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Objective:To perform a systematic literature review of the long-term safety of methotrexate (MTX) monotherapy in rheumatoid arthritis (RA).Methods:A search was performed in Medline, Cochrane and EMBASE. Adults with RA who had received MTX monotherapy for more than 2 years were studied.Results:88 published studies were included. Over 12 years of treatment, the termination rate of MTX due to toxicity was less than for sulfasalazine, gold, d-penicillamine and higher than for hydroxychloroquine (level of evidence 2a–2b). Long-term use of MTX does not appear to be a risk factor for serious infections, including herpes zoster (2b–4), and could provide a survival benefit by reducing cardiovascular mortality (2b). The prevalence of raised liver enzymes (more than twice the upper limit of normal) is close to 13% of patients; 3.7% of patients stopped MTX permanently owing to liver toxicity (2b). Data on the risk for liver fibrosis/cirrhosis are conflicting: a meta-analysis showed an incidence of fibrosis of 2.7% after 4 years of MTX (2a). However, two other studies on sequential liver biopsies did not show evidence for developing severe damage (2b). Insufficient data are available to fully assess the risk of lymphoma and malignancies, although there is no strong evidence of increased risk (2b–4).Conclusion:This systematic literature search on MTX monotherapy with relatively low-dose use during at least 2 years shows favourable long-term safety.

Background:Tumour necrosis factor α blockers in rheumatoid arthritis are known to increase the risk of serious infections defined as life-threatening, requiring hospitalisation or intravenous antibiotics. Recently, new biological agents have become available. Their safety is an important issue.Purpose:To assess if biological agents, ie rituximab, abatacept and anakinra increase the risk of serious infections in patients with rheumatoid arthritis in published randomised controlled trials.Data source:A systematic review of the literature using PUBMED, EMBASE, Cochrane library and abstracts databases (American College of Rheumatology and European League Against Rheumatism annual meetings) was performed up to October 2007. This search was completed with data from the Food and Drug Administration, the European Agency for the Evaluation of Medicinal Products and manufacturers.Data extraction:Three fixed-effect meta-analyses were performed to compare serious infection rates between each biological agent and placebo. Pooled odds ratios (ORs) were calculated, using the Mantel–Haenszel method with a continuity correction.Data synthesis:Twelve randomised controlled trials with data concerning serious infections were analysed (three for rituximab, five for abatacept and four for anakinra). They included 745 patients, 1960 patients, 2062 patients and 2112 patients treated by rituximab, abatacept, anakinra and placebo respectively. The overall pooled ORs did not reveal a statistically significant increased risk of serious infection for abatacept and rituximab; this risk was increased for high doses of anakinra (⩾100 mg daily) versus low dose and placebo (ORs = 9.63 (95% CI, 1.31 to 70.91) and 3.40 (95% CI, 1.11 to 10.46) respectively).Conclusions:These meta-analyses did not reveal a significant increase in the risk of serious infections during rituximab or abatacept treatments in patients with rheumatoid arthritis; however, high doses of anakinra may increase this risk, especially when patients have comorbidity factors. Large studies must be performed to confirm this safety profile in daily practice.

