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Because Systemic Lupus Erythematosus (SLE) is a rare disease, and due to the significant prognostic impact of early management, a diagnosis confirmed by a physician with experience in SLE is recommended, for example from an expert center. Once the diagnosis is confirmed, existing manifestations should be identified in particular, renal involvement by an assessment of proteinuria, disease activity and severity should be determined, potential complications anticipated, associated diseases searched for, and the patient's socioprofessional and family context noted. Therapeutic management of SLE includes patient education on recognizing symptoms, understanding disease progression as well as when they should seek medical advice. Patients are informed about routine checkups, treatment side effects, and the need for regular vaccinations, especially if they are receiving immunosuppressive treatment. They are also advised on lifestyle factors such as the risks of smoking, sun exposure, and dietary adjustments, especially when they are receiving corticosteroids. The importance of contraception, particularly when teratogenic medications are being used, and regular cancer screening are emphasized. Support networks can help relieve a patient's isolation. The first-line medical treatment of SLE is hydroxychloroquine (HCQ), possibly combined with an immunosuppressant and/or low-dose corticosteroid therapy. The treatment of flares depends on their severity, and typically involves HCQ and NSAIDs, but may be escalated to corticosteroid therapy with immunosuppressants or biologic therapies in moderate to severe cases. Because there is no curative treatment, the goals of therapy are patient comfort, preventing progression and flares, and preserving overall long-term health and fertility. The frequency of follow-up visits depends on disease severity and any new symptoms. Regular specialized assessments are necessary, especially when treatment changes, but a frequency of every 3 to 6 months is recommended during periods of remission and monthly during active or severe disease, especially in children. These assessments include both clinical and laboratory tests to monitor complications and disease activity, with specific attention to proteinuria., (Copyright © 2024. Published by Elsevier Masson SAS.)

Construct: Psychological distress among students is a growing concern in medical education, even more so with the advent of COVID-19 pandemic. Anxiety is among students' mental health issues. High and persistent anxiety has many negative impacts on students' academic and personal life. Early detection is essential for timely intervention. Background: Currently, medical student anxiety is assessed using tools primarily designed for psychiatric purposes. Despite their excellent validity evidence, these tools contain sensitive items and do not explore stressors related to clinical activities. There is a need for contextualized tools to better identify anxiety-provoking factors specific to the medical education environment. Approach: We previously developed the Crisis Experience Rating Scale (CERS-7), a short screening tool to identify early on anxious students participating in clinical activities during the first wave of the COVID-19 pandemic. The present study sought to produce further validity evidence for the CERS-7. Medical students in their clinical years at two Swiss and one French medical school, all involved in COVID-19 clinical activity during the second wave of the pandemic, completed the CERS-7 and the State Anxiety Inventory (STAI-A), the best known and widely used tool to measure for general anxiety. We evaluated internal structure using confirmatory factor analysis (CFA) and relation to other variables using linear regression (LR) and receiver operating characteristic (ROC) curves with thresholds defined using the Youden index. Findings: There were 372 participants. CFA confirmed the two-factor structure of the CERS-7 scale from first-wave dataset. The CERS-7 total scale and subscales demonstrated validity evidence in relationship to the STAI-A scores and categories. A CERS-7 total scale score < 27.5 identified 93% of severely anxious students. Conclusion: The CERS-7 produces reliable scores to use for monitoring anxiety status when assigning students to clinical settings as well as for improving training conditions during clinical crisis.

Objectives: To investigate whether the efficacy and safety data from drug-registration trials can be extrapolated to real-life RA patients receiving RTX., Methods: The 'AutoImmunity and Rituximab' (AIR-PR) registry is a French multicentre, prospective cohort of RA patients treated with RTX in a real-life setting. We compared treatment responses at 12 months and serious adverse events (AEs) between eligible and non-eligible patients, by retrieving the eligibility criteria of the three rituximab-registration trials. We determined critical eligibility criteria and modelled the benefit-risk ratio according to the number of fulfilled critical eligibility criteria., Results: Among 1984 RA patients, only 9-12% fulfilled all eligibility criteria. Non-eligible patients had fewer EULAR responses at 12 months (40.3% vs 46.9%, P = 0.044). Critical inclusion criteria included swollen joints count ≥4, tender joints count ≥4, CRP ≥15 mg/l and RF positivity. Critical exclusion criteria were age >80 years, RA-associated systemic diseases, ACR functional class IV, DMARD other than MTX and prednisone >10 mg/day. Only 20.8% fulfilled those critical eligibility criteria. During the first year, serious AEs occurred for 182 (9.2%) patients (70.3% serious infections) and patients with ≥1 critical exclusion criterion were at higher risk (hazard ratio 3.03; 95% CI 2.25-4.06; for ≥3 criteria vs 0). The incremental risk-benefit ratio decreased with the number of unmet critical inclusion criteria and of fulfilled exclusion criteria., Conclusion: Few real-life RA patients were eligible for the drug-registration trials. Non-eligible patients had lower chance of response, and higher risk of serious AEs. Efficacy and safety data obtained from those trials may not be generalizable to RA patients receiving RTX in real-world clinical practice., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: Inflammatory myopathies (IM), characterized by muscle inflammation and weakness, are rare systemic diseases. Our previous study estimated an IM incidence rate of 7.98 cases per million people per year (95% confidence interval 7.38-8.66) and highlighted important variations that were likely because of methodologic issues rather than true epidemiologic differences. In this study, we aimed to refine the incidence of IM, using the 2017 European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) classification criteria for IM and a quadruple-source capture-recapture method during a 6-year period in Alsace, France, a region with a population of 2 million having benefits of good access to health care and accredited IM referral centers., Methods: Clinical data of potential IM patients were obtained from 4 sources (general practitioners and community specialists, public and private hospital records, public and private laboratories, and archives from the pathology department). Patients residing in Alsace and who fulfilled the 2017 EULAR/ACR criteria for IM between January 1, 2006, and January 1, 2013, were included. We corrected potentially incomplete ascertainment of cases with capture-recapture analyses. We studied both spatial and temporal distributions of incidence of IM. We also assessed systemic manifestations of the disease., Results: Our review of 1,742 potential cases identified 106 patients with IM. No spatial or temporal heterogeneity was observed. Use of log-linear models showed an estimated 14.9 additional missed cases. Thus, the incidence rate of IM was 8.22 new cases per million inhabitants per year (95% confidence interval 6.76-9.69). Extramuscular manifestations other than dermatomyositis rash were frequently recorded., Conclusion: The stringent methodology used in our study provides an accurate estimation of the incidence of IM. This study also demonstrates, in a population-based cohort, the systemic nature of IM., (© 2023 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Objective: To report the 10-year outcome of an inception cohort of patients with early rheumatoid arthritis (RA), the ESPOIR cohort, and predictors of outcome., Methods: From 2003 to 2005, 813 patients were included if they had early arthritis (<6 months) with a high probability of RA and had never been prescribed DMARDs. Multivariate analysis was used to evaluate predictors of outcome., Results: In total, 521 (64.1%) RA patients were followed up for 10 years; 35 (4.3%) died, which appears to be similar to the French general population. Overall, 480 (92.1%) patients received a DMARD; 174 (33.4%) received at least one biologic DMARD, 13.6% within 2 years. At year 10, 273 (52.4%) patients were in DAS28 remission, 40.1% in sustained remission, 14.1% in drug-free remission, 39.7% in CDAI remission. Half of the patients achieved a health assessment questionnaire-disability index (HAQ-DI) < 0.5. SF-36 physical component and pain were well controlled. Structural progression was weak, with a mean change from baseline in modified Sharp score of 11.0  (17.9). Only 34 (6.5%) patients required major joint surgery. A substantial number of patients showed new comorbidities over 10 years. Positivity for anti-citrullinated peptides antibodies (ACPA) was confirmed as a robust predictor of long-term outcome., Conclusions: We report a very mild 10-year outcome of a large cohort of patients with early RA diagnosed in the early 2000s, which was much better than results for a previous cohort of patients who were recruited in 1993. This current favourable outcome may be related to more intensive care for real-life patients., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

The COVID-19 pandemic has led to increased staffing needs in emergency departments. The question quickly arose as to whether it was appropriate to offer medical students the opportunity to assist this staff. The dilemma stems in part from the potential impact on their psychological well-being as well as their academic and clinical performances. We sought to determine the level of anxiety of medical students during the COVID-19 outbreak, and whether it was higher among the students who chose to return to the clinical setting, especially in first-line units (i.e., emergency departments and resuscitation units). In May 2020, 1180/1502 (78.5%) undergraduate medical students at Strasbourg Medical School (France) completed a questionnaire assessing their anxiety and clinical experience. A 2018 cohort of undergraduate medical students served as the baseline. The 2020 COVID cohort had higher rates of anxiety than the 2018 cohort. This difference was specifically observed in the students who chose not to return to the clinical setting during the crisis (N = 684, 59%). At linear regression, the main factors associated with anxiety were gender (p < 0.005) and perceived clinical activity personal conditions (p < 0.001). Employment site, including COVID first-line units, was not correlated with anxiety. Working in the clinical setting during the COVID-19 outbreak is not a risk factor for anxiety in medical students. Instead, it is an active coping strategy, suggesting that there are no barriers to allowing students to return to clinical settings during a pandemic, including first-line units, in terms of their psychological well-being., (© 2021. Società Italiana di Medicina Interna (SIMI).)

