Background/Purpose:  In the SIRROUND-D study, sirukumab, a human anti–IL-6 cytokine monoclonal antibody, significantly reduced radiographic progression after 52 wks of treatment vs placebo in patients (pts) with active rheumatoid arthritis (RA) despite DMARD treatment. This post-hoc analysis of data from that study was intended to identify potential predictors of radiographic non-progression after 52 wks of sirukumab treatment.

Methods:  In this double-blind, Phase 3 study, 1,670 pts with active RA refractory to DMARDs were randomized (1:1:1) to SC sirukumab 50 mg q4w, sirukumab 100 mg q2w, or placebo q2w. In the placebo group, pts with <20% improvement in swollen/tender joints at Wks 18 or 40 or still taking placebo at Wk 52 were re-randomized to sirukumab . The change from baseline (BL) at Wk 52 in the modified Sharp/van der Heijde (SHS) radiographic damage score was evaluated as a co-primary endpoint. For this post-hoc analysis, radiographic non-progression was defined as a change from BL in the SHS score ≤0. Logistic regression analysis was used to select the list of factors associated with radiographic progression. Regression (with interaction term)/ANOVA was used to find factors that have interaction effects with treatment groups. Odds ratios and relative risk were used to compare radiographic progression between sirukumab and placebo under different levels of the factor. Observed SHS scores were used for all analyses.

Results:  In this analysis, 1,374 pts with radiographs taken at BL and post-BL were included. The proportion of radiographic non-progressors (change in SHS ≤0) at Wk 52 was significantly greater with both sirukumab doses (50 mg q4w, 55%; 100 mg q2w, 61%) vs placebo (41%; both P <0.001). Based on logistic regression analyses, both clinical characteristics (RF+, anti- CCP+) and disease activity factors (SHS >median SHS at BL, BL SHS score, disease activity scores, swollen/tender joint counts, CRP, low hemoglobin, CDAI score, SDAI score, and SJC28) were confirmed to be associated with radiographic progression. Based on regression/ANOVA analysis, the following factors were found to have an interaction effect with treatment groups on radiographic progression: CCP+, BL SHS >cohort median SHS, and BL SHS >7.5. Odds ratios showed that pts were significantly more likely to be radiographic non-progressors with sirukumab if they were anti-CCP+, had a BL SHS > cohort median SHS, or had a BL SHS >7.5 (~25% quartile cutoff for SHS). For sirukumab 50 mg q4w and 100 mg q2w vs placebo, respectively, relative risk ratios [RR (95% CI)] confirmed anti-CCP+ (1.28 [0.93, 1.77]; 1.40 [1.01, 1.94]), SHS >median (1.40 [1.05, 1.87]; 1.48 [1.12, 1.94]), and SHS >7.5 (1.53 [1.17, 2.00]; 1.55 [1.20, 2.00]) as predictive factors for radiographic non-progression with sirukumab vs placebo.

Conclusion:   In this Phase 3 study of sirukumab in pts with active RA despite DMARD treatment, pts with poor prognostic factors for RA, including those who were anti-CCP seropositive or had a BL SHS score >7.5 or > the cohort median, were more likely to have radiographic non-progression with sirukumab vs placebo.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/prediction-of-inhibition-of-radiographic-progression-by-sirukumab-an-anti-il-6-cytokine-monoclonal-antibody-in-patients-with-active-rheumatoid-arthritis-despite-disease-modifying-anti-rheuma/