G. Lukina

Highest clinical effectiveness of rituximab in autoantibody-positive patients with rheumatoid arthritis and in those for whom no more than one previous TNF antagonist has failed: pooled data from 10 European registries

Objective To assess the 6-month effectiveness of the first rituximab (RTX) course in rheumatoid arthritis (RA) and to identify possible predictors of response. Method 10 European registries submitted anonymised datasets (baseline, 3- and 6-month follow-up) from patients with RA who had started RTX, and datasets were pooled and analysed. Heterogeneity between countries was analysed by analysis of variance. Predictors of response were identified by logistic regression. Results 2019 patients were included (mean age/disease duration 53.8/12.1 years, 80.3% female, 85.6% rheumatoid factor (RF) positive and 76.8% (456/594 patients) anti-cyclic citrullinated peptide antibodies (anti-CCP) positive). For these patients an average of 2.7 disease-modifying antirheumatic drugs (DMARDs) (range 0–10) had failed, and RTX was given as the first biological agent in 36.6% of patients. There was significant heterogeneity between countries for several baseline characteristics, including the number of previous biological agents. Disease Activity Score based on 28 joint counts (DAS28) decreased from 5.8±1.4 at baseline to 4.2±1.4 at 6 months (p<0.0001) and 22.2%/42.5% achieved European League Against Rheumatism (EULAR) good/moderate response. Larger 6-month improvement in DAS28 was observed in RF-positive and anti-CCP-positive versus seronegative patients. The following predictors of EULAR good response at 6 months were identified in a multivariate analysis: anti-CCP positivity (OR=2.86, p=0.003), number of previous DMARDs (OR=0.84, p=0.06), ≤1 previous biological agents (OR=1.89, p=0.04), baseline DAS28 level (OR=0.74, p=0.003). Conclusion In this large observational cohort of patients with RA treated with RTX, seropositive patients achieved significantly greater reductions in DAS28 at 6 months than seronegative patients. Effectiveness was best when RTX was used as the first biological agent or after failure of no more than one anti-tumour necrosis factor agent.

Effectiveness of disease-modifying antirheumatic drug co-therapy with methotrexate and leflunomide in rituximab-treated rheumatoid arthritis patients: results of a 1-year follow-up study from the CERERRA collaboration

Objectives To compare the effectiveness and safety of rituximab alone or in combination with either methotrexate or leflunomide. Methods 10 European registries submitted anonymised datasets with baseline, 3, 6, 9 and 12-month clinical data from patients who started rituximab. Results 1195 patients were treated with rituximab plus methotrexate, 177 with rituximab plus leflunomide and 505 with rituximab alone. Significantly more patients achieved a European League Against Rheumatism good response at 6 months when treated with rituximab plus leflunomide (29.1%) compared with rituximab plus methotrexate (21.1%) and rituximab alone (19.3%; p=0.02 and p=0.01, respectively). Similar results were observed at 12 months. Adverse events occurred in 10.2%, 13.2% and 13.9% of patients on rituximab plus leflunomide, rituximab plus methotrexate and rituximab alone, respectively. Conclusions Leflunomide is an effective and safe alternative to methotrexate as concomitant treatment with rituximab. Slightly better results were obtained by the combination of rituximab and leflunomide than rituximab and methotrexate, raising the possibility of a synergistic effect of leflunomide and rituximab.

Effectiveness of tocilizumab with and without synthetic disease-modifying antirheumatic drugs in rheumatoid arthritis: results from a European collaborative study

Objectives To examine the effectiveness of tocilizumab (TCZ) with and without synthetic disease-modifying antirheumatic drugs (sDMARDs) in a large observational study. Methods Patients with rheumatoid arthritis treated with TCZ who had a baseline visit and information on concomitant sDMARDs were included. According to baseline data, patients were considered as taking TCZ as monotherapy or combination with sDMARDs. Main study outcomes were the change of Clinical Disease Activity Index (CDAI) and TCZ retention. The prescription of TCZ as monotherapy was analysed using logistic regression. CDAI change was analysed with a mixed-effects model for longitudinal data. TCZ retention was analysed with a stratified extended Cox model. Results Multiple-adjusted analysis suggests that prescription of TCZ as monotherapy varied according to age, corticosteroid use, country of the registry and year of treatment initiation. The change of disease activity assessed by CDAI as well as the likelihood to be in remission were not significantly different whether TCZ was used as monotherapy or in combination with sDMARDs in a covariate-adjusted analysis. Estimates for unadjusted median TCZ retention were 2.3 years (95% CI 1.8 to 2.7) for monotherapy and 3.7 years (lower 95% CI limit 3.1, upper limit not estimable) for combination therapies. In a covariate-adjusted analysis, TCZ retention was also reduced when used as monotherapy, with an increasing difference between mono and combination therapy over time after 1.5 years (p=0.002). Conclusions TCZ with or without concomitant sDMARDs resulted in comparable clinical response as assessed by CDAI change, but TCZ retention was shorter under monotherapy of TCZ.