Background: Children are underrepresented in the COVID-19 pandemic and often experience milder disease than adolescents and adults. Reduced severity is possibly due to recent and more frequent seasonal human coronaviruses (HCoV) infections. We assessed the seroprevalence of SARS-CoV-2 and seasonal HCoV specific antibodies in a large cohort in north-eastern France., Methods: In this cross-sectional seroprevalence study, serum samples were collected from children and adults requiring hospital admission for non-COVID-19 between February and August 2020. Antibody responses to SARS-CoV-2 and seasonal HCoV (229E, HKU1, NL63, OC43) were assessed using a bead-based multiplex assay, Luciferase-Linked ImmunoSorbent Assay, and a pseudotype neutralisation assay., Findings: In 2,408 individuals, seroprevalence of SARS-CoV-2-specific antibodies was 7-8% with three different immunoassays. Antibody levels to seasonal HCoV increased substantially up to the age of 10. Antibody responses in SARS-CoV-2 seropositive individuals were lowest in adults 18-30 years. In SARS-CoV-2 seronegative individuals, we observed cross-reactivity between antibodies to the four HCoV and SARS-CoV-2 Spike. In contrast to other antibodies to SARS-CoV-2, specific antibodies to sub-unit 2 of Spike (S2) in seronegative samples were highest in children. Upon infection with SARS-CoV-2, antibody levels to Spike of betacoronavirus OC43 increased across the whole age spectrum. No SARS-CoV-2 seropositive individuals with low levels of antibodies to seasonal HCoV were observed., Interpretation: Our findings underline significant cross-reactivity between antibodies to SARS-CoV-2 and seasonal HCoV, but provide no significant evidence for cross-protective immunity to SARS-CoV-2 infection due to a recent seasonal HCoV infection. In particular, across all age groups we did not observe SARS-CoV-2 infected individuals with low levels of antibodies to seasonal HCoV., Funding: This work was supported by the « URGENCE COVID-19 » fundraising campaign of Institut Pasteur, by the French Government's Investissement d'Avenir program, Laboratoire d'Excellence Integrative Biology of Emerging Infectious Diseases (Grant No. ANR-10-LABX-62-IBEID), and by the REACTing (Research & Action Emerging Infectious Diseases), and by the RECOVER project funded by the European Union's Horizon 2020 research and innovation programme under grant agreement No. 101003589, and by a grant from LabEx IBEID (ANR-10-LABX-62-IBEID)., Competing Interests: Declaration of Competing Interest MTW and SPel are inventors on provisional patent PCT/US 63/057.471 on a serological antibody-based diagnostics of SARS-CoV-2 infection. Dr. Dubos reports grants from Universite de Lille, during the conduct of the study. Dr. van der WERF reports grants from Agence Nationale de la Recherche, grants from European Union's Horizon 2020 research and innovation programme, during the conduct of the study; In addition, Dr. van der WERF has a patent USE OF PROTEINS AND PEPTIDES CODED BY THE GENOME OF A NOVEL STRAIN OF SARS ASSOCIATED CORONAVIRUS issued, and a patent SEVERE ACUTE RESPIRATORY SYNDROME (SARS) - ASSOCIATED CORONAVIRUS DIAGNOSTICS pending., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: The risk of severe COVID-19 and its determinants remain largely unknown in patients with autoimmune and inflammatory rheumatic diseases. The objective of this study was to assess the prevalence of COVID-19 infection in patients followed for rare autoimmune diseases as well as the predictors of COVID-19 and disease flare-ups., Methods: Cross-sectional phone survey from April 9, 2020, to July 2, 2020, during which patients with autoimmune diseases followed at the National Reference Center for Rare Autoimmune diseases of Strasbourg were systematically contacted by phone and sent a prescription for a SARS-CoV-2 serology., Results: One thousand two hundred thirty-two patients were contacted. One thousand fifty-five patients with a confirmed diagnosis of systemic autoimmune disease were included (4 unreachable, 4 moves abroad, 5 deaths before pandemic, 50 without consent, and 114 without autoimmune disease). Among them, 469 (44.5%) patients were tested for SARS-CoV-2 serology. Thirty-nine patients (7.9%) had SARS-CoV-2 infection (either through chest CT-scan [n = 5], RT-PCR on nasopharyngeal swab [n = 14], or serology [n = 31]) among the 496 who underwent at least one of those 3 diagnosis modalities. Of the 39 proven cases, 33 had clinical manifestations (6 asymptomatic patients were diagnosed through systematic serology testing), 31 were managed by home care, 3 were hospitalized due to a need for oxygenation, two required admission to an intensive care unit, and one died. Among patients with confirmed SARS-CoV-2 infection, reported flares were more frequent than in uninfected patients (26.3% [10/38] vs. 7.0% [32/457], p < 0.0001). Preventive sick leave had no significant impact on the prevalence of SARS-CoV-2 infection (5.8% [3/53]) compared to work continuation (7.6% [30/397], p = 0.64). Overall, the seroprevalence of SARS-CoV-2 was 6.6% (31/469) which was numerically lower to the Grand-Est general population estimated to be 9.0%., Conclusions: This systematic survey of more than 1000 patients with rare systemic autoimmune diseases reports a low prevalence of proven SARS-CoV-2 infection and very rare severe infections, probably related to good compliance with prophylactic measures in these patients., (© 2021. The Author(s).)

We investigated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific antibodies and T-cell responses against SARS-CoV-2 and human coronavirus (HCoV) 229E and OC43 in 11 SARS-CoV-2 serodiscordant couples in Strausbourg, France, in which 1 partner had evidence of mild coronavirus disease (COVID-19) and in 10 unexposed healthy controls. Patients with confirmed COVID-19 were considered index patients and their partners close contacts. All index patients displayed positive SARS-CoV-2-specific antibody and T-cell responses that lasted up to 102 days after symptom onset. All contacts remained seronegative for SARS-CoV-2; however, 6 reported COVID-19 symptoms within a median of 7 days after their partners, and 4 of those showed a positive SARS-CoV-2-specific T-cell response against 3 or 4 SARS-CoV-2 antigens that lasted up to 93 days after symptom onset. The 11 couples and controls displayed positive T-cell responses against HCoV-229E or HCoV-OC43. These data suggest that exposure to SARS-CoV-2 can induce virus-specific T-cell responses without seroconversion.

Objective: Systemic lupus is a chronic autoimmune disease characterised by its phenotypic heterogeneity. Neutropaenia is a frequent event in SLE occurring in 20%-40% of patients depending on the threshold value of neutrophil count. On a daily basis, the management of neutropaenia in SLE is difficult with several possible causes. Moreover, the infectious consequences of neutropaenia in SLE remain not well defined., Methods: 998 patients from the Lupus BioBank of the upper Rhein (LBBR), a large German and French cohort of patients with SLE, mostly of Caucasian origin (83%), were included in this study. Neutropaenia was considered when neutrophil count was below 1800×10 6 /L. An additional analysis of detailed medical records was done for 65 LBBR patients with neutropaenia., Results: 208 patients with neutropaenia (21%) were compared with 779 SLE patients without neutropaenia. Neutropaenia in SLE was significantly associated with thrombocytopaenia (OR 4.11 (2.57-10.3)), lymphopaenia (OR 4.41 (2.51-11.5)) and low C3 (OR 1.91 (1.03-4.37)) in multivariate analysis. 65 representative patients with neutropaenia were analysed. Neutropaenia was moderate to severe in 38%, chronic in 31%, and both severe and chronic in 23% of cases. Moderate to severe and chronic neutropaenia were both associated with lymphopaenia and thrombopaenia. Chronic neutropaenia was also associated anti-Ro/SSA antibodies and moderate to severe neutropaenia with oral ulcers., Conclusion: This study is to date the largest cohort to describe neutropaenia in SLE. Neutropaenia displays a strong association with other cytopaenias, suggesting a common mechanism. Chronic neutropaenia is associated with anti-Ro/SSA antibodies with or without identified Sjögren's disease., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To refine the predictive significance of muscle granuloma in patients with myositis., Methods: A group of 23 patients with myositis and granuloma on muscle biopsy (granuloma-myositis) from 8 French and Belgian centers was analyzed and compared with (1) a group of 23 patients with myositis without identified granuloma (control-myositis) randomly sampled in each center and (2) a group of 20 patients with sporadic inclusion body myositis (sIBM) without identified granuloma (control-sIBM)., Results: All but 2 patients with granuloma-myositis had extramuscular involvement, including signs common in sarcoidosis that were systematically absent in the control-myositis and the control-sIBM groups. Almost half of patients with granuloma-myositis matched the diagnostic criteria for sIBM. In these patients, other than the granuloma, the characteristics of the myopathy and its nonresponse to treatment were similar to the control-sIBM patients. Aside from 1 patient with myositis overlapping with systemic sclerosis, the remaining patients with granuloma-myositis did not match the criteria for a well-defined myositis subtype, suggesting pure sarcoidosis. Matching criteria for sIBM was the sole feature independently associated with nonresponse to myopathy treatment in patients with granuloma-myositis., Conclusion: Patients with granuloma-myositis should be carefully screened for sIBM associated with sarcoidosis in order to best tailor their care., (© 2019 American Academy of Neurology.)