Background:Rheumatoid arthritis (RA) is an autoimmune disease whose established risk factors are active and passive smoking, obesity and, with less evidence, female hormones and certain dietary profiles. The role of intestinal dysbiosis has also been suggested. Exposure to pollutants, particularly those with endocrine-disrupting effects, has been implicated in the growing incidence of autoimmune diseases, although no specific data are available for RA [1]. Non-dioxin-like polychlorinated biphenyls (PCB-NDL) and dioxins (including dioxins and dioxin-like PCB), whose sources are mainly dietary (cheese, butter, fish, meat), are groups of contaminants stored in adipose tissue and with estrogen-like effects.Objectives:To assess the impact of dietary exposure to dioxins and PCB-NDL on the risk of developing RA in the E3N prospective cohort of French women.Methods:The French E3N cohort included 98,995 women, followed prospectively since 1990. Incident cases of RA in this cohort were validated [2]. A detailed, validated dietary questionnaire was collected in 1993. From this questionnaire, average daily dietary intakes of dioxins and PCB-NDL were estimated on the basis of dietary contamination data from the second French total diet study conducted by ANSES (EAT2). Hazard ratios (HRs) for the risk of incident RA and their 95% confidence intervals [95% CI] were estimated by Cox models adjusted for age (model 1) and for the main confounding factors (model 2: adjustments for age, active smoking, passive smoking, level of education, physical activity, BMI, total energy intake excluding alcohol, total alcohol consumption/day). Analyses were performed on the entire population, and stratified according to active smoking (never/ever) and body mass index (BMI). A sensitivity analysis was performed by further adjusting daily omega3 and calcium intakes, reflecting dietary intakes of fish and dairy products.Results:The overall analysis population comprised 63,022 women, 486 of whom had incident RA occurred after collection of the dietary questionnaire. In the overall population, a statistically significant association was found between the risk of incident RA and dietary exposure to PCB-NDL, for model 1 only (HR=1.28 [1.00-1.63], ptrend=0.04). After stratification and in for both models, high exposure (4th quartile) to PCB-NDL was significantly associated with the risk of RA, compared with low exposure (1st quartile) in non-smoking women (model 2, HR=1.75 [1.20-2.60], ptrend=0.005) and in women with a BMI < 25 kg/m2 (model 2, HR=1.35 [1.02-1.90], ptrend=0.027). Results were similar after further adjustment for omega3 and calcium intakes. With regard to dietary dioxin exposure, the results in the overall population and after stratification were not statistically significant.Conclusion:Dietary exposure to PCB-NDL was significantly associated with an increased risk of developing RA in non-smoking women and in women of normal BMI in the French E3N cohort. These results bring new arguments to the hypothesis of dysbiosis induced by dietary exposure to PCN-NDL and their “estrogen-like” effects [3].REFERENCES:[1] Merrheim J et al. Estrogen, estrogen-like molecules and autoimmune diseases. Autoimmun Rev. 2020.[2] Nguyen Y et al. Improving accuracy of self-reported diagnoses of rheumatoid arthritis in the French prospective E3N-EPIC cohort: a validation study. BMJ Open. 2019.[3] Popli S et al. Persistent organic pollutants in foods, their interplay with gut microbiota and resultant toxicity. Sci Total Environ. 2022.Acknowledgements:NIL.Disclosure of Interests:Carine Salliot novartis, Roche Chugai, Pfizer, novartis, Océane Mohamed: None declared, Yann Nguyen: None declared, Fanny Artaud: None declared, Xavier Mariette: None declared, Francesca Mancini: None declared, Raphaèle Seror Novartis.

