Jean Sibilia

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.

Prognostic factors for radiographic damage in early rheumatoid arthritis: A multiparameter prospective study

OBJECTIVE To determine prognostic factors of radiologic damage and radiologic progression in early rheumatoid arthritis (RA). METHODS A cohort of 191 patients with RA whose disease duration was shorter than 1 year were prospectively followed up for 3 years. Radiologic scores (as determined by Sharps method, modified by van der Heijde) and radiologic progression were used as outcome measures. Numerous baseline clinical, laboratory, genetic, and radiographic data were obtained. RESULTS The change in the total radiologic score for the patients followed up over 3 years was a mean +/- SD increase of 6.1 +/- 6.2. Radiologic progression was observed in 71 of the 172 patients for whom there were data at the end of the study. By univariate analysis with Fishers exact test, radiologic scores and progression at followup were closely correlated with the baseline values of the erythrocyte sedimentation rate (ESR), C-reactive protein level, IgM and IgA rheumatoid factor positivity, antiperinuclear antibody positivity, radiologic scores, duration of morning stiffness, and RA-associated HLA-DRB1*04 genes. No correlation was demonstrated with sex, age, Disease Activity Score, swollen or tender joint counts, extraarticular manifestations, Health Assessment Questionnaire score, Ritchie Articular Index, patients assessment of pain, positivity for anti-heat-shock protein 90-kd antibodies, anticalpastatin antibodies, anti-RA33 antibodies, antinuclear antibodies, YKL-40, or antikeratin antibodies, and HLA-DRB1*01 genes. The logistic regression analysis revealed that the only baseline values that were predictive of the 3-year radiologic scores were IgM rheumatoid factor positivity, DRB1*04 genes, pain score, and total radiologic score. Progression of joint damage was predicted by the ESR, IgM rheumatoid factor positivity, DRB1*04 genes, and erosions score at baseline. CONCLUSION Prognostic factors for radiographic damage in early RA were identified. A combination of these baseline values allowed us to draw up a predictive arithmetic score that could be used to predict radiologic damage at 3 years and radiologic progression in individual patients.

Outcomes of a multicentre randomised clinical trial of etanercept to treat ankylosing spondylitis

Objective: A double blind, randomised, placebo controlled study to evaluate the safety and efficacy of etanercept to treat adult patients with ankylosing spondylitis (AS). Methods: Adult patients with AS at 14 European sites were randomly assigned to 25 mg injections of etanercept or placebo twice weekly for 12 weeks. The primary efficacy end point was an improvement of at least 20% in patient reported symptoms, based on the multicomponent Assessments in Ankylosing Spondylitis (ASAS) response criteria (ASAS 20). Secondary end points included ASAS 50 and ASAS 70 responses and improved scores on individual components of ASAS, the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), acute phase reactants, and spinal mobility tests. Safety was evaluated during scheduled visits. Results: Of 84 patients enrolled, 45 received etanercept and 39 received placebo. Significantly more etanercept patients than placebo patients responded at the ASAS 20 level as early as week 2, and sustained differences were evident up to week 12. Significantly more etanercept patients reported ASAS 50 responses at all times and ASAS 70 responses at weeks 2, 4, and 8; reported lower composite and fatigue BASDAI scores; had lower acute phase reactant levels; and had improved spinal flexion. Etanercept was well tolerated. Most adverse events were mild to moderate; the only between-group difference was injection site reactions, which occurred significantly more often in etanercept patients. Conclusions: Etanercept is a well tolerated and effective treatment for reducing clinical symptoms and signs of AS.

Women, men, and rheumatoid arthritis: Analyses of disease activity, disease characteristics, and treatments in the QUEST-RA Study

