Academic literature on the topic 'Biomarkers.ConclusionThese results'

ObjectiveTo identify biomarkers associated with progressive phases of MS and with neuroprotective potential.MethodsCombined analysis of the transcriptional and proteomic profiles obtained in CNS tissue during chronic progressive phases of experimental autoimmune encephalomyelitis (EAE) with the transcriptional profile obtained during the differentiation of murine neural stem cells into neurons. Candidate biomarkers were measured by ELISA in the CSF of 65 patients with MS (29 with relapsing-remitting MS [RRMS], 20 with secondary progressive MS, and 16 with primary progressive MS [PPMS]) and 30 noninflammatory neurologic controls (NINCs).ResultsIntegrative analysis of gene and protein expression data identified 2 biomarkers, the serine protease inhibitor Serpina3n and the calcium-binding protein S100A4, which were upregulated in chronic progressive EAE and whose expression was induced during neuronal differentiation. Immunofluorescence studies revealed a primarily neuronal expression of S100A4 and Serpina3n during EAE. CSF levels of SERPINA3, the human ortholog of murine Serpina3n, and S100A4 were increased in patients with MS compared with NINCs (SERPINA3: 1,320 vs 838.6 ng/mL, p = 0.0001; S100A4: 1.6 vs 0.8 ng/mL, p = 0.02). Within the MS group, CSF SERPINA3 levels were significantly elevated in patients with progressive forms, mainly patients with PPMS compared with patients with RRMS (1,617 vs 1,129 ng/mL, p = 0.02) and NINCs (1,617 vs 838.6 ng/mL, p = 0.0001). Of interest, CSF SERPINA3 levels significantly correlated with CSF neurofilament light chain levels only in the PPMS group (r = 0.62, p = 0.01).ConclusionThese results point to a role of SERPINA3 as a biomarker associated with the progressive forms of MS, particularly PPMS.

BackgroundIdentifying relevant asthma endotypes may be the first step towards improving asthma management. We aimed identifying respiratory endotypes in adults using a cluster analysis and to compare their clinical characteristics at follow-up.MethodsThe analysis was performed separately among current asthmatics (CA, n=402) and never asthmatics (NA, n=666) from the first follow-up of the French EGEA study (EGEA2). Cluster analysis jointly considered 4 demographic, 22 clinical/functional (respiratory symptoms, asthma treatments, lung function) and four blood biological (allergy-related, inflammation-related and oxidative stress-related biomarkers) characteristics at EGEA2. The clinical characteristics at follow-up (EGEA3) were compared according to the endotype identified at EGEA2.ResultsWe identified five respiratory endotypes, three among CA and two among NA: CA1 (n=53) with active treated adult-onset asthma, poor lung function, chronic cough and phlegm and dyspnoea, high body mass index, and high blood neutrophil count and fluorescent oxidation products level; CA2 (n=219) with mild asthma and rhinitis; CA3 (n=130) with inactive/mild untreated allergic childhood-onset asthma, high frequency of current smokers and low frequency of attacks of breathlessness at rest, and high IgE level; NA1 (n=489) asymptomatic, and NA2 (n=177) with respiratory symptoms, high blood neutrophil and eosinophil counts. CA1 had poor asthma control and high leptin level, CA2 had hyper-responsiveness and high interleukin (IL)-1Ra, IL-5, IL-7, IL-8, IL-10, IL-13 and TNF-α levels, and NA2 had high leptin and C reactive protein levels. Ten years later, asthmatics in CA1 had worse clinical characteristics whereas those in CA3 had better respiratory outcomes than CA2; NA in NA2 had more respiratory symptoms and higher rate of incident asthma than those in NA1.ConclusionThese results highlight the interest to jointly consider clinical and biological characteristics in cluster analyses to identify endotypes among adults with or without asthma.

