Jacques-Eric Gottenberg

EULAR Sjögren's syndrome disease activity index: development of a consensus systemic disease activity index for primary Sjögren's syndrome

Objective To develop a disease activity index for patients with primary Sjögrens syndrome (SS): the European League Against Rheumatism (EULAR) Sjögrens syndrome disease activity index (ESSDAI). Methods Thirty-nine SS experts participated in an international collaboration, promoted by EULAR, to develop the ESSDAI. Experts identified 12 organ-specific ‘domains’ contributing to disease activity. For each domain, features of disease activity were classified in three or four levels according to their severity. Data abstracted from 96 patients with systemic complications of primary SS were used to generate 702 realistic vignettes for which all possible systemic complications were represented. Using the 0–10 physician global assessment (PhGA) scale, each expert scored the disease activity of five patient profiles and 20 realistic vignettes. Multiple regression modelling, with PhGA used as the dependent variable, was used to estimate the weight of each domain. Results All 12 domains were significantly associated with disease activity in the multivariate model, domain weights ranged from 1 to 6. The ESSDAI scores varied from 2 to 47 and were significantly correlated with PhGA for both real patient profiles and realistic vignettes (r=0.61 and r=0.58, respectively, p<0.001). Compared with 57 (59.4%) of the real patient profiles, 468 (66.7%) of the realistic vignettes were considered likely or very likely to be true. Conclusions The ESSDAI is a clinical index designed to measure disease activity in patients with primary SS. Once validated, such a standardised evaluation of primary SS should facilitate clinical research and be helpful as an outcome measure in clinical trials.

Safety and efficacy of rituximab in systemic lupus erythematosus: Results from 136 patients from the French autoimmunity and rituximab registry

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.

Treatment of primary Sjögren syndrome with rituximab: a randomized trial.

