings enhancers in spatial proximity with a promoter to regulate target gene expression. Therefore, to map chromatin interactions between GWAS variants and target gene promoters we performed region-focused chromatin conformation capture assay (Capture-C) in primary human melanocytes. We baited the entire region of association for all 68 independent signals from the recent melanoma GWAS, and Capture-C interactions were called using CHiCAGO tool. Integrative analysis of Capture-C interactions with melanocyte- and melanoma-specific ATAC-sequencing, massive-parallel reporter assay (MPRA), ROADMAP chromatin imputed state model, and gene expression datasets helped prioritize target genes for functional follow-up. Capture-C assays identified physical chromatin interactions between fine-mapped risk variants and candidate causal gene (CCG) promoters at 90% of the GWAS loci; For 84% of the 68 loci, we observed at least one variant-to-gene promoter interaction longer than 100 kb, and for 20% of loci we found interactions beyond 1 Mb. For 76% of the 68 loci, the CCG-interacting variant was in annotated melanocyte or melanoma enhancer regions consistent with CCG regulation via an enhancer-promoter interaction. We observed at least one CCG-interacting variant in 63% and 51% of the 68 loci with distinct allele specific transcriptional activity in melanocyte and melanoma MPRA datasets respectively. A majority of the loci (60%) harbored CCG-linked risk variants in accessible chromatin regions in melanocytes and melanoma. Pathway enrichment analyses of Capture-C-nominated CCGs identified embryonic development, aryl hydrocarbon receptor signaling, and DNA repair pathways. Notably, we observed chromatin interactions between risk variants located near the 3’ of Rap Guanine Nucleotide Exchange Factor 1 (RAPGEF1) to the RAPGEF1 and UCK1 promoter regions. The risk allele of the lead variant (rs3780269) at this locus was associated with higher RAPGEF1 mRNA expression and was not associated with UCK1 expression in melanocytes. We performed a CRISPR knockout proliferation screen in immortalized melanocytes and identified RAPGEF1 as an essential gene for melanocyte growth or survival. Further, we validated the results of this screen by overexpressing RAPGEF1 in immortalized melanocytes and found that it leads to increased cellular growth. We are now characterizing its function in melanoma tumor incidence and progression in a zebrafish model. In summary, mapping GWAS loci chromatin interactions to target gene promoters and integrative analysis using cell-type specific datasets identified RAPGEF1 as a melanoma susceptibility gene. Citation Format: Rohit Thakur, Mai Xu, Alexandra Thornock, Hayley Sowards, Epring Long, Thomas Rheling, Karen Funderburk, Jinhu Yin, Rebecca Hennessey, Raj Chari, Tongwu Zhang, Lea Jessop, Timothy Myers, Matthew E. Johnson, Andrew D. Wells, Alessandra Chesi, Struan F. Grant, Mark I. Iles, Maria T. Landi, Matthew Law, Melanoma Meta-Analysis Consortium, Mitchell Machiela, Jiyeon Choi, Leonard I. Zon, Kevin M. Brown. Integrative analysis of 3D chromatin organization at GWAS loci identifies RAPGEF1 as a melanoma susceptibility gene. [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 5239.

It has been well-known that the Ingard-Myers impedance condition, while simple to apply, is subject to the hydrodynamic Kelvin-Helmholtz-type instability due to its use of a vortex sheet in modeling the flow at the liner boundary. Recently, in the development of a time domain boundary element method for acoustic scattering by treated surfaces, it was found that by neglecting a certain second-order spatial derivative term in the Ingard-Myers formulation, the hydrodynamic instability can be avoided. The present paper aims to provide further analysis of this modified condition, hereby referred to as the Truncated Ingard-Myers Impedance Boundary Condition (TIMIBC). It will be shown, based on the dispersion relations of linear waves, that the instability intrinsic to the Ingard-Myers condition is eliminated in the proposed new formulation. Quantitative assessments on the accuracy of the TIMIBC for scattering of acoustic waves by lined surfaces are carried out, and its effectiveness is demonstrated by a numerical example. It is found that the TIMIBC provides a good approximation to the original Ingard-Myers condition for flows of low to mid subsonic Mach numbers. As such, the proposed TIMIBC can offer a practical solution for overcoming the intrinsic instability associated with the Ingard-Myers condition. Moreover, time domain implementation of the TIMIBC is also discussed and illustrated with a numerical example using a finite difference scheme. In particular, a minimization procedure for finding the poles and coefficients of a broadband multipole expansion for the impedance function is formulated by which, unlike the commonly used vector-fitting method, passivity of the model is ensured.

Background:The “Targeting Immune Responses for Prevention of RA” (TIP-RA) collaboration studies individuals at high risk for developing rheumatoid arthritis (RA) because of serum anti-citrullinated protein antibody (ACPA) positivity in absence of arthritis at baseline, and is focused on defining how they transition from at-risk to classifiable disease. One potential mechanism is the expansion of antigen specific T cells that recognize self-antigens and acquisition of disease associated T cell phenotypes. ACPA emerge years prior to clinically apparent disease and subsequently increase in their titer and breadth of specificity. However, few studies have characterized T cells during this transition.Objectives:To identify features associated with progression to RA by examining the specificity and surface phenotype of CD4+ T cells in individuals from the TIP-RA cohort by HLA class II tetramer staining and multi-parameter flow cytometry.Methods:Tetramer staining and flow cytometry were performed on peripheral blood samples from a baseline visit from CCP3- controls (n=34), CCP3+ at-risk (n=26), CCP3+ positive individuals who transitioned in the near-term to RA (called “RA converters”, n=4), and seropositive early-RA (n=21). Our staining panel allowed us to measure the frequencies of T cells specific for citrullinated alpha-enolase, aggrecan, cartilage intermediate layer protein (CILP), fibrinogen and vimentin. We then applied both supervised phenotyping and a cluster-based computational approach to compare the phenotypic landscape and specificity of antigen specific and total CD4+ T cells in each cohort.Results:We observed higher overall frequencies of T cells that recognize citrullinated epitopes in CCP3+ at-risk subjects than CCP- controls (p< 0.05). Among the individual specificities, elevated frequencies prior to disease onset were most prominent for CILP specific T cells. Supervised phenotypic analysis revealed an increase in CCR4+ CD4+ T cells in CCP3+ at risk subjects (p< 0.001) and a corresponding decrease in CXCR3+ CD4+ T cells that was most pronounced in RA converters and seropositive early-RA (p< 0.05). Cluster-based phenotypic analysis defined ten distinct phenotypic states present within all subjects. Each of these ten immunotypes contained T cells that recognize citrullinated epitopes. However, the predominant immunotype varied for different antigens. During progression, the frequencies of Ag specific T cells diminished when onset was imminent, but rebounded shortly after diagnosis. Concomitantly, Ag specific T cells with memory phenotypes were diminished, but subsequently reverted to TSCM, Th1, and Th1-17 like phenotypes.Conclusion:Our data show that disease associated changes in the antigen specificity of CD4+ T cells are present in CCP3+ at-risk subjects. Furthermore, the number of antigen specific T cells and their phenotype are perturbed before the onset of symptoms and development of classified RA. These findings support a continuum of immunologic changes that underlie risk and drive disease, motivating new approaches for early intervention.Acknowledgments:We gratefully acknowledge the Targeting Immune Responses for Prevention of Rheumatoid Arthritis (TIP-RA) for designing and executing this collaborative studyDisclosure of Interests:Cliff Rims: None declared, Virginia Muir: None declared, Kevin Deane Grant/research support from: Janssen, Consultant of: Inova, ThermoFisher, Janseen, BMS and Microdrop, Sunil Nagpal Shareholder of: Janssen Pharmaceuticals, Employee of: Janssen Pharmaceuticals, Navin Rao Shareholder of: Janssen Pharmaceuticals, Employee of: Janssen Pharmaceuticals, Frederic Baribaud Shareholder of: Janssen Research & Development, LLC, Employee of: Janssen Research & Development, LLC, George Vratsanos Shareholder of: Janssen Pharmaceuticals, Employee of: Janssen Pharmaceuticals, V. Michael Holers Grant/research support from: Janssen, Celgene, and BMS, Peter Linsley Consultant of: BMS, Eddie A. James Grant/research support from: Janssen, Pfizer, Sanofi, Novartis, Jane Buckner Grant/research support from: Bristol-Myers Squibb, Janssen

Background:The efficacy and safety of upadacitinib (UPA), an oral Janus kinase inhibitor, in patients (pts) with active psoriatic arthritis (PsA) were demonstrated through 24 weeks in the phase 3 SELECT-PsA 1 and SELECT-PsA 2 placebo-controlled clinical trials.1,2Objectives:To describe the long-term integrated safety profile of UPA relative to adalimumab (ADA) in pts with PsA treated in the SELECT program.Methods:The SELECT-PsA program enrolled pts with prior inadequate response or intolerance to ≥1 non-biologic DMARD (SELECT-PsA 1) or ≥1 biologic DMARD (SELECT-PsA 2). Both trials include UPA 15 mg and 30 mg, and only SELECT-PsA 1 includes long-term comparison with ADA 40 mg every other week. Treatment-emergent adverse events (TEAEs: AE onset ≥first dose and ≤30 days after last dose for UPA and ≤70 days for ADA) were summarized for the following: pooled UPA 15; pooled UPA 30; and ADA. TEAEs are reported as exposure-adjusted event rates (EAERs; events/100 pts years [E/100 PY]) up to a cut-off date of 20 June 2020.Results:2257 pts received ≥1 dose of UPA 15 (N=907; 1247.2 PYs), UPA 30 (N=921; 1257.4 PYs), or ADA (N=429; 549.7 PYs), with median (max) exposures of 69 (155), 69 (154), and 68 (152) weeks, respectively. EAERs of TEAEs and serious AEs were generally similar between UPA 15 and ADA and higher with UPA 30; rates of AEs leading to study drug discontinuation were generally similar across all groups (Table 1). Similarly, rates of serious infection were comparable between UPA 15 and ADA and higher with UPA 30 (Figure 1 next page). The most common serious infection was pneumonia. Rates of herpes zoster were lower with UPA 15 than UPA 30 but higher than ADA. Most herpes zoster events involved a single dermatome; no events involved the central nervous system or other internal organs. Lower rates of opportunistic infections (OI) excluding tuberculosis were observed with UPA 15 vs UPA 30; the most common OI was mucosal candida infection. Malignancies were reported at similar rates across all treatment groups; no events of lymphoma were reported. Age-gender-adjusted standardized incidence ratios for malignancies excluding NMSC indicated no increased risk with UPA compared to the general population. Rates of adjudicated major adverse cardiovascular events and venous thromboembolic events were ≤0.3 E/100 PY for both UPA arms; all pts had ≥1 risk factor. One adjudicated gastrointestinal perforation was reported with UPA 15.Table 1.Overall Treatment-emergent AEs for Upadacitinib and Adalimumab (E/100 PY [95% CI])UPA 15 mg QDN=907(1247.2 PY)UPA 30 mg QDN=921(1257.4 PY)ADA 40 mg EOWN=429(549.7 PY)AEs263.9 (254.9, 272.9)321.5 (311.6, 331.5)286.5 (272.4, 300.7)Serious AEs10.3 (8.6, 12.1)13.2 (11.2, 15.2)9.6 (7.0, 12.2)AE leading to discontinuation6.7 (5.2, 8.1)7.8 (6.2, 9.3)7.8 (5.5, 10.2)Deathsa0.2 (-0.1, 0.4)0.2 (-0.0, 0.5)0.2 (-0.2, 0.5)aDeaths included non-treatment emergent deaths: UPA 15, 1; UPA 30, 1.ADA, adalimumab; AE, adverse event; CI, confidence interval; E, event; EOW, every other week; PY, patient years; QD, once daily; UPA, upadacitinib.Hepatic disorders were mostly transient, non-serious transaminase increases. Creatine phosphokinase elevations were reported more frequently with UPA 30 vs UPA 15; most were asymptomatic with no rhabdomyolysis reported. AEs of anemia, neutropenia, and lymphopenia were generally mild or moderate, non-serious. Except for rates of lymphopenia (higher with UPA 15), hepatic disorders, and neutropenia (both higher with ADA), lab-related TEAEs occurred at generally consistent rates between UPA 15 and ADA. Study drug discontinuation due to lab-related TEAEs was uncommon.Conclusion:The safety profiles of UPA 15 and ADA were generally similar; the rates of most AEs were higher with UPA 30 compared with ADA. Through the cut-off date, the safety profile of UPA 15 and UPA 30 in PsA pts demonstrated consistent results compared to what has been observed with UPA in rheumatoid arthritis.3References:[1]McInnes IB et al. Ann Rheum Dis, 2020; 79:12.[2]Mease PJ et al. Ann Rheum Dis, 2020.[3]Cohen SB et al. Ann Rheum Dis, 2020.Figure 1Acknowledgements:AbbVie and the authors thank the patients, study sites, and investigators who participated in this clinical trial. AbbVie, Inc was the study sponsor, contributed to study design, data collection, analysis & interpretation, and to writing, reviewing, and approval of final version. No honoraria or payments were made for authorship. Medical writing support was provided by Ramona Vladea, PhD of AbbVie Inc.Disclosure of Interests:Gerd Rüdiger Burmester Speakers bureau: AbbVie, Gilead, Lilly, Pfizer, Consultant of: AbbVie, Gilead, Lilly, Pfizer, Kevin Winthrop Consultant of: UCB Pharma, Pfizer, Bristol-Myers Squibb, Eli Lilly, AbbVie, Gilead, Galapagos, and Roche, Grant/research support from: UCB Pharma, Pfizer, Bristol-Myers Squibb, Eli Lilly, AbbVie, Gilead, Galapagos, and Roche, Ricardo Blanco Consultant of: Abbvie, Lilly, Novartis, Pfizer, Roche, Bristol-Myers, Janssen, and MSD, Grant/research support from: Abbvie, MSD and Roche, Peter Nash Consultant of: AbbVie, BMS, Roche, Pfizer, Janssen, Amgen, Sanofi-Aventis, UCB, Eli Lilly, Novartis, and Celgene, Grant/research support from: AbbVie, BMS, Roche, Pfizer, Janssen, Amgen, Sanofi-Aventis, UCB, Eli Lilly, Novartis, and Celgene, Philippe Goupille Consultant of: AbbVie, Amgen, Biogen, BMS, Celgene, Chugai, Janssen, Lilly, Medac, MSD, Nordic Pharma, Novartis, Pfizer, Sanofi and UCB, Grant/research support from: AbbVie, Amgen, Biogen, BMS, Celgene, Chugai, Janssen, Lilly, Medac, MSD, Nordic Pharma, Novartis, Pfizer, Sanofi and UCB, Valderilio F Azevedo Consultant of: AbbVie, BMS, Pfizer, Janssen, Amgen, Novartis, Eli Lilly, UCB, Celltrion and GSK, Grant/research support from: AbbVie, BMS, Pfizer, Janssen, Amgen, Novartis, Eli Lilly, UCB, Celltrion and GSK, Carlo Salvarani Consultant of: Roche, Sanofi-Genzyme, AbbVie, Pfizer, Lilly, Novartis, Amgen, Grant/research support from: Roche, Sanofi-Genzyme, AbbVie, Pfizer, Lilly, Novartis, Amgen, Andrea Rubbert-Roth Consultant of: AbbVie, BMS, Chugai, Roche, Gilead, Janssen, Lilly, Sanofi, Amgen, Novartis, Grant/research support from: AbbVie, BMS, Chugai, Roche, Gilead, Janssen, Lilly, Sanofi, Amgen, Novartis, Elizabeth Lesser Shareholder of: AbbVie, Employee of: AbbVie, Reva McCaskill Shareholder of: AbbVie, Employee of: AbbVie, Jianzhong Liu Shareholder of: AbbVie, Employee of: AbbVie, Bosny Pierre-Louis Shareholder of: AbbVie, Employee of: AbbVie, Sandra Walko Shareholder of: AbbVie, Employee of: AbbVie, Ralph Lippe Shareholder of: AbbVie, Employee of: AbbVie, Apinya Lertratanakul Shareholder of: AbbVie, Employee of: AbbVie, Eric Ruderman Consultant of: AbbVie, Amgen, Gilead, Janssen, Lilly, Novartis, and Pfizer.