BackgroundThe Programmed cell Death protein-1 (PD1) pathway promotes self-tolerance, by inhibiting immune responses. The PD1 soluble form (sPD1), by antagonizing the binding of the membrane-bound PD1 with its ligands, may lead to the blocking of the pathway’s functions. Data regarding the role of the PD1 pathway in Juvenile Idiopathic Arthritis (JIA) are still limited.ObjectivesTo investigate the immunoregulatory role of the PD1 pathway in JIA patients.MethodsJIA patients and healthy controls participated in this study with peripheral blood (PB) and/or synovial fluid (SF) samples. sPD1 levels in serum and SF were determined by ELISA. The PD1 expression on T-helper (CD4+) and T-cytotoxic (CD8+) cells in PB and SF was analyzed by flow cytometry. A search for any association between the above biomarkers, as well as their relation with JIA activity was then performed. Inactive disease was defined according to Wallace criteria.Results77 Caucasian patients (52 female) participated so far in this study, with a median (range) age of 13 (2-19) years; their JIA subtypes were: oligoarthritis (33%), polyarthritis (26%), psoriatic (12%), enthesitis-related (16%), systemic (10%) and undifferentiated (3%). Ten healthy children served as controls. As compared to controls, a subpopulation of these JIA patients (n=46) had a significantly higher median percentage of PD1+CD4+ (1.15 vs. 0.32%, p=0.029) and PD1+CD8 T cells (1.34 vs. 0.4%, p=0.006) in PB. In regard to the JIA status, patients with activity (n=33) had a significantly higher median percentage of both PD1+CD4+ and PD1+CD8 T cells in PB, as compared to those with inactive disease (n=13) (1.36 vs. 0.87%, p=0.034 and 2.03 vs. 0.45%, p<0.001, respectively). Additionally, in a sample of the patients with disease activity (n=22), the median serum sPD1 level was statistically significantly higher, as compared to a sample of those with inactive JIA (n=10) (218.3 vs. 186.7pg/ml, p=0.035). In patients with concurrent serum and SF samples (n=7), the median sPD1 level was statistically significantly higher in the SF than in the serum [1104.4 vs. 773.4pg/ml, p=0.028). No correlation was though found between the sPD1 levels and the PD1 cellular surface expression (n=16 PB/serum, n=11 SF).ConclusionThese preliminary results indicated an sPD1 compartmentalization in active JIA, as sPD1 levels were more prominently raised in the inflamed joint than in the PB. Α higher number of circulating T-helper and T-cytotoxic cells expressing PD1 were also detected in active JIA. Further investigation in a larger sample of JIA patients may verify these observations and contribute to unraveling the precise role of the PD1 pathway in the pathogenesis and persistence of the joint inflammation.References[1]Leong et al. Recent advances in our understanding of the pathogenesis of juvenile idiopathic arthritis and their potential clinical implications. Expert Rev Clin Immunol. 2018 Nov;14(11):933-944.[2]Zhang et al. The PD-1/PD-L pathway in rheumatic diseases. J Formos Med Assoc. 2021 Jan;120(1 Pt 1):48-59.Disclosure of InterestsNone declared.