Context Few trials have examined treatments for primary Sjgren syndrome (pSS). Contribution This multicenter, double-blind, placebo-controlled, randomized trial found that rituximab (given in 2 infusions over 2 weeks) alleviated some symptoms at week 6 but did not alleviate symptoms or improve global activity score at month 6 in adults with recent-onset or systemic pSS. More infusion reactions occurred with rituximab than placebo. Caution Outcome measurements may have been insensitive for detecting improvement. Implication Rituximab infusions did not produce sustained or substantial alleviation of symptoms or improvement in disease activity in adults with recent-onset or systemic pSS. The Editors Primary Sjgren syndrome (pSS) is a chronic autoimmune disorder characterized by dryness of the eyes and mouth and systemic involvement in up to 50% of cases (1). Histopathology shows lymphocytic infiltration and destruction of the lachrymal and salivary glands (2). To date, no systemic treatment has been proved to significantly affect the course of pSS (3), but clinicians may prescribe hydroxychloroquine to patients having fatigue or arthralgia and corticosteroids, methotrexate, or immunosuppressants to patients with systemic involvement. Because mounting evidence points to a central pathophysiologic role for B cells (47), B-cell depletion is being evaluated as a treatment of pSS (811). The most widely studied target for achieving B-cell depletion is the CD20 antigen, a transmembrane protein found on pre-B and mature B cells. It is neither shed from the cell surface nor internalized on antibody binding (1214). In open-label studies, the anti-CD20 antibody rituximab had a good safety profile, induced rapid B-cell depletion in blood and salivary glands, and seemed beneficial in early active pSS and in pSS with active extraglandular involvement (8, 9, 15). Two small, double-blind, randomized trials have been published (10, 11). The first included 18 patients and suggested an effect on the visual analogue scale (VAS) fatigue score after 6 months, although the primary end point, a 20% or greater decrease in the VAS fatigue score, was not achieved (10). The second trial included 30 patients with recent active pSS and showed improvements in the VAS dryness score and stimulated total salivary flow rate after 6 months (11). The purpose of the randomized, placebo-controlled TEARS (Tolerance and Efficacy of Rituximab in Primary Sjgrens Syndrome) trial reported here was to evaluate the efficacy and adverse effects of rituximab in pSS. Methods Design Overview This randomized, placebo-controlled, parallel-group trial evaluated global disease, pain, fatigue, and dryness. French rheumatologists and internists recruited the patients between 6 March 2008 and 5 January 2011. Patients were randomly assigned in a 1:1 ratio to blinded treatment with intravenous infusions of rituximab (1 g) or placebo at weeks 0 and 2. All study personnel, investigators, and patients remained blinded to the treatment group throughout the study. This study was approved by the appropriate ethics committee (CPP Ouest VI), and all patients gave written informed consent before study enrollment. The protocol was registered on ClinicalTrials.gov (NCT00740948). Setting and Participants Patients were recruited at 14 university hospitals in France if they fulfilled the AmericanEuropean Consensus Group criteria for pSS (16) and had active disease, defined as scores of at least 50 mm on at least 2 of 4 VASs (scores range from 0 [none] to 100 mm [worst]) for global disease, pain, fatigue, and dryness. Additional requirements were onset of pSS symptoms (first visit for any sign) in the past 10 years and biologically active pSS (defined as autoantibodies [anti-Ro/SSA antibodies or rheumatoid factor], cryoglobulinemia, hypergammaglobulinemia, 2-microglobulin elevation, or hypocomplementemia) or systemic pSS with at least 1 extraglandular manifestation or current parotid gland enlargement. The other inclusion criteria were informed consent, being aged 18 to 80 years, stable nonsteroidal anti-inflammatory drug regimen, no use of immunosuppressive agents for at least 4 weeks before inclusion, and use of an effective contraceptive method for patients able to conceive. Exclusion criteria were secondary Sjgren syndrome; cytotoxic drug therapy in the past 4 months; severe renal or hematologic failure; history of cancer, hepatitis B or C, HIV infection, tuberculosis, severe diabetes, or any other chronic disease; evidence of infection; history of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies; and an inability to understand the study protocol. Randomization and Interventions Randomization was stratified by site. A computer-generated random allocation sequence was prepared by our statistics department in Brest, France. The infusions were prepared after a telephone call to the statistics department by pharmacists who were not involved in any other study procedure and were instructed not to disclose the treatment group to the investigators. All patients received the same volume, but the infusion contained the solvent only (normal saline or 5% glucose) in the placebo group and the solvent plus rituximab in the rituximab group. Before each rituximab or placebo infusion, the patients received 100 mg of methylprednisolone intravenously and 500 mg of acetaminophen orally. Outcomes and Follow-up Efficacy was evaluated at weeks 6, 16, and 24. The primary outcome, chosen a priori on the basis of expert opinion, was a 30-mm or greater improvement at week 24 versus baseline on at least 2 of the 4 VAS scores. Secondary outcomes included variations from baseline in the individual VAS scores at weeks 6 and 16; disease activity, systemic manifestations, and treatment activity assessed by the investigator as present or absent and by using both a physician VAS for disease activity and the European League Against Rheumatism Sjgrens Syndrome Disease Activity Index (ESSDAI), a clinical index that is designed to measure disease activity in patients with pSS (12 domains with a total score ranging from 2 to 47) (17, 18); basal salivary flow rate; Schirmer test and van Bijsterveld scores and Chisholm grade (19, 20); C-reactive protein level and erythrocyte sedimentation rate; rheumatoid factor; antinuclear antibodies; serum IgG, IgA, and IgM levels; serum complement; cryoglobulinemia; and serum level of B-cellactivating factor (BAFF) (21). Clinicians collected open-ended adverse events and assessed severity and potential causality at each visit from baseline to week 24. At study completion, the chief investigator categorized the adverse events according to the Medical Dictionary for Regulatory Activities, which is required by European regulations. We used Lower-Level Terms in the System Organ Class system. Statistical Analysis Our power calculation was based on our primary end point assessed at week 24. To detect a difference of 30 percentage points between groups in the proportion of patients achieving the primary end point, with a 2-sided of 0.05 and 80% power, we needed 49 patients per group. We planned to enroll 120 patients to allow for withdrawals and missing data. All randomly assigned patients who did not withdraw before the first study-drug infusion were included in the efficacy analyses. They were analyzed in the group to which they had been randomly assigned, even when a protocol deviation was reported (intention-to-treat principle). We used a fully conditional specification method to do multiple imputation and to handle missing data, which were assumed to be missing at random. We used the MICE function in R, version 2.14 (R Foundation for Statistical Computing, Vienna, Austria), to generate 20 imputed data sets. The initial data set to impute contained all outcomes of interest, baseline characteristics, and center and random assignments. To build the imputation model, we used the quickpred function in R to include all predictors with an absolute correlation of at least 0.2 with the target or the response indicator. Study center and treatment group were forced to be included in the imputation model. Continuous variables that were clearly nonnormal were transformed before imputation then back-transformed to create the final imputed data set. We analyzed the primary outcome at week 24 using a generalized linear model with binomial distribution, identity link, and exchangeable correlation structure to account for study center. Although identity is not the usual link for a binary response, it can be used in the present situation (22, 23) to estimate a risk difference with the CI, as recommended by the CONSORT (Consolidated Standards of Reporting Trials) statement. Secondary outcomes were analyzed by using the same statistical method, except a normal distribution was used for continuous data. All efficacy analyses were first done for each week by using the imputed data, except for the serum BAFF level, which was not collected in all study centers and was analyzed by using the observed data. Reductions in BAFF levels were compared between the rituximab and placebo groups by using the Wilcoxon test. For the 4 VASs used to define the primary end point, longitudinal analyses were then done on the observed data by using a mixed model. In these analyses, we used treatment group, visit, and the visittreatment group interaction term as independent variables; study center as a random-effects factor; a compound symmetry covariance structure to account for repeated measures among visits; and age, sex, baseline antibody values, and recent-onset or systemic pSS information as covariates. We used SAS, version 9.3 (SAS Institute, Cary, North Carolina), for all analyses except for multiple imputation, for which we used R, version 2.14. P values less than 0.05 were considered statistically significant. We used the MICE function in R to generate imputed data sets, PROC MIANAL