BackgroundTofacitinib, an oral Janus Kinase inhibitor, is indicated for the treatment of adult patients with moderate to severe active rheumatoid arthritis (RA).ObjectivesTo describe the safety profile of Tofacitinib in a French prospective observational study DeFacTo.MethodsThe safety profile of tofacitinib was assessed using interim data from a descriptive analysis of patients who took at least one dose of tofacitinib in the DeFacTo study.ResultsAmong 314 patients enrolled in the study, 306 received tofacitinib and were included in the safety analysis, including 274 patients with a follow-up ≥ 18 months (POP2) on 03/15/22 date of analysis) with a median exposure duration of 538 [Q1; Q3: 381; 554] days. 113 patients (41.2%) were still on tofacitinib (39 discontinued, 122 missing data regarding prescription). At inclusion, 78.3% of the 306 pts were women with a mean (± standard deviation) age of 59.5 ± 11.5 years, median disease duration of 8.9 years [Q1; Q3: 4.1; 18.9]. There was a history of cardiovascular (CV) disease in 11.9% of cases (including 4.6% myocardial infarction (MI), 5.0% stroke/transient ischemic attack (TIA), 1.7% heart failure, and 1.7% peripheral arterial disease); 5.6% history of cancer, 16.8% history of infection, and 46.6% smoker/former smoker. Tofacitinib was prescribed in combination with a csDMARD in 61.1% of patients and corticosteroids in 56.2% of cases. The results showed that adverse events (AEs) were reported in 54.2% of the 306 patients, 14.4% were considered as serious. Infections were found in 22.2% of patients, no deaths were reported (Table 1).Table 1.Real-life and age-specific safety data for tofacitinibN, (%)< 65 ans (n=193)≥ 65 ans (n=111)Total (n=306*)Adverse events (AEs)104 (53.9)62 (55.9)166 (54.2)Serious adverse events21 (10.9)23 (20.7)44 (14.4)Infection41 (21.2)27 (24.3)68 (22.2)Herpes Zoster6 (3.1)6 (5.4)12 (3.9)Serious AEs of special interestSerious infection5 (2.6)4 (3.6)9 (2.9)Herpes zosterTuberculosis1 (0.5)0 (0.0)0 (0.0)2 (1.8)1 (0.3)2 (0.7)Cancer1 (0.5)1 (0.9)2 (0.7)CV eventⴕ1 (0.5)1 (0.9)2 (0.7)VTEⱡ0 (0.0)2 (1.8)2 (0.7)Death0 (0.0)0 (0.0)0 (0.0)*2 patients with missing age but counted in the total. ⴕ cardiovascular event (Evt): non-fatal MI and stroke + CV death. ⱡ VTE (venous thromboembolic disease): deep vein thrombosis + pulmonary embolism.ConclusionThese intermediate, descriptive results show a safety profile of tofacitinib in real-life RA similar to the one previously reported in clinical and observational studies. [1-2]References[1]Wollenhaupt et al. Arthritis Research & Therapy (2019) 21:89 https://doi.org/10.1186/s13075-019-1866-2[2]Kremer et al. ACR Open Rheumatology 2021. DOI 10.1002/acr2.11232AcknowledgementsThis study was sponsored by Pfizer.Disclosure of InterestsCécile Gaujoux-Viala Speakers bureau: AbbVie; Amgen; Bristol-Myers Squibb; Celgene; Eli Lilly; Galapagos; Gilead Sciences, Inc.; Janssen; Medac; Merck-Serono; Mylan; Nordic Pharma; Novartis; Pfizer; Roche; Sandoz; Sanofi; and UCB, Consultant of: AbbVie; Amgen; Bristol-Myers Squibb; Celgene; Eli Lilly; Galapagos; Gilead Sciences, Inc.; Janssen; Medac; Merck-Serono; Mylan; Nordic Pharma; Novartis; Pfizer; Roche; Sandoz; Sanofi; and UCB, Andre BASCH Consultant of: Janssen, Novartis, Amgen, BMS, Abbvie, Lilly, Pfizer, MSD, UCB, Slim Lassoued: None declared, Fabienne COURY-LUCAS Consultant of: AbbVie, Bristol-Myers Squibb, Janssen, Lilly, MSD, Novartis and Pfizer, Grant/research support from: AbbVie, Biogen, Roche Chugai, Pfizer, and UCB, Meriem Kessouri Shareholder of: Pfizer, Employee of: Pfizer, Yves Brault Shareholder of: Pfizer, Employee of: Pfizer, Thierry Lequerre Consultant of: Abbvie, BMS, Boeringher, Lilly, Medac, MSD, Nordic Pharma, Novartis, Pfizer, Roche – Chugai, Sanofi, UCB, Carine Salliot Consultant of: Biogen, Lilly, Novartis, Roche Chugai, Pfizer.