ObjectivesNew diagnostic criteria for Alzheimer’s disease (AD) include cerebrospinal fluid (CSF) biomarkers that allow diagnosis at the stage of mild cognitive impairment (MCI). However, the impact of CSF biomarkers in MCI populations in clinical practice has been poorly evaluated. The objective of this study is to assess the use and impact in clinical practice of AD CSF biomarkers in French memory clinics.DesignWe performed a nation-wide, prospective survey between March 2012 and September 2014. Data over the same period was extracted from the French National Database (Banque Nationale Alzheimer, BNA) and compared with the results of the survey.Setting29 secondary and tertiary memory clinics in France.ParticipantsClinicians prescribing lumbar puncture (LP) in order to measure AD CSF biomarkers. Clinicians completed a two-part questionnaire for each of their patients undergoing LP.Primary and secondary outcome measuresAssessment of diagnosis, level of confidence before and after CSF biomarkers and impact on management in patients who underwent LP for CSF AD biomarkers in clinical routine.Results977 questionnaires were completed, of which 61 were excluded because of unknown initial/final diagnosis or non-contributory CSF results. Of 916 patients reported, 153 (16.7%) had MCI as the initial diagnosis, of which 51 (33.3%) displayed an AD profile. CSF biomarkers resulted in a change in diagnosis in 44 patients (28.8%). Confidence level significantly increased after LP (8.3±1.4vs 6.73±1.18, p<0.0001), and CSF results modified management in 71/156 patients (46.4%), including 36 (23.5%) enrolled in clinical trials. Comparison of change in diagnosis with the BNA population revealed no difference (32.24%, p=0.4).ConclusionThis nation-wide survey, reflecting clinical practice in French memory clinics, describes the impact of CSF AD biomarkers in patients with MCI in clinical practice.

ObjectiveTo examine the long-term cognitive trajectories of individuals with normal cognition at baseline and distinct amyloid/tau/neurodegeneration (ATN) profiles.MethodsPooling data across 4 cohort studies, 814 cognitively normal participants (mean baseline age = 59.6 years) were classified into 8 ATN groups using baseline CSF levels of β-amyloid 1–42 as a measure of amyloid (A), phosphorylated tau 181 as a measure of tau (T), and total tau as a measure of neurodegeneration (N). Cognitive performance was measured using a previously validated global factor score and with the Mini-Mental State Examination. We compared the cognitive trajectories across groups using growth curve models (mean follow-up time = 7 years).ResultsUsing different model formulations and cut points for determining biomarker abnormality, only the group with abnormal levels of amyloid, tau, and neurodegeneration (A+T+N+) showed consistently greater cognitive decline than the group with normal levels of all biomarkers (A−T−N−). Replicating prior findings using the 2011 National Institute on Aging–Alzheimer's Association/suspected non–Alzheimer disease pathophysiology schema, only individuals with abnormal levels of both amyloid and phosphorylated tau 181 or total tau (stage 2) showed greater cognitive decline than those with normal biomarker levels (stage 0).ConclusionThe results are consistent with the hypothesis that both elevated brain amyloid and neurofibrillary tangles are necessary to observe accelerated neurodegeneration, which in turn leads to cognitive decline.

BackgroundA proper evaluation and management of patients with spondyloarthritis (SpA) requires the use of biomarkers, facilitating early diagnosis, reflecting disease activity and clinical response to therapies. The chronic, systemic inflammatory process is responsible for increased CV risk in SpA patients. Pentraxin 3 (PTX3) is an inflammatory marker, a member of long pentraxin superfamily, argued to be involved in pathogenesis of both inflammation and atherosclerosis. PTX3 is produced locally in the inflamed tissue, by different cell types including macrophages, endothelial cells, synoviocytes, but not hepatocytes. PTX3 is produced in walls of blood vessels, in atherosclerotic plaques, as a response to pro-inflammatory cytokines.ObjectivesThe aim of the study was to assess the role of PTX3 as a