By Martina M. McGrath, MD
March 2, 2017
Publication of the RAVE and Rituxivas trials ushered in a new era of treatment of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Previously, cyclophosphamide was first-line therapy, but treatment was commonly complicated by infection and malignancy, leading to the search for less toxic alternative regimens. RAVE and Rituxivas demonstrated equivalent efficacy in treatment of AAV with either cyclophosphamide or rituximab, with similar numbers of adverse events.1,2 Unexpectedly, more malignancies were observed in rituximab-treated patients in both studies. However, absolute numbers were small, and the significance of this finding was unclear. Follow-up data and clinical experience would suggest that rituximab is well tolerated for treatment of AAV, including when used as maintenance therapy.3,4
Looking further into the risk of malignancy, a research group from Cambridge, UK, recently published their single center experience in follow-up of 323 AAV patients, followed between 2000 and 2014 and treated with either cyclophosphamide or rituximab.5 Mean follow-up was relatively short at 5.6 years, but 45 malignancies occurred in 33 patients. The most common malignancy was nonmelanoma skin cancer (squamous cell carcinoma and basal cell carcinoma), with a 4.58-fold increased incidence in cyclophosphamide-treated patients as compared to those treated with rituximab. In general, cyclophosphamide-treated patients had 4.61-fold increased malignancy risk compared to the rituximab-treated patients, and a standardized incidence ratio of 3.10 compared to the general population5. The majority of this increased risk was attributable to increased incidence of nonmelanoma skin cancers, with a nonsignificant increase in risk of other cancers. Interestingly, patients treated with rituximab had similar risk of malignancy to the general population. Historically, use of cyclophosphamide has been associated with increased risk of hematological malignancies and bladder cancer. This was not observed in this study, possibly due to lower cumulative cyclophosphamide doses being used in recent years, relatively short follow-up, or simply a lack of power to detect this effect.
The findings of this study are consistent with several others published recently, showing an overall increase in skin cancer rates in patients with AAV. The findings are somewhat reassuring, demonstrating that, at least for medium-term follow-up, risks of more serious malignancies are not substantially elevated with either treatment regimen. However, this study adds to the growing body of evidence indicating that rituximab is a safe, effective, and well-tolerated agent in the treatment of AAV and may be preferable to cyclophosphamide for many patients.
- 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, Tervaert JW, Hauser T, et al. Rituximab versus cyclophosphamide in ANCA-associated renal vasculitis. N Engl J Med 2010;363:211-20.
- Guillevin L, Pagnoux C, Karras A, et al. Rituximab versus azathioprine for maintenance in ANCA-associated vasculitis. N Engl J Med 2014;371:1771-80.
- Pendergraft WF, 3rd, Cortazar FB, Wenger J, et al. Long-term maintenance therapy using rituximab-induced continuous B-cell depletion in patients with ANCA vasculitis. Clinical Journal of the American Society of Nephrology : CJASN 2014;9:736-44.
- van Daalen EE, Rizzo R, Kronbichler A, et al. Effect of rituximab on malignancy risk in patients with ANCA-associated vasculitis. Annals of the Rheumatic Diseases 2016.
Dr. Martina McGrath is an Instructor in Medicine at Harvard Medical School, and a member of the Renal Division, Department of Medicine, at Brigham and Women’s Hospital, both in Boston. Dr. McGrath is the Medical Editor for the Trends in Medicine blog.