Aleth Perdriger

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

Maintenance of infliximab treatment in ankylosing spondylitis: Results of a one‐year randomized controlled trial comparing systematic versus on‐demand treatment

OBJECTIVE Continuous treatment with the anti-tumor necrosis factor alpha (anti-TNFalpha) antibody infliximab is efficacious in ankylosing spondylitis (AS), whereas treatment discontinuation results in disease relapse, with variable delay. This study was undertaken to compare the efficacy of continuous treatment with infliximab with that of a treatment regimen adapted to symptom recurrence. Methotrexate (MTX) in combination with infliximab was also tested. METHODS Patients with active AS were randomly assigned at week 0 to receive infliximab every 6 weeks (continuous treatment) or upon symptom recurrence (on-demand treatment), following infusions at weeks 4, 6, and 10. Patients in the on-demand group were randomly assigned to receive either MTX in combination with infliximab or infliximab alone. Patients were monitored for 1 year. The primary end point was the proportion of patients who met the ASsessment in AS International Working Group criteria for 20% improvement (ASAS20) at week 58. RESULTS Of 247 patients, 124 were assigned to receive infliximab every 6 weeks and 123 to receive on-demand treatment. Among the latter, 62 received MTX, and 61 received infliximab alone. A greater proportion of patients receiving infliximab every 6 weeks fulfilled ASAS20 response criteria at week 58 than did patients receiving on-demand treatment (75% versus 46%; P<0.0001). Patients in the continuous treatment group received more infliximab infusions after week 10 than did those in the on-demand group (mean+/-SD 5.8+/-2.2 versus 3.5+/-2; P<0.0001). Addition of MTX did not significantly affect the proportion of patients with an ASAS20 response at week 58, nor the number of infliximab infusions administered. CONCLUSION These findings indicate that continuous treatment of AS with infliximab is more efficacious than on-demand treatment, and that the addition of MTX to infliximab provides no significant benefit.

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.

Tocilizumab in refractory adult Still's disease

There is an unmet need for the treatment of adult Stills disease (ASD), the pathogenesis of which may involve interleukin‐6 (IL‐6). We report the first series of patients with ASD treated with tocilizumab (TCZ), a humanized anti–IL‐6 receptor antibody.

Influence of shared epitope–negative HLA–DRB1 alleles on genetic susceptibility to rheumatoid arthritis

OBJECTIVE Most patients with rheumatoid arthritis (RA) express the shared epitope (SE). It is not known whether SE-negative HLA-DRB1 alleles influence the development of RA. This study examined the influence of SE-negative HLA-DR alleles (DRB1*X) on the development of RA in 3 different French populations. METHODS HLA-DRB1 alleles were defined by polymerase chain reaction with sequence-specific oligonucleotide hybridization or sequence-specific primers. SE-negative alleles were classified according to the electric charge of their P4 pocket. HLA-DRB1 alleles *0103, *0402, *07, *08, *11 (except *1107), *12, and *13 have a neutral or negative P4 charge and are called DRB1*XP4n. HLA-DRB1*03, *0403, *0406, *0407, *0901, *1107, *14, *15, and *16 have a positive P4 charge and are called DRB1*XP4p. RESULTS Among the SE-negative subjects, DRB1 genotypes with 1 or 2 DRB1*XP4n alleles were significantly overrepresented in the control subjects compared with the RA patients, whereas DRB1*XP4p/XP4p genotypes were equally represented in the patients and controls. In single-dose SE-positive subjects, SE/XP4n genotypes were equally represented in the patients and controls. However, SE/XP4p genotypes were significantly overrepresented in the RA patients. CONCLUSION The DRB1*X allele polymorphism influences susceptibility to RA. Alleles that have a neutral or negative electric charge in their P4 pocket (DRB1*XP4n), such as DRB1*0103, *0402, *07, *08, *11 (except *1107), *12, and *13, protect against RA. Alleles that have a positive electric charge in their P4 pocket (DRB1*XP4p), such as DRB1*03, *0403, *0406, *0407, *0901, *1107, *14, *15, and *16, have no influence on the predisposition to RA.