biomarker in patients with SpA and to evaluate the relationship between PTX3 and CV risk markers (carotid intima-media thickness (cIMT), lipid profile).MethodsThe study group consisted of 40 consecutive patients with SpA: 29 patients with psoriatic arthritis (PsA) and 11 patients with ankylosing spondylitis (AS). The group consisted of 16 (40%) women and 24 (60%) men, with the mean (SD) age 43.9 (12.0) (range 25–68) and disease duration 7,8 (7,6) years (range 1–32). An assessment of the disease activity included: laboratory inflammatory parameters (erythrocyte sedimentation rate (ESR), C-reactive protein, CRP) and clinical assessment (in patients with peripheral SpA (pSpA) joints counts and disease activity score in 28 joints (DAS28); in patients with axial SpA (axSpA) Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Functional Index (BASFI) and pain of the spine according to the patient in visual analogue scale (VAS). A measurement of carotid intima-media thickness (cIMT) was performed using high-resolution B-mode ultrasonography to estimate features of atherosclerosis (cIMT> 0.9 mm and/or presence of atherosclerotic plaques).ResultsThe median (IQR) PTX3 concentration in SpA patients was 3.39 (2.22-3.88) ng/ml. The mean (SD) value of ESR was 27.7 (28.3) mm/h and CRP concentration 13.6 (19.9) mg/l.The mean values of clinical indices were as follows: DAS28 3.8 (1.1), BASDAI 4.02 (2.1), BASFI 4.22 (2.2), VAS spine pain 41.4 (24.0).The mean (SD) cIMT value was 0.77 (0.23) mm (range 0.48-1.33). The features of atherosclerosis were detected in 7 (17.5%) patients.No significant correlations were found between PTX3 and other inflammatory markers (ESR, CRP). There were no correlations between PTX3 concentration the clinical indices of the disease activity (DAS28, BASDAI, BASFI, VAS spine pain). No differences of PTX3 concentrations were detected between pSpA and axSpA patients.The PTX3 concentrations were significantly higher in patients with definite atherosclerosis (cIMT > 0.9 mm) than in patients with subclinical or no atherosclerosis (cIMT=< 0.9) (5.79 (3.84-8.59) vs 3.06 (2.0-3.52) ng/ml, p=0.01), as well as in patients with atherosclerotic plaques in comparison with no plaques (6.79 (4.86-8.59) vs 3.26 (2.0-3.71) ng/ml, p=0.02) (Figure 1).ConclusionThe results of our study suggest that in patients with SpA, PTX3 could be regarded as a biomarker indicating intensity of atherosclerosis. However PTX3 was not associated with parameters of disease activity in patients with SpA.References[1]Maksymowych WP. Biomarkers in axial spondyloarthritis. Curr Opin Rheumatol. 2015 Jul;27(4):343-8. doi: 10.1097/BOR.0000000000000180.[2]Nisihara R, Skare TL, Zeni JO, Rasera H, Lidani K, Messias-Reason I. Plasma levels of pentraxin 3 in patients with spondyloarthritis. Biomarkers. 2018 Feb;23(1):14-17. doi: 10.1080/1354750X.2016.1278265.Disclosure of InterestsNone declared

BackgroundAdult-onset Still’s disease (AOSD) is a rare systemic autoinflammatory disorder with unknown etiology. The main problem for rheumatologists is a lack of generally accepted methods for assessing AOSD activity.ObjectivesTo compare the usefulness of traditional and novel biomarkers for assessing the AOSD activityMethodsThe cross-sectional study included 27 patients over the age of 18 with a relapse of AOSD who were examined at the Almazov National Medical Research Centre from 2018 to 2021.All patients fulfilled the AOSD classification criteria by Yamaguchi. Clinical manifestations were scored in a Pouchot AOSD activity score. The serum concentrations of IL-1, IL-6, IL-18, ferritin, calgranulin, procalcitonin and the level of glycosylated ferritin (GF) were examined. Standard commercial reagents were used for detection clinical analysis of blood, C-reactive protein (CRP) and aminotransferases. Statistical analysis was performed using the licensed statistical applications Statistica 10.0 for Windows (StatSoft Inc., USA), and Prisma GraphPad 8.0 (GraphPad Software, USA). Results were expressed as median (25th–75th percentile) and analysed for statistical significance using nonparametric tests. For quantitative features comparison, the Mann–Whitney U test was used. The correlation coefficient was obtained by nonparametric Spearman’s rank correlation test. P