A time domain boundary integral equation with Burton-Miller reformulation is presented for acoustic scattering by surfaces with liners in a uniform mean flow. The Ingard-Myers impedance boundary condition is implemented using a broadband multipole impedance model which is in turn converted into time domain differential equations to augment the boundary integral equation. The coupled integral-differential equations are solved numerically by a March-On-in-Time (MOT) scheme. While the Ingard-Myers condition is known to support Kelvin-Helmholtz instability due to its use of a vortex sheet interface between the flow and the lined surface, it is found that by neglecting a second-order derivative term in the current time domain impedance boundary condition formulation, the instability can be effectively avoided in computation. Proposed formulation and implementation are validated with numerical examples. Moreover, a minimization procedure for finding the poles and coefficients of the broadband multiple impedance expansion is formulated by which, unlike the commonly used vector-fitting method, passivity of the model is ensured. Numerical tests show the proposed minimization approach is effective for modeling liners that are commonly used in aeroacoustic applications.

Background:The “Targeting Immune Responses for Prevention of RA” (TIP-RA) collaboration studies individuals at high risk for developing RA because of serum anti-citrullinated protein antibody positivity in absence of arthritis, and is focused on defining how they transition from at-risk to classifiable disease. One potential mechanism is through alterations in epigenetics patterns in adaptive immune cells.Objectives:Previous studies showed that DNA methylation patterns of early RA (ERA) synoviocytes differ from long-standing RA, suggesting that abnormal methylation occurs early in synovium and evolves over time. To extend these observations, we performed a cross-sectional analysis in TIP-RA of DNA methylation signatures in peripheral blood cells in ERA, at-risk anti-CCP3+ individuals and demographically matched CCP- controls.Methods:Genomic DNA was isolated from two independent cohorts of CCP- (cohorts 1 and 2, respectively: B cell: n = 17/34; memory T cell: n = 21/34; and naïve T cell: n = 21/33), CCP3+ (B cell: n = 18/37; memory T cell: n = 20/36; and naïve T cell: n = 20/35), and CCP3+ ERA (B cell: n = 4/18; memory T cell: n = 5/18; and naïve T cell: n = 5/18) after separating PBMCs using antibodies and magnetic beads. Methylation was measured by Illumina Infinium MethylationEPIC chip. Differentially methylated loci (DMLs) were identified using Welch’s t-test and mapped to gene promoter regions to define DM genes (DMGs). Principal component analysis (PCA) was used to represent relationship among groups. Pathway analysis was applied by Reactome.Results:For the initial cohort, 1494, 1097 and 1330 DMLs were identified among CCP+, CCP- and ERA in B cells, memory T cells and naïve T cells, respectively. For the confirmatory cohort, 523, 793 and 548 DMLs were found in corresponding cell populations. The DML overlap between the 2 cohorts was highly significant (p= 2.48E-77). The DMLs were combined for both groups and corresponded to 411, 412, and 351 DMGs in B cells, memory T cells and naïve T cells. Of these, we found 246, 198 and 195 DMGs between CCP3+ and ERA in each peripheral blood cell population, respectively. PCA showed separation of CCP+, CCP- and ERA in each of the three blood cell types by DMLs (Fig. 1). DMGs were mapped to biological pathways to identify DM pathways. Although most were not significant, there were several highly significant differences comparing CCP+, ERA and CCP- in memory T cells involving pathways, including “Interferon gamma signaling” (FDR 7.48E-14), “PD-1 signaling” (FDR 8.71E-10), “Translocation of ZAP-70 to Immunological synapse” (FDR 4.75E-10), and “Phosphorylation of CD3 and TCR zeta chains” (FDR 8.71E-10).Figure 1.PCA shows the separation of CCP+, CCP- and ERA patients in memory T cells in confirmatory cohort.Conclusion:We identified reproducible methylation signatures of CCP-, CCP+, and ERA in peripheral blood B cells, memory T cells and naïve T cells in initial and confirmatory cohorts. The methylome of ERA also demonstrated a distinctive pattern from CCP+, indicating that progression to RA is accompanied by epigenetic remodeling, especially in T cell signaling and interferon responses. These signatures identify critical pathways in CCP positivity and classifiable RA and could provide the basis of novel interventions to prevent disease.Disclosure of Interests:Rizi Ai: None declared, David Boyle: None declared, Deepa Hammaker: None declared, Kevin Deane Grant/research support from: Janssen, Consultant of: Inova, ThermoFisher, Janseen, BMS and Microdrop, V. Michael Holers Grant/research support from: Janssen, Celgene, and BMS, Andre Matti: None declared, William Robinson: None declared, Jane Buckner Grant/research support from: Bristol-Myers Squibb, Janssen, Navin Rao Shareholder of: Janssen Pharmaceuticals, Employee of: Janssen Pharmaceuticals, Frederic Baribaud Shareholder of: Janssen Research & Development, LLC, Employee of: Janssen Research & Development, LLC, Alyssa Johnsen Employee of: Janssen, Sunil Nagpal Shareholder of: Janssen Pharmaceuticals, Employee of: Janssen Pharmaceuticals, Wei Wang: None declared, Gary Firestein Grant/research support from: Lilly, Janssen, Abbvie

Background:Lipid mediators are endogenously derived from the metabolism of omega-3 and omega-6 polyunsaturated fatty acids (PUFAs) and have important roles in promoting and resolving inflammation in the body (1). Epidemiological studies have shown higher omega-3 PUFA status to be associated with a lower risk of both autoimmunity and progression to inflammatory arthritis (IA) (2,3).Objectives:To determine the association of lipid mediators with progression from rheumatoid arthritis (RA)-related autoimmunity to inflammatory arthritis (IA).Methods:We conducted a prospective cohort study using data from the Studies of the Etiologies of Rheumatoid Arthritis (SERA). SERA enrolled first-degree relatives (FDRs) of individuals with RA (FDR cohort) and individuals who screened positive for RA-related autoantibodies at health fairs (screened cohort). We followed 133 anti-CCP3.1 positive participants, of which 29 developed IA (22 classified as RA by 2010 ACR/EULAR criteria). We quantified lipid mediators from stored plasma samples via liquid chromatography tandem mass spectrometry methods validated against the collection and storage methods used in the study. A priori, we selected 5S-HETE, 15S-HETE and 17S-HDHA because they are precursors to leukotrienes, Lipoxin A4 and Resolvin D series lipid mediators, respectively. We fit Cox proportional hazard models for each lipid mediator as a time-varying covariate. For lipid mediators significantly associated with progression to IA we then examined IL-1β, IL-6, IL-8 and TNF-α (Bio-Plex Pro™ assay) as potential mediators of this relationship.Results:Higher plasma 5S-HETE levels were associated with an increased risk of incident IA after adjusting for age at baseline, cohort (FDR or screened), and shared epitope (SE) status (Table 1). The models examining 15S-HETE and 17S-HDHA had the same trend but did not reach statistical significance. We did not find evidence that the association between 5S-HETE and IA risk was mediated by the tested pro-inflammatory cytokines, suggesting a direct role for this lipid mediator in conversion to IA.Table 1.Hazard ratios and 95% confidence intervals of lipid mediator concentrations associated with IA, n=29 IA casesLipid mediatorCrudeAdjustedb5S-HETE2.10 (1.12, 3.92)2.41 (1.43, 4.07)15S-HETE1.61 (0.88, 2.93)1.52 (0.87, 2.65)17-HDHAa1.59 (0.68, 3.74)1.61 (0.72, 3.56)adichotomized as <limit of detection (reference) or detectedbAdjusted for SE, age at baseline and cohortConclusion:In a prospective cohort of anti-CCP positive individuals, higher circulating levels of 5S-HETE, an important precursor to pro-inflammatory leukotrienes, was associated with subsequent IA. Our findings highlight the potential pathologic and prognostic significance of these PUFA metabolites in inflammatory processes in pre-RA populations.References:[1]Serhan CN. Pro-resolving lipid mediators are leads for resolution physiology. Nature. 2014;510(7503):92-101.[2]Gan RW, Bemis EA, Demoruelle MK, Striebich CC, Brake S, Feser ML, et al. The association between omega-3 fatty acid biomarkers and inflammatory arthritis in an anti-citrullinated protein antibody positive population. Rheumatology. 2017.[3]Gan RW, Young KA, Zerbe GO, Demoruelle MK, Weisman MH, Buckner JH, et al. Lower omega-3 fatty acids are associated with the presence of anti-cyclic citrullinated peptide autoantibodies in a population at risk for future rheumatoid arthritis: a nested case-control study. Rheumatology. 2016;55(2):367-76.Disclosure of Interests:Kristen Polinski: None declared, Elizabeth Bemis: None declared, Kristen Demoruelle Grant/research support from: Pfizer, Jennifer Seifert: None declared, Tessa Crume: None declared, Fan Yang: None declared, William Robinson: None declared, Michael Clare-Salzler: None declared, Kevin Deane Grant/research support from: Janssen, Consultant of: Inova, ThermoFisher, Janseen, BMS and Microdrop, Michael Holers Shareholder of: AdMIRx, Grant/research support from: AdMIRx, Pfizer, Janssen R&D, Consultant of: AdMIRx, Janssen R&D, Celgene, Bristol-Myers Squibb, Jill Norris Grant/research support from: Janssen R&D, Pfizer, Consultant of: Celgene, BMS

Abstract Background: Although different patterns and changes in DNA methylation play an important role in cancer progression and tumor subtype differentiation, methylation remains relatively less understood in the context of tumor heterogeneity. Intra-tumor heterogeneity influences chemotherapy response, resistance development, and metastatic progression, and can be identified with liquid biopsy, a non-invasive approach to monitor cancer progression and provide predictive information. In this study, we sequenced circulating tumor cells (CTCs) to interrogate whole-genome methylation at single-cell level and single-base resolution. Methods: We enumerated CTCs in 7.5ml of whole blood samples from over 130 metastatic breast cancer patients using CellSearch, and selected blood samples with more than 20 CTCs to be further processed by DEPArray. After single-cell library construction using the Swift Accel-NGS Adaptase Module, whole-genome bisulfite sequencing (WGBS) was performed. The sequencing data were then aligned to the reference genome, and the methylation information was extracted by Bismark. We compared methylation profiles between CTC and WBC samples from each patient to identify differentially methylated regions (DMRs) using Methylkit. Multiple-comparison was conducted by SMART2 to identify DMRs within CTCs. Heatmap was plotted based on the regional methylation rates of DMRs. CpG and genic annotations were performed by annotatr. The pathway and function enrichment analyses (KEGG and GO) were conducted using clusterProfiler. Genomic region-based enrichment was conducted using LOLA. t-SNE clustering was used to investigate intra-patient heterogeneity. Results: A total of 376 cells from nine patients that passed our selection criteria were isolated for WGBS. The mean sequencing depth of all single cells was 0.8×, and an average mapping rate of 54% was achieved. We first compared CTCs and WBCs, and observed a global hypo-methylation pattern in CTCs (average methylation rate 68.8% in CTCs vs. 76.7% in WBCs). Moreover, approximately 2,000 highly differentially methylated regions were found in each patient, with hundreds of hypo- or hyper-methylated genes related to these DMRs. Hypo-methylated DMRs showed genomic region-based enrichment in breast-, prostate-, and fibroblast-related region sets. Then, we investigated methylation heterogeneity within CTCs, where t-SNE clustering identified four different subsets in one representative patient. About 1,500 hypo-methylated DMRs were found, differentiating those four subgroups. KEGG pathway analysis indicated enrichment in the Rap1 signaling pathway and focal adhesion. GO enrichment analysis highlighted the regulation of GTPase activity and membrane potential. Conclusions: Our study identified differentially methylated regions in CTCs of metastatic breast cancer patients, and demonstrated intra-patient heterogeneity based on cellular methylation information. Future studies are warranted to validate our findings and explore their biological mechanisms and clinical relevance. Citation Format: Rui Luo, Weelic Chong, Zhenchao Zhang, Maysa Abu-Khalaf, Daniel Silver, Frederick Fellin, Rebecca Jaslow, AnaMaria Lopez, Terrence Cescon, Kevan Ip, Ronald Myers, Qiang Wei, Bingshan Li, Chun Wang, Hushan Yang. Whole-genome bisulfite sequencing of single circulating tumor cells identifies cellular methylation heterogeneity in metastatic breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P5-06-05.

