SUSTAINED IMPROVEMENT IN RHEUMATOID ARTHRITIS FOLLOWING B LYMPHOCYTE DEPLETION.
Jonathan C Edwards, Geraldine Cambridge, Maria J Leandro
Purpose: Work on B lymphocyte survival led to the hypothesis that rheumatoid arthritis (RA) is propagated by a vicious cycle in which autoreactive B lymphocytes (usually IgG rheumatoid factor (RF) committed) perpetuate their existence by generating their own antigen (IgG RF) in self-complexing form and by using surface RF to obtain non-specific T cell help. This hypothesis predicts that total/subtotal B lymphocyte depletion may induce long term remission as long as RF levels fall significantly before B lymphocytes return. Surprisingly, B lymphocyte depletion produces no clinically relevant immunosuppression and has proved safe in lymphoma. An open study of B lymphocyte depletion was undertaken in RA.
Methods: 5 patients with refractory erosive seropositive RA, mean duration 22 yrs, all functional grade III, having failed at least 5 disease modifying drugs (DMARDs), stopped all DMARDs and underwent a 3 week course of B lymphocyte depletion using monoclonal anti-CD20 antibody (rituximab 2.1gm), prednisolone (10 days 60mg then 12 days 30mg p.o.) and cyclophosphamide (750mg IV x 2). Mean follow up is 17 months.
Results: All patients achieved ACR50, and three ACR70 (pts 1,2,3), at 6 months. Patients 1,3,5 maintained/extended improvement at 1 year (ACR70,70,70) and show no sign of relapse. Patients 2 and 4 relapsed at 7 and at 9 months, but have also now achieved ACR70 after repeat B lymphocyte depletion with lower doses of anti-CD20. All DMARD were successfully withdrawn and none has been introduced. B lymphocyte counts remained low for several months after depletion. As predicted, relapses coincided with the return of B lymphocytes, and only in those cases where RF titres remained high. Adverse events were limited to respiratory tract episodes in 2 patients with histories of similar episodes, and mild thrombocytopenia down to 100,000 in 1.
Conclusions: These findings suggest that B lymphocyte depletion may be safe and cost-effective therapy for refractory RA. Statistical analysis indicates that a minimum of 48% (binomial, Documenta Geigy, 55% by direct binomial) of further similar patients treated in the same way can be expected, with 95% confidence, to achieve at least ACR50, and ACR70 if retreatment is included. Retreatment does not appear to pose problems. More recent treatments in 10 further patients have been followed by similar early responses and indicate that cyclophosphamide increases the speed of remission and the response rate but is not essential for major improvement and conversion to seronegativity. A formal controlled trial will follow.
Disclosure: Setting up the work described was assisted by a grant in aid from Hoffman la Roche equivalent to 30% of drug costs (£7,000 sterling). A further contractual arrangement has been set up to advise Hoffman la Roche on further work in return for £43,000... |