Background:Targeted therapies for asthma, such as mepolizumab, benralizumab, dupilumab, tezepelumab, and omalizumab, represent a significant advancement in the management of severe asthma, as well as other diseases, including atopic dermatitis and nasal-sinus polyposis. New onsets of inflammatory rheumatism have been reported in the literature under these treatments, although the number of cases is currently limited (the largest series being n=11).Objectives:The aim of this study was to describe the characteristics and management of inflammatory rheumatism resulting from targeted therapies for asthma.Methods:A retrospective multicenter observational study was conducted. The study included patients who met the following criteria: (i) inflammatory rheumatism, (ii) occurring de novo, and (iii) under biologic therapy for asthma (given for either asthma or a related disease). The cases were reported by multiple investigators from different hospitals to the main investigator who collected the data.Results:The results showed that out of 30 patients with suspected inflammatory rheumatism, 12 met the criteria for inflammatory rheumatism (7 female, 5 males, aged 52.5 years, range 25 – 84). Seven patients were treated with dupilumab and five with mepolizumab for asthma (n=10), nasal-sinus polyposis (n=6), and atopic dermatitis (n=1). The median time between the introduction of these treatments and the onset of joint symptoms was 9.5 months (range 1-25). Only one patient was receiving corticosteroid therapy at the first articular symptoms (prednisone 20 mg/day).At the initial rheumatologic evaluation, all patients presented with peripheral joint involvement, while none had axial involvement. The median number of tender and swollen joints was 7 (range 3-26) and 3 (range 0-10), respectively. The median CRP level was 33 mg/L (range 3-66). Three patients (25%) tested positive for ACPA (median: 163.8 UI/L, range 13-293.2), 2 (16.5%) for rheumatoid factor, 3 (20%) had antinuclear antibodies (1/160 to 1/640), and 1 (8%) had anti-dsDNA (27,8 UI/L). Radiographs of hands and/or feet showed erosions in 2 out of 12 patients (17%). Extra-articular manifestations were present in 3 patients (25%), including cutaneous psoriasis (n=1, 8%), edema of the hands resembling RS3PE (n=1, 9%), and erythema nodosum (n=1, 8%). The diagnoses were rheumatoid arthritis (n=3), psoriatic arthritis (n=3), polymyalgia rheumatica (n=4), RS3PE syndrome (n=1), and sarcoidosis (n=1).Four out of twelve patients (33%) discontinued their targeted therapy for asthma, and two of them experienced an asthma relapse, which was treated with corticosteroids. Two patients switched to another targeted therapy for asthma (one received dupilumab and the other benralizumab), resulting in resolution of the rheumatism without rheumatological treatment. One patient resumed the same biologic therapy and one patient stopped treatment completely, both requiring rheumatologic treatment.Eight out of 12 patients (67%) continued targeted therapy for asthma.Rheumatic diseases were treated with corticosteroids (n=6, 50%; 5 mg/day range 5-20), methotrexate (n=7, 58%; 20 mg/week range 15-25) and/or targeted therapy for rheumatic diseases (n=2, 16.5%, including etanercept: n=1, tocilizumab: n=1, ixekizumab: n=1).No serious side effects were reported, including no infections, hospitalizations, or deaths related to side effects. After a follow-up of 2.5 months (range 0-26), 11 out of 12 patients achieved remission of their inflammatory rheumatism.Conclusion:In conclusion, inflammatory rheumatism may occur within the first few months of initiating targeted therapies for asthma. This series found that discontinuing targeted therapy for asthma resulted in asthma relapse in 50% of cases, while the rheumatism resolved in 50% of cases. In this series, the use of targeted therapy for asthma maintenance, in combination with methotrexate, and targeted therapy for inflammatory rheumatism (when methotrexate was ineffective), proved to be both effective and safe.REFERENCES: NIL. Acknowledgements:NIL.Disclosure of Interests:None declared.

Objectives:To develop evidence-based recommendations for the use of methotrexate in daily clinical practice in rheumatic disorders.Methods:751 rheumatologists from 17 countries participated in the 3E (Evidence, Expertise, Exchange) Initiative of 2007–8 consisting of three separate rounds of discussions and Delphi votes. Ten clinical questions concerning the use of methotrexate in rheumatic disorders were formulated. A systematic literature search in Medline, Embase, Cochrane Library and 2005–7 American College of Rheumatology/European League Against Rheumatism meeting abstracts was conducted. Selected articles were systematically reviewed and the evidence was appraised according to the Oxford levels of evidence. Each country elaborated a set of national recommendations. Finally, multinational recommendations were formulated and agreement among the participants and the potential impact on their clinical practice was assessed.Results:A total of 16 979 references was identified, of which 304 articles were included in the systematic reviews. Ten multinational key recommendations on the use of methotrexate were formulated. Nine recommendations were specific for rheumatoid arthritis (RA), including the work-up before initiating methotrexate, optimal dosage and route, use of folic acid, monitoring, management of hepatotoxicity, long-term safety, mono versus combination therapy and management in the perioperative period and before/during pregnancy. One recommendation concerned methotrexate as a steroid-sparing agent in other rheumatic diseases.Conclusions:Ten recommendations for the use of methotrexate in daily clinical practice focussed on RA were developed, which are evidence based and supported by a large panel of rheumatologists, enhancing their validity and practical use.