Increase of B cell-activating factor of the TNF family (BAFF) after rituximab treatment: insights into a new regulating system of BAFF production

Background: The cytokine B cell-activating factor of the TNF family (BAFF) is involved in the pathogenesis of autoimmune diseases. Objective: To access changes in serum protein and mRNA levels of BAFF after rituximab treatment. Methods: Serum and peripheral blood mononuclear cells (PBMCs) were isolated from five patients (two with lupus, two with Sjögren’s syndrome, one with rheumatoid arthritis) before and 12 weeks (range 7–17) after a first course of rituximab infusion. Monocytes and B cells were selected from healthy controls and cocultured for 72 h. BAFF protein and mRNA levels were assessed by ELISA and real-time PCR, respectively. Results: After rituximab treatment, median serum BAFF protein level and BAFF to actin mRNA ratio in PBMCs significantly increased. In monocytes cocultured with autologous B cells, BAFF protein level decreased, whereas the mRNA level was stable. In one closely monitored patient, the mRNA ratio of BAFF to actin in PBMCs increased later than the BAFF serum level. Conclusions: Two distinct mechanisms are probably involved in the increase in BAFF level after B cell depletion: (1) the decrease in its receptors leading to a release of BAFF; (2) a delayed regulation of BAFF mRNA transcription. This could favour the re-emergence of autoreactive B cells.

Registries in rheumatoid arthritis and autoimmune diseases: data from the French registries

OBJECTIVES Clinical registries have shown their effectiveness in capturing the long-term benefit of drugs in routine care. In France, two types of registry have been established to analyse the safety and efficacy of biological agents. METHODS The Research Axed on Tolerance of Biotherapies (RATIO) registry was designed to prospectively collect all cases of lymphoma and opportunistic infections occurring in patients receiving anti-TNF blockers for any indication. We also examined the results from nationwide prospective cohorts in order to investigate the safety and efficacy of rituximab (RTX), abatacept (ABA) and tocilizumab in RA and other autoimmune diseases. RESULTS Analysis of the RATIO registry demonstrated an increased risk of Legionella pneumophila infection in patients receiving anti-TNF therapy, a higher risk of tuberculosis [odds ratio (OR) (95% CI): 13.3 (2.6, 69.0) and 17.1 (3.6, 80.6) for infliximab and adalimumab vs etanercept, respectively], opportunistic infections and incidence of lymphoma, with mAb than with soluble-receptor anti-TNF. The characteristics of RA patients in RTX and ABA registries showed that some patients did not receive previous TNF blockers [20% in autoimmunity and RTX (AIR) and 13% in Orencia and RA (ORA)] and one-third of them were treated without concomitant DMARDs. Patients receiving RTX showed an increased proportion of severe infections (5.0/100 patient-years). Lung and cardiac comorbidities, extra-articular involvement and low immunoglobulin G before RTX were predictive factors of severe infections. In addition, the AIR registry suggested the effectiveness of RTX in patients with SLE. CONCLUSION The establishment of biological registries in rheumatic diseases, in France, with their different methods, has already provided additional data to controlled trials, mainly on the risk of severe infections and lymphoma.