Objective: To refine the spectrum of anti-Ku-associated disease, a condition that is equivocally described by current diagnostic criteria for connective tissue diseases., Methods: Among 42 consecutive patients harbouring anti-Ku antibodies, subgroups with similar phenotypes and prognosis were delineated without an a priori diagnosis using hierarchical clustering analysis of the cumulative clinico-biological features recorded during the follow-up. Features present at baseline that most efficiently predicted the outcomes were then identified using a sensitivity-specificity sum maximisation approach., Results: Clinico-biological features were clustered into three groups. Glomerulonephritis and ILD, the two fatal complications in this cohort, were unequally distributed between the three clusters that additionally differed on six clinico-biological features.Among features present at baseline, elevated serum level of creatine kinase (CK) and anti-dsDNA antibodies were generally mutually exclusive and most efficiently predicted the cluster belonging at last follow-up. Anti-Ku patients with elevated CK had a 22-fold higher risk of ILD while anti-Ku patients with anti-dsDNA antibodies had a 13-fold higher risk of glomerulonephritis CONCLUSION: "Anti-Ku with elevated CK" syndrome and "anti-Ku with anti-dsDNA" syndrome represent two distinct entities that are important to recognise in order to best tailor patient care., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: APS mainly affects women who are of child-bearing age. We aimed to describe the clinical and immunological features of APS patients diagnosed after the age of 60., Methods: The Elderly-Phospholipid study is a national, multicentre, retrospective study involving all APS (2006 Miyakis criteria) patients followed in five French tertiary university centres including four national referral lupus and APS centres. Clinical and serological data of patients in whom APS onset occurred after the age of 60 were analysed and compared with patients included in the Euro-Phospholipid cohort., Results: Forty-four patients (30 women (68.2%); 68.7 (7) years at diagnosis; 72.7% of primary APS) were included in the Elderly-Phospholipid study. Stroke was the most common manifestation at diagnosis (38.6%) and during follow-up (11.4%). LA, aCL and anti-β2-glycoprotein I antibodies were detected in 70.4%, 72.7% and 65.9% of patients, respectively; 43.2% of patients were triple-positive for aPL antibodies. All patients were treated with antithrombotic treatment including antiplatelet agents (31.8%) and/or oral anticoagulants (77.3%). Over a 5.3 (3.8) years follow-up, nine (20.5%) patients displayed a new arterial (n = 8) or venous (n = 1) thrombotic event. Only three (6.8%) patients developed major bleeding. As compared with Euro-Phospholipid APS patients (mean age of 34 (13) years at disease onset), patients in the Elderly-Phospholipid study were more frequently male (P < 0.05) and had a higher frequency of primary APS (<0.05), stroke (<0.0001) and LA (P < 0.05)., Conclusion: APS patients with elderly onset share a distinct disease profile, with a higher frequency of LA, triple aPL positivity and arterial thrombosis., (© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: To describe the clinical and microbiological characteristics and outcomes after antibiotic treatment of a national cohort of patients with Lyme arthritis confirmed by PCR testing on synovial fluid and by serology, when available., Methods: Using the French National Reference Center for Borrelia database, patients with a positive PCR on synovial fluid for Borrelia were identified. Patient clinical and biological characteristics were reviewed from patient records. Long-term outcomes after treatment were studied through a questionnaire and with follow-up data., Results: Among 357 synovial fluid testing by PCR between 2010 and 2016, 37 (10.4%) were positive for Borrelia. Patients' median age was 36 years (range 6-78) with 61% of men and 28% patients under 18. The presentation was monoarticular in 92% and the knee was involved in 97%. Contrary to the Borrelia species repartition in European ticks, B. burgdorferi sensu stricto was the most prevalent species found in synovial fluid (54%) followed by B. azfelii (29%) and B. garinii (17%). Antibiotic treatments were mainly composed of doxycycline (n = 24), ceftriaxone (n = 10) and amoxicillin (n = 6), for a median duration of 4 weeks (range 3-12). Despite a properly conducted treatment, 34% of patients (n = 12) developed persistent synovitis for at least 2 months (median duration 3 months, range 2-16). Among those, 3 developed systemic inflammatory oligo- or polyarthritis in previously unaffected joints with no signs of persistent infection (repeated PCR testing negative), which mandated Disease-Modifying Antirheumatic Drugs (DMARD) introduction, leading to remission., Conclusion: In France and contrary to ticks ecology, Lyme arthritis is mainly caused by B. burgdorferi sensu stricto. Despite proper antibiotic therapy, roughly one third of patients may present persistent inflammatory synovitis and a small proportion may develop systemic arthritis. In such cases, complete remission can be reached using DMARD., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objectives: To evaluate the short-term efficacy of vitamin D (cholecalciferol) supplementation on functional disability in RA patients., Methods: 1) Patients: RA (ACR 1987 revised criteria) in non-remission (DAS28 >2.6) whose treatment was not expected to be changed over a 3-month period following inclusion and presenting with vitD deficits (serum 25OHD <30ng/mL). 2) Study design: prospective randomised placebo-controlled trial (NCT02243800). 3) Study arms: either vitD ampoules (cholecalciferol 100,000IU) or placebo. 4) Outcome measures: primary: improvement in patients' functional disability using the Health Assessment questionnaire (HAQ); secondary: improvement in DAS28ESR, DAS28CRP, ESR, CRP, RAID score, fatigue (EVA and FACIT), and SF36., Results: Overall, 59 patients were included, 83.1% females, aged 59.8±10.9 years on average, with RA for 17.0±9.7 years. Thirty patients received placebo and 29 vitD. At 6 months, HAQ scores tended to be increased in the placebo group (+0.08±0.25), while slightly numerically decreased in the vitD group (-0.03±0.23) (p=0.11). After adjusting for age, gender, season, and initial vitD status, the between-group difference achieved statistically significance (p=0.046). After adjusting for age, gender, season, and initial vitD status, there was no significant difference in the secondary criteria between the 2 groups except for ESR and CRP (p=0.002 and 0.04, respectively)., Conclusions: In this randomised, double-blind, placebo-controlled clinical trial in patients with RA and VitD deficiency, high doses of cholecalciferol resulted in a statistically significant improvement in functional disability at month 6, which, however, was clinically not relevant.

Objectives: Assess the frequency of paradoxical reactions encountered in daily practice under tocilizumab, using the REGATE (Registry-RoActemra) registry. The secondary objectives were to determine the type of paradoxical reaction and the consequences of these reactions., Methods: The REGATE registry is an independent prospective registry, promoted by the French Society of Rheumatology, consisting of patients treated with tocilizumab for rheumatoid arthritis. The paradoxical reaction was retained if it was a paradoxical precipitation of a condition for which tocilizumab was indicated, if tocilizumab was being used for an alternative indication, and if it appeared after at least one tocilizumab infusion., Results: Among the 1491 patients included with at least one follow-up visit (3429 patient-years), a paradoxical reaction occurred in 9 patients (0.60% of patients; 2.62/1000 patient-years). These were 7 de novo pathologies (3 vasculitis, 3 uveitis, 1 lupus) and 2 exacerbations of pre-existing conditions (1 vasculitis, 1 lupus). Permanent discontinuation of tocilizumab was chosen for 5 patients., Conclusions: In the REGATE registry, the occurrence of paradoxical reactions in patients treated with tocilizumab was rare., (Copyright © 2017 Société française de rhumatologie. Published by Elsevier SAS. All rights reserved.)