Background:Therapeutic strategies for rheumatoid arthritis (RA) are based on national and international recommendations, having as main aim achieving remission or a low level of activity using a ‘treat-to-target’ strategy. In this context, targeted therapies are used more frequently and at an earlier stage.Objectives:-To describe the characteristics of RA patients initiating TNFi in real life and included in the ART-SFR registry, and to assess if they have been treated according to current recommendations.-To compare RA patients included in ART-SFR to other RA populations treated by TNFi, either in contemporary randomized controlled trials, and in previous national or international registries.Methods:The recent multicenter French registry ART-SFR (NCT03062865) included RA patients initiating a TNFi between 2016 and 2022, with a 5-year prospective follow-up. We described here patient characteristics at inclusion in the registry. The adherence to recent guidelines on TNFi initiation (EULAR, ACR and French society for rheumatology (SFR)) was assessed by the percentage of patients treated according these guidelines. Then, a systematic review was performed to compare characteristics of patients of the ART-SFR registry to other RA patients treated by TNFi in previous registries or cohort studies (including > 1000 patients treated with anti TNF). Finally, another systematic review on trial registration platforms (clinicaltrial.gov...) was carried out to identify all randomized controlled trials (RCT) with a TNFi arm including RA patients over the same period as inclusion in the ART-SFR registry. The main eligibility criteria for these trials were collected, and eligibility of patients from the ART-SFR registry to inclusion in these trials was assessed.Results:1483 RA patients were included (1078 (73%) female, mean age = 55.6 yrs ± 14.1, mean disease duration = 7.6 yrs). 47% of patients had erosive status, 80% had positive ACPA and/or RF, and 86% had moderate to high disease activity (mean DAS-28 CRP: 4.1 ± 1.1). Patients were mostly biologic-naïve at enrollment (n = 1182, 80%). TNFi were Etanercept in 782 (53%), Adalimumab (23%). TNFi was associated with csDMARD in 83% and glucocorticoids in 49% (9.1 mg/day ± 7.3).In biologic-naïve patients, TNFi was initiated in accordance to EULAR 2016, ACR 2015 and SFR 2014 recommendations in 98 % for each, and in patients with previous biologic use in 100, 74 and 100 % respectively.Systematic review identified 20 observational studies conducted from 1999 to 2020. Compared to these studies, patients in ART-SFR registry had similar age (43 to 56 yrs), and gender (women 73-100%). They tended to have a shorter disease duration (lower than 17/20 registries), similar proportion of RF/ACPA positivity (69 to 85%), but lower disease activity (DAS28 4.4, vs DAS 28 > 5.1, in all except 3 registries).When compared to RCT recruiting during the same period as ART-SFR registry, according to trial 4 to 72% of patients of ART-SFR registry (< 50% for 21/27 trials) met the main eligibility criteria (including RA activity criteria, ESR/CPR, erosive status, DMARD use). In trial requiring increased acute phase reactants (ESR and/or CRP), this rate ranged from 4.4 to 25%, while it was between 60.1 and 71.8% for other trials.Conclusion:Data from the ART-SFR national registry show that TNFi, the oldest class of biologics in RA, are still used predominantly as first-line biologic. Given the design of the registry, their characteristics can be considered representative of those of patients initiating TNFi for RA in France. Most patients in the registry were treated in accordance with recommendations. Conversely, the eligibility of patients for trial inclusion criteria was highly heterogeneous, and particularly low when acute phase reactants were part of eligibility criteria. These results suggest that trial and real-life populations are not similar, and specifically, that generalizability of results of trials requiring elevated acute phase reactant for inclusion should be interpreted with caution. Their characteristics are also quite different from previous observational studies, it will provide new data on the real-life efficacy and safety of TNFi.REFERENCES:NIL.Acknowledgements:NIL.Disclosure of Interests:None declared.