values < 0.05 were considered statistically significant. Data from commercial test systems are taken as the basis for normal biomarker indicators.ResultsClinical data were available from 27 patients with AOSD (6 male and 21 female). The median age was 41.3 [26;50]. The median Pouchot activity score was 6 [4.5;7]. The course of AOSD was monocyclic in 1 patient, polycyclic in 23, and chronic in 3. Elevated leukocyte count > 10,000/μl was detected in 17 patients (63%), 9 patients (33%) had an elevated leukocyte count > 15,000/μl.An increase in biomarkers was detected in most patients: calgranulin was increased in 24 out of 26 patients (92.3%), ferritin was increased and GF was decreased in 21 out of 25 patients (84%). Among those 25 patients, the decrease in GF was less than 20% in 13 patients (52%). IL-18 increased in 17 patients (63%), IL-6 increased in 22 patients (81.5%), and procalcitonin increased in 16 out of 26 patients (61.6%). The median of procalcitonin concentration was 0.08 [0.01; 30.1]. No increase in IL-1 beta was detected.A correlation analysis revealed a direct relationship between the concentration of IL-18, ferritin and the Pouchot system score. An inverse relationship existed between these indicators and the level of GF (rs=0.803, p=0.001) and between calgranulin and IL-6 (rs=0.46, p=0.02). It was noted that the younger the age of the patients, the higher the concentration of IL-18 (rs=-0.449, p=0.019).ConclusionThe most promising additional laboratory biomarkers for assessing AOSD activity are calprotectin, IL-18, and ferritin. Despite a slight increase in procalcitonin as one of the indicators of the acute phase of inflammation, it remains an effective biomarker of sepsis; however, it is recommended to focus on threshold concentrations above 0.5.References[1]Ruscitti P, Cipriani P, Masedu F, Iacono D, Ciccia F, Liakouli V, Guggino G, Carubbi F, Berardicurti O, Di Benedetto P, Valenti M, Triolo G, Valentini G, Giacomelli R. Adult-onset Still’s disease: evaluation of prognostic tools and validation of the systemic score by analysis of 100 cases from three centers. BMC Med. 2016 Dec 1;14(1):194. doi: 10.1186/s12916-016-0738-8.[2]Feist E, Mitrovic S, Fautrel B. Mechanisms, biomarkers and targets for adult-onset Still’s disease. Nat Rev Rheumatol. 2018 Oct;14(10):603-618. doi: 10.1038/s41584-018-0081-x.[3]Lapin S, Maslyansky A., Lazareva N., Vasilyeva E., Totolyan A. The significance of the quantitative determination of procalcitonin for the diagnosis of septic complications in patients with autoimmune rheumatic diseases. Clinical laboratory diagnostics. 2013. No. 1.Disclosure of InterestsValentina Myachikova Speakers bureau: Novartis, Sobi, Evgenii Kuvardin: None declared, Kira Zotkina Speakers bureau: Novartis Amgen, Olga Tkachenko: None declared, Sergey Lapin: None declared, Alexey Maslyanskiy Speakers bureau: Boehringer Ingelheim Pharmaceuticals, Novartis, R-PHARM. Eli Lilly

AbstractAimsCathepsin S has been reported to be a biomarker of spinal microglial activation, a process suggested to be involved in the pathophysiology of chronic neuropathic pain. So far this has been shown only in animal experiments. The aim of this study was to investigate the concentrations of cathepsin S in human cerebrospinal fluid (CSF) samples from a well-defined patient cohort suffering from neuropathic pain as compared to controls.MethodsCSF samples from patients suffering from chronic neuropathic pain (n = 14) were analyzed for cathepsin S levels using commercial sandwich ELISAs (DY1183, R&D Systems, Minneapolis, MN, USA). Control CSF was sampled from patients undergoing minor urological surgical procedures under spinal anaesthesia (n = 70), having no obvious pain suffering.ResultsThe neuropathic pain group had significantly higher levels of CSF cathepsin S (median 15189 pg/mL, range 3213–40,040), than the control group (median 5911 pg/mL, range 1909–17,188) (p < 0.005, Mann–Whitney U-test).ConclusionThe results support the existence of microglial activation in chronic neuropathic pain patients. CSF Cathepsin S may serve as a potential biomarker for this specific mechanism linked to neuropathic pain. In the future, Cathepsin S inhibiting drugs might become a new treatment alternative for neurophatic pain.