Objectives: Observational studies have already reported the risk of serious infections in RA treated with tocilizumab, but in limited samples. The aim of this study was to investigate the predictive risk factors for serious infections in the largest European registry of patients treated with tocilizumab for RA., Methods: A total of 1491 RA patients included in the French REGistry-RoAcTEmra were analysed to calculate the incidence rate of first serious infections rate after initiation of tocilizumab. To identify independent factors associated with serious infections, a Cox model was performed., Results: Among the 1491 patients, average age 56.6 (13.6) years, 125 serious infections occurred in 122 patients (incidence rate of serious infection: 4.7/100 patient-years). Univariate analysis identified initial ACPA positivity as the only factor associated with a lower risk of serious infection [hazard ratio (HR) = 0.56, 95% CI: 0.36, 0.88]. Other factors significantly associated with a higher risk of serious infections were DAS28, concomitant Leflunomide (LEF) treatment, and absolute neutrophil count (ANC) at baseline. Initial ANC above 5.0 × 109/l (HR = 1.94, 95% CI: 1.32, 2.85; P < 0.001), negative ACPA (HR = 1.79, 95% CI: 1.15, 2.78; P = 0.012) at baseline and concomitant LEF treatment (LEF alone vs no treatment, HR = 2.18, 95% CI: 1.22, 3.88; P = 0.009) remained significantly associated with first serious infections in multivariate analysis after imputation for missing data., Conclusion: The rate of first serious infections in current practice is similar to that reported in clinical trials. High ANC (above 5.0 × 109 at baseline), negative ACPA and concomitant therapy with LEF are predictive factors of serious infection, requiring in this case a tighter surveillance., (© The Author 2017. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com)

Purpose: To develop French recommendations about the management of vaccinations, the screening of cervical cancer and the prevention of pneumocystis pneumonia in systemic lupus erythematosus (SLE)., Methods: Thirty-seven experts qualified in internal medicine, rheumatology, dermatology, nephrology and pediatrics have selected recommendations from a list of proposition based on available data from the literature. For each recommendation, the level of evidence and the level of agreement among the experts were specified., Results: Inactivated vaccines do not cause significant harm in SLE patients. Experts recommend that lupus patient should receive vaccinations accordingly to the recommendations and the schedules for the general public. Pneumococcal vaccination is recommended for all SLE patients. Influenza vaccination is recommended for immunosuppressed SLE patients. Live attenuated vaccines should be avoided in immunosuppressed patients. Yet, recent works suggest that they can be considered in mildly immunosuppressed patients. Experts have recommended a cervical cytology every year for immunosuppressed patients. No consensus was obtained for the prevention of pneumocystis pneumonia., Conclusion: These recommendations can be expected to improve clinical practice uniformity and, in the longer term, to optimize the management of SLE patients., (Copyright © 2016 Société nationale française de médecine interne (SNFMI). Published by Elsevier SAS. All rights reserved.)

Antisynthetase syndrome (aSS) corresponds to an overlapping inflammatory myopathy identified by various myositis-specific autoantibodies (directed against tRNA-synthetases). Myocardial involvement in this condition is poorly described.From a registry of 352 aSS patients, 12 cases of myocarditis were retrospectively identified on the basis of an unexplained increase in troponin T/I levels associated with either suggestive cardiac magnetic resonance imaging (MRI) findings, nonsignificant coronary artery abnormalities or positive endomyocardial biopsy.The prevalence of myocarditis in aSS is 3.4% and was not linked to any autoantibody specificity: anti-Jo1 (n = 8), anti-PL7 (n = 3), and anti-PL12 (n = 1). Myocarditis was a part of the first aSS manifestations in 42% of the cases and was asymptomatic (n = 2) or revealed by an acute (n = 4) or a subacute (n = 6) cardiac failure. It should be noted that myocarditis was always associated with an active myositis. When performed (n = 11), cardiac MRI revealed a late hypersignal in the T1-images in 73% of the cases (n = 8). Half of the patients required intensive care. Ten patients (83%) received dedicated cardiotropic drugs. Steroids and at least 1 immunosuppressive drug were given in all cases. After a median follow-up of 11 months (range 0-84) 9 (75%) patients recovered whereas 3 (25%) developed a chronic cardiac insufficiency. No patient died.The prevalence of myocarditis in aSS is similar to that of other inflammatory myopathies. Although the prognosis is relatively good, myocarditis is a severe condition and should be carefully considered as a possible manifestation in active aSS patients.

The clinical presentation and outcome of hepatitis E virus (HEV) infection in inflammatory rheumatic diseases are unknown. We aimed to investigate the severity of acute HEV infection and the risk of chronic viral replication in patients with inflammatory arthritides treated with immunosuppressive drugs. All rheumatology and internal medicine practitioners belonging to the Club Rhumatismes et Inflammation in France were sent newsletters asking for reports of HEV infection and inflammatory arthritides. Baseline characteristics of patients and the course of HEV infection were retrospectively assessed by use of a standardized questionnaire. From January 2010 to August 2013, we obtained reports of 23 cases of HEV infection in patients with rheumatoid arthritis (n = 11), axial spondyloarthritis (n = 5), psoriatic arthritis (n = 4), other types of arthritides (n = 3). Patients received methotrexate (n = 16), antitumor necrosis factor α agents (n = 10), rituximab (n = 4), abatacept (n = 2), tocilizumab (n = 2), and corticosteroids (n = 10, median dose 6 mg/d, range 2-20). All had acute hepatitis: median aspartate and alanine aminotransferase levels were 679 and 1300 U/L, respectively. Eleven patients were asymptomatic, 4 had jaundice. The HEV infection diagnosis relied on positive PCR results for HEV RNA (n = 14 patients) or anti-HEV IgM positivity (n = 9). Median follow-up was 29 months (range 3-55). Treatment included discontinuation of immunosuppressants for 20 patients and ribavirin treatment for 5. Liver enzyme levels normalized and immunosuppressant therapy could be reinitiated in all patients. No chronic infection was observed. Acute HEV infection should be considered in patients with inflammatory rheumatism and elevated liver enzyme values. The outcome of HEV infection seems favorable, with no evolution to chronic hepatitis or fulminant liver failure.

Opsonization and apoptotic cell elements are critical in systemic lupus erythematosus (SLE) and could act through the activation of the innate immunity. C-reactive protein (CRP) belongs to opsonins, and polymorphisms of CRP gene have been shown to be associated with SLE susceptibility. Accumulating evidences show that SLE and systemic sclerosis (SSc) share some genetic susceptibility factors. To determine whether polymorphisms of CRP confer susceptibility to SSc, four SNPs (rs1130864, rs1205, rs1800947 and rs1341665), chosen using Hapmap linkage disequilibrium data and published data, were genotyped in a cohort of 651 SSc patients (569 with antinuclear antibodies, 258 with anti-centromere and 153 with anti-topoisomerase I) and 442 controls. All individuals were of French Caucasian origin. The four polymorphisms were in Hardy-Weinberg equilibrium in the control population. Allelic and genotypic frequencies for these four polymorphisms were found to be similar in SSc patients and controls. Moreover, subphenotype analyses in particular for subgroups having antinuclear antibodies did not detect any difference between SSc patients and controls. These results obtained through a large cohort of European Caucasian SSc patients do not support the implication of CRP gene in the pathogenesis of SSc.

Objective: We used data from the AutoImmunity and Rituximab (AIR) registry to investigate the safety of surgery for patients with rheumatoid arthritis receiving rituximab (RTX) in routine care., Methods: Data for patients included in the AIR registry and undergoing surgery during the year following an infusion of RTX were reviewed to describe the frequency of postsurgical complications, compare patients with and without complications, and identify factors associated with complications., Results: We examined data for 133 patients with a known date of surgery and at least 1 followup visit, corresponding to 140 procedures, including 94 orthopedic surgeries (67%) and 23 abdominal surgeries (16.5%). The median delay between surgery and the last RTX infusion was 6.4 months (interquartile range 4.3– 8.7 months), without any difference between patients with and without complications. Nine patients (6.7%) experienced 12 complications (8.5%), including 8 surgical site infections (5.7%) and 1 death due to septic shock. Postoperative complications occurred after 4.3% of abdominal surgeries (1 of 23) and 7.4% of orthopedic surgeries (7 of 95). On univariate analysis, spine surgery was associated with postoperative complications (P = 0.048)., Conclusion: In common practice, the risk of complications may be more important in case of spine surgery, but does not seem to be linked to the time between the last RTX infusion and surgery.

Increasing rituximab prescription for ANCA-associated necrotizing vasculitides justifies the publication of recommendations for clinicians. Rituximab is approved in the United States to induce and maintain remission. In Europe, rituximab was recently approved for remission induction. However, governmental agencies' approvals cannot replace clinical practice guidelines. Herein, the French Vasculitis Study Group Recommendations Committee, comprised of physicians with extensive experience in the treatment of vasculitides, presents its consensus guidelines based on literature analysis, the results of prospective therapeutic trials and personal experience., (Copyright © 2013. Published by Elsevier Masson SAS.)

Objective: The European League Against Rheumatism (EULAR) Sjögren's Syndrome (SS) Disease Activity Index (ESSDAI) and the EULAR SS Patient-Reported Index (ESSPRI) were recently developed. We aimed to determine whether patients' symptoms differed between patients with and without systemic involvement and if the disease-specific indices correlated with each other in primary SS., Methods: Fifteen French centers included 395 primary SS patients in the Assessment of Systemic Signs and Evolution in Sjögren's Syndrome Cohort. At enrollment, physicians completed the ESSDAI, the SS Disease Activity Index (SSDAI), and the Sjögren's Systemic Clinical Activity Index (SCAI), and patients completed the ESSPRI, the Sicca Symptoms Inventory, and the Profile of Fatigue and Discomfort. All scores were compared between patients with and without systemic involvement. Correlations between scores of systemic activity and patients' symptoms were obtained., Results: At enrollment, 120 (30.4%) patients had never experienced systemic complication and 155 (39.2%) patients and 120 (30.4%) patients had, respectively, only past or current systemic manifestations. Past or current systemic patients had higher levels of symptoms, except dryness. The ESSDAI did not correlate with the patient-scored ESSPRI (rho = 0.06, P = 0.30), whereas the SSDAI and the SCAI, which include subjective items, did correlate (rho = 0.28 and 0.25, respectively; P < 0.0001 for both)., Conclusion: Alterations of common patient-reported outcomes are present in all patients with primary SS, including those with systemic complications. However, patient symptoms and systemic complications are 2 different facets of primary SS. Therefore, the use of both systemic and patients' indices, such as the ESSDAI and ESSPRI, are useful. Since these 2 facets weakly overlap, one should identify which of both components is the main target of the treatment to test, when designing clinical trials in primary SS., (Copyright © 2013 by the American College of Rheumatology.)

