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Randomized Controlled Trial
. 2019 Feb;78(2):179-185.
doi: 10.1136/annrheumdis-2017-212763. Epub 2018 Dec 1.

Effects of B-cell directed therapy on the preclinical stage of rheumatoid arthritis: the PRAIRI study

Danielle M Gerlag  1   2 , Mary Safy  1 , Karen I Maijer  1 , Man Wai Tang  1 , Sander W Tas  1 , Mirian J F Starmans-Kool  3 , Astrid van Tubergen  4 , Matthijs Janssen  5 , Maria de Hair  1 , Monika Hansson  6 , Niek de Vries  1 , Aeilko H Zwinderman, Paul P Tak  7
Affiliations
Randomized Controlled Trial

Effects of B-cell directed therapy on the preclinical stage of rheumatoid arthritis: the PRAIRI study

Danielle M Gerlag et al. Ann Rheum Dis. 2019 Feb.

Abstract

Objectives: We explored the effects of B-cell directed therapy in subjects at risk of developing autoantibodypositive rheumatoid arthritis (RA), who never experienced inflammatory arthritis before, and explored biomarkers predictive of arthritis development.

Methods: Individuals positive for both anti-citrullinated peptide antibodies and rheumatoid factor but without arthritis were included in a randomised, double-blind, placebo-controlled study to receive a single infusion of 1000 mg rituximab or placebo.

Results: Eighty-one individuals received treatment and were followed up for a mean of 29.0 (0-54) months, during which 30/81 (37%) individuals developed arthritis. The observed risk of developing arthritis in the placebo-treated group was 40%, which was decreased by 55% (HR 0.45, 95% CI 0.154 to 1.322) in the rituximab-treated group at 12 months. Rituximab treatment caused a delay in arthritis development of 12 months compared with placebo treatment at the point when 25% of the subjects had developed arthritis (p<0.0001). Erythrocyte sedimentation rate and the presence of anti-citrullinated α-enolase peptide 1 at baseline were significant predictors of arthritis development.

Conclusions: A single infusion of 1000 mg rituximab significantly delays the development of arthritis in subjects at risk of developing RA, providing evidence for the pathogenetic role of B cells in the earliest, prearthritis stage of autoantibody positive RA.

Keywords: cure; pre-rheumatoid arthritis; prevention; rheumatoid arthritis; rituximab.

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Conflict of interest statement

Competing interests: PPT is a former employee and DMG a current employee of GlaxoSmithKline, UK. GlaxoSmithKline was not involved in the design and/or execution of the study. NdV reports grants from AbbVie, Janssen Biologics, Ergomed Clinical Research, GlaxoSmithKline, Pfizer, Boehringer Ingelheim, and Roche, as well as personal fees from MSD, UCB, Janssen, non-financial support from Roche, personal fees and non-financial support from Pfizer, all outside the submitted work. In addition, NdV has a patent method for determining the risk of developing arthritis pending. MS reports a research grant from AstraZeneca (received in August 2015). AstraZeneca was not involved in this study.

Figures

Figure 1
Figure 1
Trial profile. CRP, C-reactive protein; RF, rheumatoid factor.
Figure 2
Figure 2
Kaplan-Meier survival plot for primary endpoint of arthritis development. Arthritis-free survival (%) depicted over time in months. At the 25th percentile, a difference of 12 months between the group receiving placebo (blue) versus rituximab (red) was observed (black horizontal line). The number of individuals at risk in each group at every follow-up time point is shown below the graph, follow-up was discontinued after development of arthritis.
Figure 3
Figure 3
(A–F) Changes of B-cell numbers and B-cell related biomarkers. Total number of B cells (Log10 109/L; A), serum IgA rheumatoid factor (RF) (Log kU/L; B), IgM-RF (Log kU/L; C), IgG-RF (Log kU/L; D); IgM (Log g/L; E), and anti-citrullinated cyclic peptide (CCP) test levels (Log kAU/L; F) from baseline to follow-up time points (days) measured in the individuals treated with placebo (red) and rituximab (green). The thin lines represent changes in the individuals and the thick lines represent the mean numbers/levels for each group. Vertical lines represent the 95% CIs. Statistically significant differences (shown p values) between the two treatment groups were found for all values depicted here, except for the serum IgG-RF and anti-CCP levels.
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