Bruton’s Tyrosine Kinase Is Involved in miR-346-Related Regulation of IL-18 Release by Lipopolysaccharide-Activated Rheumatoid Fibroblast-Like Synoviocytes

MicroRNAs (miRNAs) have emerged as key players in the regulation of expression of target mRNAs expression. They have been associated with diverse biological processes, and recent studies have demonstrated that miRNAs play a role in inflammatory responses. We reported previously that LPS-activated fibroblast-like synoviocytes (FLS) isolated from rheumatoid arthritis (RA) patients express IL-18 mRNA but they do not release IL-18. Based on the observation that this inhibition was due to a rapid degradation of IL-18 mRNA, our group has conducted a study to identify miRNAs that could play a role in the “antiinflammatory” response of LPS-activated RA FLS. LPS challenge modulated the expression of 63 miRNAs as assessed by microarray analysis. Fifteen miRNAs were up-regulated, including miR-346, for which overexpression upon LPS treatment was validated by quantitative RT-PCR. We then transfected FLS with an antisense oligonucleotide targeting miR-346 and found that, in these conditions, IL-18 release could be measured upon LPS activation of FLS. Moreover, we also demonstrated that miR-346 indirectly regulated IL-18 release by indirectly inhibiting LPS-induced Bruton’s tyrosine kinase expression in LPS-activated RA FLS. These findings suggest that miRNAs function as regulators that help to fine-tune the inflammatory response in RA.

Efficacy of rituximab in systemic manifestations of primary Sjögren's syndrome: results in 78 patients of the AutoImmune and Rituximab registry

Objectives To evaluate the efficacy and safety of rituximab in patients with primary Sjögrens syndrome (pSS). Methods The AutoImmune and Rituximab registry has included 86 patients with pSS treated with rituximab, prospectivey followed up every 6 months for 5 years. Results Seventy-eight patients with pSS (11 men, 67 women), who already had at least one follow-up visit, were analysed. Median age was 59.8 years (29–83), median duration of disease was 11.9 years (3–32). Indications for treatment were systemic involvement for 74 patients and only severe glandular involvement in four patients. The median European Sjögrens Syndrome disease activity index (ESSDAI) was 11 (2–31). 17 patients were concomitantly treated with another immunosuppressant agent. Median follow-up was 34.9 months (6–81.4) (226 patient-years). Overall efficacy according to the treating physician was observed in 47 patients (60%) after the first cycle of rituximab. Median ESSDAI decreased from 11 (2–31) to 7.5 (0–26) (p<0.0001). Median dosage of corticosteroid decreased from 17.6 mg/day (3–60) to 10.8 mg/day (p=0.1). Forty-one patients were retreated with rituximab. Four infusion reactions and one delayed serum sickness-like disease resulted in rituximab discontinuation. Three serious infections (1.3/100 patient-years) and two cancer-related deaths occurred. Conclusions In common practice, the use of rituximab in pSS is mostly restricted to patients with systemic involvement. This prospective study shows good efficacy and tolerance of rituximab in patients with pSS and systemic involvement.

Effects of Hydroxychloroquine on Symptomatic Improvement in Primary Sjögren Syndrome: The JOQUER Randomized Clinical Trial