Objective: To evaluate the efficacy and safety of rituximab (RTX) in several subsets of spondyloarthritis (SpA) using the data of the AIR (Autoimmunity and Rituximab) registry., Methods: All patients receiving RTX for SpA, and prospectively included in the AIR registry from September 2005 to September 2010, were retrospectively analyzed. The response to treatment was evaluated by the Bath Ankylosing Spondylitis Disease Activity Index for axial disease, joint count for peripheral disease, and C-reactive protein reduction., Results: Among the 595 patients included in the AIR registry, 26 patients with SpA from 13 centers were reported: ankylosing spondylitis (10), undifferentiated SpA (7), and psoriatic arthritis (9). Mean disease duration was 8.8 years (range 1-40). The extraarticular features found were psoriasis, 12 cases; uveitis, 4 cases; and Crohn's disease, 3 cases. The mean number of disease-modifying antirheumatic drugs before RTX was 2.4; previous anti-tumor necrosis factor (TNF) agents were taken in 23 cases. The mean number of RTX courses was 1.5 (range 1-5), with a total of 35.6 patient-years. Efficacy was noted in 11/23 cases: 3 out of 3 anti-TNF-naive patients and 8 out of 20 anti-TNF nonresponder patients. No predictive factors of response could be identified, particularly in diagnosis subsets or clinical presentation (axial or peripheral)., Conclusion: In this nationwide study of several subsets of SpA, RTX had only a moderate efficacy that was more marked in patients who were anti-TNF-naive.

Objectives: To evaluate the efficacy of rituximab in central nervous system (CNS) manifestations of patients with primary Sjögren's syndrome (pSS)., Methods: Prospective data from patients with pSS and CNS involvement included in the French AutoImmunity and Rituximab registry were analysed. All patients had diffuse white matter T2-weigted hypersignals. Neurological response was defined as improvement or disappearance of neurological signs., Results: Eleven patients (mean age 55 years [38-77]) were treated with rituximab for their neurological involvement. The mean duration of pSS was 9 years (4-24). Mean baseline ESSDAI score was 17 (5-25). Neurological features were progressive multiple sclerosis-like manifestations (n=6), transverse myelitis (n=1), anxiety and depression disorder (n=1) and cognitive dysfunction (n=3). Mean Expanded Disability Status Score (EDSS) before rituximab was 4 (3-5.5). The mean follow-up was of 13 months (6-58). No neurological change occurred in all 6 patients with multiple sclerosis-like symptoms, in 2/3 patients with cognitive dysfunction or in the patient with anxiety-depression. One patient with depression and cognitive dysfunction disclosed subjective improvement. One patient with transverse myelitis, refractory to cyclophosphamide had an improvement of his walk perimeter (160 meters vs. 116). Mean EDSS score and ESSDAI remained stable., Conclusions: Rituximab does not seem to be effective in progressive multiple sclerosis-like manifestations of patients with pSS-related CNS involvement.

Objective: Sjögren's syndrome (SS)-related peripheral neuropathy is responsible for disability, but no treatment has been shown to improve its outcome. In some cases, intravenous immunoglobulin (IVIG) therapy has been associated with some benefit. In this study, we investigated the effectiveness of IVIG in SS-related peripheral neuropathy., Methods: We assessed the efficacy and tolerance of IVIG in 19 patients with primary SS-related neuropathy without any necrotizing vasculitis in a retrospective national multicentric study. The evaluation of the response was assessed using the disability Modified Rankin Scale (MRS) and a global evaluation by the practitioner., Results: Eight patients (42%) exhibited a decrease of the MRS score corresponding to a clinical improvement, 10 patients (52%) exhibited a stable MRS score, and 1 patient (6%) showed an increase of MRS score. According to the global evaluation by the practitioner, 9 (47%) of the 19 patients were improved, 6 patients (31%) were stable, and 4 patients (21%) worsened. All the patients with sensorimotor (n = 5) or nonataxic sensory neuropathy (n = 4) were improved or stabilized. However, among the patients with ataxic neuropathy (n = 9), only 2 improved and 4 worsened. Ten of the 13 patients treated with corticosteroids could have had the prednisone dosage decreased from 15 mg/day (range 7.5-60) to 10 mg/day (range 5-20) with IVIG. Only 1 patient stopped the treatment after 1 dose because of a minor side effect and lack of initial efficacy., Conclusion: IVIG may be useful in the treatment of SS-associated sensorimotor neuropathies or nonataxic sensory neuropathy without any necrotizing vasculitis. The benefit of such therapy in the SS-related ataxic neuropathy seems less clear., (Copyright © 2011 by the American College of Rheumatology.)

Objective: To evaluate the safety and efficacy of rituximab (RTX) in juvenile dermatomyositis (JDM) in off-trial patients., Methods: We conducted a multicenter prospective study of patients with JDM included in the French Autoimmunity and Rituximab (AIR) registry., Results: Nine patients with severe JDM were studied. The main indication for RTX treatment was severe and/or refractory muscle involvement (7 patients), severe calcinosis (1 patient), or severe chronic abdominal pain associated with abdominal lipomatosis (1 patient). RTX was associated with corticosteroids, immunosuppressive drugs, and plasma exchange therapy in 9/9, 5/9, and 2/9 patients, respectively. Mild infections of the calcinosis sites occurred in 2 patients and an infusion-related event in 1. Complete clinical response was achieved in 3/6 patients treated with RTX for muscle involvement. In these responders steroid therapy was stopped or tapered to < 15% of the baseline dosage, with no relapse, with a followup ranging from 1.3 to 3 years. Calcinosis did not improve in the 6 affected patients., Conclusion: This small series suggests that rituximab may be effective for treating muscle and skin involvement in a small subset of children with severe JDM, and that its safety profile was satisfactory. Further studies are needed to identify predictive factors of response to RTX in patients with severe JDM.

Objective: Accumulating evidence shows that shared autoimmunity is critical for the pathogenesis of many autoimmune diseases. Systemic sclerosis (SSc) belongs to the connective tissue disorders, and recent data have highlighted strong associations with autoimmunity genes shared with other autoimmune diseases. To determine whether novel risk loci associated with systemic lupus erythematosus or multiple sclerosis may confer susceptibility to SSc, we tested single-nucleotide polymorphisms (SNP) from ITGAM, ITGAX, and CD58 for associations., Methods: SNP harboring associations with autoimmune diseases, ITGAM rs9937837, ITGAX rs11574637, and CD58 rs12044852, were genotyped in 2 independent cohorts of European Caucasian ancestry: 1031 SSc patients and 1014 controls from France and 1038 SSc patients and 691 controls from the USA, providing a combined study population of 3774 individuals. ITGAM rs1143679 was additionally genotyped in the French cohort., Results: The 4 polymorphisms were in Hardy-Weinberg equilibrium in the 2 control populations, and allelic frequencies were similar to those expected in European Caucasian populations. Allelic and genotypic frequencies for these 3 SNP were found to be statistically similar in SSc patients and controls. Subphenotype analyses for subgroups having diffuse cutaneous subtype disease, specific autoantibodies, or fibrosing alveolitis did not reveal any difference between SSc patients and controls., Conclusion: These results obtained through 2 large cohorts of SSc patients of European Caucasian ancestry do not support the implication of ITGAM, ITGAX, and CD58 genes in the genetic susceptibility of SSc, although they were recently identified as autoimmune disease risk genes.

Objectives: To compare efficacy and tolerance of infliximab versus rituximab to treat refractory Wegener's granulomatosis (WG), and clarify their respective indications., Methods: Patients with systemic WG refractory to, or intolerant to steroids and consecutive immunosuppressant lines, including oral cyclophosphamide, were randomly assigned to receive infliximab or rituximab and their ongoing regimen. The primary endpoint was partial (PR) or complete remission (CR) at month 12. The secondary endpoint was the occurrence of adverse events. Long-term follow-up data were subjected to post-hoc analysis., Results: Between 2004 and 2007, 9 infliximab and 8 rituximab patients were included. At M12, we observed 2 infliximab and 4 rituximab CR, 1 infliximab and 1 rituximab PR, 5 infliximab and 2 rituximab failures and 2 deaths (NS). Post-hoc analysis was conducted after 30.6±15.4 months of follow-up. Among the 15 survivors, 2 infliximab patients and 1 rituximab patient relapsed. Among 5 infliximab non-responders, 4 were successfully switched to rituximab. During follow-up, one patient from each group died. Over the long term, 10/17 (59%) patients responded to rituximab, 1 to infliximab, 2 to other strategies and 2 died. Despite the 2 deaths, tolerance of both drugs was considered acceptable in terms of WG severity before treatment and previous treatment lines., Conclusions: Our observations demonstrate the usefulness of infliximab and/or rituximab to obtain remission of refractory WG with a trend at M12 favouring rituximab. During long-term follow-up, rituximab was better able at obtaining and maintaining remission.

