I. Ancuta

Access to biologic treatment for rheumatoid arthritis in Central and Eastern European (CEE) countries

Summary Background The aim of this study was to assess and compare patients’ access to biologic anti-RA drugs in selected Central and Eastern European (CEE) countries and to analyze the determinants of differences between countries. Material/Methods This is a multi-country survey study, based on a combination of desk research and direct contact with national RA stakeholders. Data was collected using a pre-defined questionnaire. Affordability was measured using an affordability index, calculated comparing the index of health care expenditures to the price index, using Poland as an index of 1. Results The percentage of patients on biologic treatment in 2009 was highest in Hungary (5% RA patients on biologic treatment), followed by Slovenia (4.5%), Slovakia (3.5%), Czech Republic (2.92%), Romania (2.2%), Estonia (1.8%), and Croatia, Serbia, Poland (below 1.5%). Infliximab, etanercept, adalimumab and rituximab were included in the reimbursement system in all countries, but abatacept and tocilizumab were included only in Slovakia. In Slovenia, public payer covered 75% of the price, and 25% is covered by supplementary health insurance; in Bulgaria public payer covered 50% of etanercept and adalimumab costs, and 75% of rituximab cost. In other countries, biologic drugs are reimbursed at 100%. Affordability index for biologic drugs was the lowest in Slovenia (0.4). In each country national guidelines define which patients are eligible for biologic treatment. Disease Activity Score (DAS28) of over 5.1 and failure of 2 or more disease-modifying anti-RA drugs, including methotrexate, are commonly used criteria. Conclusions The most important factors limiting access to biologic anti-RA treatment in the CEE region are macroeconomic conditions and restrictive treatment guidelines.

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.

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

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.

FRI0169 Smoking and Response to Rituximab in Anti-CCP Positive and Negative Rheumatoid Arthritis – Results from an International European Collaboration

Background Smoking is a negative predictor of response to antirheumatic therapy. Objectives To assess whether smoking influence the response to rituximab (RTX) in Rheumatoid Arthritis (RA). Methods Pooled data from the Collaborating European Registries for RTX in RA (CERERRA) were used. Patients who received at least 1 cycle with RTX were included. Smoking status was defined as smokers (current smokers) and non-smokers (never and ex-smokers). Analysis of co-variance (ANCOVA) was performed with DeltaDAS28 at 6 months as the dependent variable and smoking status as well as other baseline variables (age, sex, disease duration, number of prior biologic DMARDs) as covariates. Separate analyses were made for anti-CCP positive and negative patients. Results A total of 2274 patients were included - 1815 (80%) non-smokers and 459 (20%) smokers. 81% were female and 80% (out of 1199 patients with available anti-CCP) were anti-CCP positive. Smokers had shorter disease duration than non-smokers (median (IQR) 8 (4-13) years vs. 10 (5-16), p<0.0001), higher number of prior biologic DMARDs (median (IQR) 1 (0-2) vs. 1 (0-1), p<0.0001) and lower DAS28 at baseline (5.3±1.6 vs. 5.8±1.5, p<0.0001). Smokers had less improvement in disease activity than non-smokers at 6 months (mean ± SD DeltaDAS28 -1.5±1.7 vs. -1.8±1.7, respectively, p=0.04). However, the difference was no longer significant after adjustment for baseline differences (p=0.40). When the analysis was stratified by anti-CCP status, smoking did not influence the response to therapy in the anti-CCP negative subset (p=0.39) but there was a trend in the anti-CCP positive subset (p=0.06, figure 1). For the anti-CCP negative patients, 67% of non-smokers and 69% of smokers achieved EULAR response (p=0.6), while in the anti-CCP positive the respective response rates were 76% among non-smokers and 70% among smokers (p=0.09). Conclusions Smoking was negatively associated with the response to rituximab therapy in RA patients who were anti-CCP positive. References Khan A. et al. Smoking, rheumatoid factor status and responses to rituximab. Ann Rheum Dis 2012;71:1587-1588 doi:10.1136/annrheumdis-2012-201758 Saevarsdottir S. et al. Patients with early rheumatoid arthritis who smoke are less likely to respond to treatment with methotrexate and tumor necrosis factor inhibitors: observations from the Epidemiological Investigation of Rheumatoid Arthritis and the Swedis Reumatology register cohorts. Arthritis Rheum 2011;63:26–36. Chatzidionysiou K. et al. 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. Ann Rheum Dis 2011;70:1575–80. Disclosure of Interest K. Chatzidionysiou: None declared, E. Lie: None declared, E. Nasonov: None declared, G. Lukina: None declared, M. Hetland: None declared, E. Hauge: None declared, K. Pavelka Consultant for: MSD, AbbVie, Pfizer, Roche, BMS, C. Gabay Grant/research support from: Roche, Merck, Abbvie, Consultant for: Roche, Abbvie, Pfizer, BMS, Sanofi-Aventis, Merck, AB2 Bio, D. Nordström Consultant for: AbbVie, BMS, MSD, Pfizer, Roche, UCB, H. Canhão: None declared, M. Tomsic: None declared, P. van Riel: None declared, J. Gomez-Reino: None declared, I. Ancuta: None declared, T. Kvien: None declared, R. van Vollenhoven Grant/research support from: AbbVie, BMS, GSK, Pfizer, Roche, UCB, Consultant for: AbbVie, Biotest, BMS, GSK, Janssen, Lilly, Merck, Pfizer, Roche, UCB, Vertex, S. Saevarsdottir: None declared