BackgroundThe complete response rate of cervical high-grade squamous intraepithelial lesion (cHSIL) patients to imiquimod immunotherapy is approximately 60%. Consequently, many patients are exposed to unnecessary adverse effects of imiquimod. On the other hand, conventional surgical large loop excision therapy is associated with increased risk of premature births in subsequent pregnancies. An in-depth analysis of the cHSIL immune microenvironment was performed in order to identify and develop a predictive biomarker for response to imiquimod, to maximize therapy efficacy and to avoid adverse effects in patients unlikely to respond.MethodsBiopsies of 35 cHSIL patients, before and 10 weeks on imiquimod treatment, were analyzed by two multispectral seven-color immunofluorescence panels for T cell and myeloid cell composition in relation to treatment response. Based on these results a simplified immunohistochemical detection protocol was developed. Samples were scanned with the Vectra multispectral imaging system and cells were automatically identified using machine learning.ResultsThe immune microenvironment of complete responders (CR) is characterized by a strong and coordinated infiltration by T helper cells (activated PD1+/type 1 Tbet+), M1-like macrophages (CD68+CD163-) and dendritic cells (CD11c+) prior to imiquimod. The lesions of non-responders (NRs) displayed a high infiltration by CD3+FOXP3+regulatory T cells. At 10 weeks on imiquimod, a strong influx of intraepithelial and stromal CD4+T cells was observed in CR but not NR patients. A steep decrease in macrophages occurred both in CR and NR patients, leveling the pre-existing differences in myeloid cell composition between the two groups. Based on the pre-existing immune composition differences, the sum of intraepithelial CD4 T cell, macrophage and dendritic cell counts was used to develop a quantitative simplified one color immunohistochemical biomarker, the CHSIL immune biomarker for imiquimod (CIBI), which can be automatically and unbiasedly quantified and has an excellent predictive capacity (receiver operating characteristic area under the curve 0.95, p<0.0001).ConclusionThe capacity of cHSIL patients to respond to imiquimod is associated with a pre-existing coordinated local immune process, fostering an imiquimod-mediated increase in local T cell infiltration. The CIBI immunohistochemical biomarker has strong potential to select cHSIL patients with a high likelihood to experience a complete response to imiquimod immunotherapy.

BackgroundOvarian cancer is a leading cause of gynaecological cancer-related morbidity and mortality. There has been increasing interest in the potential utility of anti-human epidermal growth factor receptor 2 (anti-HER2) agents in the treatment of this disease, with the attendant need to identify suitable predictive biomarkers of response to treatment.Aims/methodsThe authors studied the prevalence of HER2 genomic amplification and overexpression in 85 ovarian tumours in the local patient cohort of this study, as well as the concordance rate between immunohistochemistry, fluorescent in situ hybridisation (FISH) and a dual-colour HER2/chromosome 17 centromere chromogenic in situ hybridisation (CISH) assay.ResultsThe authors identified HER2 genomic amplification and protein overexpression in 35.3% (6/17) and 29.4% (5/17), respectively, of primary ovarian mucinous carcinomas. No other cancer subtypes displayed HER2 amplification or protein overexpression. The authors also found a perfect concordance between FISH and dual-colour CISH analysis (κ coefficient 1.0, p<0.001).ConclusionThe results of this study support existing reports that HER2 genomic amplification and protein overexpression are predominantly found in primary ovarian mucinous carcinomas. Given the perfect concordance between the FISH and dual-colour CISH assays and the advantages of CISH over FISH analysis, future clinical trials investigating the use of anti-HER2 therapeutics in ovarian carcinomas should incorporate dual-colour CISH as part of the HER2 status assessment algorithm.