Effectiveness of two different doses of rituximab for the treatment of rheumatoid arthritis in an international cohort: data from the CERERRA collaboration.

BackgroundThe approved dose of rituximab (RTX) in rheumatoid arthritis is 1000 mg × 2, but some data have suggested similar clinical efficacy with 500 mg × 2. The purpose of this study was to compare the effectiveness of the regular and low doses given as first treatment course.MethodsTwelve European registries participating in the CERERRA collaboration (The European Collaborative Registries for the Evaluation of Rituximab in Rheumatoid Arthritis) submitted anonymized datasets with demographic, efficacy and treatment data for patients who had started RTX. Treatment effectiveness was assessed by DAS28 reductions and EULAR responses after 6 months.ResultsData on RTX dose were available for 2,873 patients, of whom 2,625 (91.4 %) and 248 (8.6 %) received 1000 mg × 2 and 500 mg × 2, respectively. Patients treated with 500 mg × 2 were significantly older, had longer disease duration, higher number of prior DMARDs, but lower number of prior biologics and lower baseline DAS28 than those treated with 1000 mg × 2. Fewer patients in the low-dose group received concomitant DMARDs but more frequently received concomitant corticosteroids.Both doses led to significant clinical improvements at 6 months. DAS28 reductions at 6 months were comparable in the 2 dose regimens [mean DeltaDAS28 ± SD -2.0 ± 1.3 (high dose) vs. -1.7 ± 1.4 (low dose), p = 0.23 adjusted for baseline differences]. Similar percentages of patients achieved EULAR good response in the two dose groups, 18.4 % vs. 17.3 %, respectively (p = 0.36).ConclusionsIn this large observational cohort initial treatment with RTX at 500 mg × 2 and 1000 mg × 2 led to comparable clinical outcomes at 6 months.

The Effects of Rituximab on Lipids, Arterial Stiffness, and Carotid Intima-Media Thickness in Rheumatoid Arthritis

The aim of the study was to examine lipid profiles, arterial stiffness (AS), carotid intima-media thickness (cIMT), in 55 women with RA without overt cardiovascular disease (СVD) treated with rituximab (RTX).The following parameters were recorded before and 24 weeks after RTX therapy (2 infusions of 500 or 1,000 mg RTX intravenously, fortnightly): plasma total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycerides, DAS 28-ESR, serum C-reactive protein (CRP), RF IgM, AS (SI - stiffness index, RI – reflection index) by digital volume pulse contour analysis (Micro Medical, UK), and common cIMT by high-resolution B-mode carotid ultrasound. Based on the European League Against Rheumatism (EULAR) criteria, patients were divided into two groups: 1) moderate/good response to RTX therapy after 24 weeks (41 patients, 75%), 2) no response to RTX therapy (14 patients, 25%). Effective RTX therapy resulted in 9% increase in TC, 23% increase in HDL-C and 14% decrease in atherogenic index, 57% decrease in SI and 24% decrease in RI. We observed a 9% decrease of cIMTmax at 24 weeks. The improvement of cardiovascular parameters was accompanied by statistically significant decreases of CRP, ESR, RF IgM and DAS 28 in group 1 (P < 0.05). There were not significant changes in lipid profile, AS parameters, and cIMT in group 2. Two infusions of RTX in case of moderate/good EULAR effect of therapy exerted favorable effects on lipid profile, AS and cIMT in women with RA without overt CVD.

Rituximab Downregulates Gene Expression Associated with Cell Proliferation, Survival, and Proteolysis in the Peripheral Blood from Rheumatoid Arthritis Patients: A Link between High Baseline Autophagy-Related ULK1 Expression and Improved Pain Control

Objective. To clarify molecular mechanisms for the response to rituximab in a longitudinal study. Methods. Peripheral blood from 16 RA patients treated with rituximab for a single treatment course and 26 healthy controls, blood and knee articular cartilages from 18 patients with long-standing RA, and cartilages from 14 healthy subjects were examined. Clinical response was assessed using ESR, ACPA, CRP, RF, DAS28 levels, CD19+ B-cell counts, bone erosion, and joint space narrowing scores. Protein expression in PBMCs was quantified using ELISA. Gene expression was performed with quantitative real-time PCR. Results. A decrease (p < 0.05) in DAS28, ESR, and CRP values after rituximab treatment was associated with the downregulation of MTOR, p21, caspase 3, ULK1, TNFα, IL-1β, and cathepsin K gene expression in the peripheral blood to levels found in healthy subjects. MMP-9 expression remained significantly higher compared to controls although decreased (p < 0.05) versus baseline. A negative correlation between baseline ULK1 gene expression and the number of tender joints at the end of follow-up was observed. Conclusions. The response to rituximab was associated with decreased MTOR, p21, caspase 3, ULK1, TNFα, IL-1β, and cathepsin K gene expression compared to healthy subjects. Residual increased expression in MMP-9, IFNα, and COX2 might account for remaining inflammation and pain. High baseline ULK1 gene expression indicates a good response in respect to pain.

