Rituximab as Effective as Cyclophosphamide

The New England Journal of Medicine recently published two international multicentre trials examining the role of rituximab in the initial treatment of ANCA associated vasculitides such as Wegener’s granulomatosis and microscopic polyangiitis.

Rituximab is a monoclonal antibody that has been used in the treatment of a type of gland cancer called lymphoma for many years. It is specifically directed against cells in the immune system called B cells that can produce antibodies. Anti-neutrophil cytoplasmic antibodies (ANCA) are characteristically found in the serum of patients with Wegener’s granulomatosis and microscopic polyangiitis. Depleting B cells that produce ANCA would be a rationale approach to treating these conditions, given that it is likely that ANCA are involved in the development of these diseases.

Cyclophosphamide, a chemotherapy agent , has been the ‘gold standard’ for the treatment of systemic vasculitis since the 1970s. Although it is very effective at inducing disease remission, it is also very toxic with numerous side-effects including infections, cancer and infertility. Two large controlled trials (with the acronyms RAVE and RITUXVAS) investigated whether rituximab was as effective as cyclophosphamide followed by azathioprine in the treatment of severe vasculitis but without the toxicity associated with cyclophosphamide. Patients enrolled into the studies had active vasculitis and were randomized to receive either rituximab weekly for four weeks or cyclophosphamide for three to six months followed by azathioprine. All patients received treatment with high doses of corticosteroids with doses being reduced during the trials. The outcome of the studies was disease remission.

The results were similar in both trials and showed that rituximab was as effective at inducing disease remission as cyclophosphamide.  However, the promise of fewer side-effects in the rituximab treated patients was not achieved – in both trials the rate of side-effects especially from infections was similar. The reasons for the high rate of side effects are not clear but may have been related to the older age of the patients, the severity of their disease, previous exposure to immunosuppressive treatments and the high doses of corticosteroids used. Steroids are associated with many side-effects including the risk of infections.

In both trials, a small proportion of patients failed to achieve the pre-specified end-point of remission and were deemed to be treatment failures whether they received rituximab or cyclophosphamide. Furthermore, there were a few patients in both trials who went on to have disease flares despite initially responding to treatment.

These two large pivotal trials represent a significant advance in the treatment of ANCA associated vasculitides and raise the prospect of reducing or even eliminating the need to use cyclophosphamide in the initial treatment of these serious diseases. However, the high rate of adverse effects in both studies, even in the rituximab treated patients, and the reasons why some patients fail to respond to treatment will need to be addressed before this approach becomes the standard of care.

References:

Stone JH, Merkel PA, Spiera R, et al. Rituximab versus cyclophosphamide for ANCA-associated vasculitis. N Engl J Med 2010;363:221-32.

Jones RB, Cohen Tervaert JW, Hauser T, et al. Rituximab versus cyclophosphamide in ANCA-associated renal vasculitis. N Engl J Med 2010;363:211-20.