Is Newer Safer? Adverse Events Associated with First-Line Therapies for ANCA-Associated Vasculitis and Lupus Nephritis

Abstract

Clinical outcomes in ANCA-associated vasculitis (AAV) and lupus nephritis have improved greatly with treatment regimens containing high-dose glucocorticoids and cyclophosphamide. However, with the use of these medications come significant adverse events, most notably infections, cytopenias, malignancies, and reproductive abnormalities. Multiple recent randomized controlled trials in AAV and lupus nephritis have compared cyclophosphamide-based regimens with agents such as rituximab, mycophenolate mofetil, and azathioprine, with the hope of providing better clinical outcomes with improved safety profiles. Although some of these newer regimens are now considered first-line treatments of these diseases, their adverse event profiles have been disappointingly similar to those of cyclophosphamide-based protocols. Physicians and patients should consider the adverse event profiles generated by these trials in the context of their extensive use in other patient populations, as well as available measures to prevent such events, when choosing the ideal regimen for an individual patient.

Limitations of Standard Immunosuppressive Treatment in ANCA-Associated Vasculitis and Lupus Nephritis

“…A similarly high infection rate was also reported for patients with lupus (32-45% with corticosteroids combined with cyclophosphamide compared to 7-12% in patients treated with corticosteroids only [18]). Out of 1,000 European patients with SLE, infections occurred in 36% of them during 10-year follow-up.…”

“…Newer cyclophosphamide-free therapeutic regimens, e.g. rituximab, may not have a lower rate of adverse events [18], possibly because of still very common use of high-dose corticosteroids. In future studies greater attention will be paid to shortening corticosteroid exposure as is already the case in the PEXIVAS and RITAZAREM studies [19].…”

“…Overall risk of developing menopause with a single course of induction treatment of AAV or LN with cyclophosphamide is generally reported to be lower than 5%, but the cumulative rate of amenorrhea in patients treated with cyclophosphamide may be higher (15-27%) although amenorrhea may be only transient in some patients [18]. High risk of amenorrhea is associated with a cumulative dose of cyclophosphamide of about 20 g in the women aged 20-30 years, but the critical cumulative dose of cyclophosphamide may be as low as 5 g in the age group 40-50 years [35].…”

Outcomes of Elderly Patients with Anti-Neutrophil Cytoplasmic Autoantibody-Associated Vasculitis Treated with Immunosuppressive Therapy

“…Treatment with immunosuppressive therapy has improved outcomes in AAV [5], but it is recognised that current therapies are associated with significant risks of morbidity and mortality [4]. AAV in the elderly population is associated with a poor prognosis with higher rates of death and progression to end-stage renal disease (ESRD) compared to the younger AAV population [3,4,6].…”

“…Cyclophosphamide has remained a key component of most AAV treatment regimens for over 4 decades, usually in combination with glucocorticoids [5,6,8,9]. It is associated with dose-dependent toxicity resulting in leukopenia and increased susceptibility to infections [5,6,8,10].…”