B Cell-Directed Therapy May Delay RA Development in High-Risk Patients

A single infusion of 1,000 mg of rituximab may significantly delay the onset of clinical signs and symptoms of arthritis in subjects at high risk of developing seropositive rheumatoid arthritis (RA), according to the exploratory, randomized, double-blind, placebo-controlled PRAIRI (prevention of clinically manifest rheumatoid arthritis by B cell directed therapy in the earliest phase of the disease) study.¹ The results were published in the February 2019 issue of Annals of the Rheumatic Diseases, and the initial presentation of the abstract was made during the 2016 ACR/ARHP Annual Meeting.²

“We have created the first experimental evidence in humans that B cells play a critical role in the pathogenesis of RA during the preclinical stage of the disease,” says the study’s lead author Paul Peter Tak, MD, PhD, FMedSci, professor of medicine in the Division of Clinical Immunology and Rheumatology at the Academic Medical Center of the University of Amsterdam, The Netherlands.

“These findings also support future studies aimed at secondary prevention of RA, including by the use of targeted treatments,” Dr. Tak says.³

Previous research identified rheumatoid factor (RF) and anti-citrullinated peptide antibodies (ACPAs) in the peripheral blood of individuals less than 10 years before they develop autoantibody positive RA.^4,5 B cells are known to be efficient antigen-presenting cells that produce autoantibodies and may activate T cells in the context of co-stimulatory signals, producing a variety of cytokines.⁶

A New Target for Early RA
The PRAIRI study explored biomarkers predictive of arthritis development and investigated the effects of B cell-directed therapy in subjects at risk of developing autoantibody positive RA who had not experienced inflammatory arthritis.

The findings are based on results from 81 subjects with arthralgia and without evidence of clinical arthritis in 66 joints examined. These patients were recruited from seven rheumatology outpatient clinics across The Netherlands between January 2010 and December 2013. The patients tested positive for IgM-RF, as well as ACPA (a-CCP2; Immunoscan CCPlus [Euro Diagnostica No RA-96plus] ELISA tests), and had never experienced inflammatory arthritis or been treated with a disease-modifying anti-rheumatic drug (DMARD). The subjects all had C-reactive protein (CRP) levels greater than 0.6 mg/L at screening (the lower limit of detection of the high-sensitivity CRP assay) or subclinical synovitis, as determined by ultrasound or MRI using gadolinium performed in the context of routine clinical care.

The subjects were randomized in a 1:1 ratio to receive either 1,000 mg of rituximab or placebo intravenously. Patients also received 100 mg methylprednisolone prior to treatment to prevent infusion-related adverse events. Randomization was stratified by age (older or younger than 40 years), as well as sex.

The primary outcome of the study was time to development of clinical arthritis in subjects in both treatment groups. Clinical arthritis was defined as swollen and tender joints observed by two independent, blinded investigators.

Researchers found that, compared with placebo, a single infusion of rituximab reduced the baseline risk of arthritis development by 55% at 12 months (hazard ratio [HR] 0.45, 95% confidence interval [CI] 0.15 to 1.32; P=0.15) and 53% at 18 months (HR 0.48, 95% CI 0.19 to 1.19). In total, 30 participants developed arthritis. At the point in the study when 25% of subjects had developed arthritis, rituximab treatment caused a delay in arthritis development of 12 months compared with placebo.

Research Implications
Based on the inclusion criteria, Dr. Tak says they are able to identify about 40% of individuals at risk of developing seropositive RA.

“We hypothesize this prediction model can be improved by including body mass index, smoking history, vagus nerve tone and, possibly, such biomarkers as anti-citrullinated alpha-enolase peptide 1 levels,” Dr. Tak says. “Our work also generates new hypotheses about the possible benefit of repeated treatment with a single infusion of rituximab once a year or specific targeting of autoreactive B cells during the preclinical stage of the disease.”

For research application, Dr. Tak believes he and his team are “clearly capable of identifying individuals when they are at risk of developing seropositive RA, but before the onset of arthritis.”

He says this work paves the way for further experimental studies during the “preventive window of opportunity” to optimize prediction models and preventative interventions.

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Carina Stanton is a freelance science journalist based in Denver.

References

1. Gerlag DM, Safy M, Maijer KI, et al. Effects of B-cell directed therapy on the preclinical stage of rheumatoid arthritis: The PRAIRI study. Ann Rheum Dis. 2019 Feb;78(2):179–185.
2. Gerlag DM, Safy M, Maijer KI, et al. A single infusion of rituximab delays the onset of arthritis in subjects at high risk of developing RA [abstract]. Arthritis Rheumatol. 2016 Oct; 68(suppl 10).
3. Gerlag DM, Norris JM, Tak PP. Towards prevention of autoantibody-positive rheumatoid arthritis: From lifestyle modification to preventive treatment. Rheumatology (Oxford). 2016 Apr;55(4):607–614.
4. Aho K, Palosuo T, Raunio V, Puska P, Aromaa A, Salonen JT. When does rheumatoid disease start? Arthritis Rheum.1985 May;28(5):485–489.
5. Rantapää-Dahlqvist S, de Jong BA, Berglin E, et al. Antibodies against cyclic citrullinated peptide and IgA rheumatoid factor predict the development of rheumatoid arthritis. Arthritis Rheum. 2003 Oct;48(10):2741–2749.
6. Doerner T, Kinnman N, Tak PP. Targeting B cells in immune-mediated inflammatory disease: a comprehensive review of mechanisms of action and identification of biomarkers. Pharmacol Ther. 2010 Mar;125(3):464–475.