-Sandra L. Richards, Judy S.J. Stone, Theatre. London: Macmillan Caribbean, 1994. xii + 268 pp.-Lowell Fiet, Errol Hill, The Jamaican stage, 1655-1900: profile of a colonial theatre. Amherst: University of Massachusetts Press, 1992. xiv + 346 pp.-Supriya Nair, Bruce King, V.S. Naipaul. New York: St. Martin's Press, 1993. viii + 170 pp.-Agnes Lugo-Ortiz, Donald E. Rice, The rhetorical uses of the authorizing figure: Fidel Castro and José Martí. Westport CT: Praeger, 1992. xviii + 163 pp.-Graciella Cruz-Taura, Juan A. Martínez, Cuban art and national identity: The Vanguardia painters, 1927-1950. Gainesville: University Press of Florida, 1994. xiv + 189 pp.-Graciella Cruz-Taura, Luis Camnitzer, New art of Cuba. Austin; University of Texas Press, 1994. xxx + 400 pp.-Gary Brana-Shute, Richard Price ,On the mall: Presenting Maroon tradition-bearers at the 1992 festival of American folklife. 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Zutphen, Netherlands: De Walburg Pers, 1993. 191 pp.-Wim Hoogbergen, Bea Brommer, Ik ben eigendom van ...: Slavenhandel en plantageleven. Wijk en Aalburg, Netherlands: Pictures Publishers, 1993. 144 pp.-Gert Oostindie, Ben Scholtens, Bosnegers en overheid in Suriname: De ontwikkeling van de politieke verhouding 1651-1992. Paramaribo: Afdeling Cultuurstudies/Minov, 1994. 237 pp.-Edward M. Dew, Marten Schalkwijk, Suriname: Het steentje in de Nederlandse schoen: Van onafhankelijkheid tot raamverdrag. Paramaribo: Firgos Suriname, 1994. 356 pp.

Abstract Background Fecal Microbiota, live-jslm (RBL) is a rectally administered, pre-packaged, live biotherapeutic approved in November 2022 for the prevention of recurrence of Clostridioides difficile infection (rCDI) in adults. As the first FDA-approved microbiota product, this new agent may pose challenges in administration, particularly with Infectious Disease (ID) or other specialties not typically providing rectally administered therapies. As part of an ongoing real-world study of RBL, the purpose of this study is to develop and report a simple protocol for the administration of RBL in clinical practice. Methods We reviewed electronic health records, administration records and internal databases for patients receiving RBL since February 2023. Records were reviewed for patient demographics, setting of care, time from order to treatment, logistics from order to administration and payor details. Results Six rCDI patients (73±14 years; female: 67%) have received RBL; 1 treated in an ID practice and the other 5 in GI practices. Following insurance approval and scheduling of the patient, RBL was ordered from the distributor and shipped to the practices in a 150mL pre-packaged frozen suspension. RBL was thawed for 24 hours and administered within 5 days. Average time from order to treatment was 18±5 days. Administration of RBL was performed by registered nurses or licensed vocational nurses. Reported RBL administration time was 5 minutes, with an additional 15 minutes for observation. Medicare (MCR) was the most common payor (71%) with traditional MCR (n=3), MCR Advantage (n=2), and one commercially insured. There have been no payor denials. Criteria for approval differed slightly between payors, but all required at least 1 prior episode of CDI. All plans required prior authorization except traditional MCR. Reimbursement was adequate for both the medication and instillation protocols. Conclusion Early experience with RBL administration found more treatment by GI than ID physician practices. Authorizations were granted as expected with the administration and visit surprisingly brief and simple. RBL holds promise as a feasible office-based therapy for prevention of rCDI. Disclosures Jonathan A. Rosenberg, MD, Aimmune: Advisor/Consultant|Ferring Pharmaceuticals: Advisor/Consultant Timothy E. Ritter, MD, Abbvie: Advisor/Consultant|Ardelyx: Advisor/Consultant|Arena: Advisor/Consultant|Boehringer Ingelheim: Advisor/Consultant|Bristol Myers Squibb/Celgene: Advisor/Consultant|Eli Lilly: Advisor/Consultant|Ferring: Advisor/Consultant|Ferring: Data Adjudication Committee|Genetech/Roche: Advisor/Consultant|Gilead: Advisor/Consultant|Intercept: Advisor/Consultant|Iterative Scopes: Expert Testimony|Iterative Scopes: Ownership Interest|Janssen: Advisor/Consultant|Nestle/Seres: Advisor/Consultant|Pfizer: Advisor/Consultant|Prometheus: Advisor/Consultant|Rebiotix: Data Adjudication Committee|Sanofi: Advisor/Consultant|Takeda Pharmaceuticals: Advisor/Consultant Lucinda J. Van Anglen, PharmD, ADMA Biologics, Inc.: Grant/Research Support|Ferring Pharmaceuticals: Grant/Research Support|Novartis: Grant/Research Support|Octapharma: Grant/Research Support|Paratek Pharmaceuticals: Grant/Research Support Amy Guo, PhD, Ferring Pharmaceuticals: Employee Mielad Moosapanah, PharmD, Ferring Pharmaceuticals: Employee Min Yang, MD, PhD, Analysis Group, Inc.: I am an employee of Analysis Group, Inc., which has received consulting fees from Ferring for the conduct of this study. Kevin W. Garey, PharmD, MS, Acurx: Grant/Research Support|Ferring: Advisor/Consultant|Paratek: Grant/Research Support

Ajzenstat, Janet, Paul Romney, Ian Gentles and William D. Gairdner, eds. Canada's Founding Debates. By Alan Cairns 847Lazar, Harvey, ed. Canada: The State of the Federation 1999/2000: Toward a New Mission Statement for Canadian Fiscal Federalism. By Hugh Mellon 848Mouchon, Jean. La politique sous l'influence des médias; Monière, Denis. Démocratie médiatique et représentation politique: analyse comparative de quatre journaux télévisés : Radio-Canada, France 2, RTBF (Belgique) et TSR (Suisse); et Gingras, Anne-Marie. Médias et démocratie. Le grand malentendu. Par Maud Vuillardot 850Livingstone, D. W., D. Hart and L. E. Davie. Public Attitudes towards Education in Ontario 1998: The Twelfth OISE/UT Survey; and O'Sullivan, Edmund. Transformative Learning: Educational Vision for the 21st Century. By Benjamin Levin 853Perrier, Yvan et Raymond Robert. Savoir Plus : outils et méthodes de travail intellectuel. Par Veronique Bell 855Salazar, Debra J. and Donald K. Alper, eds. Sustaining the Forests of the Pacific Coast: Forging Truces in the War in the Woods. By Jeremy Rayner 856DeLuca, Kevin Michael. Image Politics: The New Rhetoric of Environmental Activism. By Michael Howlett 857Beem, Christopher. The Necessity of Politics: Reclaiming American Public Life. By Loralea Michaelis 858Kennedy, Moorhead, R. Gordon Hoxie and Brenda Repland, eds. The Moral Authority of Government: Essays to Commemorate the Centennial of the National Institute of Social Sciences. By Joseph M. Knippenberg 860Atkinson, Hugh and Stuart Wilks-Heeg. Local Government from Thatcher to Blair: The Politics of Creative Autonomy. By G. W. Jones 862Geoghegan, Patrick M. The Irish Act of Union: A Study in High Politics, 1798-1801. By Gary Owens 863Sabetti, Filippo. The Search for Good Government: Understanding the Paradox of Italian Democracy. By Grant Amyot 864Stein, Eric. Thoughts from a Bridge: A Retrospective of Writings on New Europe and American Federalism. By Manuel Mertin 866Janos, Andrew C. East Central Europe in the Modern World: The Politics of the Borderlands from Pre- to Post-Communism. By Paul G. Lewis 869Higley, John and Gyorgy Lengyel, eds. Elites after State Socialism: Theories and Analysis. By Marta Dyczok 870Lomnitz, Larissa Adler and Ana Melnick. Chile's Political Culture and Parties: An Anthropological Explanation. By Ken Roberts 872Itzigsohn, José. Developing Poverty: The State, Labor Market Deregulation, and the Informal Economy in Costa Rica and the Dominican Republic. By Andrew Schrank 873Davenport, Rodney and Christopher Saunders. South Africa: A Modern History. By Hermann Giliomee 875Matthes, Melissa M. The Rape of Lucretia and the Founding of Republics. By Lori J. Marso 877Gorham, Eric B. The Theater of Politics: Hannah Arendt, Political Science, and Higher Education. By Herman van Gunsteren 878Dodd, Nigel. Social Theory and Modernity. By J. C. Myers 879Sciabarra, Chris Matthew. Total Freedom: Toward a Dialectical Libertarianism. By Paul Safier 881Sztompka, Piotr. Trust: A Sociological Theory. By Fiona M. Kay 882 Laugier, Sandra. Recommencer la philosphie. La philosophie américaine aujourd'hui. Par Dalie Giroux 884Bishop, John Douglas, ed. Ethics and Capitalism. By Raino Malnes 886Orend, Brian. War and International Justice: A Kantian Perspective. By Howard Williams 888Buchanan, Allen, Dan W. Brock, Norman Daniels and Daniel Wikler. From Chance to Choice: Genetics and Justice. By Travis D. Smith 889Young, Iris Marion. Inclusion and Democracy. By Jeff Spinner-Halev 891Shapiro, Ian and Stephen Macedo, eds. Designing Democratic Institutions. By John S. Dryzek 893O'Brien, Robert, Anne Marie Goetz, Jan Aart Scholte and Marc Williams. Global Governance: Multilateral Economic Institutions and Global Social Movements. By Stephen McBride 894Giddens, Anthony. Runaway World: How Globalization Is Reshaping Our Lives. By Trevor Salmon 896Haglund, David G., ed. Pondering NATO's Nuclear Options: Gambits for a Post-Westphalian World. By T.V. Paul 897Bertsch, Gary K. and William C. Potter, eds. Dangerous Weapons, Desperate States: Russia, Belarus, Kazakstan, and Ukraine. By Benjamin E. Goldsmith 898Shlaim, Avi. The Iron Wall: Israel and the Arab World. By Salim Mansur 900Aldecoa, Francisco and Michael Keating, eds. Paradiplomacy in Action: The Foreign Relations of Subnational Governments. By Hans J. Michelmann 901Davis, James W. Threats and Promises: The Pursuit of International Influence. By David Rousseau 903Lavoy, Peter R., Scott D. Sagan and James J. Wirtz, eds. Planning the Unthinkable: How New Powers Will Use Nuclear, Biological, and Chemical Weapons. By Greg Dinsmore 905

Pelo menos desde 1960, cartografias produzidas pelo urbanismo no campo dos deslocamentos urbanos têm se limitado ao posicionamento geográfico do observador, desconsiderando, em boa medida, a experiência encarnada dos sujeitos para além do visual, bem como os atores e agentes político-estratégicos de formação do território. Em 1965, Kevin Lynch, Donald Appleyard e John Myer publicam “The view from the road” e estabelecem uma metodologia de análise da qualidade da forma visual da cidade contemporânea a partir de estradas. Inauguram, em certa medida, uma leitura através do para-brisa do automóvel em movimento, engendrando, assim, um estudo por eles alcunhado de “estética das estradas urbanas”. Tal obra foca no posicionamento geográfico de dentro do automóvel e não considera em seu escopo quaisquer relações político-estratégicas acerca da aproximação desses sujeitos com aquele percurso ou espaço produzido. Nesse sentido, este artigo considera que é a partir da virada cartográfica e tecnológica ocorrida nos anos 1980 que a cidade contemporânea tem demandado uma complexidade cada vez maior na realização de leituras dos deslocamentos urbanos, que ocorrem enquanto disputa entre fluxos distintos experimentados e suas cartografias. De uma maneira incipiente, este problema aparece em “The view from the road”, mas bastante vinculado ao que se vê na paisagem, desconsiderando a diversidade e qualidade dos fluxos das vias. Para esta comunicação, busca-se dar visibilidade às importantes considerações metodológicas elencadas pelos planejadores nesta obra, no que diz respeito à ampliação do repertório do urbanismo a partir da imagem em movimento, indicando a necessidade de atualização das mesmas e de inserção de uma camada política do ato de cartografar, em conexão ao que Fredric Jameson alcunhou como “nova estética do mapeamento cognitivo”.