Serum Levels of Beta2-Microglobulin and Free Light Chains of Immunoglobulins Are Associated with Systemic Disease Activity in Primary Sjögren’s Syndrome. Data at Enrollment in the Prospective ASSESS Cohort

Objectives To analyze the clinical and immunological characteristics at enrollment in a large prospective cohort of patients with primary Sjögrens syndrome (pSS) and to investigate the association between serum BAFF, beta2-microglobulin and free light chains of immunoglobulins and systemic disease activity at enrollment. Methods Three hundred and ninety five patients with pSS according to American-European Consensus Criteria were included from fifteen centers of Rheumatology and Internal Medicine in the “Assessment of Systemic Signs and Evolution of Sjögrens Syndrome” (ASSESS) 5-year prospective cohort. At enrollment, serum markers were assessed as well as activity of the disease measured with the EULAR Sjögrens Syndrome Disease Activity Index (ESSDAI). Results Patient median age was 58 (25th–75th: 51–67) and median disease duration was 5 (2–9) years. Median ESSDAI at enrollment was 2 (0–7) with 30.9% of patients having features of systemic involvement. Patients with elevated BAFF, beta2-microglobulin and kappa, lambda FLCS had higher ESSDAI scores at enrollment (4 [2]–[11] vs 2 [0–7], P = 0.03; 4 [1]–[11] vs 2 [0–7], P< 0.0001); 4 [2]–[10] vs 2 [0–6.6], P< 0.0001 and 4 [2–8.2] vs 2 [0–7.0], P = 0.02, respectively). In multivariate analysis, increased beta2-microglobulin, kappa and lambda FLCs were associated with a higher ESSDAI score. Median BAFF and beta2-microglobulin were higher in the 16 patients with history of lymphoma (1173.3(873.1–3665.5) vs 898.9 (715.9–1187.2) pg/ml, P = 0.01 and 2.6 (2.2–2.9) vs 2.1 (1.8–2.6) mg/l, P = 0.04, respectively). Conclusion In pSS, higher levels of beta2-microglobulin and free light chains of immunoglobulins are associated with increased systemic disease activity.

Long-term effects of therapeutic education for patients with rheumatoid arthritis

INTRODUCTION The objective of this study was to assess the effects of an educational program on the course of rheumatoid arthritis (RA) after 3 years. METHODS From December 2002 to December 2003, 39 RA patients participated in a 3-day education program delivered to groups of four or five patients. Effects of the program were evaluated after 3 years in 33 patients, comparatively to baseline, based on the following variables: knowledge of RA (self-questionnaire), disease activity (DAS 28), functional impairment (health assessment questionnaire [HAQ]) and quality of life (arthritis impact measurement scale 2 [AIMS2], short-form). We also compared patient knowledge in the educational program participants and in 38 controls with RA. Direct questions were used to evaluate the program after 3 years. RESULTS Patient knowledge 3 years after the education program was significantly improved compared to baseline (P<0.0001) and was significantly better than in the controls (P<0.0001). Disease activity was significantly lower in the education group after 3 years than at baseline (DAS28, 3.1 vs. 3.8, P<0.005). Neither the HAQ nor the AIMS2 scores changed significantly after 3 years compared to baseline. The replies to the direct questions indicated a very high level of overall satisfaction with the educational program. CONCLUSION An educational program tailored to patient needs can produce lasting improvements in knowledge of the disease and may help to control the activity of RA. These results warrant the development of education programs for patients with chronic inflammatory joint disease.

Non–TNF-Targeted Biologic vs a Second Anti-TNF Drug to Treat Rheumatoid Arthritis in Patients With Insufficient Response to a First Anti-TNF Drug: A Randomized Clinical Trial

Importance One-third of patients with rheumatoid arthritis show inadequate response to tumor necrosis factor α (TNF-α) inhibitors; little guidance on choosing the next treatment exists. Objective To compare the efficacy of a non-TNF-targeted biologic (non-TNF) vs a second anti-TNF drug for patients with insufficient response to a TNF inhibitor. Design, Setting, and Participants A total of 300 patients (conducted between 2009-2012) with rheumatoid arthritis, with persistent disease activity (disease activity score in 28 joints-erythrocyte sedimentation rate [DAS28-ESR]  ≥ 3.2 [range, 0-9.3]) and an insufficient response to anti-TNF therapy were included in a 52-week multicenter, pragmatic, open-label randomized clinical trial. The final follow-up date was in August 2013. Interventions Patients were randomly assigned (1:1) to receive a non-TNF-targeted biologic agent or an anti-TNF that differed from their previous treatment. The choice of the biologic prescribed within each randomized group was left to the treating clinician. Main Outcomes and Measures The primary outcome was the proportion of patients with good or moderate response according to the European League Against Rheumatism (EULAR) scale at week 24. Secondary outcomes included the EULAR response at weeks 12 and 52; at weeks 12, 24, and 52; DAS28ESR, low disease activity (DAS28 ≤3.2), remission (DAS28 ≤2.6); serious adverse events; and serious infections. Results Of the 300 randomized patients (243 [83.2%] women; mean [SD] age, 57.1 [12.2] years; baseline DAS28-ESR, 5.1 [1.1]), 269 (89.7%) completed the study. At week 24, 101 of 146 patients (69%) in the non-TNF group and 76 (52%) in the second anti-TNF group achieved a good or moderate EULAR response (OR, 2.06; 95% CI, 1.27-3.37; P = .004, with imputation of missing data; absolute difference, 17.2%; 95% CI, 6.2% to 28.2%). The DAS28-ESR was lower in the non-TNF group than in the second anti-TNF group (mean difference adjusted for baseline differences, -0.43; 95% CI, -0.72 to -0.14; P = .004). At weeks 24 and 52, more patients in the non-TNF group vs the second anti-TNF group showed low disease activity (45% vs 28% at week 24; OR, 2.09; 95% CI, 1.27 to 3.43; P = .004 and 41% vs 23% at week 52; OR, 2.26; 95% CI, 1.33 to 3.86; P = .003). Conclusions and Relevance Among patients with rheumatoid arthritis previously treated with anti-TNF drugs but with inadequate primary response, a non-TNF biologic agent was more effective in achieving a good or moderate disease activity response at 24 weeks than was the second anti-TNF medication. Trial Registration clinicaltrials.gov Identifier: NCT01000441.

