Target Audience and Goal Statement:Rheumatologists, immunologists, hematologists, and emergency department physicians
The goal is to understand the effects of B-cell directed therapy in subjects at risk of developing autoantibody-positive rheumatoid arthritis (RA), who never experienced inflammatory arthritis before, and to explore biomarkers predictive of arthritis development.
Background
RA is a chronic inflammatory condition, affecting the small joints of the hands and feet. The annual
prevalence of RA has been estimated to be about 1% in Caucasians, and to vary between 0.1% (in rural Africans) and 5% (in Pima, Blackfeet, and Chippewa Indians). Worldwide
estimates were expected to increase by ∼22% during 2005 and 2025 due to the aging population.
Unlike the wear-and-tear damage of osteoarthritis, this autoimmune condition affects the lining of the joints, resulting in swelling and pain. Unabated inflammation without infection or injury leads to a disease process and, in some cases, joint damage.
Classically, the
natural history of the disease has been divided into four stages:
- Stage 1: Early RA involves symptoms such as joint pain, swelling, and stiffness. This is indicative of inflammation in the joint capsule and swelling of the synovial tissue. This stage has traditionally been regarded as difficult to diagnose, as the signs and symptoms mimic those of other diseases. Early and aggressive treatment has been shown to greatly improve outcomes, confirming the existence of a “therapeutic window of opportunity.”
- Stage 2: Once inflammation of the synovial tissue intensifies, resulting in cartilage damage, it is referred to as moderate RA.
- Stage 3: Joint cartilage and bone deterioration during severe RA symptoms include possible physical deformities of the joint, increased pain and swelling, and less mobility and muscle strength.
- Stage 4: Once joints stop functioning – usually reflecting the culmination of the inflammatory process – the patients are said to be in the end stage of RA. Primary symptoms are still pain, swelling, stiffness, and loss of mobility.
Because the initial standard of care and conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) can only manage symptoms and do not represent a cure, the clinical impetus in recent years has been to diagnose and treat the disease as early as possible.
Van Steenburgen and colleagues have suggested that the European League Against Rheumatism (EULAR) terminology for preclinical RA phases would serve as a reasonable starting point for use in clinical trials focused on this asymptomatic stage, in their 2018 paper that appeared in
Nature Reviews Rheumatology. In a 2016 article published in
Rheumatology, Gerlag and colleagues outlined their definition of preclinical stage RA; subjects with autoantibodies and arthralgia have a 40%-70% chance of developing RA within 4 years. Taken together with other RA-related autoantibodies against post-translationally modified proteins (such as those against carbamylated proteins), these biomarkers may be predictive of patients at high risk for developing RA. Furthermore, studies suggest that tissues other than the joints may be early sites for RA-related autoimmunity.
Questions Addressed By This Study
Can the disease be prevented in patients at high risk for this condition by blocking autoantibodies known to trigger the subclinical synovitis that could progress to RA? Simply put, does a window of opportunity exist to treat the disease and forestall its debilitating symptomatic consequences? That was the underlying
impetus for this exploratory, randomized, double-blind, placebo-controlled study.
While different cells participate in the pathogenesis of RA, B cells are known to be producers of diagnostic autoantibodies, including rheumatoid factor (RF) and anti-citrullinated peptide antibodies (ACPAs). Additional roles for
B cells include antigen presentation, cytokine secretion, and organization of other cells such as T cells. Interestingly, RF and ACPAs are present in the peripheral blood of individuals >10 years before the clinical manifestation of RA. This creates the opportunity for a targeted intervention during the asymptomatic phase of the disease to potentially delay the development of autoantibody-positive RA.
Rituximab is a cytolytic antibody directed against the CD20 antigen on B cells that already received
FDA approval for treatment of several diseases, including, as part of a combination regimen for select adult patients with moderately-to severely-active RA.
Earlier research has suggested that B cell directed therapy may offer a means of delaying the onset of clinical RA in adults. Therefore, researchers investigated the effects of this strategy in asymptomatic patients at risk for developing seropositive RA and they also explored biomarkers predictive of RA development.