Introduction Ireland did not have a tradition of printed cookbooks prior to the 20th century. As a consequence, Irish culinary manuscripts from before this period are an important primary source for historians. This paper makes the case that the manuscripts are a unique way of accessing voices that have quotidian concerns seldom heard above the dominant narratives of conquest, colonisation and famine (Higgins; Dawson). Three manuscripts are examined to see how they contribute to an understanding of Irish social and culinary history. The Irish banking crisis of 2008 is a reminder that comments such as the one in the title of this paper may be more then a casual remark, indicating rather an underlying anxiety. Equally important is the evidence in the manuscripts that Ireland had a domestic culinary tradition sited within the culinary traditions of the British Isles. The terms “vernacular”, representing localised needs and traditions, and “polite”, representing stylistic features incorporated for aesthetic reasons, are more usually applied in the architectural world. As terms, they reflect in a politically neutral way the culinary divide witnessed in the manuscripts under discussion here. Two of the three manuscripts are anonymous, but all are written from the perspective of a well-provisioned house. The class background is elite and as such these manuscripts are not representative of the vernacular, which in culinary terms is likely to be a tradition recorded orally (Gold). The first manuscript (NLI, Tervoe) and second manuscript (NLI, Limerick) show the levels of impact of French culinary influence through their recipes for “cullis”. The Limerick manuscript also opens the discussion to wider social concerns. The third manuscript (NLI, Baker) is unusual in that the author, Mrs. Baker, goes to great lengths to record the provenance of the recipes and as such the collection affords a glimpse into the private “polite” world of the landed gentry in Ireland with its multiplicity of familial and societal connections. Cookbooks and Cuisine in Ireland in the 19th Century During the course of the 18th century, there were 136 new cookery book titles and 287 reprints published in Britain (Lehmann, Housewife 383). From the start of the 18th to the end of the 19th century only three cookbooks of Irish, or Anglo-Irish, authorship have been identified. The Lady’s Companion: or Accomplish’d Director In the whole Art of Cookery was published in 1767 by John Mitchell in Skinner-Row, under the pseudonym “Ceres,” while the Countess of Caledon’s Cheap Receipts and Hints on Cookery: Collected for Distribution Amongst the Irish Peasantry was printed in Armagh by J. M. Watters for private circulation in 1847. The modern sounding Dinners at Home, published in London in 1878 under the pseudonym “Short”, appears to be of Irish authorship, a review in The Irish Times describing it as being written by a “Dublin lady”, the inference being that she was known to the reviewer (Farmer). English Copyright Law was extended to Ireland in July 1801 after the Act of Union between Great Britain and Ireland in 1800 (Ferguson). Prior to this, many titles were pirated in Ireland, a cause of confusion alluded to by Lehmann when she comments regarding the Ceres book that it “does not appear to be simply a Dublin-printed edition of an English book” (Housewife 403). This attribution is based on the dedication in the preface: “To The Ladies of Dublin.” From her statement that she had a “great deal of experience in business of this kind”, one may conclude that Ceres had worked as a housekeeper or cook. Cheap Receipts and Hints on Cookery was the second of two books by Catherine Alexander, Countess of Caledon. While many commentators were offering advice to Irish people on how to alleviate their poverty, in Friendly Advice to Irish Mothers on Training their Children, Alexander was unusual in addressing her book specifically to its intended audience (Bourke). In this cookbook, the tone is of a practical didactic nature, the philosophy that of enablement. Given the paucity of printed material, manuscripts provide the main primary source regarding the existence of an indigenous culinary tradition. Attitudes regarding this tradition lie along the spectrum exemplified by the comments of an Irish journalist, Kevin Myers, and an eminent Irish historian, Louis Cullen. Myers describes Irish cuisine as a “travesty” and claims that the cuisine of “Old Ireland, in texture and in flavour, generally resembles the cinders after the suttee of a very large, but not very tasty widow”, Cullen makes the case that Irish cuisine is “one of the most interesting culinary traditions in Europe” (141). It is not proposed to investigate the ideological standpoints behind the various comments on Irish food. Indeed, the use of the term “Irish” in this context is fraught with difficulty and it should be noted that in the three manuscripts proposed here, the cuisine is that of the gentry class and representative of a particular stratum of society more accurately described as belonging to the Anglo-Irish tradition. It is also questionable how the authors of the three manuscripts discussed would have described themselves in terms of nationality. The anxiety surrounding this issue of identity is abating as scholarship has moved from viewing the cultural artifacts and buildings inherited from this class, not as symbols of an alien heritage, but rather as part of the narrative of a complex country (Rees). The antagonistic attitude towards this heritage could be seen as reaching its apogee in the late 1950s when the then Government minister, Kevin Boland, greeted the decision to demolish a row of Georgian houses in Dublin with jubilation, saying that they stood for everything that he despised, and describing the Georgian Society, who had campaigned for their preservation, as “the preserve of the idle rich and belted earls” (Foster 160). Mac Con Iomaire notes that there has been no comprehensive study of the history of Irish food, and the implications this has for opinions held, drawing attention to the lack of recognition that a “parallel Anglo-Irish cuisine existed among the Protestant elite” (43). To this must be added the observation that Myrtle Allen, the doyenne of the Irish culinary world, made when she observed that while we have an Irish identity in food, “we belong to a geographical and culinary group with Wales, England, and Scotland as all counties share their traditions with their next door neighbour” (1983). Three Irish Culinary Manuscripts The three manuscripts discussed here are held in the National Library of Ireland (NLI). The manuscript known as Tervoe has 402 folio pages with a 22-page index. The National Library purchased the manuscript at auction in December 2011. Although unattributed, it is believed to come from Tervoe House in County Limerick (O’Daly). Built in 1776 by Colonel W.T. Monsell (b.1754), the Monsell family lived there until 1951 (see, Fig. 1). The house was demolished in 1953 (Bence-Jones). William Monsell, 1st Lord Emly (1812–94) could be described as the most distinguished of the family. Raised in an atmosphere of devotion to the Union (with Great Britain), loyalty to the Church of Ireland, and adherence to the Tory Party, he converted in 1850 to the Roman Catholic religion, under the influence of Cardinal Newman and the Oxford Movement, changing his political allegiance from Tory to Whig. It is believed that this change took place as a result of the events surrounding the Great Irish Famine of 1845–50 (Potter). The Tervoe manuscript is catalogued as 18th century, and as the house was built in the last quarter of the century, it would be reasonable to surmise that its conception coincided with that period. It is a handsome volume with original green vellum binding, which has been conserved. Fig. 1. Tervoe House, home of the Monsell family. In terms of culinary prowess, the scope of the Tervoe manuscript is extensive. For the purpose of this discussion, one recipe is of particular interest. The recipe, To make a Cullis for Flesh Soups, instructs the reader to take the fat off four pounds of the best beef, roast the beef, pound it to a paste with crusts of bread and the carcasses of partridges or other fowl “that you have by you” (NLI, Tervoe). This mixture should then be moistened with best gravy, and strong broth, and seasoned with pepper, thyme, cloves, and lemon, then sieved for use with the soup. In 1747 Hannah Glasse published The Art of Cookery, Made Plain and Easy. The 1983 facsimile edition explains the term “cullis” as an Anglicisation of the French word coulis, “a preparation for thickening soups and stews” (182). The coulis was one of the essential components of the nouvelle cuisine of the 18th century. This movement sought to separate itself from “the conspicuous consumption of profusion” to one where the impression created was one of refinement and elegance (Lehmann, Housewife 210). Reactions in England to this French culinary innovation were strong, if not strident. Glasse derides French “tricks”, along with French cooks, and the coulis was singled out for particular opprobrium. In reality, Glasse bestrides both sides of the divide by giving the much-hated recipe and commenting on it. She provides another example of this in her recipe for The French Way of Dressing Partridges to which she adds the comment: “this dish I do not recommend; for I think it an odd jumble of thrash, by that time the Cullis, the Essence of Ham, and all other Ingredients are reckoned, the Partridges will come to a fine penny; but such Receipts as this, is what you have in most Books of Cookery yet printed” (53). When Daniel Defoe in The Complete English Tradesman of 1726 criticised French tradesmen for spending so much on the facades of their shops that they were unable to offer their customers a varied stock within, we can see the antipathy spilling over into other creative fields (Craske). As a critical strategy, it is not dissimilar to Glasse when she comments “now compute the expense, and see if this dish cannot be dressed full as well without this expense” at the end of a recipe for the supposedly despised Cullis for all Sorts of Ragoo (53). Food had become part of the defining image of Britain as an aggressively Protestant culture in opposition to Catholic France (Lehmann Politics 75). The author of the Tervoe manuscript makes no comment about the dish other than “A Cullis is a mixture of things, strained off.” This is in marked contrast to the second manuscript (NLI, Limerick). The author of this anonymous manuscript, from which the title of this paper is taken, is considerably perplexed by the term cullis, despite the manuscript dating 1811 (Fig. 2). Of Limerick provenance also, but considerably more modest in binding and scope, the manuscript was added to for twenty years, entries terminating around 1831. The recipe for Beef Stake (sic) Pie is an exact transcription of a recipe in John Simpson’s A Complete System of Cookery, published in 1806, and reads Cut some beef steaks thin, butter a pan (or as Lord Buckingham’s cook, from whom these rects are taken, calls it a soutis pan, ? [sic] (what does he mean, is it a saucepan) [sic] sprinkle the pan with pepper and salt, shallots thyme and parsley, put the beef steaks in and the pan on the fire for a few minutes then put them to cool, when quite cold put them in the fire, scrape all the herbs in over the fire and ornament as you please, it will take an hour and half, when done take the top off and put in some coulis (what is that?) [sic]. Fig. 2. Beef Stake Pie (NLI, Limerick). Courtesy of the National Library of Ireland. Simpson was cook to Lord Buckingham for at least a year in 1796, and may indeed have travelled to Ireland with the Duke who had several connections there. A feature of this manuscript are the number of Cholera remedies that it contains, including the “Rect for the cholera sent by Dr Shanfer from Warsaw to the Brussels Government”. Cholera had reached Germany by 1830, and England by 1831. By March 1832, it had struck Belfast and Dublin, the following month being noted in Cork, in the south of the country. Lasting a year, the epidemic claimed 50,000 lives in Ireland (Fenning). On 29 April 1832, the diarist Amhlaoibh Ó Súilleabháin notes, “we had a meeting today to keep the cholera from Callan. May God help us” (De Bhaldraithe 132). By 18 June, the cholera is “wrecking destruction in Ennis, Limerick and Tullamore” (135) and on 26 November, “Seed being sown. The end of the month wet and windy. The cholera came to Callan at the beginning of the month. Twenty people went down with it and it left the town then” (139). This situation was obviously of great concern and this is registered in the manuscript. Another concern is that highlighted by the recommendation that “this receipt is as good as the bank. It has been obligingly given to Mrs Hawkesworth by the chief book keeper at the Bank of Ireland” (NLI, Limerick). The Bank of Ireland commenced business at St. Mary’s Abbey in Dublin in June 1783, having been established under the protection of the Irish Parliament as a chartered rather then a central bank. As such, it supplied a currency of solidity. The charter establishing the bank, however, contained a prohibitory clause preventing (until 1824 when it was repealed) more then six persons forming themselves into a company to carry on the business of banking. This led to the formation, especially outside Dublin, of many “small private banks whose failure was the cause of immense wretchedness to all classes of the population” (Gilbert 19). The collapse that caused the most distress was that of the Ffrench bank in 1814, founded eleven years previously by the family of Lord Ffrench, one of the leading Catholic peers, based in Connacht in the west of Ireland. The bank issued notes in exchange for Bank of Ireland notes. Loans from Irish banks were in the form of paper money which were essentially printed promises to pay the amount stated and these notes were used in ordinary transactions. So great was the confidence in the Ffrench bank that their notes were held by the public in preference to Bank of Ireland notes, most particularly in Connacht. On 27 June 1814, there was a run on the bank leading to collapse. The devastation spread through society, from business through tenant farmers to the great estates, and notably so in Galway. Lord Ffrench shot himself in despair (Tennison). Williams and Finn, founded in Kilkenny in 1805, entered bankruptcy proceedings in 1816, and the last private bank outside Dublin, Delacours in Mallow, failed in 1835 (Barrow). The issue of bank failure is commented on by writers of the period, notably so in Dickens, Thackery, and Gaskill, and Edgeworth in Ireland. Following on the Ffrench collapse, notes from the Bank of Ireland were accorded increased respect, reflected in the comment in this recipe. The receipt in question is one for making White Currant Wine, with the unusual addition of a slice of bacon suspended from the bunghole when the wine is turned, for the purpose of enriching it. The recipe was provided to “Mrs Hawkesworth by the chief book keeper of the bank” (NLI, Limerick). In 1812, a John Hawkesworth, agent to Lord CastleCoote, was living at Forest Lodge, Mountrath, County Laois (Ennis Chronicle). The Coote family, although settling in County Laois in the seventeenth century, had strong connections with Limerick through a descendent of the younger brother of the first Earl of Mountrath (Landed Estates). The last manuscript for discussion is the manuscript book of Mrs Abraham Whyte Baker of Ballytobin House, County Kilkenny, 1810 (NLI, Baker). Ballytobin, or more correctly Ballaghtobin, is a townland in the barony of Kells, four miles from the previously mentioned Callan. The land was confiscated from the Tobin family during the Cromwellian campaign in Ireland of 1649–52, and was reputedly purchased by a Captain Baker, to establish what became the estate of Ballaghtobin (Fig. 3) To this day, it is a functioning estate, remaining in the family, twice passing down through the female line. In its heyday, there were two acres of walled gardens from which the house would have drawn for its own provisions (Ballaghtobin). Fig. 3. Ballaghtobin 2013. At the time of writing the manuscript, Mrs. Sophia Baker was widowed and living at Ballaghtobin with her son and daughter-in-law, Charity who was “no beauty, but tall, slight” (Herbert 414). On the succession of her husband to the estate, Charity became mistress of Ballaghtobin, leaving Sophia with time on what were her obviously very capable hands (Nevin). Sophia Baker was the daughter of Sir John Blunden of Castle Blunden and Lucinda Cuffe, daughter of the first Baron Desart. Sophia was also first cousin of the diarist Dorothea Herbert, whose mother was Lucinda’s sister, Martha. Sophia Baker and Dorothea Herbert have left for posterity a record of life in the landed gentry class in rural Georgian Ireland, Dorothea describing Mrs. Baker as “full of life and spirits” (Herbert 70). Their close relationship allows the two manuscripts to converse with each other in a unique way. Mrs. Baker’s detailing of the provenance of her recipes goes beyond the norm, so that what she has left us is not just a remarkable work of culinary history but also a palimpsest of her family and social circle. Among the people she references are: “my grandmother”; Dorothea Beresford, half sister to the Earl of Tyrone, who lived in the nearby Curraghmore House; Lady Tyrone; and Aunt Howth, the sister of Dorothea Beresford, married to William St Lawrence, Lord Howth, and described by Johnathan Swift as “his blue eyed nymph” (195). Other attributions include Lady Anne Fitzgerald, wife of Maurice Fitzgerald, 16th knight of Kerry, Sir William Parsons, Major Labilen, and a Mrs. Beaufort (Fig. 4). Fig. 4. Mrs. Beauforts Rect. (NLI, Baker). Courtesy of the National Library of Ireland. That this Mrs. Beaufort was the wife of Daniel Augustus Beaufort, mother of the hydrographer Sir Francis Beaufort, may be deduced from the succeeding recipe supplied by a Mrs. Waller. Mrs. Beaufort’s maiden name was Waller. Fanny Beaufort, the elder sister of Sir Francis, was Richard Edgeworth’s fourth wife and close friend and confidante of his daughter Maria, the novelist. There are also entries for “Miss Herbert” and “Aunt Herbert.” While the Baker manuscript is of interest for the fact that it intersects the worlds of the novelist Maria Edgeworth and the diarist Dorothea Herbert, and for the societal references that it documents, it is also a fine collection of recipes that date back to the mid-18th century. An example of this is a recipe for Sligo pickled salmon that Mrs. Baker, nee Blunden, refers to in an index that she gives to a second volume. Unfortunately this second volume is not known to be extant. This recipe features in a Blunden family manuscript of 1760 as referred to in Anelecta Hibernica (McLysaght). The recipe has also appeared in Cookery and Cures of Old Kilkenny (St. Canices’s 24). Unlike the Tervoe and Limerick manuscripts, Mrs. Baker is unconcerned with recipes for “cullis”. Conclusion The three manuscripts that have been examined here are from the period before the famine of 1845–50, known as An Gorta Mór, translated as “the big hunger”. The famine preceding this, Bliain an Áir (the year of carnage) in 1740–1 was caused by extremely cold and rainy weather that wiped out the harvest (Ó Gráda 15). This earlier famine, almost forgotten today, was more severe than the subsequent one, causing the death of an eight of the population of the island over one and a half years (McBride). These manuscripts are written in living memory of both events. Within the world that they inhabit, it may appear there is little said about hunger or social conditions beyond the walls of their estates. Subjected to closer analysis, however, it is evident that they are loquacious in their own unique way, and make an important contribution to the narrative of cookbooks. Through the three manuscripts discussed here, we find evidence of the culinary hegemony of France and how practitioners in Ireland commented on this in comparatively neutral fashion. An awareness of cholera and bank collapses have been communicated in a singular fashion, while a conversation between diarist and culinary networker has allowed a glimpse into the world of the landed gentry in Ireland during the Georgian period. References Allen, M. “Statement by Myrtle Allen at the opening of Ballymaloe Cookery School.” 