Objective: A number of open-label studies have suggested the potential benefit of rituximab (RTX) in systemic lupus erythematosus (SLE). However, in 2 recent randomized controlled trials (RCTs) of RTX, the primary end points were not met. We undertook this study to evaluate the safety and efficacy of RTX in off-trial patients with SLE seen in regular clinical practice., Methods: We analyzed prospective data from the French AutoImmunity and Rituximab (AIR) registry, which includes data on patients with autoimmune disorders treated with RTX., Results: One hundred thirty-six patients received treatment for SLE. The mean +/- SD score on the Safety of Estrogens in Lupus Erythematosus: National Assessment (SELENA) version of the SLE Disease Activity Index (SLEDAI) was 11.3 +/- 8.9 at baseline. Severe infections were noted in 12 patients (9%), corresponding to a rate of 6.6/100 patient-years. Most severe infections occurred within the first 3 months after the last RTX infusion. Five patients died, due to severe infection (n = 3) or refractory autoimmune disease (n = 2). Overall response was observed in 80 of 113 patients (71%) by the SELENA-SLEDAI assessment. Efficacy did not differ significantly between patients receiving RTX monotherapy and those receiving concomitant immunosuppressive agents (who had higher baseline disease activity). Articular, cutaneous, renal, and hematologic improvements were noted in 72%, 70%, 74%, and 88% of patients, respectively. Among responders, 41% experienced a relapse of disease, with a response in 91% after retreatment with RTX., Conclusion: Data from the AIR registry show a satisfactory tolerance profile and clinical efficacy of RTX in patients with SLE. The contrasting results with those from recent RCTs leave open the question of the therapeutic use of RTX in SLE. Additional controlled studies with new designs are needed to define the place of RTX in the therapeutic arsenal for SLE.

Objective: Serotonin is a key contributing factor in pulmonary arterial hypertension (PAH) by inducing pulmonary arterial smooth muscle cell (PA-SMC) proliferation. This relates specifically to the internalization process in PA-SMC of the serotonin transporter (SLC6A4 or 5-HTT). A long (L)/short (S) (44 base pair insertion) functional polymorphism within the promoter of the transporter SLC6A4 gene has been reported to be associated with familial and idiopathic PAH. Our objective was to determine whether polymorphisms of SLC6A4 confer susceptibility to SSc and its vascular phenotype., Methods: Three Tag single-nucleotide polymorphisms (SNP) (rs2066713, rs1042173, rs6354) chosen using Hapmap and linkage disequilibrium data were genotyped in a total cohort of 667 SSc patients (56 with PAH, 207 with digital ulcerations) and 447 controls. All individuals were of French Caucasian origin. L/S polymorphism genotyping was determined by polymerase chain reaction in a random subgroup of 364 SSc patients (34 with PAH, 138 with digital ulcerations) and 218 controls., Results: Three polymorphisms (L/S, rs2066713, rs1042173) were in Hardy-Weinberg equilibrium in the control population, but rs6354 deviated. Allelic and genotypic frequencies for these 3 polymorphisms were similar in SSc patients and controls. Subphenotype analyses of subsets with PAH and digital ulceration did not detect any difference between SSc patients compared to controls., Conclusion: These results from a large cohort of European Caucasian SSc patients do not support the implication of SLC6A4 in the pathogenesis of SSc and its vascular subphenotypes. However, serotonin pathways remain good candidates to contribute to the vasculopathy of SSc.

Objective: To assess the prevalence and potential associations with the systemic sclerosis (SSc) phenotype of additional autoimmune diseases (AID)., Methods: A multicenter study was performed in France and Italy to recruit consecutive European Caucasian patients with SSc systematically assessed for the coexistence of predefined AID known to occur with connective tissue diseases., Results: We recruited 585 French and 547 Italian patients with SSc. Specific AID were found in 114/585 (19%) French and 179/547 (33%) Italians with SSc (p < 0.0001). Sjögren's syndrome and thyroiditis were the predominant AID in both cohorts (12% for Sjögren's syndrome and 6% for thyroiditis in the combined populations). The frequency of myositis, primary biliary cirrhosis, rheumatoid arthritis, and systemic lupus erythematosus was low (< 4%) and similar in both cohorts. The coexistence of at least 1 of the AID in the whole cohort was associated in multivariate analysis with the limited cutaneous subtype, the presence of antinuclear antibodies, and a lower prevalence of digital ulcers., Conclusion: Our study shows that 21% of this large series of European Caucasian patients with SSc have developed at least 1 AID. This latter condition identified a subset of patients with milder disease. Thus, associations of AID and autoimmune background in SSc have to be considered for further therapeutic and biological investigations in SSc.

Objective: To determine whether the functional BANK1 variants rs3733197 and rs10516487 are associated with systemic sclerosis (SSc) in 2 European Caucasian populations and to investigate the putative gene-gene interactions between BANK1 and IRF5 as well as STAT4., Methods: BANK1 single-nucleotide polymorphisms were genotyped in a total population of 2,432 individuals. The French cohort consisted of 874 SSc patients and 955 controls (previously genotyped for both IRF5 rs2004640 and STAT4 rs7574865). The German cohort consisted of 421 SSc patients and 182 controls., Results: The BANK1 variants were found to be associated with diffuse cutaneous SSc (dcSSc) in both cohorts, providing an odds ratio (OR) of 0.77 for the rs10516487 T rare allele in the combined populations of dcSSc patients as compared with the combined populations of controls (95% confidence interval [95% CI] 0.64-0.93) and an OR of 0.73 (95% CI 0.61-0.87) for the rs3733197 A rare allele. BANK1 haplotype analysis found the A-T haplotype to be protective in dcSSc patients (OR 0.70 [95% CI 0.57-0.86], P = 3.39 x 10(-4)) and the G-C haplotype to be a risk factor (OR 1.25 [95% CI 1.06-1.47], P = 0.008). Significant differences were also observed when the limited cutaneous subset of SSc was compared with the dcSSc subset, both for the rare alleles and for the haplotypes. The BANK1, IRF5, and STAT4 risk alleles displayed a multiplicatively increased risk of dcSSc of 1.43-fold., Conclusion: Our results establish BANK1 as a new SSc genetic susceptibility factor and show that BANK1, IRF5, and STAT4 act with additive effects.

Objective: Systemic sclerosis (SSc) belongs to the group of connective tissue disorders (CTDs), among which are several disorders characterized by a type I interferon (IFN) signature. The recent identification of an association between IRF5 and SSc further highlights a key role for IFN. STAT4, which encodes STAT-4, contributes to IFN signaling, and its genetic variants were found to be associated with CTDs. The aim of this study was to determine whether the STAT4 rs7574865 single-nucleotide polymorphism is associated with SSc, and whether it interacts with IRF5., Methods: Both the STAT4 rs7574865 and IRF5 rs2004640 polymorphisms were genotyped in 1,855 individuals of French Caucasian origin comprising a discovery set of 440 patients with SSc and 485 control subjects and a replication set of 445 patients with SSc and an additional 485 control subjects., Results: STAT4 rs7574865 was shown to be associated with SSc (P=0.001, odds ratio [OR] 1.29, 95% confidence interval [95% CI] 1.11-1.51). This association was not restricted to a particular phenotype. An additive effect of the STAT4 rs7574865 T allele and the IRF5 rs2004640 T allele was observed, resulting in a multiple increased 1.28-fold risk of SSc. The OR for SSc was 2.72 (95% CI 1.86-3.99) for combinations of genotypes with >or=3 risk alleles. An additive effect was also detected for fibrosing alveolitis: carriage of at least 3 risk alleles appeared to be an independent risk factor (P=2.2x10(-4), OR 1.97, 95% CI 1.28-3.04)., Conclusion: Our results establish STAT4 rs7574865 as a new SSc genetic susceptibility factor. STAT4 and IRF5 act with additive effects in terms of susceptibility to both SSc and SSc-related fibrosing alveolitis.

Objective: An algorithm for the detection of pulmonary arterial hypertension (PAH), based on the presence of dyspnea and the findings of Doppler echocardiographic evaluation of the velocity of tricuspid regurgitation (VTR) and right-sided heart catheterization (RHC), which was applied in a large multicenter systemic sclerosis (SSc) population, estimated the prevalence of PAH to be 7.85%. The aim of this observational study was to investigate the incidence of PAH and pulmonary hypertension (PH) during a 3-year followup of patients from the same cohort (the ItinérAIR-Sclérodermie Study)., Methods: Patients with SSc and without evidence of PAH underwent evaluation for dyspnea and VTR at study entry and during subsequent visits. Patients in whom PAH was suspected because of a VTR of 2.8-3.0 meters/second and unexplained dyspnea or a VTR of >3.0 meters/second underwent RHC to confirm the diagnosis., Results: A total of 384 patients were followed up for a mean+/-SD of 41.03+/-5.66 months (median 40.92 months). At baseline, 86.7% of the patients were women, and the mean+/-SD age of the patients was 53.1+/-12.0 years. The mean+/-SD duration of SSc at study entry was 8.7+/-7.6 years. After RHC, PAH was diagnosed in 8 patients, postcapillary PH in 8 patients, and PH associated with severe pulmonary fibrosis in 2 patients. The incidence of PAH was estimated to be 0.61 cases per 100 patient-years. Two patients who exhibited a mean pulmonary artery pressure of 20-25 mm Hg at baseline subsequently developed PAH., Conclusion: The estimated incidence of PAH among patients with SSc was 0.61 cases per 100 patient-years. The high incidence of postcapillary PH highlights the value of RHC in investigating suspected PAH.

