Mycophenolate Mofetil Versus Cyclophosphamide for the Induction of Remission in Nonlife-Threatening Relapses of Antineutrophil Cytoplasmic Antibody-Associated Vasculitis: Randomized, Controlled Trial

Abstract

Background and objectives: Cyclophosphamide has been the mainstay of treatment of ANCA-associated vasculitis. However, cyclophosphamide has unfavorable side effects and alternatives are needed. Evidence suggests that mycophenolate mofetil can induce sustained remission in nonlife-threatening disease. The purpose of this study was to compare the efficacy and safety of mycophenolate mofetil versus cyclophosphamide for the induction treatment of nonlife-threatening relapses of proteinase 3-ANCA- and myeloperoxidase-ANCA-associated vasculitis.

Design, setting, participants, & measurements: We conducted a multicenter randomized, controlled trial. Participants with a first or second relapse of ANCA-associated vasculitis were randomized to induction treatment with cyclophosphamide or mycophenolate mofetil both in combination with glucocorticoids. Maintenance therapy consisted of azathioprine in both arms. Primary outcome was remission at 6 months, and secondary outcomes included disease-free survival at 2 and 4 years.

Results: Eighty-four participants were enrolled, of whom 41 received mycophenolate mofetil and 43 received cyclophosphamide. Eighty-nine percent of participants were proteinase 3-ANCA positive. At 6 months, 27 (66%) mycophenolate mofetil-treated participants versus 35 (81%) cyclophosphamide-treated participants were in remission (P=0.11). Disease-free survival rates at 2 and 4 years were 61% and 39% for cyclophosphamide, respectively, and 43% and 32% for mycophenolate mofetil, respectively (at 4 years, log rank test, P=0.17).

Conclusions: We did not demonstrate mycophenolate mofetil to be similarly effective as cyclophosphamide in inducing remission of relapsed ANCA-associated vasculitis. However, mycophenolate mofetil might be an alternative to cyclophosphamide for the treatment of selected patients with nonlife-threatening relapses.

Keywords: ANCA; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies; Antineutrophil Cytoplasmic; Mycophenolic Acid; Recurrence; Remission Induction; cyclophosphamide; mycophenolate mofetil; randomized controlled trials; relapse; vasculitis.

Graphical abstract

Figure 1.

Flowchart of randomized and analyzed participants. CYC, cyclophosphamide; MMF, mycophenolate mofetil; SAE, serious adverse event.

Figure 2.

Secondary outcome: disease-free survival among patients who attained remission at 6 months did not differ between CYC and MMF treated patients. CYC, cyclophosphamide; MMF, mycophenolate mofetil.

Figure 3.

Time to stable remission according to treatment allocation did not differ between cyclophosphamide and MMF treated patients. CYC, cyclophosphamide; MMF, mycophenolate mofetil.

Figure 4.

At 6 months remission rate in the highest BVAS tertile was higher in the cyclophosphamide than MMF arm. This was an exploratory subgroup analysis. Hazard ratio (HR) reflects time to treatment failure. Birmingham Vasculitis Activity Score (BVAS) tertile 1: BVAS<14; BVAS tertile 2: BVAS=14–19; and BVAS tertile 3: BVAS>19. 95% CI, 95% confidence interval; CYC, cyclophosphamide; MMF, mycophenolate mofetil.

Figure 5.

Course of eGFR of participants with kidney involvement during follow-up did not differ between CYC and MMF arms. The lines represent the mean eGFR using the Chronic Kidney Disease Epidemiology Collaboration equation during follow-up. Whiskers represent one SD above and below the mean. CYC, cyclophosphamide; MMF, mycophenolate mofetil.