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This study appears to confirm the role of B cells in the early pathogenesis of RA and sheds light on an avenue for further investigation.
Gerlag and fellow researchers1 in the Netherlands have discovered that by targeting B cells with rituximab in patients at increased risk for rheumatoid arthritis (RA) later in life, the signs and symptoms of arthritis can be delayed.
B cells and RA
Antibody-positive RA is often preceded by a phase of systemic autoimmunity characterized by circulating autoantibodies, acute-phase reactants, pro-inflammatory cytokines, and chemokines. IgM rheumatoid factor (IgM-RF), anti-citrullinated peptide antibodies (ACPA), and other RA-specific antibodies can be detected in blood samples of patients who later receive a diagnosis of seropositive RA, with a median of 5 years before arthritis becomes evident.
It is clear that B cells play an important role leading up to clinical RA. The authors sought to determine whether B-cell depletion could alter the development of RA in persons at high risk as well as to identify biomarkers predictive of arthritis development.
The authors conducted the Prevention of Clinically Manifest Rheumatoid Arthritis by B-Cell Directed Therapy In the Earliest Phase of Disease Study (PRAIRI), a phase IIb, randomized, double-blind, placebo-controlled investigation that looked at 82 patients with arthralgia but no evidence of clinical arthritis. Subjects were randomized to receive either rituximab 1000 mg once or placebo.
The participants were adults without inflammatory arthritis or previous antirheumatic drug use who had baseline C-reactive protein levels higher than 0.6 mg/L or subclinical synovitis. They were monitored for clinical arthritis thereafter.
Next: the results and take-home points for clinicians
After 81 subjects were treated (41 received rituximab and 40 placebo), follow-up of a median of 29 months was available (interquartile range, 14–40; range, 0–54 months; one subject developed arthritis 3 weeks after treatment).
The risk of development of arthritis over the total follow-up time in the placebo group was 40%. Treatment with infusion of rituximab reduced the baseline risk of arthritis development by 55% at 12 months and 53% at 18 months. The treatment led to a delay of arthritis development of 12.0 months at the point at which 25% of the subjects in both treatment groups developed arthritis.
The risk of arthritis development over the total follow-up time after a single infusion was not statistically significant (P = .448) between the two groups. Only the erythrocyte sedimentation rate and the presence of anti-citrullinated Î±-enolase peptide 1 in the serum at baseline were positively correlated with the development of arthritis. A clear and highly significant decrease in the total number of B cells was observed within 4 weeks after treatment in the subjects receiving rituximab (P < .0001).
• Rituximab is well tolerated and may delay clinical symptoms of RA by as much as a year in patients with arthralgia who are at risk for developing RA in the future.
• Early initiation of treatment in RA may lead to less pain and morbidity, but for now B-cell directed therapy only seems to delay the disease.
• These results appear to confirm the role of B cells in the early pathogenesis of RA.
Next: final thoughts
• While these results ultimately have few clinical implications, this study sheds light on an avenue for further investigation.
• The holy grail of medical therapeutics in general is prevention of disease; much like a vaccine is to smallpox, a silver bullet that can halt RA before it begins would be the end game.
• Directed preclinical therapy that possibly targets B cells clearly delays clinical RA, and future study may focus on continued therapy rather than on a single dose of rituximab.
• As with the vast majority of scientific investigations, turning over one stone most often results in discovering more stones to turn.
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. 2018 Dec 1. pii: annrheumdis-2017-212763. doi:10.1136/annrheumdis-2017-212763. [Epub ahead of print]