Objective: To compare rheumatologists' prescription for first disease modifying antirheumatic drug (DMARD) in early rheumatoid arthritis (RA) in real-life settings with 2 clinical practice guidelines (CPG), the French Society of Rheumatology/STPR 2004 and EULAR/ESCISIT 2007, and thus assess the gap between practices and guidelines. Method. ESPOIR was a French multicenter cohort study of 813 patients with early arthritis between 2002 and 2005. "Definite" and "probable" RA were defined according to ACR criteria and the level of diagnostic certainty. The objectives were to assess conformity between the observed first-line DMARD prescribed for those patients and the DMARD recommended in the guidelines; and to conduct a mail survey of patients' usual rheumatologists to investigate the reasons for their nonconformity with guidelines., Results: In total 627 patients with definite or probable RA were identified. Conformity rates were 58% for STPR guidelines and 54% for EULAR guidelines. At 6 months, 83 (34%) patients with early RA did not receive any DMARD. Main determinants associated with conformity to guidelines were disease activity and presence of severity-predictive factors. The main reason leading to a discrepancy between guidelines and daily practice appeared to be diagnostic uncertainty, i.e., the difficulty to reliably assess RA diagnosis as early as the first visits to the rheumatologist., Conclusion: There is a substantial gap between CPG and rheumatologists' daily practice concerning the first DMARD to prescribe in early RA. This is explained mainly by diagnostic uncertainty. More attention should be paid in future guidelines to the diagnostic difficulties of early RA.

Objectives: This longitudinal study investigated survival, risk factors and causes of death in the multicentre ItinérAIR-Sclérodermie cohort of patients with SSc without severe pulmonary fibrosis or severe left heart disease at baseline., Methods: At 3-year follow-up, vital status was obtained from investigators or French national death records. Causes of death were classified as SSc-related or otherwise. Data were censored at 37 months, time of death or loss to follow-up, whichever was earlier. Survival was estimated using the Kaplan-Meier method. Multivariate survival analyses were conducted using the Cox model., Results: In total, 546 patients were followed for a median duration of 37 months, representing 1547 patient-years. At baseline, the majority of patients were female, with lcSSc, mean age 54.9 +/- 13.0 years and mean duration of SSc of 8.8 +/- 8.1 years. In total, 47 patients died, giving a 3-year survival of 91.1% and cumulative mortality of 3.04 deaths per 100 patient-years; 17 deaths (32.2%) resulted from pulmonary arterial hypertension (PAH) and eight (17.1%) from cancer. Of the 47 patients with PAH at baseline, 20 died during follow-up, giving a 3-year survival of 56.3%. In a multivariate analysis, PAH [hazard ratio (HR) 7.246], age at first symptom (HR 1.052), duration of SSc (HR 1.047 per year) and Rodnan skin score (per one point) (HR 1.045) were associated with increased mortality., Conclusion: This 3-year study observed survival and mortality estimates that were comparable with previous reports. PAH increased the HR for mortality in patients with SSc, justifying yearly echocardiographic screening.

Objective: To determine whether angiotensin-converting enzyme (ACE) polymorphisms including I/D and 2 single-nucleotide polymorphisms (SNP) affect susceptibility to systemic sclerosis (SSc) in a large French Caucasian population., Methods: A case-control study was performed in 494 patients with SSc and 280 healthy controls for I/D polymorphism. Two supplementary exonic SNP of ACE gene (rs4309, rs4362) were genotyped in 659 patients with SSc and 511 matched healthy controls. Among the whole SSc population, 453 (67%) patients with SSc had the limited cutaneous subtype, 47 (7%) had precapillary pulmonary arterial hypertension, 209 (32%) had digital ulcers, and 10 (1.5%) had renal crisis. A combined analysis of the available results for ACE I/D genotypes in Caucasians was also performed., Results: There was no association between the 3 polymorphic markers and SSc for allelic and genotype frequencies. No association was observed for the different vascular subsets of the disease. Haplotype analyses did not detect any association. The lack of association for ACE I/D was confirmed by the combined analysis., Conclusion: These results in a large cohort of European Caucasian patients with SSc do not support that the ACE gene is implicated in the pathogenesis of SSc and its vascular damage.

Objective: Systemic sclerosis (SSc) is a connective tissue disease characterized by generalized microangiopathy leading to chronic hypoxia. The aim of this study was to determine whether polymorphisms of the hypoxia-inducible factor 1A gene (HIF1A) affects susceptibility to SSc in a large French European Caucasian population., Methods: A case-control study was performed in 659 SSc patients and 511 healthy matched controls. Three tag single nucleotide polymorphisms (SNPs) of the HIF1A gene (rs12434438 A/G, rs1957757 C/T, and rs11549465 C/T) were genotyped allowing whole gene coverage according to HapMap data., Results: The frequency of genotypes carrying at least one G allele (A/G and/or GG) of the rs12434438 SNP was significantly higher in SSc patients than in controls [p(corr) = 0.018, odds ratio (OR) 1.44, 95% confidence interval (CI) 1.08-1.91]. Regarding SSc subgroup analyses, the heterozygous genotype A/G was associated with SSc (p(corr) = 0.012, OR 1.47, 95% CI 1.13-1.9), with the limited cutaneous form of SSc (p(corr) = 0.04, OR 1.43, 95% CI 1.08-1.91), and with positive anti-centromere antibodies (ACA; p(corr) = 0.016, OR 1.61, 95% CI 1.16-2.23). No association was detected for the remaining two HIF1A SNPs tested. Haplotype analyses did not detect any association with SSc., Conclusions: We observed an association between the HIF1A gene and SSc in a European Caucasian population, supporting a role for HIF1 in the pathophysiology of SSc.

Objective: To determine whether genetic variants of the PTPN22 gene, including the R620W (1858C>T) missense single-nucleotide polymorphism (SNP), are associated with systemic sclerosis (SSc). Since PTPN22 is involved in multiple autoimmune diseases, we also examined the occurrence of a concomitant autoimmune disease. We then conducted a meta-analysis of the most recent studies of SSc in order to verify the association or lack of association between the PTPN22 1858C>T variant and SSc., Methods: Seven PTPN22 SNPs were analyzed in a French Caucasian cohort of 659 SSc patients and 504 healthy controls. All SSc patient sera were tested for the presence of autoantibodies against topoisomerase I (anti-topo I) and for anticentromere antibodies (ACAs)., Results: The co-occurrence of an autoimmune disease was observed in 22% of the 416 SSc patients who were exhaustively screened. In 33 of the 416 patients (8%), the concomitant autoimmune disease was known to be associated with PTPN22 1858T; these patients were excluded prior to analysis. No association was detected for any of the SNPs tested. PTPN22 haplotype analysis identified a strong association between SSc and the presence of a risk haplotype carrying the 1858T allele (P = 1.52 x 10(-7)) and a protective haplotype carrying the 1858C allele (P = 2.20 x 10(-16)) in our French Caucasian population. The meta-analysis provided evidence that the PTPN22 1858T allele is involved in the genetic susceptibility to SSc in Caucasian (P = 8.39 x 10(-3), OR 1.08 [95% CI 1.02-1.15]) and mixed (P = 3.11 x 10(-3), OR 1.09 [95% CI 1.04-1.16]) populations, particularly in the anti-topo I-positive subset., Conclusion: Our results indicate that PTPN22, a shared genetic factor of multiple autoimmune diseases, also contributes to the genetic background of SSc.

Objective: Evidence suggests that systemic sclerosis (SSc) belongs to the fibrillinopathic disorders. Significant associations have been found with the fibrillin-1 gene (FBN1) in Choctaw and Japanese populations. We investigated FBN1 polymorphisms in cohorts of European Caucasian patients., Methods: We investigated 6 FBN1 polymorphisms in 2 cohorts: one with 399 French subjects (243 SSc patients/156 matched healthy controls), another with 319 Italian subjects (266 SSc patients/153 matched healthy controls). The 6 FBN1 polymorphisms included one single-nucleotide polymorphism (SNP) in intron C to replicate its genetic association and 5 microsatellite markers (D15S1028 in the 5' region, intragenic MTS2 and MTS3, and D15S123 and D15S143 in the 3' region). Then we investigated the French cohort enlarged to 362 SSc patients/162 matched healthy controls for 5 tagging single nucleotide polymorphisms (tagSNP) that account for the common genetic diversity according to HapMap data. We used Arlequin, Cocaphase, Phase 2 software, and Fisher's exact test for statistical analyses., Results: All markers were in Hardy-Weinberg equilibrium. No association was detected between polymorphic markers and disease in either the French or Italian cohorts, even for specific phenotypes. No significant differences between patients and controls were detected for the 5 tagSNP., Conclusion: In contrast with data from Choctaw and Japanese patients, no association was detected between the polymorphic markers of FBN1 and SSc in 2 European Caucasian populations. These discrepancies may be explained by ethnic specificities and heterogeneity associated with this multigenic disease.

