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

Abstract

ObjectivesWe 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.MethodsIndividuals 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.ResultsEighty-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.ConclusionsA 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.

Population-based estimates of humoral autoimmunity from the U.S. National Health and Nutrition Examination Surveys, 1960–2014

“…Although a fraction of mild cases might never progress, clinical and public health surveillance of the full spectrum of AID disease is essential, because a significant fraction of patients progress from preclinical illness (positive autoantibodies or biomarkers only) to subclinical illness (few or no clinical symptoms but positive autoantibody, laboratory, and/or imaging studies) to overt, classically active disease [28,29]. Individuals with preclinical, autoantibody-positive disease have been shown recently to be at high risk of developing AID such as family members of AID cases, [30], and clinical prevention trials in rheumatoid arthritis and autoimmune diabetes are currently addressing this concern [31][32][33][34][35]. Most cases of subclinical AID and many cases of mild AID are not currently detected; in the general population, the number of persons at risk of AID and those with undiagnosed AID may be large.…”

The road to rheumatoid arthritis prevention: challenges and opportunities

“…Beyond the question of acceptable risk, as Alpziar-Rodriguez D. and Finckh A. note, the results of RA prevention trials thus far have been relatively disappointing. Several RA prevention studies did demonstrate the ability of pharmacotherapy to delay onset of disease, including: the PROMPT study [4] among the ACPA-positive subset of patients treated with low-dose methotrexate for early undifferentiated arthritis, the ADJUST trial [5] using abatacept in ACPA-positive patients with undifferentiated arthritis plus symptomatic clinical synovitis of at least 2 joints, and the PRAIRI study [6] using rituximab in double-positive (IgM-RF and ACPA) patients with arthralgias plus at least one of the following: CRP >0.6 mg/L at screening or subclinical synovitis on ultrasound or MRI. Nevertheless, the fact remains that no pre-clinical RA trial to date has been able to prevent the development of RA in a population of patients.…”

How Are Rheumatologists Managing Anticyclic Citrullinated Peptide Antibodies–positive Patients Who Do Not Have Arthritis?

“…There is no evidence for the management of these (often symptomatic) at-risk individuals, but it is possible that the right intervention in this phase may prevent clinical arthritis 5,6 . This hypothesis is being explored in clinical trials (e.g., rituximab delayed, but did not prevent, arthritis onset in at-risk individuals) 7 . We were interested in how such at-risk individuals are managed by UK rheumatologists in the absence of guidelines.…”