A9.15 Remission as the Main Therapeutic Target: Comparative Efficacy of Four Treatment Regimens in Early Rheumatoid Arthritis (RA) Patients (Pts)

Background Early RA contains the “the window of opportunities” for achieving the best results of therapy including remissions. It is very important to determine the influence of different treatment regimens on the remission rate in patients (pts) with early RA. Objectives To compare development of remissions in pts with early (<2 years duration) RA who were randomly assigned to receive four different strategies of DMARDs treatment. Methods One hundred forty-one pts with RA of less than 2 years duration (122 women, mean age 51 years, mean disease duration 24 weeks, mean DAS28 5.9; 64% RF-positive, 59% ACCP-positive) were randomised to receive one of the following treatment regimens: methotrexate (MTX, up to 20 mg/week, 35 pts); MTX plus prednisolone (P) 10 mg daily (MTX-P, 34 pts); MTX-P plus methylprednisolone (MP) 1000 mg intravenously on the first day of treatment (MTX-P-MP, 35 pts); leflunomide 20 mg daily (LEF, 37 pts). Duration of treatment was one year. Efficacy of therapy was assessed by EULAR criteria. Control points were 3, 6 and 12 months from the beginning of therapy. The primary endpoint was the development of remission. Results At baseline all groups were comparable in their demographic, clinical and radiographic characteristics. One hundred twenty-seven pts completed the study. By the 3d month in the MTX group only 3.1% of the patients reached clinical remission, while in the combination groups of MTX with GC (including MP intravenously) 21.3% and 28.6%, respectively. By the 6th month the same tendency continued: combination of MTX with GC showed the greatest frequency of remissions – 33.3% and 23.5%, respectively. In the MTX and LEF monotherapy groups the corresponding figures were 15.2% and 20.6%, respectively. By the 12th month the frequency of remissions was significantly higher in pts treated with the combination of MTX and GC, including high doses of MP (37.5% and 29.4%, respectively) than in the MTX and LEF monotherapy groups (11.4% and 16.2%, respectively). Conclusions In pts with early RA combined treatment with MTX and GC led to the significantly higher remission rate as compared with MTX and LEF monotherapy.

SAT0036 Retention of Tocilizumab Therapy: A Comparison between Tocilizumab in Monotherapy and in Combination with DMARDS Based on the Tocerra Collaboration

Background Clinical trials have shown that tocilizumab (TCZ) is efficacious as monotherapy and in combination with methotrexate (MTX) or other DMARDs. However, longitudinal TCZ retention data from large registry populations have been missing. Objectives To examine retention of TCZ administered alone or in combination with DMARDs in rheumatoid arthritis (RA) patients included in the TOcilizumab Collaboration of European Registries in RA (TOCERRA). Methods RA patients treated with TCZ who had baseline (BL) data and not immediately lost to follow-up were included. Patients were considered as taking TCZ in monotherapy (mono) or combination with DMARDs (combo) based on their BL DMARD co-therapy. Time on TCZ was defined by the time between TCZ start and discontinuation with censoring occurring at date of last visit on TCZ. Crude median TCZ retention with 95% CIs were estimated for mono and combo therapy. The hazard for TCZ discontinuation was modeled using a country-stratified, covariate-adjusted Cox proportional hazards model applied to patients with complete BL covariate information for sex, age, disease duration, number of prior biologics, corticosteroid use, seropositivity (rheumatoid factor or anti-CCP), DAS28, HAQ, and therapy. Results A total of 1271 eligible treatment courses (TCs) were retrieved from 8 registries by April 2013. Of these, 328 (26%) were started as mono and 943 as combo therapy. For 83% of TCs, DMARD co-therapy was stable over time. In 471 TCs (37%) (of which 124 mono) TCZ was discontinued. Main causes of discontinuation were lack of effectiveness (52% for both therapies) or safety issues (34% and 26% for mono and combo). Crude median TCZ retention was 2.2 years (95% CI: 1.7-3) for mono and 3.5 years (95% CI: 2.7-NA) for combo, (P=0.08). Of the 1271 TCs 856 were included in the country-stratified, covariate-adjusted analysis. Significant results were obtained for seropositivity (HR: 0.64 (pos vs neg), 95% CI: (0.49, 0.84), P=0.001) and HAQ (HR: 1.25 (per unit increase), 95% CI: (1.04, 1.49), P=0.014) at BL. Therapy was not significant (HR: 1.16 (mono vs combo), 95% CI: (0.89, 1.52), P=0.27). Conclusions In routine care, TCZ retention is better in patients who are seropositive and have lower HAQ at BL, but comparable for mono and combo therapy. Disclosure of Interest C. Gabay Grant/research support: Roche, M. Riek: None declared, M. Hetland Grant/research support: Roche, E. Hauge Grant/research support: Roche, K. Pavelka Grant/research support: Roche, M. Tomsic Grant/research support: Roche, H. Canhao Grant/research support: Roche, K. Chatzidionysiou Grant/research support: Roche, R. van Vollenhoven Grant/research support: Roche, G. Lukina Grant/research support: Roche, D. Nordström Grant/research support: Roche, E. Lie Grant/research support: Roche, I. Ancuta Grant/research support: Roche, E. Loza Santamaria Grant/research support: Roche, P. van Riel Grant/research support: Roche, T. Kvien Grant/research support: Roche DOI 10.1136/annrheumdis-2014-eular.2806