Tak and co-authors explained that because B cells have been implicated in the pathogenesis of RA through mechanisms including antigen presentation and T cell activation, and the depletion of these cells with rituximab has demonstrated efficacy in patients with established disease, the team undertook a phase IIb randomized trial to explore the possibility of altering the course of disease through B cell depletion before clinical RA develops.
Study Synopsis and Perspective
The Prevention of RA by Rituximab (PRAIRI) study ran at seven Dutch centers during 2010 and 2013. The team enrolled 81 eligible patients who had arthralgia and were positive for IgM-RF and ACPA and had C-reactive protein (CRP) levels above 0.6 mg/L or subclinical synovitis detected on imaging, and randomized the participants to a single intravenous infusion of 1,000 mg of rituximab or placebo.
The majority of patients in the study were women, and mean age was 53. Baseline CRP concentration was 3 mg/L and erythrocyte sedimentation rate (ESR) was 10 mm/h.
Overall, treatment responses were determined using Kaplan-Meier survival curves to determine the times until 25% of the patients developed RA. During a median follow-up at 29 months, 40% of patients in the placebo group developed RA, at a median time of 11.5 months. In the rituximab group, 34% of patients developed RA after a median time of 16.5 months.
Among individuals who were seropositive, but had no evidence of rheumatoid arthritis (RA) at baseline and were given a single infusion of rituximab (Rituxan or MabThera) or placebo, rituximab treatment caused a delay in arthritis development of 12 months compared with placebo at the point when 25% of the subjects had developed arthritis (P<0.0001), according to Paul P. Tak, MD, PhD, of the Academic Medical Center in Amsterdam, and colleagues.
And, while the risk of developing arthritis with rituximab decreased by 55% at 12 months, this was not statistically significant (HR 0.45, 95% CI 0.15-1.32, P=0.15), the researchers reported online.
The researchers also conducted an exploratory analysis of biomarkers, and found associations with RA for baseline ESR (HR 1.03, 95% CI 1.01-1.06, P=0.016) and anti-citrullinated α-enolase peptide 1 (HR 3.71, 95% CI 1.51-9.18, P=0.01). Within 4 weeks of treatment, there was “a clear and highly significant” decline in B-cell numbers, followed by a decrease in levels of IgA-RF, IgM-RF, IgG-RF, and ACPA.
Study treatment was generally well-tolerated with only mild infusion-related symptoms and no serious infections. Observed serious adverse events were unrelated to treatment, according to the researchers.
A limitation of the study, they said, was the small sample size.
Source Reference:
Study Highlights: Explanation of Findings
Compared with placebo, this interventional, proof-of-concept study shows that a solo rituximab infusion is well-tolerated and leads to a 12-month delay in the occurrence of clinical arthritis at the time interval when 25% of the study subjects had developed arthritis. In keeping with earlier reports, the background risk of developing arthritis was 40% and this decreased by 55% at 12 months follow-up after treatment.
An approach gaining favor among rheumatologists is to provide treatment sooner rather than later to increase the chances of better radiographic outcomes and long-term remission – also known as the “therapeutic window of opportunity.” This exploratory study shows that patients at-risk for RA can now be identified before the onset of symptoms, thus opening up the possibility of investigating a “preventive window of opportunity.”
The observation that the single rituximab infusion did not fully prevent RA onset and merely delayed it may have resulted from the persistence of some B cells in tissues and subsequent repopulation. “It is tempting to speculate that repeated treatment, perhaps with a single infusion of rituximab once a year, might be sufficient to control B cell numbers and prevent clinically manifest disease in a population at high risk of developing RA,” the researchers said.
Additional approaches could include targeting the subpopulation of specific autoreactive B cells and proinflammatory innate immune cells.
“The results presented here are clearly consistent with the critical role of B cells in the pathogenesis of RA during the earliest stages of the disease and support future studies aimed at secondary prevention of RA, including by the use of targeted treatments,” the investigators concluded.
Nancy Walsh wrote the original story for MedPage Today.
Primary Source
Annals of the Rheumatic Diseases