14 Nov. 1983. Ballaghtobin. “The Grounds”. nd. 13 Mar. 2013. ‹http://www.ballaghtobin.com/gardens.html›. Barrow, G.L. “Some Dublin Private Banks.” Dublin Historical Record 25.2 (1972): 38–53. Bence-Jones, M. A Guide to Irish Country Houses. London: Constable, 1988. Bourke, A. Ed. Field Day Anthology of Irish Writing Vol V. Cork: Cork UP, 2002. Craske, M. “Design and the Competitive Spirit in Early and Mid 18th Century England”, Journal of Design History 12.3 (1999): 187–216. Cullen, L. The Emergence of Modern Ireland. London: Batsford, 1981. Dawson, Graham. “Trauma, Memory, Politics. The Irish Troubles.” Trauma: Life Stories of Survivors. Ed. Kim Lacy Rogers, Selma Leydesdorff and Graham Dawson. New Jersey: Transaction P, 2004. De Bhaldraithe,T. Ed. Cín Lae Amhlaoibh. Cork: Mercier P, 1979. Ennis Chronicle. 12–23 Feb 1812. 10 Feb. 2013 ‹http://astheywere.blogspot.ie/2012/12/ennis-chronicle-1812-feb-23-feb-12.html› Farmar, A. E-mail correspondence between Farmar and Dr M. Mac Con Iomaire, 26 Jan. 2011. Fenning, H. “The Cholera Epidemic in Ireland 1832–3: Priests, Ministers, Doctors”. Archivium Hibernicum 57 (2003): 77–125. Ferguson, F. “The Industrialisation of Irish Book Production 1790-1900.” The Oxford History of the Irish Book, Vol. IV The Irish Book in English 1800-1891. Ed. J. Murphy. Oxford: Oxford UP, 2011. Foster, R.F. Luck and the Irish: A Brief History of Change from 1970. Oxford: Oxford UP, 2008. Gilbert, James William. The History of Banking in Ireland. London: Longman, Rees, Orme, Brown, Green, and Longman, 1836. Glasse, Hannah. The Art of Cookery Made Plain and Easy by a Lady: Facsimile Edition. Devon: Prospect, 1983. Gold, C. Danish Cookbooks. Seattle: U of Washington P, 2007. Herbert, D. Retrospections of an Outcast or the Life of Dorothea Herbert. London: Gerald Howe, 1929. Higgins, Michael D. “Remarks by President Michael D. Higgins reflecting on the Gorta Mór: the Great famine of Ireland.” Famine Commemoration, Boston, 12 May 2012. 18 Feb. 2013 ‹http://www.president.ie/speeches/ › Landed Estates Database, National University of Galway, Moore Institute for Research, 10 Feb. 2013 ‹http://landedestates.nuigalway.ie/LandedEstates/jsp/family-show.jsp?id=633.› Lehmann, G. The British Housewife: Cookery books, cooking and society in eighteenth-century Britain. Totnes: Prospect, 1993. ---. “Politics in the Kitchen.” 18th Century Life 23.2 (1999): 71–83. Mac Con Iomaire, M. “The Emergence, Development and Influence of French Haute Cuisine on Public Dining in Dublin Restaurants 1900-2000: An Oral History”. Vol. 2. PhD thesis. Dublin Institute of Technology. 2009. 8 Mar. 2013 ‹http://arrow.dit.ie/tourdoc/12›. McBride, Ian. Eighteenth Century Ireland: The Isle of Slaves. Dublin: Gill and Macmillan, 2009. McLysaght, E.A. Anelecta Hibernica 15. Dublin: Irish Manuscripts Commission, 1944. Myers, K. “Dinner is served ... But in Our Culinary Dessert it may be Korean.” The Irish Independent 30 Jun. 2006. Nevin, M. “A County Kilkenny Georgian Household Notebook.” Journal of the Royal Society of Antiquaries of Ireland 109 (1979): 5–18. (NLI) National Library of Ireland. Baker. 19th century manuscript. MS 34,952. ---. Limerick. 19th century manuscript. MS 42,105. ---. Tervoe. 18th century manuscript. MS 42,134. Ó Gráda, C. Famine: A Short History. New Jersey: Princeton UP, 2009. O’Daly, C. E-mail correspondence between Colette O’Daly, Assistant Keeper, Dept. of Manuscripts, National Library of Ireland and Dorothy Cashman. 8 Dec. 2011. Potter, M. William Monsell of Tervoe 1812-1894. Dublin: Irish Academic P, 2009. Rees, Catherine. “Irish Anxiety, Identity and Narrative in the Plays of McDonagh and Jones.” Redefinitions of Irish Identity: A Postnationalist Approach. Eds. Irene Gilsenan Nordin and Carmen Zamorano Llena. Bern: Peter Lang, 2010. St. Canice’s. Cookery and Cures of Old Kilkenny. Kilkenny: Boethius P, 1983. Swift, J. The Works of the Rev Dr J Swift Vol. XIX Dublin: Faulkner, 1772. 8 Feb. 2013. ‹http://www.google.ie/search?tbm=bks&hl=en&q=works+of+jonathan+swift+Vol+XIX+&btnG=› Tennison, C.M. “The Old Dublin Bankers.” Journal of the Cork Historical and Archeological Society 1.2 (1895): 36–9.

Over the past century, many books for general readers have styled sharks as “monsters of the deep” (Steele). In recent decades, however, at least some writers have also turned to representing how sharks are seriously threatened by human activities. At a time when media coverage of shark sightings seems ever increasing in Australia, scholarship has begun to consider people’s attitudes to sharks and how these are formed, investigating the representation of sharks (Peschak; Ostrovski et al.) in films (Le Busque and Litchfield; Neff; Schwanebeck), newspaper reports (Muter et al.), and social media (Le Busque et al., “An Analysis”). My own research into representations of surfing and sharks in Australian writing (Brien) has, however, revealed that, although reporting of shark sightings and human-shark interactions are prominent in the news, and sharks function as vivid and commanding images and metaphors in art and writing (Ellis; Westbrook et al.), little scholarship has investigated their representation in Australian books published for a general readership. While recognising representations of sharks in other book-length narrative forms in Australia, including Australian fiction, poetry, and film (Ryan and Ellison), this enquiry is focussed on non-fiction books for general readers, to provide an initial review. Sampling holdings of non-fiction books in the National Library of Australia, crosschecked with Google Books, in early 2021, this investigation identified 50 Australian books for general readers that are principally about sharks, or that feature attitudes to them, published from 1911 to 2021. Although not seeking to capture all Australian non-fiction books for general readers that feature sharks, the sampling attempted to locate a wide range of representations and genres across the time frame from the earliest identified text until the time of the survey. The books located include works of natural and popular history, travel writing, memoir, biography, humour, and other long-form non-fiction for adult and younger readers, including hybrid works. A thematic analysis (Guest et al.) of the representation of sharks in these texts identified five themes that moved from understanding sharks as fishes to seeing them as monsters, then prey, and finally to endangered species needing conservation. Many books contained more than one theme, and not all examples identified have been quoted in the discussion of the themes below. Sharks as Part of the Natural Environment Drawing on oral histories passed through generations, two memoirs (Bradley et al.; Fossa) narrate Indigenous stories in which sharks play a central role. These reveal that sharks are part of both the world and a wider cosmology for Aboriginal and Torres Strait Islander people (Clua and Guiart). In these representations, sharks are integrated with, and integral to, Indigenous life, with one writer suggesting they are “creator beings, ancestors, totems. Their lifecycles reflect the seasons, the landscape and sea country. They are seen in the movement of the stars” (Allam). A series of natural history narratives focus on zoological studies of Australian sharks, describing shark species and their anatomy and physiology, as well as discussing shark genetics, behaviour, habitats, and distribution. A foundational and relatively early Australian example is Gilbert P. Whitley’s The Fishes of Australia: The Sharks, Rays, Devil-fish, and Other Primitive Fishes of Australia and New Zealand, published in 1940. Ichthyologist at the Australian Museum in Sydney from the early 1920s to 1964, Whitley authored several books which furthered scientific thought on sharks. Four editions of his Australian Sharks were published between 1983 and 1991 in English, and the book is still held in many libraries and other collections worldwide. In this text, Whitley described a wide variety of sharks, noting shared as well as individual features. Beautiful drawings contribute information on shape, colouring, markings, and other recognisable features to assist with correct identification. Although a scientist and a Fellow and then President of the Royal Zoological Society of New South Wales, Whitley recognised it was important to communicate with general readers and his books are accessible, the prose crisp and clear. Books published after this text (Aiken; Ayling; Last and Stevens; Tricas and Carwardine) share Whitley’s regard for the diversity of sharks as well as his desire to educate a general readership. By 2002, the CSIRO’s Field Guide to Australian Sharks & Rays (Daley et al.) also featured numerous striking photographs of these creatures. Titles such as Australia’s Amazing Sharks (Australian Geographic) emphasise sharks’ unique qualities, including their agility and speed in the water, sensitive sight and smell, and ability to detect changes in water pressure around them, heal rapidly, and replace their teeth. These books also emphasise the central role that sharks play in the marine ecosystem. There are also such field guides to sharks in specific parts of Australia (Allen). This attention to disseminating accurate zoological information about sharks is also evident in books written for younger readers including very young children (Berkes; Kear; Parker and Parker). In these and other similar books, sharks are imaged as a central and vital component of the ocean environment, and the narratives focus on their features and qualities as wondrous rather than monstrous. Sharks as Predatory Monsters A number of books for general readers do, however, image sharks as monsters. In 1911, in his travel narrative Peeps at Many Lands: Australia, Frank Fox describes sharks as “the most dangerous foes of man in Australia” (23) and many books have reinforced this view over the following century. This can be seen in titles that refer to sharks as dangerous predatory killers (Fox and Ruhen; Goadby; Reid; Riley; Sharpe; Taylor and Taylor). The covers of a large proportion of such books feature sharks emerging from the water, jaws wide open in explicit homage to the imaging of the monster shark in the film Jaws (Spielberg). Shark!: Killer Tales from the Dangerous Depths (Reid) is characteristic of books that portray encounters with sharks as terrifying and dramatic, using emotive language and stories that describe sharks as “the world’s most feared sea creature” (47) because they are such “highly efficient killing machines” (iv, see also 127, 129). This representation of sharks is also common in several books for younger readers (Moriarty; Rohr). Although the risk of being injured by an unprovoked shark is extremely low (Chapman; Fletcher et al.), fear of sharks is prevalent and real (Le Busque et al., “People’s Fear”) and described in a number of these texts. Several of the memoirs located describe surfers’ fear of sharks (Muirhead; Orgias), as do those of swimmers, divers, and other frequent users of the sea (Denness; de Gelder; McAloon), even if the author has never encountered a shark in the wild. In these texts, this fear of sharks is often traced to viewing Jaws, and especially to how the film’s huge, bloodthirsty great white shark persistently and determinedly attacks its human hunters. Pioneer Australian shark expert Valerie Taylor describes such great white sharks as “very big, powerful … and amazingly beautiful” but accurately notes that “revenge is not part of their thought process” (Kindle version). Two books explicitly seek to map and explain Australians’ fear of sharks. In Sharks: A History of Fear in Australia, Callum Denness charts this fear across time, beginning with his own “shark story”: a panicked, terror-filled evacuation from the sea, following the sighting of a shadow which turned out not to be a shark. Blake Chapman’s Shark Attacks: Myths, Misunderstandings and Human Fears explains commonly held fearful perceptions of sharks. Acknowledging that sharks are a “highly emotive topic”, the author of this text does not deny “the terror [that] they invoke in our psyche” but makes a case that this is “only a minor characteristic of what makes them such intriguing animals” (ix). In Death by Coconut: 50 Things More Dangerous than a Shark and Why You Shouldn’t Be Afraid of the Ocean, Ruby Ashby Orr utilises humour to educate younger readers about the real risk humans face from sharks and, as per the book’s title, why they should not be feared, listing champagne corks and falling coconuts among the many everyday activities more likely to lead to injury and death in Australia than encountering a shark. Taylor goes further in her memoir – not only describing her wonder at swimming with these creatures, but also her calm acceptance of the possibility of being injured by a shark: "if we are to be bitten, then we are to be bitten … . One must choose a life of adventure, and of mystery and discovery, but with that choice, one must also choose the attendant risks" (2019: Kindle version). Such an attitude is very rare in the books located, with even some of the most positive about these sea creatures still quite sensibly fearful of potentially dangerous encounters with them. Sharks as Prey There is a long history of sharks being fished in Australia (Clark). The killing of sharks for sport is detailed in An American Angler in Australia, which describes popular adventure writer Zane Grey’s visit to Australia and New Zealand in the 1930s to fish ‘big game’. This text includes many bloody accounts of killing sharks, which are justified with explanations about how sharks are dangerous. It is also illustrated with gruesome pictures of dead sharks. Australian fisher Alf Dean’s biography describes him as the “World’s Greatest Shark Hunter” (Thiele), this text similarly illustrated with photographs of some of the gigantic sharks he caught and killed in the second half of the twentieth century. Apart from being killed during pleasure and sport fishing, sharks are also hunted by spearfishers. Valerie Taylor and her late husband, Ron Taylor, are well known in Australia and internationally as shark experts, but they began their careers as spearfishers and shark hunters (Taylor, Ron Taylor’s), with the documentary Shark Hunters gruesomely detailing their killing of many sharks. The couple have produced several books that recount their close encounters with sharks (Taylor; Taylor, Taylor and Goadby; Taylor and Taylor), charting their movement from killers to conservationists as they learned more about the ocean and its inhabitants. Now a passionate campaigner against the past butchery she participated in, Taylor’s memoir describes her shift to a more respectful relationship with sharks, driven by her desire to understand and protect them. In Australia, the culling of sharks is supposedly carried out to ensure human safety in the ocean, although this practice has long been questioned. In 1983, for instance, Whitley noted the “indiscriminate” killing of grey nurse sharks, despite this species largely being very docile and of little threat to people (Australian Sharks, 10). This is repeated by Tony Ayling twenty-five years later who adds the information that the generally harmless grey nurse sharks have been killed to the point of extinction, as it was wrongly believed they preyed on surfers and swimmers. Shark researcher and conservationist Riley Elliott, author of Shark Man: One Kiwi Man’s Mission to Save Our Most Feared and Misunderstood Predator (2014), includes an extremely critical chapter on Western Australian shark ‘management’ through culling, summing up the problems associated with this approach: it seems to me that this cull involved no science or logic, just waste and politics. It’s sickening that the people behind this cull were the Fisheries department, which prior to this was the very department responsible for setting up the world’s best acoustic tagging system for sharks. (Kindle version, Chapter 7) Describing sharks as “misunderstood creatures”, Orr is also clear in her opposition to killing sharks to ‘protect’ swimmers noting that “each year only around 10 people are killed in shark attacks worldwide, while around 73 million