Smoking and response to rituximab in rheumatoid arthritis: results from an international European collaboration

Objectives: To investigate whether smoking habits predict response to rituximab (RTX) in rheumatoid arthritis (RA). Method: We included patients from the CERERRA international cohort receiving the first treatment cycle with available smoking status (n = 2481, smokers n = 528, non-current smokers n = 1953) and at least one follow-up visit. Outcome measures were change in Disease Activity Score based on 28-joint count (ΔDAS28) and European League Against Rheumatism (EULAR) good response at 6 months, with non-current smokers as the referent group. Results: Compared with non-smokers at baseline, smokers were more often rheumatoid factor (RF)/anti-citrullinated protein antibody (ACPA) positive and males, had shorter disease duration, lower DAS28 and Health Assessment Questionnaire (HAQ) score, a higher number of prior biological disease-modifying anti-rheumatic drugs, and were more likely to receive concomitant conventional synthetic disease-modifying anti-rheumatic drug (csDMARDs). Disease activity had decreased less in smokers at 6 months (ΔDAS28 = 1.5 vs 1.7, p = 0.006), although the difference was no longer significant after correction for baseline DAS28 (p = 0.41). EULAR good response rates did not differ between smokers and non-smokers overall or stratified by RF/ACPA status, although smokers had lower good response rates among seronegative patients (ACPA-negative: 6% vs 14%, RF-negative: 11% vs 18%). Smoking did not predict good response [odds ratio (OR) = 1.04, 95% confidence interval (CI) = 0.76–1.41], while ACPA, DAS28, HAQ, and concomitant csDMARDs were significant predictors for good response. However, when stratified by country, smokers were less likely to achieve good response in Sweden (unadjusted OR = 0.24, 95% CI = 0.07–0.89), and a trend was seen in the Czech Republic (OR = 0.45, 95% CI = 0.16–1.02). Conclusion: In this large, observational, multinational RA cohort, smokers starting RTX differed from non-smokers by having shorter disease duration and lower disease activity, but more previous treatments. The overall results do not support smoking as an important predictor for response to RTX in patients with RA.

Rituximab Retreatment in Rheumatoid Arthritis in a Real-life Cohort: Data from the CERERRA Collaboration.

Objective. Several aspects of rituximab (RTX) retreatment in rheumatoid arthritis (RA) need to be further elucidated. The aim of this study was to describe the effect of repeated courses of RTX on disease activity and to compare 2 retreatment strategies, fixed-interval versus on-flare retreatment, in a large international, observational, collaborative study. Methods. In the first analysis, patients with RA who received at least 4 cycles with RTX were included. In the second analysis, patients who received at least 1 RTX retreatment and for whom information about the strategy for retreatment was available were identified. Two retreatment strategies (fixed-interval vs on-flare) were compared by fitting-adjusted, mixed-effects models of 28-joint Disease Activity Score (DAS28) over time for first and second retreatment. Results. A total of 1530 patients met the eligibility criteria for the first analysis. Significant reductions of mean DAS28 between the starts of subsequent treatment cycles were observed (at start of first treatment cycle: 5.5; second: 4.3; third: 3.8; and fourth: 3.5), suggesting improved response after each additional cycle (p < 0.0001 for all pairwise comparisons). A total of 800 patients qualified for the second analysis: 616 were retreated on flare and 184 at fixed interval. For the first retreatment, the fixed-interval retreatment group yielded significantly better results than the on-flare group (estimated marginal mean DAS28 = 3.8, 95% CI 3.6–4.1 vs 4.6, 95% CI 4.5–4.7, p < 0.0001). Similar results were found for the second retreatment. Conclusion. Repeated treatment with RTX leads to further clinical improvement after the first course of RTX. A fixed-interval retreatment strategy seems to be more effective than on-flare retreatment.