BackgroundTofacitinib, an oral JAK inhibitor, is indicated for the treatment of adult patients with moderate to severe active rheumatoid arthritis (RA) for which we have no real-life effectiveness data in a French RA population.ObjectivesTo describe tofacitinib effectiveness profile according to concomitant use of csDMARD in a French prospective observational study, DeFacTo.MethodsDeFacTo, is an ongoing observational study with the primary objective of identifying predictive factors of Tofacitinib maintenance in real-life RA patients. The results described here are based on a descriptive interim analysis of its effectiveness at 18 months.ResultsAmong 314 pts enrolled in the study, 301 (POP1) were included in this effectiveness analysis, including 274 (POP2) patients with follow-up ≥ 18 months on 03/15/2022 (date of analysis) with a median exposure duration of 538 [Q1; Q3: 381; 554] days. At baseline, among POP2: 168 (POP3) patients were treated with tofacitinib used concomitantly with at least one csDMARDs vs 106 (POP4) tofacitinib monotherapy. In POP3 vs POP4 respectively, 76.8% vs 84.9% were female, with a mean (± SD) age of 59.5 (10.8) vs 59.9 (12.1), median disease duration of 8.6 years [Q1;Q3: 3.2; 18.6] vs 11.1 [Q1;Q3: 5.3; 19.4)], 40.3% vs 52.4% patients had erosions, 80.5% vs 76.5% had FR+ and 77.7% vs 75.0% had ACPA+. Median CRP was 7.0 [Q1;Q3: 2.9; 18.0] vs 8.0 [Q1;Q3: 3.0; 18.1], and mean DAS28-4 CRP was 4.4 ±1.1 vs 4.7 ±1.0, in POP3 and POP4 respectively. Result showed a decrease in inflammatory markers, pain, and DAS28-CRP activity scores in both groups. At 18 months of follow-up, 24.4% and 24.5% of the pts achieved DAS28-CRP remission in POP 3 and POP 4 respectively (Table 1). Note that missing data and treatment discontinuation were considered as failures which resulted in an underestimation of LDA and remission at 18 months.Table 1.Characteristics at inclusion and effectiveness at 18 monthsBaseline, n=274At 18 month, n=274Difference from baseline to M18Variables in LS mean ± SE or % of ptsPatients with at least one concomitant csDMARD treatment (N=168)Patients without concomitant csDMARD treatment (N=106)Patients with at least one concomitant csDMARD treatment (N=168)Patients without concomitant csDMARD treatment (N=106)Patients with at least one concomitant csDMARD treatment (N=168)Patients without concomitant csDMARD treatment (N=106)PtGA*57.78 ± 1.6761.43 ± 2.0929.68 ± 2.9735.40 ± 3.38-28.10± 3.15-26.03± 3.87CRP* (mg/l)15.25± 1.8813.67± 1.455.16± 0.974.87± 0.82-10.09 ± 2.00-8.80 ± 1.52DAS28-4 CRP*4.38 ±0.094.68 ±0.102.49 ± 0.142.85 ± 0.13-1.88 ± 0.15-1.83 ± 0.16ACR-EULAR boolean criteriaⴕ3.00.912.514.29.513.3LDAⴕ, % pts- DAS28 CRP ≤3,2- DAS28 VS ≤3,211.97.13.82.835.723.237.725.523.816.133.922.7Remissionⴕ, % pts- DAS28 CRP <2,6- DAS28 VS <2,65.43.62.81.924.416.124.512.319.012.521.710.4* Missing data handled with mixed models for repeated measures ⱡ Missing data and treatment discontinuations considered failures (122 patients with missing data, 39 treatment discontinuations).ConclusionThis intermediate analysis from real-life study showed that tofacitinib in RA patients is effective with or without csDMARD.AcknowledgementsThis study was sponsored by Pfizer.Disclosure of InterestsCécile Gaujoux-Viala Speakers bureau: AbbVie; Amgen; Bristol-Myers Squibb; Celgene; Eli Lilly; Galapagos; Gilead Sciences, Inc.; Janssen; Medac; Merck-Serono; Mylan; Nordic Pharma; Novartis; Pfizer; Roche; Sandoz; Sanofi; and UCB, Consultant of: AbbVie; Amgen; Bristol-Myers Squibb; Celgene; Eli Lilly; Galapagos; Gilead Sciences, Inc.; Janssen; Medac; Merck-Serono; Mylan; Nordic Pharma; Novartis; Pfizer; Roche; Sandoz; Sanofi; and UCB, Andre BASCH Consultant of: Janssen, Novartis, Amgen, BMS, Abbvie, Lilly, Pfizer, MSD, UCB, Slim Lassoued: None declared, Fabienne COURY-LUCAS Consultant of: AbbVie, Bristol-Myers Squibb, Janssen, Lilly, MSD, Novartis and Pfizer, Grant/research support from: AbbVie, Biogen, Roche Chugai, Pfizer, and UCB, Meriem Kessouri Shareholder of: Pfizer, Employee of: Pfizer, Amine Saighi Shareholder of: Pfizer, Employee of: Pfizer, Yves Brault Shareholder of: Pfizer, Employee of: Pfizer, Pierre-Alexandre Squara Shareholder of: Pfizer, Employee of: Pfizer, Thierry Lequerre Consultant of: Abbvie, BMS, Boeringher, Lilly, Medac, MSD, Nordic Pharma, Novartis, Pfizer, Roche – Chugai, Sanofi, UCB, Carine Salliot Consultant of: Biogen, Lilly, Novartis, Roche Chugai, Pfizer.