Our objective was to evaluate the prevalence of autoantibodies to cyclic citrullinated peptides (anti-CCP aAbs) in a cohort of patients with a variety of inflammatory or non-inflammatory rheumatic diseases other than rheumatoid arthritis (RA). Six hundred and nine serum samples were tested for anti-CCP aAbs and for rheumatoid factor (RF) using enzyme-linked immunosorbent assays and immunonephelometry. The prevalence of anti-CCP aAbs and RF reached 10% and 25%, respectively, using the positive cutoff value suggested by the manufacturers. Using a higher cutoff value (50 U/ml) for both aAbs, the prevalence was lower with 6% and 16%, respectively. The specificity of both markers for RA thus reached 94% and 84%, respectively. Anti-CCP aAbs were found to be elevated in inflammatory and also in non-inflammatory rheumatic diseases in the same proportion. Clinical data obtained for 36 positive patients showed that 17% developed RA within 5 years. In conclusion, anti-CCP aAbs are clearly more specific than RF for RA. Follow-up of anti-CCP aAbs-positive patients with inflammatory or non-inflammatory rheumatic diseases other than RA could be important considering the predictive value of these aAbs for the development of RA.

Objectives: To update French Society for Rheumatology guidelines regarding the use of TNFalpha antagonists for treating patients with rheumatoid arthritis (RA)., Methods: Existing guidelines were updated using the AGREE instrument. Items that required updating were selected by a task force, the relevant literature was critically appraised, and new wording was suggested by a limited committee of experts then validated by the task force and subsequently by a panel of external reviewers. The three-topic structure of the recommendations (indication, initiation, and adjustment) and the final algorithm format were maintained., Results: Of the 12 items, five were selected for updating; one pertained to the indication for treatment with TNFalpha antagonists, two to treatment initiation, and two to treatment adjustment. Of the four initially recommended criteria for determining that TNFalpha antagonist therapy is indicated, the first three were left unchanged (confirmed diagnosis of RA; active disease for more than 1month with objective evidence of inflammation or progressive structural damage, or dependency on glucocorticoid therapy, or progressive radiographic damage; and failure to respond adequately to methotrexate - or another agent when methotrexate is contraindicated - in the optimal tolerated dosage). The fourth and last criterion was modified as follows: co-morbidities should be evaluated in order to distinguish absolute contraindications from relative contraindications that require referral to a specialist. Of the four initial recommendations about TNFalpha antagonist initiation, the first and fourth were left unchanged (a workup should be performed prior to treatment initiation, and the patient should receive regular standardized follow-up); the second and third recommendations were modified as follows: there is no evidence that one TNFalpha antagonist is more effective than the others, and concomitant methotrexate therapy is generally advisable, regardless of the TNFalpha antagonist used. Of the four recommendations about treatment adjustment, the first two were modified as follows: the goal of treatment is to achieve the EULAR response criteria or better; and in non-responders, the dosage or dosing interval can be modified when infliximab is used, methotrexate should be added when the TNFalpha antagonist is used alone, and in all other situations the patient should be switched to a different TNFalpha antagonist. The other two recommendations about treatment adjustment were left unchanged (patients who fail to tolerate one TNFalpha antagonist can be switched to another TNFalpha antagonist if allowed by the nature of the adverse event; and when a remission is achieved, reduction or discontinuation of symptomatic drugs - most notably glucocorticoids - is appropriate, followed in the event of a prolonged remission by changes in the dosage and/or dosing interval of the TNFalpha antagonist or concomitant disease-modifying drug)., Conclusion: These recommendations are designed to help practitioners optimize the use of TNFalpha antagonists in patients with RA seen in everyday practice. They do not constitute regulations.

Objectives: The French Society of Rheumatology initiated a large national multicenter, longitudinal and prospective cohort, the so-called "ESPOIR cohort study" in order to set up databases to allow various investigations on diagnosis, prognostic markers, epidemiology, pathogenesis and medico-economic factors in the field of early arthritis and rheumatoid arthritis., Methods: Patients were recruited if they had undifferentiated arthritis or rheumatoid arthritis, of less than 6 months disease duration and if they were DMARD and steroids naïve. Patients have then to be followed every 6 months during the first 2 years then every year during at least 10 years. Clinical, biological, radiographic and medico-economic databases have been constituted to fit in the different objectives of the project and more than 20 scientific studies have already been accepted by the scientific committee., Results: 813 patients were included (76.75% were female). The mean age was 48.07+/-12.55 years. The mean delay from the onset of symptoms to referral to the rheumatologist was 74.8+/-76.6 days. Baseline swollen and tender joint counts were 7.19+/-5.37 and 8.43+/-7.01; DAS28 score was 5.11+/-1.31. CRP was abnormal in 38.9% of the patients; 44.2%, 45.8% and 38.8% had respectively IgM rheumatoid factor (RF), IgA RF and anti-CCP antibodies. HLA DRB1*01 or 04 genes were found in 56.7% of them. Finally, 22% of these patients had erosions on hand or feet at baseline.

Objectives: To develop recommendations for TNFalpha-antagonist therapy in patients with rheumatoid arthritis (RA) seen in everyday practice, under the aegis of the French Society for Rheumatology., Method: We used the methods recommended by the French Agency for Healthcare Accreditation and Evaluation, the AGREE collaboration, and the European League against Rheumatism (EULAR). The recommendations focus on patient selection, monitoring, and treatment adjustments., Results: Criteria for selecting patients eligible for TNFalpha-antagonist treatment of RA include: 1) a definitive diagnosis of RA; 2) disease activity for longer than 1 month, including presence of objective signs of inflammation; or radiographic progression; 3) previous failure of methotrexate in the highest tolerated dosage or of another disease-modifying antirheumatic drug in patients with contraindications to methotrexate; 4) absence of contraindications to TNFalpha-antagonist therapy. When starting TNFalpha-antagonist therapy 1) a thorough baseline evaluation should be conducted; 2) any of the three available agents can be used, as no differences in efficacy have been identified in patient populations; 3) concomitant methotrexate therapy is recommended regardless of the TNFalpha antagonist used; and 4) patients should receive standardized follow-up at regular intervals. Treatment adjustments should be based on the following: 1) the treatment objective is achievement of a EULAR response; 2) when such a response is not achieved, the dosage or dosing interval can be changed, or the patient can be switched to another TNFalpha antagonist; 3) in patients who experience intolerance to a TNFalpha antagonist, another TNFalpha antagonist may be tried, depending on the nature of the adverse event; 4) occurrence of a remission should lead to a reduction in symptomatic medications, most notably glucocorticoids where used; in the event of a prolonged remission, either the TNFalpha antagonist or the concomitant disease-modifying antirheumatic drug may be reduced., Conclusion: These recommendations are intended to help physicians use TNFalpha antagonists in their everyday practice with RA patients. They do not constitute regulations.

Objective: To determine the incidence, prevalence, and principal characteristics of the different forms of juvenile idiopathic arthritis (JIA) in the region of Alsace, northeastern France, using the new classification of the International League of Associations for Rheumatology (ILAR)., Methods: In 2002 we performed a retrospective epidemiologic study pertaining to the year 2001. The pediatricians, rheumatologists, ophthalmologists, orthopedic surgeons, and physicians involved in functional reeducation in the Alsace region were interviewed, and all patients were classified according to the new ILAR classification using the criteria revised in Durban in 1997., Results: Among the 361 clinicians contacted, the participation rate was 97.8%. The study identified 67 children followed for JIA in Alsace in 2001, from a total population of 1.8 million inhabitants including 339,095 children under age 16 years. The incidence was calculated to be 3.2 cases/100,000/year and the prevalence 19.8 cases/100,000 children under age 16 years. Among these 67 cases of JIA, the most frequent forms were oligoarthritis (n = 27, 40.3%), polyarthritis without rheumatoid factor (RF; n = 15, 22.4%), and enthesitis related arthritis (n = 12, 17.9%). Other forms, notably systemic arthritis (n = 6, 8.9%) and psoriatic arthritis (n = 3, 4.5%), were more rare and in this study there was no case of polyarthritis with RF. Only 4 patients (6%) were classified in the undifferentiated arthritis group using the new classification. Antinuclear antibodies (ANA; by indirect immunofluorescence, HEp >/= 1/80) were detected in patients with oligoarthritis (81%) and polyarthritis without RF (79%). Uveitis occurred in 41% of children with oligoarthritis and in 14% of those with polyarthritis without RF., Conclusion: Our results are comparable to those of other studies carried out in Caucasian populations with regard to incidence and prevalence. This work also highlights the frequent presence of ANA and uveitis in patients with oligoarthritis or polyarthritis without RF.