sharks are killed by humans”. She adds the question and answer, “sounds unfair? Of course it is, but when an attack is all over the news and the people are baying for shark blood, it’s easy to lose perspective. But culling them? Seriously?” (back cover). The condemnation of culling is also evident in David Brooks’s recent essay on the topic in his collection of essays about animal welfare, conservation and the relationship between humans and other species, Animal Dreams. This disapproval is also evident in narratives by those who have been injured by sharks. Navy diver Paul de Gelder and surfer Glen Orgias were both bitten by sharks in Sydney in 2009 and both their memoirs detail their fear of sharks and the pain they suffered from these interactions and their lengthy recoveries. However, despite their undoubted suffering – both men lost limbs due to these encounters – they also attest to their ongoing respect for these creatures and specify a shared desire not to see them culled. Orgias, instead, charts the life story of the shark who bit him alongside his own story in his memoir, musing at the end of the book, not about himself or his injury, but about the fate of the shark he had encountered: great whites are portrayed … as pathological creatures, and as malevolent. That’s rubbish … they are graceful, mighty beasts. I respect them, and fear them … [but] the thought of them fighting, dying, in a net upsets me. I hope this great white shark doesn’t end up like that. (271–271) Several of the more recent books identified in this study acknowledge that, despite growing understanding of sharks, the popular press and many policy makers continue to advocate for shark culls, these calls especially vocal after a shark-related human death or injury (Peppin-Neff). The damage to shark species involved caused by their killing – either directly by fishing, spearing, finning, or otherwise hunting them, or inadvertently as they become caught in nets or affected by human pollution of the ocean – is discussed in many of the more recent books identified in this study. Sharks as Endangered Alongside fishing, finning, and hunting, human actions and their effects such as beach netting, pollution and habitat change are killing many sharks, to the point where many shark species are threatened. Several recent books follow Orr in noting that an estimated 100 million sharks are now killed annually across the globe and that this, as well as changes to their habitats, are driving many shark species to the status of vulnerable, threatened or towards extinction (Dulvy et al.). This is detailed in texts about biodiversity and climate change in Australia (Steffen et al.) as well as in many of the zoologically focussed books discussed above under the theme of “Sharks as part of the natural environment”. The CSIRO’s Field Guide to Australian Sharks & Rays (Daley et al.), for example, emphasises not only that several shark species are under threat (and protected) (8–9) but also that sharks are, as individuals, themselves very fragile creatures. Their skeletons are made from flexible, soft cartilage rather than bone, meaning that although they are “often thought of as being incredibly tough; in reality, they need to be handled carefully to maximise their chance of survival following capture” (9). Material on this theme is included in books for younger readers on Australia’s endangered animals (Bourke; Roc and Hawke). Shark Conservation By 1991, shark conservation in Australia and overseas was a topic of serious discussion in Sydney, with an international workshop on the subject held at Taronga Zoo and the proceedings published (Pepperell et al.). Since then, the movement to protect sharks has grown, with marine scientists, high-profile figures and other writers promoting shark conservation, especially through attempts to educate the general public about sharks. De Gelder’s memoir, for instance, describes how he now champions sharks, promoting shark conservation in his work as a public speaker. Peter Benchley, who (with Carl Gottlieb) recast his novel Jaws for the film’s screenplay, later attested to regretting his portrayal of sharks as aggressive and became a prominent spokesperson for shark conservation. In explaining his change of heart, he stated that when he wrote the novel, he was reflecting the general belief that sharks would both seek out human prey and attack boats, but he later discovered this to be untrue (Benchley, “Without Malice”). Many recent books about sharks for younger readers convey a conservation message, underscoring how, instead of fearing or killing sharks, or doing nothing, humans need to actively assist these vulnerable creatures to survive. In the children’s book series featuring Bindi Irwin and her “wildlife adventures”, there is a volume where Bindi and a friend are on a diving holiday when they find a dead shark whose fin has been removed. The book not only describes how shark finning is illegal, but also how Bindi and friend are “determined to bring the culprits to justice” (Browne). This narrative, like the other books in this series, has a dual focus; highlighting the beauty of wildlife and its value, but also how the creatures described need protection and assistance. Concluding Discussion This study was prompted by the understanding that the Earth is currently in the epoch known as the Anthropocene, a time in which humans have significantly altered, and continue to alter, the Earth by our activities (Myers), resulting in numerous species becoming threatened, endangered, or extinct. It acknowledges the pressing need for not only natural science research on these actions and their effects, but also for such scientists to publish their findings in more accessible ways (see, Paulin and Green). It specifically responds to demands for scholarship outside the relevant areas of science and conservation to encourage widespread thinking and action (Mascia et al.; Bennett et al.). As understanding public perceptions and overcoming widely held fear of sharks can facilitate their conservation (Panoch and Pearson), the way sharks are imaged is integral to their survival. The five themes identified in this study reveal vastly different ways of viewing and writing about sharks. These range from seeing sharks as nothing more than large fishes to be killed for pleasure, to viewing them as terrifying monsters, to finally understanding that they are amazing creatures who play an important role in the world’s environment and are in urgent need of conservation. This range of representation is important, for if sharks are understood as demon monsters which hunt humans, then it is much more ‘reasonable’ to not care about their future than if they are understood to be fascinating and fragile creatures suffering from their interactions with humans and our effect on the environment. Further research could conduct a textual analysis of these books. In this context, it is interesting to note that, although in 1949 C. Bede Maxwell suggested describing human deaths and injuries from sharks as “accidents” (182) and in 2013 Christopher Neff and Robert Hueter proposed using “sightings, encounters, bites, and the rare cases of fatal bites” (70) to accurately represent “the true risk posed by sharks” to humans (70), the majority of the books in this study, like mass media reports, continue to use the ubiquitous and more dramatic terminology of “shark attack”. The books identified in this analysis could also be compared with international texts to reveal and investigate global similarities and differences. While the focus of this discussion has been on non-fiction texts, a companion analysis of representation of sharks in Australian fiction, poetry, films, and other narratives could also be undertaken, in the hope that such investigations contribute to more nuanced understandings of these majestic sea creatures. 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Introduction The proliferation of non-fungible tokens has transformed cryptocurrency artefacts into a legitimised art form now considered in mainstream art collecting as an emerging high-yield commodity based on scarcity. As photography was debated “of being art” in the late 19th century, video art in the 1960s, virtual reality in the 1990s, and augmented reality in the 2010s, NFT art is the next medium of artwork tied to emergent cultural forms. From the concept of “introducing scarcity from born-digital assets for the first time ever, NFTs or crypto or digital collectibles, as they are also referred to, have already shown glimpses of their potential'” (Valeonti et al. 1). Yet for NFT art, “numerous misconceptions still exist that are partly caused by the complexity of the technology and partly by the existence of many blockchain variants” (Treiblmaier 2). As the discussion of NFT art is still centred on questions of justifying the legitimacy of the medium and its financial trading, critical analysis outside of these key points is still limited to blogs and online articles as the mainstay of debate. To distance NFTs from a common assumption that they are in some form or another a populous digital fad, cryptocurrencies are intended primarily as currencies, even if they maintain some asset-like properties (Baur et al.). In a broader sense, NFTs have positioned digital art as a collectable staple as “the most common types are collectibles and artworks, objects in virtual worlds, and digitalised characters from sports and other games” (Dowling). As a point of origin "NFTs were originally developed using the Ethereum blockchain, [while] many other blockchain networks now facilitate trade and exchange of NFTs” (Wilson et al.). “Given NFTs link to underlying assets that are unique in some way and cannot be exchanged like for like” (Bowden and Jones), this article will consider how artists respond to this uniqueness, which separates the art as simply trading an artefact on a crypto platform, to instead consider a different approach that attests to legitimising the medium as a conceptual space. The concept of NFTs was first introduced in 2012 with Bitcoin’s “Colored Coins”, which referred to tokens that represent any type of physical asset “such as real estate properties, cars and bonds” (Rosenfeld). To that end, the origins of NFTs, as we know, attach themselves to rarities, much the same as any other luxury trading artefact. But where NFTs differ is, as a system, in the non-fungibility of their agency and, as an artefact, the singularity of their rarity and uniqueness. As an example in art, consider a Van Gogh painting where its rarity sustains its value, as there are only a certain number of Van Gogh paintings in circulation. Thus, the value of a Van Gogh painting in the domain of rarity is determined by its metadata with attention to the verification of the authenticity of the artefact and, among others, its subsequent details of the year it was painted. NFTs work along with the same premise: both the Van Gogh painting’s data and an NFT are non-fungible because they cannot be forged, but the painting is fungible because it can be forged. From here, there are two components to associate with NFT art. The first is the NFT, which is the data of a digital token registered on a blockchain. The second is the artefact associated with the NFT, which we know as NFT art. But the system by which NFTs exists as a blockchain is different from, say, buying shares listed in a stock market. Therefore, to find a conceptuality in NFT art, the idea of an NFT artwork as a singular tradable commodity needs to be rethought as not the artefact per se, but the effect of the condition brought about by a combination of the artefact, the currency, and nature of its transaction system. To think of these key points as an independent singularity dismantles any sense of a conceptual framework by which NFT art can exist beyond its form. As McLoughlin argues, “unlike the commercial gallery business model, NFTs are designed to cut out the need for art dealers, enabling artists to trade directly online, typically via specialist auction sites” (McLoughlin). With regards to the GLAM sector, the conceptuality of this disruption positions both the born-digital artefact and the system of trading of the artefact as inextricably linked together. Yet the way this link is considered, even by galleries and curators alike, invites further attention to see NFT art not as a fad, but as a beginning of an entirely new system of the digital genre. Background From an aesthetics perspective, recent hostility surrounding the acceptance of NFT art within the establishment has predictably taken issue with the low-brow nature of mainstream avatar-oriented NFT art; for example, Bored Ape Yacht Club and Cryptopunks not surprisingly have been at odds with “proper” art. More so, other artists who have used blockchain in their practice, including Kevin McCoy, Mitchel F. Chan, and Rhea Myers, contributed to early crypto art especially in the 2010s to be inclusive of the proliferation of NFT art as a fine arts medium. Yet despite these contributions, the polarising of NFT art within the art world, as Widdington asserts, has accounted for assumptions that NFT art is identified as being of populous kitsch, lowbrow images, where contemporary art is in opposition to the critique it subjectifies itself against. The art establishment’s disdain towards the aesthetics of NFTs is historically predictable. Early NFT art focussed on pop culture references that have significance within the crypto community (Pepe memes, collectible CryptoKitties), and similarly, in the 1980s, Jeff Koons forced the world of “high art” to confront and accept his works rejoicing in pop culture (Michael Jackson, Pink Panther; Widdington). A key point from Widdington’s claim can be attested for other art that came before Postmodernism, linked firmly to artists using identifiers as part of their studio practice. Moreover, the tying of artwork to a non-fungible identifier is not new. Sol LeWitt's Wall Drawing #793B Certificate (LeWitt) compounded his manifesto that “the idea becomes a machine that makes the art” (LeWitt). By adopting the practice that each of his artworks was accompanied by an authenticity certificate, where the identification code forced a fungible asset to be associated with a unique non-fungible asset, it is the ownership of a certificate of authenticity, or a smart contract on the blockchain in the case of an NFT, that makes the artist’s work unique and therein valuable (Widdington). The scarcity of born-digital assets drives demand for collecting NFT art and joins a financial aspect tied to the process of buying and selling crypto assets. This is obviously different from a crypto conceptuality which exists outside the process and thereby manifests in the idea of what intersects the process, and, in the case of NFT artworks, the subject of the image being traded. Just as LeWitt’s certificate of ownership was thought to raise questions about authenticity and uniqueness through abstract thinking, the concept of art derived from NFT art is fundamentally no different. Both use non-fungibility as a condition of their agency to first address what can be copied and what remains as unique. Second, the mechanism of a ledger that, for NFTs, is blockchain and, for a certificate of authenticity, is the assigned number of the unique identifier, regulates scarcity by using a system to define uniqueness. Adopting this manifesto invites a different way to consider NFT art when the main conversation about NFT art in popular journalism or blogging is a narrow discussion either about the legitimacy of NFTs as an authentic financial stock or about the amount of money they transact in collecting the artefacts. One such conceptuality is in the recent NFT artwork of Damien Hirst. NFT Art Damien Hirst’s The Currency “is composed of 10,000 NFTs linked to 10,000 individual spot paintings on paper” (Hawkins) which are inclusive of added security devices within the paper itself to make the physical asset unique. The purchaser can decide if they would like to own the NFT “or ... keep the physical work and relinquish rights to the blockchain-based artwork” (Goldstein). Perspectives of the project, despite the fact that “Hirst has become a renewed critical target in the left and left-liberal media” (White 197) for his NFT project, not to mention being lamented as “Thatcher’s Warhol” (Lemmey), range from indicating “greater fool theory” (Hawkins) to the questioning of a “responsibility to other NFT artists in the market” (Meyohas). However, discussion on the conceptuality created by The Currency, especially its ontology, is muted if not ignored altogether, which this article considers a fundamental oversight in any credible critical assessment of NFT art. Given that Hirst’s artwork has consistently been moulded around conceptual art, whereby the idea of art becomes the artwork not necessarily found in the hand-made aspect of the artefact itself, the idea of The Currency is to question the role and relationship of art and money through an allegory. One might argue that its conceptuality then affords the idea of the artwork being a currency in itself. It speaks to divisibility, just as the cryptocurrency used to purchase the artworks is divisible of its own tender. The disjuncture in this accord is that “NFTs are not currencies themselves, but rather more like records of ownership” (Cornelius 2). The dot paintings on paper are created as unique artefacts where their uniqueness makes them rare, and this uniqueness makes the rarity an increase in financial value. However, subverting this are Hirst’s physical creations, where the legal tender’s conceptuality is manufactured with watermarks, security embeds, and financial markings the same as traded bills. If this perspective is considered a concept, not a digital selling point, then The Currency prompts further debate on how NFT art can, on the one hand, disrupt the way we might think about the financial systems within cryptocurrencies, and on the other hand, fuel debate on how collecting art within traditional markets has been transformed through the emergence of cryptocurrencies. These once excluded forms of money, often thought of as scams, vapourware, and Ponzi schemes from collectable trade, now dwarf digital art auction sales at an exponential margin; see, for example, the recent Christie's sale of Beeple’s NFT