Background:Sjögren’s disease (SjD) is a heterogenous autoimmune disease, with a wide range of symptoms, from dryness, fatigue, pain, to systemic manifestations, and an increased risk of lymphoma. Recently, three clusters of patients with SjD have been described based on unsupervised clustering analysis according to symptoms, clinical signs and biologic parameters: 1/ BA-LS (B-cell active with low symptoms); 2/ HSA (High systemic activity); 3/ LSA-HS (Low systemic activity with high symptoms). These findings suggest potential heterogeneity in pathophysiological mechanisms.Objectives:To investigate this hypothesis, we examined whether these three clusters were associated with distinct biomarkers.Methods:This study involved SjD patients meeting AECG criteria from the ASSESS cohort. The following biomarkers were measured in sera at the time of inclusion: for IFN pathways—IFN-alpha 2, IFN gamma, CXCL-10; for B cell activation—CXCL-13, BAFF, B2-microglobulin, FLT-3; for T cell activation—IL-7, CCL-19, TNF-RII. Additionally, the IFN signature was assessed using transcriptomic analysis. Kruskal-Wallis rank sum test was used to compare different clusters for continuous variables. Additionally, the risk of lymphoma and of new immunosuppressive drugs prescriptions were compared according to the IFN signature.Results:This analysis included 395 (94% female, median age 53 [43-63] years) patients from the ASSESS cohorts. The three clusters displayed differences in the IFN pathways (IFN signature), primarily driven by type I IFN (IFN-a2 level) elevated only in BA-LS and HSA clusters and not in the LSA-HS cluster (p=0.001). IFN gamma and CXCL-10 were not different between the 3 clusters.The same clusters that exhibit high level of type 1 IFN also had higher CXCL-13 levels (p=0.0032) reflecting B-cell activation, higher IL-7 (p=0.0042) and TNFRII (p<0.001) levels reflecting T-cell activation. Higher levels of FLT-3 were found in the HSA cluster. BAFF level was not different between the 3 clusters.Lastly, there were a trend indicating an increased risk of lymphoma in patients with positive IFN signature (HR 2.53; 95%CI 0.67–9.55), and an increased risk of immunosuppressant prescription during follow-up (HR 2.81; 95%CI 1.26-6.29).Conclusion:The two clusters BA-LS and HSA have a very distinct cytokine signature than the patients with LSA-HS. These two active clusters share a high type 1 IFN level, and elevated markers of both B-cell and T-cell activation. Patients from the BA-LS cluster being younger, it is likely that this cluster represent an earlier disease stage than HSA cluster. In order to go towards personalized medicine, work is in progress for deciphering patients in these two active clusters exhibiting one predominant pathways among type 1 IFN, B-cell and T-cell activation.REFERENCES:[1] Nguyen Y, Nocturne G, Henry J. Identification of distinct phenotypes of Sjögren disease by cluster analysis based on clinical and biological manifestations: data from the cross-sectional Paris-Saclay and the prospective ASSESS cohorts. Lancet Rheumatology 2024.Acknowledgements:The authors are indebted to all patients for their participation, and to all physicians who included patients in the Paris-Saclay and ASSESS cohorts. The Assessment of Systemic Signs and Evolution in Sjögren’s Syndrome (ASSESS) national multicenter prospective cohort was formed in 2006 with a French Ministry of Health grant (Programme Hospitalier de Recherche Clinique 2005 P060228). The ASSESS cohort is promoted by the French Society of Rheumatology and receives research grants from