Development of the Sjögren’s Syndrome Responder Index, a data-driven composite endpoint for assessing treatment efficacy

OBJECTIVES To determine which outcome measures detected rituximab efficacy in the Tolerance and Efficacy of Rituximab in Sjögrens Disease (TEARS) trial and to create a composite endpoint for future trials in primary SS (pSS). METHODS Post hoc analysis of the multicentre randomized placebo-controlled double-blind TEARS trial. The results were validated using data from two other randomized controlled trials in pSS, assessing rituximab (single-centre trial in the Netherlands) and infliximab, respectively. RESULTS Five outcome measures were improved by rituximab in the TEARS trial: patient-assessed visual analogue scale scores for fatigue, oral dryness and ocular dryness, unstimulated whole salivary flow and ESR. We combined these measures into a composite endpoint, the SS Responder Index (SSRI), and we defined an SSRI-30 response as a ≥30% improvement in at least two of five outcome measures. In TEARS, the proportions of patients with an SSRI-30 response in the rituximab and placebo groups at 6, 16 and 24 weeks were 47% vs 21%, 50% vs 7% and 55% vs 20%, respectively (P < 0.01 for all comparisons). SSRI-30 response rates after 12 and 24 weeks in the single-centre rituximab trial were 68% (13/19) vs 40% (4/10) and 74% (14/19) vs 40% (4/10), respectively. No significant differences in SSRI-30 response rates were found between infliximab and placebo at any of the time points in the infliximab trial. CONCLUSION A core set of outcome measures used in combination suggests that rituximab could be effective and infliximab ineffective in pSS. The SSRI might prove useful as the primary outcome measure for future therapeutic trials in pSS.

The effect of tocilizumab on bone mineral density, serum levels of Dickkopf-1 and bone remodeling markers in patients with rheumatoid arthritis.

UNLABELLED Previous studies showed that the control of inflammation by biological therapies has a positive effect on bone in inflammatory diseases. The objective of this study was to assess the effects on bone mineral density (BMD) and bone remodeling of an anti-IL-6 monoclonal antibody (tocilizumab (TCZ)) in patients with rheumatoid arthritis (RA). METHODS One hundred and three patients (75% women, 52±12years) with active RA were treated with TCZ 8mg/kg + methotrexate (MTX) every 4 weeks during 48 weeks. Hip and lumbar spine BMDs were measured at baseline and after 48 weeks by dual energy X-ray absorptiometry (DXA). Pro-collagen serum type I N-terminal propeptide (PINP), serum C-terminal cross-linked telopeptide of type I collagen (CTX-I), and serum levels of total Dickkopf-1 (Dkk-1) and sclerostin were assessed at baseline, 12 and 48 weeks. RESULTS BMD was available for 76 patients at baseline and at the end of the study. There was no change in lumbar spine and hip BMD over 48 weeks. Serum PINP increased from baseline by 22% (P≤0.001) and 19% (P≤0.001) at week 12 and week 48, whereas serum CTX-I remained stable. Serum DKK-1 significantly decreased from baseline by -31% (P≤0.001) and -25% (P=0.025) at week 12 and 48. Similar results were observed in the patients receiving low doses of oral corticosteroids. CONCLUSION In this 1-year prospective open study, patients with active RA receiving TCZ and MTX had no change in BMD, a decrease in serum DKK-1 and an increase in bone formation marker.