art. When dissecting The Currency through a conceptuality, it is important to state that this is not the first time that artists have used currency to conceptualise social questions about money. At a system level, Marcel Duchamp created his work Monte Carlo Bond (Duchamp), which “advertised a series of bonds by which he claimed he would exploit a system he had developed to make money while at the roulette wheel in Monaco” (Russeth). At an artefact level, artist Mark Wagner “deconstructed dollar bills to make portraits of presidents, recreations of famous paintings and other collages” (Ryssdal and Hollenhorst). Most notoriously, “Jens Haaning was loaned 534,000 kroner ($116,106) in cash to recreate his old artworks using the banknotes [but] pocketed the money and sent back blank canvases with a new title: "Take the Money and Run" (ABC News). If anything, The Currency is merely one of many artists' responses in a long history of exploring art and money. Yet the conceptuality of Hirst’s tender lends itself to deploying a conceptual currency system that says more about the money transactions of the art world than it does about the art sold as a financial transaction. More so, a clever subversion by Hirst, whose ongoing thematic produces artworks about mortality, life, and death, places this thematic back on the purchasers of The Currency to decide if they will “kill” the tethered artwork; that is, if they accept the NFT and not the assigned NFT art, the artwork will be destroyed by an act of burning. Hirst’s conceptuality from The Currency forces the consumer to “play God” by deciding which component is destroyed or not, posing the moral question of how we value the immorality of destroying an artwork for the sake of profitability from a born-digital token. The twist at the end is that Hirst melds such a moral choice with “an experiment in the highly irrational economics of collectibles and blockchain technology” (Hawkins). While this article acknowledges that the extreme wealth of Hirst plays a determining factor in how The Currency has been received by the public, one might argue that such polarising opinions are of no value to the critical assessment of The Currency nor the conceptualities of NFT art when determining the mechanical aspects of the artworks. The same invalidation emerged in December 2021, when “a group of Wikipedia editors ... voted not to categorize NFTs as art—at least for now” (Artnews). This standpoint contradicts the New York Times, which referred to Beeple as the “third-highest-selling artist alive” after his Christie’s sale (Artnews). Bowden and Jones provide insight into this kind of hesitation in legitimising NFT art, saying that “the tension between innovation and incumbency also contributes to the scepticism that always surrounds such new technologies” (Bowden and Jones). Another example, Beautiful Thought Coins from Australian artist Shaun Wilson, is made up of 200 digital hand-drawn colour field NFT artworks that are an allegorical investigation into bureaucracy, emotion, and currency. “The project is complete with a virtual exhibition, digital art prints, art book, and a soundtrack of AI hosted podcasts exploring everything from NFTs to chihuahuas” (Lei). As with The Currency, Beautiful Thought Coins approaches a conceptuality about NFT art through its subject, but also in the embodiment of the currency embedded within the NFT digital ecosystem. Not surprisingly, the artwork depicts coins sharing a direct relationship to the roundel paintings of Jasper John and Peter Blake, but instead with the design proportions of the iconic Type C.1 roundels adopted by the Royal Air Force between 1942 and 1947. Merging these similarities between its pop-art heritage and historical references, the allegorical discussion in Beautiful Thought Coins centres around the pretext of bureaucracy that extends to the individual artwork’s metadata. As featured on its OpenSea sales window, each of the coins has substantial metadata that, when expanded to view, reveal a secondary narrative found in the qualities each NFT has linked to its identifier. Once compared with other tokens, these metadata expand into a separate story with the NFT artworks, using fictitious qualities that link directly to the titles of each artwork in the digital collection to describe how each of the coins is feeling. One might argue that in this instance, the linking of metadata narratives to the artworks functions as an ontological framework. Wilson’s coins draw similarly to philosophical questions raised by Cross, who asks “what, exactly, is the ontological status of an NFT in relation to the work linked to it?” (Cross). Likewise, in the exhibition catalogue of Beautiful Thoughts Coins, Church states that the ontology of this series appears to be linked to a conceptuality with more questions than answers about the ‘lifestyle’ bureaucracy attached to NFT art, where the branding of the artwork by a digital token will make you feel better with the promise to also make you potentially wealthy. (Church) When considering the nature of the artwork's divisibility, ontology plays a part in finding a link between its allegory and aesthetic. Given that each image of the roundels is identical, except for the colours that fill each of its four rings, the divisibility of the hue in the subject is likened to the divisibility of the cryptocurrency that purchases NFTs. Conclusion This article has discussed NFT art in the context of its emergent conceptuality. Through assessment of the crypto artwork of Hirst and Wilson, it has proposed a way of thinking about how this conceptuality can remove NFT art from a primary attachment to financial exchange, to instead give rise to considerations of the allegory surmounting both fungible and non-fungible artefacts linked to digital tokens. Both series of works draw allegorical commentary about the nature of currency. Hirst takes a literal approach to manufacture physical artworks as a mock currency linked to minted NFTs to discuss the transactions of money in art. Wilson manufactures digital artworks by creating images of coins linked to minted NFTs to discuss the transactions of AI-generated lifestyle bureaucracy controlling money. The assessment of both series has considered that each artist uses NFT art as modularity to represent their contexts, rather than a singularity lacking in conversation about the ontological implications of the medium. While NFT art is still in its infancy, this article invites a wider conversation about how artists can deploy crypto art in a conceptual space. It is by this factor that the plausibility of meaningful dialogue is active in determining the medium as a legitimised art form. At the same time, it explores the possibilities now and yet to come, to attest to defining a new dynamic art form, already changing the way artists think about their work as both a currency and a conceptual effect. References ABC News. “Danish Artist Takes Payment for Art, Sends Museum Blank Canvasses Titled Take the Money and Run.” 30 Sep. 2021. <https://www.abc.net.au/news/2021-09-30/danish-artist-jens-haaning-take-the-money-and-run/100502338>. ———. “What’s behind the NFT Digital Craze?” 19 Mar. 2021. <https://www.youtube.com/watch?app=desktop&v=_e7TOBV43y8>. 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In light of an ongoing debate over the authorship of the Redfern address (was it then Prime Minister Paul Keating or his speechwriter, Don Watson, who was responsible for this historic piece?), the authors of this article consider notions of ownership, authorship, and acknowledgement as they relate to the crafting, delivery, and reception of historical political speeches. There is focus, too, on the often-remarkable partnership that evolves between speechwriters and those who deliver the work. We argue that by drawing on the expertise of an artist or—in the case of the article at hand—speechwriter, collaboration facilitates the ‘translation’ of the politician’s or patron’s vision into a delivered reality. The article therefore proposes that while a speech, perhaps like a commissioned painting or sculpture, may be understood as the product of a highly synergistic collaboration between patron and producer, the power-bearer nonetheless retains essential ‘ownership’ of the material. This, we argue, is something other than the process of authorship adumbrated above. Leaving aside, for the present, the question of ownership, the context in which a speech is written and given may well intensify questions of authorship: the more politically significant or charged the context, the greater the potential impact of a speech and the more at stake in terms of its authorship. In addition to its focus on the latter, this article therefore also reflects on the considerable cultural resonance of the speech in question and, in so doing, assesses its significant impact on Australian reconciliation discourse. In arriving at our conclusions, we employ a method assemblage approach including analogy, comparison, historical reference, and interview. Comprising a range of investigative modalities such as those employed by us, John Law argues that a “method assemblage” is essentially a triangulated form of primary and secondary research facilitating the interrogation of social phenomena that do not easily yield to more traditional modes of research (Law 7). The approach is all the more relevant to this article since through it an assessment of the speech’s historical significance may be made. In particular, this article extensively compares the collaboration between Keating and Watson to that of United States President John F. Kennedy and Special Counsel and speechwriter Ted Sorensen. As the article reveals, this collaboration produced a number of Kennedy’s historic speeches and was mutually acknowledged as a particularly important relationship. Moreover, because both Sorensen and Watson were also key advisers to the leaders of their respective nations, the comparison is doubly fertile.On 10 December 1992 then Prime Minister Paul Keating launched the International Year of the World’s Indigenous People by delivering an address now recognised as a landmark in Australian, and even global, oratory. Alan Whiticker, for instance, includes the address in his Speeches That Shaped the Modern World. Following brief instruction from Keating (who was scheduled to give two orations on 10 December), the Prime Minister’s speechwriter and adviser, Don Watson, crafted the speech over the course of one evening. The oration that ensued was history-making: Keating became the first of all who held his office to declare that non-Indigenous Australians had dispossessed Aboriginal people; an unequivocal admission in which the Prime Minister confessed: “we committed the murders” (qtd. in Whiticker 331). The impact of this cannot be overstated. A personal interview with Jennifer Beale, an Indigenous Australian who was among the audience on that historic day, reveals the enormous significance of the address:I felt the mood of the crowd changed … when Keating said “we took the traditional lands” … . “we committed [the murders]” … [pauses] … I was so amazed to be standing there hearing a Prime Minister saying that… And I felt this sort of wave go over the crowd and they started actually paying attention… I’d never in my life heard … anyone say it like that: we did this, to you… (personal communication, 15 Dec. 2016)Later in the interview, when recalling a conversation in the Channel Seven newsroom where she formerly worked, Beale recalls a senior reporter saying that, with respect to Aboriginal history, there had been a ‘conservative cover up.’ Given the broader context (her being interviewed by the present authors about the Redfern Address) Beale’s response to that exchange is particularly poignant: “…it’s very rare that I have had these experiences in my life where I have been … [pauses at length] validated… by non-Aboriginal people” (op. cit.).The speech, then, is a crucial bookend in Australian reconciliation discourse, particularly as an admission of egregious wrongdoing to be addressed (Foye). The responding historical bookend is, of course, Kevin Rudd’s 2008 ‘Apology to the Stolen Generations’. Forming the focal point of the article at hand, the Redfern Address is significant for another reason: that is, as the source of a now historical controversy and very public (and very bitter) falling out between politician and speechwriter.Following the publication of Watson’s memoir Recollections of a Bleeding Heart, Keating denounced the former as having broken an unwritten contract that stipulates the speechwriter has the honour of ‘participating in the endeavour and the power in return for anonymity and confidentiality’ (Keating). In an opinion piece appearing in the Sydney Morning Herald, Keating argued that this implied contract is central to the speech-writing process:This is how political speeches are written, when the rapid business of government demands mass writing. A frequency of speeches that cannot be individually scripted by the political figure or leader giving them… After a pre-draft conference on a speech—canvassing the kind of things I thought we should say and include—unless the actual writing was off the beam, I would give the speech more or less off the printer… All of this only becomes an issue when the speechwriter steps from anonymity to claim particular speeches or words given to a leader or prime minister in the privacy of the workspace. Watson has done this. (Keating)Upon the release of After Words, a collection of Keating’s post-Prime Ministerial speeches, senior writer for The Australian, George Megalogenis opined that the book served to further Keating’s argument: “Take note, Don Watson; Keating is saying, ‘I can write’” (30). According to Phillip Adams, Keating once bluntly declared “I was in public life for twenty years without Don Watson and did pretty well” (154). On the subject of the partnership’s best-known speech, Keating claims that while Watson no doubt shared the sentiments invoked in the Redfern Address, “in the end, the vector force of the power and what to do with it could only come from me” (Keating).For his part, Watson has challenged Keating’s claim to being the rightfully acknowledged author of the Redfern Address. In an appearance on the ABC’s Q&A he asserted authorship of the material, listing other famous historical exponents of his profession who had taken credit for their place at the wheel of government: “I suppose I could say that while I was there, really I was responsible for the window boxes in Parliament House but, actually, I was writing speeches as speechwriters do; as Peggy Noonan did for Ronald Reagan; as Graham Freudenberg did for three or four Prime Ministers, and so on…” (Watson). Moreover, as Watson has suggested, a number of prominent speechwriters have gone on to take credit for their work in written memoirs. In an opinion piece in The Australian, Denis Glover observes that: “great speechwriters always write such books and have the good sense to wait until the theatre has closed, as Watson did.” A notable example of this after-the-era approach is Ted Sorensen’s Counselor in which the author nonetheless remains extraordinarily humble—observing that reticence, or ‘a passion for anonymity’, should characterise the posture of the Presidential speechwriter (131).In Counselor, Sorensen discusses his role as collaborator with Kennedy—likening the relationship between political actor and speechwriter to that between master and apprentice (130). He further observes that, like an apprentice, a speechwriter eventually learns to “[imitate] the style of the master, ultimately assisting him in the execution of the final work of art” (op. cit., 130-131). Unlike Watson’s claim to be the ‘speechwriter’—a ‘master’, of sorts—Sorensen more modestly declares that: “for eleven years, I was an apprentice” (op. cit., 131). At some length Sorensen focuses on this matter of anonymity, and the need to “minimize” his role (op. cit.). Reminiscent of the “unwritten contract” (see above) that Keating declares broken by Watson, Sorensen argues that his “reticence was [and is] the result of an implicit promise that [he] vowed never to break…” (op. cit.). In implying that the ownership of the speeches to which he contributed properly belongs to his President, Sorensen goes on to state that “Kennedy did deeply believe everything I helped write for him, because my writing came from my knowledge of his beliefs” (op. cit. 132). As Herbert Goldhamer observes in The Adviser, this knowing of a leader’s mind is central to the advisory function: “At times the adviser may facilitate the leader’s inner dialogue…” (15). The point is made again in Sorensen’s discussion of his role in the writing of Kennedy’s Profiles in Courage. In response to a charge that he [Sorensen] had ghost-written the book, Sorensen confessed that he might have privately boasted of having written much of it. (op. cit., 150) But he then goes on to observe that “the book’s concept was his [Kennedy’s], and that the selection of stories was his.” (op. cit.). “Like JFK’s speeches”, Sorensen continues, “Profiles in Courage was a collaboration…” (op. cit.).Later in Counselor, when discussing Kennedy’s inaugural address, it is interesting to note that Sorensen is somewhat less modest about the question of authorship. While the speech was and is ‘owned’ by Kennedy (the President requested its crafting, received it, edited the final product many times, and—with considerable aplomb—delivered it in the cold midday air of 20 January 1961), when discussing the authorship of the text Sorensen refers to the work of Thurston Clarke and Dick Tofel who independently conclude that the speech was a collaborative effort (op. cit. 227). Sorensen notes that while Clarke emphasised the President’s role and Tofel emphasised his own, the matter of who was principal craftsman will—and indeed should—remain forever clouded. To ensure that it will permanently remain so, following a discussion with Kennedy’s widow in 1965, Sorensen destroyed the preliminary manuscript. And, when pressed about the similarities between it and the final product (which he insists was revised many times by the President), he claims not to recall (op. cit. 227). Interestingly, Robert Dallek argues that while ‘suggestions of what to say came from many sources’, ‘the