IntroductionGender as a predictor of outcomes of rheumatoid arthritis (RA) has evoked considerable interest over the decades. Historically, there is no consensus whether RA is worse in females or males. Recent reports suggest that females are less likely than males to achieve remission. Therefore, we aimed to study possible associations of gender and disease activity, disease characteristics, and treatments of RA in a large multinational cross-sectional cohort of patients with RA called Quantitative Standard Monitoring of Patients with RA (QUEST-RA).MethodsThe cohort includes clinical and questionnaire data from patients who were seen in usual care, including 6,004 patients at 70 sites in 25 countries as of April 2008. Gender differences were analyzed for American College of Rheumatology Core Data Set measures of disease activity, DAS28 (disease activity score using 28 joint counts), fatigue, the presence of rheumatoid factor, nodules and erosions, and the current use of prednisone, methotrexate, and biologic agents.ResultsWomen had poorer scores than men in all Core Data Set measures. The mean values for females and males were swollen joint count-28 (SJC28) of 4.5 versus 3.8, tender joint count-28 of 6.9 versus 5.4, erythrocyte sedimentation rate of 30 versus 26, Health Assessment Questionnaire of 1.1 versus 0.8, visual analog scales for physician global estimate of 3.0 versus 2.5, pain of 4.3 versus 3.6, patient global status of 4.2 versus 3.7, DAS28 of 4.3 versus 3.8, and fatigue of 4.6 versus 3.7 (P < 0.001). However, effect sizes were small-medium and smallest (0.13) for SJC28. Among patients who had no or minimal disease activity (0 to 1) on SJC28, women had statistically significantly higher mean values compared with men in all other disease activity measures (P < 0.001) and met DAS28 remission less often than men. Rheumatoid factor was equally prevalent among genders. Men had nodules more often than women. Women had erosions more often than men, but the statistical significance was marginal. Similar proportions of females and males were taking different therapies.ConclusionsIn this large multinational cohort, RA disease activity measures appear to be worse in women than in men. However, most of the gender differences in RA disease activity may originate from the measures of disease activity rather than from RA disease activity itself.

Risk factors for severe infections in patients with rheumatoid arthritis treated with rituximab in the autoimmunity and rituximab registry

OBJECTIVE The risk of severe infection is a crucial factor in the assessment of the short-term risk:benefit ratio of biologic drugs in rheumatoid arthritis (RA). There is no increase in severe infections in RA patients treated with rituximab (RTX) in controlled trials, but this has not yet been assessed in daily practice. We undertook this study to investigate the occurrence of and risk factors for severe infections in off-trial patients using data from the AutoImmunity and Rituximab (AIR) registry. METHODS The AIR registry was set up by the French Society of Rheumatology. The charts of patients with severe infections were reviewed. RESULTS Of the enrolled patients, 1,303 had at least 1 followup visit at 3 months or later, with a mean ± SD followup period of 1.2 ± 0.8 years (1,629 patient-years). Eighty-two severe infections occurred in 78 patients (5.0 severe infections per 100 patient-years), half of them in the 3 months following the last RTX infusion. Multivariate analysis showed that chronic lung disease and/or cardiac insufficiency (odds ratio 3.0 [95% confidence interval 1.3-7.3], P = 0.01), extraarticular involvement (odds ratio 2.9 [95% confidence interval 1.3-6.7], P = 0.009), and low IgG level (<6 gm/liter) before initiation of RTX treatment (odds ratio 4.9 [95% confidence interval 1.6-15.2], P = 0.005) were significantly associated with increased risk of a severe infection. CONCLUSION The rate of severe infections in current practice is similar to that reported in clinical trials. The risk factors for severe infections include chronic lung and/or cardiac disease, extraarticular involvement, and low IgG before RTX treatment. This suggests that serum IgG should be checked and the risk:benefit ratio of RTX discussed for patients found to have low levels of IgG.

Prevalence of Pulmonary Hypertension in Systemic Sclerosis in European Caucasians and Metaanalysis of 5 Studies

Objective. To measure the prevalence of different types of pulmonary hypertension (PH) and to identify patients with systemic sclerosis (SSc) at highest risk in a multicenter European sample, with a metaanalysis of relevant studies. Methods. Consecutive patients with SSc recruited at 11 French and Italian centers underwent detailed evaluations, including Doppler echocardiography, chest computed tomography, pulmonary function tests, and right-heart catheterization (RHC), to detect the presence and causes of PH. A metaanalysis was performed, including data from 4 other studies. Results. Among 206 patients in whom it was suspected, PH was confirmed by RHC in 83 patients (7%). Precapillary PH was found in 64 patients (5%), of whom 42 had pulmonary arterial hypertension (PAH) and 22 had PH secondary to interstitial lung disease (ILD). RHC identified 17 patients (1%) with postcapillary PH secondary to left-heart disease. Patients with DLCO/alveolar volume < 70% were more likely to have precapillary PH (87.5% vs 42%; p < 0.0001). Precapillary and postcapillary PH were associated with advanced age (68 ± 14 vs 59 ± 12 yrs, p < 0.0001, and 74 ± 16 vs 61.5 ± 10 yrs, p < 0.0001, respectively). The metaanalysis of 3818 patients showed a prevalence of precapillary PH of 9% (95% CI 6%–12%) and identified advanced age, longer disease duration, and limited cutaneous disease subset as risk factors for this condition. Conclusion. The prevalence of precapillary PH in our multicenter study of SSc was 5%, and in the metaanalysis 9%. Our observations support use of RHC to confirm the presence of precapillary PH suspected by noninvasive testing. We also identified patients at high risk who should be carefully monitored.