FRI0328 Fixed versus On-Flare Retreatment with Rituximab in RA – Results from the Cererra Collaboration

Background The data on how to optimally retreat patients with RA with rituximab (RTX) have been limited so far. Objectives The aim of this analysis was to compare two common retreatment strategies: A fixed retreatment approach and retreatment when a flare occurs. Methods Pooled data from the Collaborating European Registries for Rituximab in RA (CERERRA) project were used. We identified RA patients who had received at least 2 retreatments (3 courses) with RTX and who had available information about the strategy for retreatment (according to the physicians opinion). The two retreatment strategies were compared by applying an adjusted mixed model analysis with DAS28 improvement as the dependent variable. Results A total of 800 patients were retreated at least twice: 616 patients retreated because of a flare (442 at 1st and 174 at 2nd retreatment) and 184 receiving fixed retreatment (128 at 1st and 56 at 2nd retreatment). Baseline characteristics (incl. age, sex, seropositivity, disease duration, number of prior DMARDs and biologics) at first course of RTX did not differ significantly between the two groups. However, patients retreated on flare had, as expected, a significantly higher DAS28-ESR at the time of 1st retreatment (5.1±1.3 vs. 4.1±1.4, p<0.0001), and a higher HAQ (1.5±0.7 vs. 1.3±0.8, p=0.001). They had also a slightly higher baseline (at the time of RTX start) DAS28 (6.3±1.0 vs. 6.1±1.2, p=0.03). Those retreated on flare were more likely to be treated with corticosteroids (58% vs. 46%, p=0.01) but less likely to receive concomitant DMARDs (82% vs. 92%, p=0.005). The baseline (=start of each cycle) deltaDAS28 (compared to the DAS28 at the time of RTX start) for the two groups is shown in figure 1. Patients receiving fixed retreatment had a significantly higher (in absolute number) deltaDAS28 (p<0.0001) at the start of each cycle, compared to those retreated on-flare. In the adjusted mixed model analysis, we compared the two retreatment groups for the 1st and the 2nd retreatment separately using estimated marginal means. For the 1st retreatment a fixed retreatment yielded significantly better results than the “on-flare”: mean deltaDAS28=-2.4 (95% CI: -3.0; -1.7) vs. -1.8 (95% CI: -3.6; -0.03), p<0.0001. Similar results were found for the 2nd retreatment: mean deltaDAS28=-2.6 (95% CI: -3.1; -2.2) vs. -1.6 (95% CI: -1.8; -1.4), p<0.0001. Conclusions A fixed RTX retreatment strategy in RA seems to be more effective than the retreatment “on-flare” strategy. Disclosure of Interest K. Chatzidionysiou: None declared, E. Lie: None declared, E. Nasonov: None declared, G. Lukina: None declared, M. Hetland: None declared, U. Tarp: None declared, K. Pavelka: None declared, C. Gabay: None declared, D. Nordström: None declared, H. Canhão: None declared, M. Tomsic: None declared, P. van Riel: None declared, J. Gomez-Reino: None declared, I. Ancuta: None declared, T. Kvien Grant/research support: research funding to the Diakonhjemmet Hospital from AbbVie, BMS, MSD/Schering-Plough, Pfizer/Wyeth, Roche and UCB, Consultant for: AbbVie, BMS, Celltrion, Eli Lilly, Hospira, MSD/Schering-Plough, Orion Pharma, Pfizer/Wyeth, Roche, UCB, R. van Vollenhoven: None declared DOI 10.1136/annrheumdis-2014-eular.2571