final version [of the speech] came from Kennedy’s hand’ (324). What history does confirm is that both Kennedy and Sorensen saw their work as fundamentally collaborative. Arthur Schlesinger Jr. records Kennedy’s words: “Ted is indispensable to me” (63). In the same volume, Schlesinger observes that the relationship between Sorensen and Kennedy was ‘special’ and that Sorensen felt himself to have a unique facility to know [Kennedy’s] mind and to ‘reproduce his idiom’ (op.cit.). Sorensen himself makes the point that his close friendship with the President made possible the success of the collaboration, and that this “could not later be replicated with someone else with whom [he] did not have that same relationship” (131). He refers, of course, to Lyndon Johnson. Kennedy’s choice of advisers (including Sorensen as Special Counsel) was, then, crucial—although he never ceded to Sorensen sole responsibility for all speechwriting. Indeed, as we shortly discuss, at critical junctures the President involved others (including Schlesinger, Richard Goodwin, and Myer Feldman) in the process of speech-craft and, on delivery day, sometimes departed from the scripts proffered.As was the case with Keating’s, creative tension characterised Kennedy’s administration. Schlesinger Jr. notes that it was an approach practiced early, in Kennedy’s strategy of keeping separate his groups of friends (71). During his Presidency, this fostering of creative tension extended to the drafting of speeches. In a special issue of Time, David von Drehle notes that the ‘Peace’ speech given 10 June 1963 was “prepared by a tight circle of advisers” (97). Still, even here, Sorensen’s role remained pivotal. One of those who worked on that speech (commonly regarded as Kennedy’s finest) was William Forster, Director of the Arms Control and Disarmament Agency. As indicated by the conditional “I think” in “Ted Sorensen, I think, sat up all night…”, Forster somewhat reluctantly concedes that while a group was involved, Sorensen’s contribution was central: “[Sorensen], with his remarkable ability to polish and write, was able to send each of us and the President the final draft about six or seven in the morning…” (op. cit.).In most cases, however, it fell on Sorensen alone to craft the President’s speeches. While Sorenson’s mind surely ‘rolled in unison’ with Kennedy’s (Schlesinger Jr. 597), and while Sorensen’s words dominated the texts, the President would nonetheless annotate scripts, excising redundant material and adding sentences. In the case of less formal orations, the President was capable of all but abandoning the script (a notable example was his October 1961 oration to mark the publication of the first four volumes of the John Quincy Adams papers) but for orations of national or international significance there remained a sense of careful collaboration between Kennedy and Sorensen. Yet, even in such cases, the President’s sense of occasion sometimes encouraged him to set aside his notes. As Arthur Schlesinger Jr. observes, Kennedy had an instinctive feel for language and often “spoke extemporaneously” (op. cit.). The most memorable example, of course, is the 1961 speech in Berlin where Kennedy (appalled by the erection of the Berlin Wall, and angry over the East’s churlish covering of the Brandenburg Gate) went “off-script and into dangerous diplomatic waters” (Tubridy 85). But the risky departure paid off in the form of a TKO against Chairman Khrushchev. In late 1960, following two independent phone calls concerning the incarceration of Martin Luther King, Kennedy had remarked to John Galbraith that “the best strategies are always accidental”—an approach that appears to have found its way into his formal rhetoric (Schlesinger Jr. 67).Ryan Tubridy, author of JFK in Ireland, observes that “while the original draft of the Berlin Wall speech had been geared to a sense of appeasement that acknowledged the Wall’s presence as something the West might have to accept, the ad libs suggested otherwise” (85). Referencing Arthur Schlesinger Jr.’s account of the delivery, Tubridy notes that the President’s aides observed the orator’s rising emotion—especially when departing from the script as written:There are some who say that Communism is the way of the future. Let them come to Berlin. And there are some who say in Europe and elsewhere we can work with the Communists. Let them come to Berlin … Freedom has many difficulties and democracy is not perfect, but we have never had to put up a wall to keep our people in.That the speech defined Kennedy’s presidency even more than did his inaugural address is widely agreed, and the President’s assertion “Ich bin ein Berliner” is one that has lived on now for over fifty years. The phrase was not part of the original script, but an addition included at the President’s request by Kennedy’s translator Robert Lochner.While this phrase and the various additional departures from the original script ‘make’ the speech, they are nonetheless part of a collaborative whole the nature of which we adumbrate above. Furthermore, it is a mark of the collaboration between speechwriter and speech-giver that on Air Force One, as they flew from West Germany to Ireland, Kennedy told Sorensen: “We’ll never have another day like this as long as we live” (op. cit. 88; Dallek 625). The speech, then, was a remarkable joint enterprise—and (at least privately) was acknowledged as such.It seems unlikely that Keating will ever (even semi-publicly) acknowledge the tremendous importance of Watson to his Prime Ministership. There seems not to have been a ‘Don is indispensable to me’ moment, but according to the latter the former Prime Minister did offer such sentiment in private. In an unguarded moment, Keating allegedly said that Watson would “be able to say that [he, Watson, was] the puppet master for the biggest puppet in the land” (Watson 290). If this comment was indeed offered, then Keating, much like Kennedy, (at least once) privately acknowledged the significant role that his speechwriter played in his administration. Watson, for his part, was less reticent. On the ABC’s Q&A of 29 August 2011 he assessed the relationship as being akin to a [then] “requited” love. Of course, above and beyond private or public acknowledgement of collaboration is tangible evidence of such: minuted meetings between speechwriter and speech-giver and instructions to the speechwriter that appear, for example, in a politician’s own hand. Perhaps more importantly, the stamp of ownership on a speech can be signalled by marginalia concerning delivery and in the context of the delivery itself: the engagement of emphases, pause, and the various paralinguistic phenomena that can add so much character to—and very much define—a written text. By way of example we reference again the unique and impassioned delivery of the Berlin speech, above. And beyond this again, as also suggested, are the non-written departures from a script that further put the stamp of ownership on an oration. In the case of Kennedy, it is easy to trace such marginalia and resultant departures from scripted material but there is little evidence that Keating either extensively annotated or extemporaneously departed from the script in question. However, as Tom Clark points out, while there are very few changes to Watson’s words there are fairly numerous “annotations that mark up timing, emphasis, and phrase coherence.” Clark points out that Keating had a relatively systematic notational schema “to guide him in the speech performance” (op. cit.). In engaging a musical analogy (an assemblage device that we ourselves employ), he opines that these scorings, “suggest a powerful sense of fidelity to the manuscript as authoritative composition” (op. cit.). While this is so, we argue—and one can easily conceive Keating arguing—that they are also marks of textual ownership; the former Prime Minister’s ‘signature’ on the piece. This is a point to which we return. For now, we note that matters of stress, rhythm, intonation, gesture, and body language are crucial to the delivery of a speech and reaffirm the point that it is in its delivery that an adroitly rendered text might come to life. As Sorensen (2008) reflects:I do not dismiss the potential of the right speech on the right topic delivered by the right speaker in the right way at the right moment. It can ignite a fire, change men’s minds, open their eyes, alter their votes, bring hope to their lives, and, in all these ways, change the world. I know. I saw it happen. (143)We argue that it is in its delivery to (and acceptance by) the patron and in its subsequent delivery by the patron to an audience that a previously written speech (co-authored, or not) may be ‘owned’. As we have seen, with respect to questions of authorship or craftsmanship, analogies (another device of method assemblage) with the visual and musical arts are not uncommon—and we here offer another: a reference to the architectural arts. When a client briefs an architect, the architect must interpret the client’s vision. Once the blueprints are passed to the client and are approved, the client takes ownership of work that has been, in a sense, co-authored. Ownership and authorship are not the same, then, and we suggest that it is the interstices that the tensions between Keating and Watson truly lie.In crafting the Redfern address, there is little doubt that Watson’s mind rolled in unison with the Prime Minister’s: invisible, intuited ‘evidence’ of a fruitful collaboration. As the former Prime Minister puts it: “Watson and I actually write in very similar ways. He is a prettier writer than I am, but not a more pungent one. So, after a pre-draft conference on a speech—canvassing the kind of things I thought we should say and include—unless the actual writing was off the beam, I would give the speech more or less off the printer” (Keating). As one of the present authors has elsewhere observed, “Watson sensed the Prime Minister’s mood and anticipated his language and even the pattern of his voice” (Foye 19). Here, there are shades of the Kennedy/Sorensen partnership. As Schlesinger Jr. observes, Kennedy and Sorensen worked so closely together that it became impossible to know which of them “originated the device of staccato phrases … or the use of balanced sentences … their styles had fused into one” (598). Moreover, in responding to a Sunday Herald poll asking readers to name Australia’s great orators, Denise Davies remarked, “Watson wrote the way Keating thought and spoke” (qtd. in Dale 46). Despite an uncompromising, pungent, title—‘On that historic day in Redfern, the words I spoke were mine’—Keating’s SMH op-ed of 26 August 2010 nonetheless offers a number of insights vis-a-vis the collaboration between speechwriter and speech-giver. To Keating’s mind (and here we might reflect on Sorensen’s observation about knowing the beliefs of the patron), the inspiration for the Prime Minister’s Redfern Address came from conversations between he and Watson.Keating relates an instance when, on a flight crossing outback Western Australia, he told Watson that “we will never really get Australia right until we come to terms with them (Keating).” “Them”, Keating explains, refers to Aborigines. Keating goes on to suggest that by “come to terms”, he meant “owning up to dispossession” (op. cit.)—which is precisely what he did, to everyone’s great surprise, in the speech itself. Keating observes: I remember well talking to Watson a number of times about stories told to me through families [he] knew, of putting “dampers” out for Aborigines. The dampers were hampers of poisoned food provided only to murder them. I used to say to Watson that this stuff had to be owned up to. And it was me who established the inquiry into the Stolen Generation that Kevin Rudd apologised to. The generation who were taken from their mothers.So, the sentiments that “we did the dispossessing … we brought the diseases, the alcohol, that we committed the murders and took the children from their mothers” were my sentiments. P.J. Keating’s sentiments. They may have been Watson’s sentiments also. But they were sentiments provided to a speechwriter as a remit, as an instruction, as guidance as to how this subject should be dealt with in a literary way. (op. cit.)While such conversations might not accurately be called “guidance” (something more consciously offered as such) or “instruction” (as Keating declares), they nonetheless offer to the speechwriter a sense of the trajectory of a leader’s thoughts and sentiments. As Keating puts it, “the sentiments of the speech, that is, the core of its authority and authorship, were mine” (op. cit.). As does Sorensen, Keating argues that that such revelation is a source of “power to the speechwriter” (op. cit.). This he buttresses with more down to earth language: conversations of this nature are “meat and drink”, “the guidance from which the authority and authorship of the speech ultimately derives” (op. cit.). Here, Keating gets close to what may be concluded: while authorship might, to a significant extent, be contingent on the kind of interaction described, ownership is absolutely contingent on authority. As Keating asserts, “in the end, the vector force of the power and what to do with it could only come from me” (op. cit.). In other words, no Prime Minister with the right sentiments and the courage to deliver them publicly (i.e. Keating), no speech.On the other hand, we also argue that Watson’s part in crafting the Redfern Address should not be downplayed, requiring (as the speech did) his unique writing style—called “prettier” by the former Prime Minister. More importantly, we argue that the speech contains a point of view that may be attributed to Watson more than Keating’s description of the speechwriting process might suggest. In particular, the Redfern Address invoked a particular interpretation of Australian history that can be attributed to Watson, whose manuscript Keating accepted. Historian Manning Clark had an undeniable impact on Watson’s thinking and thus the development of the Redfern address. Per Keating’s claim that he himself had “only read bits and pieces of Manning’s histories” (Curran 285), the basis for this link is actual and direct: Keating hired Clark devotee Watson as a major speech writer on the same day that Clark died in 1991 (McKenna 71). McKenna’s examination of Clark’s history reveals striking similarities with the rhetoric at the heart of the Redfern address. For example, in his 1988 essay The Beginning of Wisdom, Clark (in McKenna) announces:Now we are beginning to take the blinkers off our eyes. Now we are ready to face the truth about our past, to acknowledge that the coming of the British was the occasion of three great evils: the violence against the original inhabitants of the of the country, the Aborigines, the violence against the first European labour force in Australia, the convicts and the violence done to the land itself. (71)As the above quote demonstrates, echoes of Clark’s denouncement of Australia’s past are evident in the Redfern Address’ rhetoric. While Keating is correct to suggest that Watson and he shared the sentiments behind the Address, it may be said that it took Watson—steeped as he was in Clark’s understanding of history and operating closely as he did with the Prime Minister—to craft the Redfern Address. Notwithstanding the concept of ownership, Keating’s claim that the “vector force” for the speech could only come from him unreasonably diminishes Watson’s role.ConclusionThis article has considered the question of authorship surrounding the 1992 Redfern Address, particularly in view of the collaborative nature of speechwriting. The article has also drawn on the analogous relationship between President Kennedy and his Counsel, Ted Sorensen—an association that produced historic speeches. Here, the process of speechwriting has been demonstrated to be a synergistic collaboration between speechwriter and speech-giver; a working partnership in which the former translates the vision of the latter into words that, if delivered appropriately, capture audience attention and sympathy. At its best, this collaborative relationship sees the emergence of a synergy so complete that it is impossible to discern who wrote what (exactly). While the speech carries the imprimatur and original vision of the patron/public actor, this originator nonetheless requires the expertise of one (or more) who might give shape, clarity, and colour to what might amount to mere instructive gesture—informed, in the cases of Sorensen and Watson, by years of conversation. While ‘ownership’ of a speech then ultimately rests with the power-bearer (Keating requested, received, lightly edited, ‘scored’, and delivered—with some minor ad libbing, toward the end—the Redfern text), the authors of this article consider neither Keating nor Watson to be the major scribe of the Redfern Address. Indeed, it was a distinguished collaboration between these figures that produced the speech: a cooperative undertaking similar to the process of writing this article itself. Moreover, because an Australian Prime Minister brought the plight of Indigenous Australians to the attention of their non-Indigenous counterparts, the address is seminal in Australian history. It is, furthermore, an exquisitely crafted document. And it was also delivered with style. As such, the Redfern Address is memorable in ways similar to Kennedy’s inaugural, Berlin, and Peace speeches: all products of exquisite collaboration and, with respect to ownership, emblems of rare leadership.ReferencesAdams, Phillip. Backstage Politics: Fifty Years of Political Memories. London: Viking, 2010.Beale, Jennifer. Personal interview. 15 Dec. 2016.Clark, Tom. “Paul Keating’s Redfern Park Speech and Its Rhetorical Legacy.” Overland 213 (Summer 2013). <https://overland.org.au/previous-issues/issue-213/feature-tom-clarke/ Accessed 16 January 2017>.Curran, James. The Power of Speech: Australian Prime Ministers Defining the National Image. Melbourne: Melbourne UP, 2004.Dale, Denise. “Speech Therapy – How Do You Rate the Orators.” Sun Herald, 9 Mar.2008: 48.Dallek, Robert. An Unfinished Life: John F. Kennedy 1917-1963. New York: Little Brown, 2003.Foye, Jonathan. Visions and Revisions: A Media Analysis of Reconciliation Discourse, 1992-2008. Honours Thesis. 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