IMPORTANCE Primary Sjögren syndrome is a systemic autoimmune disease characterized by mouth and eye dryness, pain, and fatigue. Hydroxychloroquine is the most frequently prescribed immunosuppressant for the syndrome. However, evidence regarding its efficacy is limited. OBJECTIVE To evaluate the efficacy of hydroxychloroquine for the main symptoms of primary Sjögren syndrome: dryness, pain, and fatigue. DESIGN, SETTING, AND PARTICIPANTS From April 2008 to May 2011, 120 patients with primary Sjögren syndrome according to American-European Consensus Group Criteria from 15 university hospitals in France were randomized in a double-blind, parallel-group, placebo-controlled trial. Participants were assessed at baseline, week 12, week 24 (primary outcome), and week 48. The last follow-up date for the last patient was May 15, 2012. INTERVENTIONS Patients were randomized (1:1) to receive hydroxychloroquine (400 mg/d) or placebo until week 24. All patients were prescribed hydroxychloroquine between weeks 24 and 48. MAIN OUTCOMES AND MEASURES The primary end point was the proportion of patients with a 30% or greater reduction between weeks 0 and 24 in scores on 2 of 3 numeric analog scales (from 0 [best] to 10 [worst]) evaluating dryness, pain, and fatigue. RESULTS At 24 weeks, the proportion of patients meeting the primary end point was 17.9% (10/56) in the hydroxychloroquine group and 17.2% (11/64) in the placebo group (odds ratio, 1.01; 95% CI, 0.37-2.78; P = .98). Between weeks 0 and 24, the mean (SD) numeric analog scale score for dryness changed from 6.38 (2.14) to 5.85 (2.57) in the placebo group and 6.53 (1.97) to 6.22 (1.87) in the hydroxychloroquine group. The mean (SD) numeric analog scale score for pain changed from 4.92 (2.94) to 5.08 (2.48) in the placebo group and 5.09 (3.06) to 4.59 (2.90) in the hydroxychloroquine group. The mean (SD) numeric analog scale for fatigue changed from 6.26 (2.27) to 5.72 (2.38) in the placebo group and 6.00 (2.52) to 5.94 (2.40) in the hydroxychloroquine group. All but 1 patient in the hydroxychloroquine group had detectable blood levels of the drug. Hydroxychloroquine had no efficacy in patients with anti-SSA autoantibodies, high IgG levels, or systemic involvement. During the first 24 weeks, there were 2 serious adverse events in the hydroxychloroquine group and 3 in the placebo group; in the last 24 weeks, there were 3 serious adverse events in the hydroxychloroquine group and 4 in the placebo group. CONCLUSIONS AND RELEVANCE Among patients with primary Sjögren syndrome, the use of hydroxychloroquine compared with placebo did not improve symptoms during 24 weeks of treatment. Further studies are needed to evaluate longer-term outcomes. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00632866.

Markers of B-lymphocyte activation are elevated in patients with early rheumatoid arthritis and correlated with disease activity in the ESPOIR cohort.

IntroductionLittle is known about systemic B-cell activation in early rheumatoid arthritis (RA). We therefore evaluated the serum levels of markers of B-cell activation in patients included in the ESPOIR early arthritis cohort.MethodsIn the ESPOIR early arthritis cohort (at least 2 swollen joints for more than 6 weeks but less than 6 months), 710 patients were assessed at 1 year and either met the 1987 American College of Rheumatology criteria for RA (n = 578) or had undifferentiated arthritis (n = 132). Baseline serum samples of patients naïve to corticosteroid and disease-modifying antirheumatic drug treatment were assessed for beta2-microglobulin, IgG, IgA, IgM, immunoglobulin free light chains of immunoglobulins, and B-cell activating factor of the tumor necrosis factor family (BAFF). The BAFF gene 871T>C polymorphism was genotyped in all patients.ResultsAll markers of B-cell activation except BAFF and IgM were significantly higher in patients with early RA than those with undifferentiated arthritis. Anti-cyclic citrullinated peptide (anti-CCP) and beta2-microglobulin were associated with a diagnosis of early RA in the multivariate analysis. Markers of B-cell activation, except BAFF, were associated with disease activity, rheumatoid factor and anti-CCP secretion. The BAFF gene polymorphism was not associated with early RA.ConclusionsMarkers of B-cell activation are elevated in patients with early RA, compared with undifferentiated arthritis, independently of any systemic increase in BAFF secretion, and correlate with disease activity. This study sheds new light on the early pathogenic role of B-lymphocytes in RA and suggests that targeting them might be a useful therapeutic strategy in early RA.

Classification criteria for Sjögren's syndrome: we actually need to definitively resolve the long debate on the issue

A new approach for the classification of patients with Sjögrens syndrome (SS) has been recently proposed. Although these new criteria substantially differ from the American European Consensus Group criteria, which have represented the gold standard for the last decade, when compared with each other the two sets show a high statistical degree of agreement. However, the fact that two different criteria to classify patient with SS could be available may introduce some additional difficulties in the scientific communication, making cohorts of patients selected by using different methods less than completely equivalent, and the results of epidemiological studies and therapeutic trials not entirely comparable. Consequently, to reach a consensus agreement on universally accepted classification criteria for SS seems to be a very desirable objective.