Katerina Chatzidionysiou

Disease activity patterns over time in patients with SLE: analysis of the Hopkins Lupus Cohort

Objective To describe SLE disease activity patterns in the Hopkins Lupus Cohort. Methods Disease activity was studied in 1886 patients followed-up for 1–28 years. Disease activity patterns were defined using (1) Physician Global Assessment (PGA) and (2) modified SLE Disease Activity Index (M-SLEDAI) as follows: long quiescent (LQ), M-SLEDAI=0/PGA=0 at all visits; relapsing-remitting (RR), periods of activity (M-SLEDAI>0/PGA>0) interspersed with inactivity (M-SLEDAI=0/PGA=0); chronic active (CA), M-SLEDAI>0/PGA>0 at all visits. The pattern of first 3 consecutive follow-up years was determined in 916 patients as: persistent LQ (pLQ), persistent RR (pRR) and persistent CA (pCA), LQ, RR and CA pattern in each of the 3 years, respectively; mixed, at least two different pattern types were identified. Results The RR pattern accounted for the greatest proportion of follow-up time both by M-SLEDAI and PGA, representing 53.8% and 49.9% of total patient-years, respectively. The second most frequent pattern was LQ based on M-SLEDAI (30.7%) and CA based on PGA (40.4%). For the first 3-year intervals, the mixed pattern type was the most common (56.6%). The pRR was the second most frequent (M-SLEDAI 33.3%, PGA 26.5%), while pLQ (M-SLEDAI 6.4%, PGA 0.7%) and pCA were less frequent (M-SLEDAI 3.7%, PGA 16.3%). Conclusions The RR pattern was the most prevalent pattern. LQ was achieved in a subset of patients, using the M-SLEDAI. However, the PGA captured mild activity missed on the M-SLEDAI in these patients. Over a 3-year perspective, less than half of patients maintained their original pattern.

Induction maintenance with tumour necrosis factor-inhibitor combination therapy with discontinuation versus methotrexate monotherapy in early rheumatoid arthritis: a systematic review and meta-analysis of efficacy in randomised controlled trials

Objective To determine whether an induction-maintenance strategy of combined therapy (methotrexate (MTX)+tumour necrosis factor (TNF) inhibitor (TNFi)) followed by withdrawal of TNFi could yield better long-term results than a strategy with MTX monotherapy, since it is unclear if the benefits from an induction phase with combined therapy are sustained if TNFi is withdrawn. Methods We performed a meta-analysis of trials using the initial combination of MTX+TNFi in conventional synthetic disease-modifying antirheumatic drug-naïve patients with early rheumatoid arthritis (RA). A systematic literature search was performed for induction-maintenance randomised controlled trials (RCTs) where initial combination therapy was compared with MTX monotherapy in patients with clinically active early RA. Our primary outcome was the proportion of patients who achieved low disease activity (LDA; Disease Activity Score (DAS)28<3.2) and/or remission (DAS28<2.6) at 12–76 weeks of follow-up. A random-effects model was used to pool the risk ratio (RR) for LDA and remission and heterogeneity was explored by subgroup analyses. Results We identified 6 published RCTs, 4 of them where MTX+adalimumab was given as initial therapy and where adalimumab was withdrawn in a subset of patients after LDA/remission had been achieved. 2 additional trials used MTX+infliximab as combination therapy. The pooled RRs for achieving LDA and clinical remission at follow-up after withdrawal of TNFi were 1.41 (95% CI 1.05 to 1.89) and 1.34 (95% CI 0.95 to 1.89), respectively. There was significant heterogeneity between trials due to different treatment strategies, which was a limitation to this study. Conclusions Initial therapy with MTX+TNFi is associated with a higher chance of retaining LDA and/or remission even after discontinuation of TNFi.