the French Society of Rheumatology.Disclosure of Interests:Yann Nguyen: None declared, Xavier Mariette Xavier Mariette received consulting fees from Astra Zeneca, Bristol Myer Squib, Galapagos, GSK, Novartis and Pfizer, Maxime Beydon: None declared, Divi Cornec: None declared, Jacques-Olivier Pers: None declared, Jacques MorelJacques Morel received honoraria from Abbvie, Boehringer Ingelheim, Biogen, Lilly, Mylan, Pfizer, Sanofi, Bristol Myers Squib, Fresenius Kabi, Galapagos, Medac, Novartis, Roche Chugai;,Jacques Morel received grants from Bristol Myers Squib, Fresenius Kabi, Lilly, Novartis, Pfizer, and Roche-Chugaï;, Aleth PERDRIGER: None declared, Emmanuelle Dernis Emmanuelle Dernis received consulting fees from BMS, Celgène, Lilly, MSD, Novartis, UCB; honoria for lectures from Abbvie, BMS, Janssen, Lilly, Medac, MSD, Novartis, Roche-Chugaï, Sanofi, UCB, Celgène, Amgen, Galapagos;, Valerie Devauchelle-Pensec: None declared, Damien Sene: None declared, Philippe Dieudé Philippe Dieudé received consulting fees from Pfizer, Roche Chugai, Bristol Myers Squibb, Abbvie, MSD., Philippe Dieudé received grants from Novartis, Marion Couderc: None declared, Anne-Laure Fauchais: None declared, Claire Larroche: None declared, Olivier Vittecoq: None declared, Carine Salliot Carine Salliot received Honoria from Novartis, Roche Chugaï, Eric Hachulla: None declared, Véronique Le Guern: None declared, Jacques-Eric Gottenberg Jacques-Eric Gottenberg consulting fees from Abbvie, Astra Zeneca, Sanofi, Lilly, Galapagos, Gilead, Roche Chugai, Pfizer, Bristol Myer Squib, MSD., Jacques-Eric Gottenberg received grants from Pfizer, Abbvie, Lilly, Raphaèle Seror Raphaèle Seror received consulting fees from GSK, Bristol Myer Squib, Boerhinger and Janssen; honoraria from GSK, Bristol Myer Squib, Boehringer, Amgen, Pfizer and Roche; travel fees from Amgen and GSK;, Gaetane Nocturne: None declared.

Objective: To evaluate the efficacy of anti-tumour necrosis factor (TNF) treatments (given for rheumatological manifestations) in reducing uveitis flares in patients with spondylarthropathy in daily practice. Methods: A retrospective observational study of all patients with spondylarthropathy with at least one uveitis flare treated with anti-TNF in one centre (December 1997–December 2004). The number of uveitis flares per 100 patient-years was compared before and during anti-TNF treatment; each patient was his or her own control. The relative risk (RR) and the number needed to treat (NNT) were calculated. Results: 46 patients with spondylarthropathy treated with anti-TNF drugs had at least one uveitis flare (33 treated with anti-TNF antibodies, infliximab or adalimumab, and 13 with soluble TNF receptor, etanercept). The mean age at first symptoms was 26 years, 71% were men. Patients were followed for 15.2 years (mean) before anti-TNF versus 1.2 years during anti-TNF treatment. The number of uveitis flares per 100 patient-years before and during anti-TNF were, respectively: for all anti-TNF treatments,—51.8 v 21.4 (p = 0.03), RR = 2.4, NNT = 3 (95% confidence interval (CI) 2 to 5); for soluble TNF receptor—54.6 v 58.5 (p = 0.92), RR = 0.9; and for anti-TNF antibodies—50.6 v 6.8 (p = 0.001), RR = 7.4, NNT = 2 (95% CI 2 to 5). Conclusion: Anti-TNF treatments were efficacious in decreasing the number of uveitis flares in patients with spondylarthropathy. Anti-TNF antibodies decreased the rate of uveitis flares, whereas soluble TNF receptor did not seem to decrease this rate. These results could have consequences for the choice of anti-TNF treatment in certain patients.