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

Work disability remains a major problem in rheumatoid arthritis in the 2000s: Data from 32 countries in the QUEST-RA Study

IntroductionWork disability is a major consequence of rheumatoid arthritis (RA), associated not only with traditional disease activity variables, but also more significantly with demographic, functional, occupational, and societal variables. Recent reports suggest that the use of biologic agents offers potential for reduced work disability rates, but the conclusions are based on surrogate disease activity measures derived from studies primarily from Western countries.MethodsThe Quantitative Standard Monitoring of Patients with RA (QUEST-RA) multinational database of 8,039 patients in 86 sites in 32 countries, 16 with high gross domestic product (GDP) (>24K US dollars (USD) per capita) and 16 low-GDP countries (<11K USD), was analyzed for work and disability status at onset and over the course of RA and clinical status of patients who continued working or had stopped working in high-GDP versus low-GDP countries according to all RA Core Data Set measures. Associations of work disability status with RA Core Data Set variables and indices were analyzed using descriptive statistics and regression analyses.ResultsAt the time of first symptoms, 86% of men (range 57%-100% among countries) and 64% (19%-87%) of women <65 years were working. More than one third (37%) of these patients reported subsequent work disability because of RA. Among 1,756 patients whose symptoms had begun during the 2000s, the probabilities of continuing to work were 80% (95% confidence interval (CI) 78%-82%) at 2 years and 68% (95% CI 65%-71%) at 5 years, with similar patterns in high-GDP and low-GDP countries. Patients who continued working versus stopped working had significantly better clinical status for all clinical status measures and patient self-report scores, with similar patterns in high-GDP and low-GDP countries. However, patients who had stopped working in high-GDP countries had better clinical status than patients who continued working in low-GDP countries. The most significant identifier of work disability in all subgroups was Health Assessment Questionnaire (HAQ) functional disability score.ConclusionsWork disability rates remain high among people with RA during this millennium. In low-GDP countries, people remain working with high levels of disability and disease activity. Cultural and economic differences between societies affect work disability as an outcome measure for RA.

Association between the IRF5 rs2004640 functional polymorphism and systemic sclerosis: A new perspective for pulmonary fibrosis

OBJECTIVE There is now growing evidence that connective tissue diseases, including systemic sclerosis (SSc), share a common genetic background. Microarray studies support a pivotal role of type I interferon (IFN) in the pathophysiology of connective tissue diseases. Interferon regulatory factors coordinate the expression of type I IFNs, and the IRF5 gene has been identified as a susceptibility gene of systemic lupus and Sjögrens syndrome. The aim of this study was to determine whether the IRF5 rs2004640 single-nucleotide polymorphism is associated with SSc. METHODS The IRF5 rs2004640 (GT) functional polymorphism was genotyped in 1,641 subjects of French European Caucasian origin: a discovery set comprising 427 patients with SSc and 380 control subjects and a replication set comprising 454 patients with SSc and 380 control subjects. RESULTS In both the discovery set and the replication set, the TT genotype was significantly more common in patients with SSc than in control subjects, with an odds ratio (OR) for the combined populations of 1.58 (95% confidence interval [95% CI] 1.18-2.11 [P for trend 0.002]). Analyses of the whole SSc population showed a significant association between homozygosity for the T allele and the presence of antinuclear antibodies (corrected P [Pcorr]=0.04, OR 1.59, 95% CI 1.16-2.17) and fibrosing alveolitis (Pcorr=0.001, OR 2.07, 95% CI 1.38-3.11). In a multivariate analysis model including the diffuse cutaneous subtype of SSc and positivity for anti-topoisomerase I antibodies, the IRF5 rs2004640 TT genotype remained associated with fibrosing alveolitis (P=0.029, OR 1.92, 95% CI 1.07-3.44). CONCLUSION The IRF5 rs2004640 GT substitution is associated with susceptibility to SSc. These data provide new insight into the pathogenesis of SSc, including clues to the mechanisms leading to fibrosing alveolitis.

The three-year incidence of pulmonary arterial hypertension associated with systemic sclerosis in a multicenter nationwide longitudinal study in France.

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.