Relationship between glucocorticoid dose and adverse events in systemic lupus erythematosus: data from a randomized clinical trial

Objective: The aim was to obtain a better understanding of the relationship between exposure to glucocorticoids (GCs) and adverse events (AEs) reported in a randomized controlled trial (RCT) in systemic lupus erythematosus (SLE) patients. Method: We used data from the BLISS-76 trial on belimumab. The data were accessed through an agreement under the SHARE mechanism. AEs were grouped according to medical relevance, i.e. based on similarity of symptoms and pathophysiology. We studied the relationship between AEs and exposure to GCs at baseline and at any time-point, and compared the frequencies of each AE and groups of AEs between tertiles of cumulative GC dose. Results: In total, 991 AEs were reported in the 819 patients of the trial. The frequencies of anaemia, pyrexia, oral herpes, and malaise were significantly higher (p < 0.05) in patients who were on GCs at baseline than in those who were not. The frequencies of several other AEs, including nausea, seasonal allergy, bacterial sinusitis, and viral upper respiratory infection, were significantly higher in patients without GCs. For cumulative GCs, tachycardia and proteinuria were significantly more frequent in the highest tertile than in the lowest tertile, but other AEs and groups of AEs were significantly more frequent in the lowest tertile. Conclusion: This study highlights the feasibility of post-hoc analyses of RCTs using the SHARE mechanism and demonstrates the association of GCs with various AEs. Contrary to expectations, there were also associations between lower cumulative GC dose and several other AEs.

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.

FRI0190 Induction-Maintenance in Early RA: A Meta-Analysis of Trials Using MTX plus TNF-Inhibitor as Induction Therapy

Background The goal of rheumatoid arthritis (RA) treatment is remission or, when not achievable, low-disease-activity (LDA). Initial combined therapy with MTX + TNF-inhibitor (TNFi) achieves these goals more often than MTX alone, but at a high cost. Some trials have therefore used the combined treatment for a limited time only (“induction-maintenance”). Objectives It has remained unclear if the benefits from the induction phase are sustained during maintenance, and individual trials may not have been sufficiently powered to resolve this issue. Therefore, we performed a meta-analysis of trials using the initial combination of MTX+ TNFi in DMARD-naïve early RA-patients. Methods A systematic literature search was performed for induction-maintenance randomized controlled trials where initial combination therapy was compared with MTX-monotherapy in patients with clinically active early RA. Our primary outcome was the proportion of patients who achieved LDA (DAS28<3.2) and/or remission (DAS28<2.6), at 12–76 weeks of follow-up comparing patients who started with MTX+TNFi to those who started with MTX alone. A random effects model was used to pool the risk ratio (RR) for LDA and clinical remission. Results The literature search identified 1269 studies that matched the predefined search terms. We identified six published randomized trials, four of them where MTX+ADA was given as initial therapy and where ADA was withdrawn in a subset of patients after LDA/remission had been achieved. For two of these trials (Guépard and Hit-Hard) original data were re-examined, for the other two (Optima and Opera) only published data were available. Two of the additional identified trials (T20 and BeST) used MTX+Infliximab as initial combination- therapy. For BeST, only LDA could be assessed. As expected, the RR of achieving LDA or clinical remission with combination therapy was significantly greater than with MTX monotherapy; 1.70 (95%CI 1.21–2.38) and 1.67 (95%CI 1.42–1.95), respectively. The pooled RRs for achieving LDA and clinical remission at follow-up after discontinuation of TNFi were 1.41 (95%CI 1.05–1.89) and 1.34 (95%CI 0.95–1.89), respectively, with significant heterogeneity between trials (Figure 1). Conclusions This meta-analysis supports the hypothesis that in early RA, initial therapy with MTX+TNFi is associated with a higher chance of retaining LDA and/or remission even after discontinuation of TNFi. Acknowledgement Dr. Marc Quinn at York Teaching Hospital. Disclosure of Interest S. Emamikia: None declared, E. Arkema: None declared, J. Detert: None declared, K. Chatzidionysiou: None declared, M. Dougados Consultant for: Maxime Dougados has participated at symposia and advisory boards organized by ABBVIE, PFIZER, UCB, MERCK, SANOFI, NOVARTIS, ROCHE, BMS, G. Burmester Grant/research support from: Abbott, R. van Vollenhoven Grant/research support from: AbbVie, Amgen, BMS, GSK, Pfizer, Roche, UCB, Consultant for: AbbVie, Biotest, BMS, Crescendo, GSK, Janssen, Lilly, Merck, Pfizer, Roche, UCB, Vertex