B-lymphocyte depletion with rituximab (Rituxan®, Genentech/Biogen Idec) produces improvements lasting for an average of 15 months in patients with otherwise refractory rheumatoid arthritis (RA) and can be repeated for 5 cycles without losing efficacy or causing major adverse effects, C. Popa et al report in Rheumatology.1 This "real world" use of rituximab provides reassuring data regarding the possibility for repeated use of the drug but also raises concerns about development of lower respiratory problems in some patients and about cumulative effects on immunoglobulin levels in a subgroup of patients.
In an accompanying editorial, Thomas Dörner, MD, and Gerd R. Burmester, MD, comment, "Although reoccurring B cells apparently do not necessarily indicate relapse of RA, Popa et al nicely demonstrate...that relapse did not occur without peripheral B cell. ...[T]he dogma ‘no B cells—no RA relapse' was confirmed by re-treatment analyses."2
The investigators, led by Jonathan C. W. Edwards, MD, at University College London's Centre for Rheumatology, in the UK, present data on 37 patients with refractory RA, 22 of whom were followed for more than 5 years of repeated rituximab treatment, and 14 of whom were observed for 3 to 5 years. Patients received up to 5 cycles of rituximab over the period of this open-label study.
All of the patients had moderate-to-severe RA that was not adequately controlled by, intolerant of, or unsuitable for methotrexate, intramuscular gold, leflunomide, and TNF inhibitors. Additionally, patients had a variety of comorbid conditions.
The decision to repeat treatment was based on clinical judgment and the patients' assessments of benefits and risks and their meeting four criteria: reappearance of peripheral B cells, return of RA symptoms, rise in C-reactive protein (CRP) following at least a 50% decrease during the previous course of rituximab, and adequate levels of circulating immunoglobulin G.
At the time of the December 2005 analysis, total follow-up was 180 patient-years, one patient had declined follow-up, and four had intermittent follow-up, but their current status was known. Two patients had received 5 cycles of rituximab, five had received 4 cycles, eight had received 3 cycles, 13 had received 2 cycles, and nine had received only 1 cycle.
Still not clear how to decide when to re-treat
Popa et al used CRP as a marker of improvement. They found that the level of CRP decrease was sustained throughout repeated courses of treatment, which alleviated concerns about decreasing efficacy with repeated use.
The average duration of benefit after each cycle was 15 months, but the range was 5 to 43 months. The average time to re-treatment was 20 months (range 5-60 months), "reflecting the logistics of planning and executing re-treatment and in 2 cases temporary retrial of standard agents," the authors write.
Drs. Dörner and Burmester add, "[O]ne patient even had a response for up to 43 months after a single cycle of rituximab, indicating that the time of response varies and precludes regular re-treatment as we practice with TNF blockers and other small molecule DMARDs." They recommend combining clinical judgment with Disease Activity Score (DAS28) parameters in deciding when to repeat rituximab in a patient who has had a good response to a previous cycle.
Nineteen patients remain on the treatment program, including 10 of the 22 who have reached 5 years of follow-up. Five patients were withdrawn due to lack of efficacy, including all four who were rheumatoid factor negative (RF-). The authors comment that it seems likely in retrospect that these four patients should have been classified as "rheumatoid-type" psoriatic arthropathy and that "neither psoriasis nor associated arthropathy is likely to respond to B-lymphocyte depletion."
Of 16 lower respiratory episodes in 10 patients, 12 were considered to be infective. The other four events occurred within 5 days of the second infusion, and the researchers suspect these events had a hypersensitivity component.
Immunoglobulin levels remained normal in most patients even after 5 cycles of treatment, confirming that repeated use of rituximab can be undertaken without jeopardizing protective immunity in most RA patients. However, of all classes of immunoglobulins (IgM, IgG, IgA), IgM fell progressively in 12 patients and below detectable levels in three patients after repeat cycles; IgG levels fell to below normal in seven patients, and IgA levels fell to below normal in one. The low IgG levels were not associated with infections or adverse clinical events except for exacerbation of cough and sputum production in one patient who had bronchiectasis.
"Two caveats remain: a suggestion that lower respiratory tract problems may be more common and evidence for cumulative effects on total immunoglobulin levels, in particular IgM, following repeated cycles. The issue of lower respiratory tract problems requires continued surveillance," the authors write.
The decision of when to repeat B-cell depletion in patients remains a difficult one, in view of the wide range of response duration. "The possibility of antibody profiling over time has not been explored in re-treatment studies but would be of utmost interest for daily practice because of its feasibility," Drs. Dörner and Burmester suggest. "Overall," they conclude, "the first fully published study on repeated treatment cycles with rituximab in RA patients reports robust and comparable efficacy in subsequent treatments but also points our interest toward the needs for biomarkers (B-cell subsets, autoantibody profile, Ig levels, etc) that allow improved patient-tailored therapy."
References
1. Popa C, Leandro MJ, Cambridge G, Edwards JCW. Repeated B lymphocyte depletion with rituximab in rheumatoid arthritis over 7 yrs. Rheumatology. 2007;46:626-630.
2. Dörner T, Burmester GR. No B cells—no active RA? Advances in B cell depletion in RA—repeated therapy under conditions of clinical practice. Rheumatology. 2007;46:563-564.
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