Mycophenolate mofetil withdrawal in patients with systemic lupus erythematosus: a multicentre, open-label, randomised controlled trial

Abstract

Background: Mycophenolate mofetil is an immunosuppressant commonly used to treat systemic lupus erythematosus (SLE) and lupus nephritis. It is a known teratogen associated with significant toxicities, including an increased risk of infections and malignancies. Mycophenolate mofetil withdrawal is desirable once disease quiescence is reached, but the timing of when to do so and whether it provides a benefit has not been well-studied. We aimed to determine the effects of mycophenolate mofetil withdrawal on the risk of clinically significant disease reactivation in patients with quiescent SLE on long-term mycophenolate mofetil therapy.

Methods: This multicenter, open-label, randomised trial was conducted in 19 centres in the USA. Eligible patients were aged between 18 and 70 years old, met the American College of Rheumatology (ACR) 1997 SLE criteria, and had a clinical SLEDAI score of less than 4 at screening. Mycophenolate mofetil therapy was required to be stable or decreasing for 2 years or more if initiated for renal indications, or for 1 year or more for non-renal indications. Participants were randomly allocated in a 1:1 ratio to a withdrawal group, who tapered off mycophenolate mofetil over 12 weeks, or a maintenance group who maintained their baseline dose (1-3g per day) for 60 weeks. Adaptive random allocation ensured groups were balanced for study site, renal versus non-renal disease, and baseline mycophenolate mofetil dose (≥2 g per day vs <2 g per day). Clinically significant disease reactivation by week 60 following random allocation, requiring increased doses or new immunosuppressive therapy was the primary endpoint, in the modified intention-to-treat population (all randomly allocated participants who began study-provided mycophenolate mofetil). Non-inferiority was evaluated using an estimation-based approach. The trial was registered at ClinicalTrials.gov (NCT01946880) and is completed.

Findings: Between Nov 6, 2013, and April 27, 2018, 123 participants were screened, of whom 102 were randomly allocated to the maintenance group (n=50) or the withdrawal group (n=52). Of the 100 participants included in the modified intention-to-treat analysis (49 maintenance, 51 withdrawal), 84 (84%) were women, 16 (16%) were men, 40 (40%) were White, 41 (41%) were Black, and 76 (76%) had a history of lupus nephritis. The average age was 42 (SD 12·7). By week 60, nine (18%) of 51 participants in the withdrawal group had clinically significant disease reactivation, compared to five (10%) of 49 participants in the maintenance group. The risk of clinically significant disease reactivation was 11% (95% CI 5-24) in the maintenance group and 18% (10-32) in the withdrawal group. The estimated increase in the risk of clinically significant disease reactivation with mycophenolate mofetil withdrawal was 7% (one-sided upper 85% confidence limit 15%). Similar rates of adverse events were observed in the maintenance group (45 [90%] of 50 participants) and the withdrawal group (46 [88%] of 52 participants). Infections were more frequent in the mycophenolate mofetil maintenance group (32 [64%]) compared with the withdrawal group (24 [46%]).

Interpretations: Mycophenolate mofetil withdrawal is not significantly inferior to mycophenolate mofetil maintenance. Estimates for the rates of disease reactivation and increases in risk with withdrawal can assist clinicians in making informed decisions on withdrawing mycophenolate mofetil in patients with stable SLE.

Funding: The National Institute of Allergy and Infectious Diseases and the National Institute of Arthritis and Musculoskeletal and Skin Diseases.

Figure 1:

Trial Profile. One hundred twenty-three individuals initially consented to participate in the study, and 100 individuals were analyzed as part of the mITT population.

Figure 2:

Kaplan-Meier curves for disease flares in the mITT population (n=100 participants). The y-axis gives the probability of survival without reaching the endpoint. A: Kaplan-Meier curve of time to clinically significant disease reactivation (CSDR) by treatment allocation. B: Curve of time to any SELENA-SLEDAI flare by treatment allocation as measured by the SELENA-SLEDAI flare index. C: Curve of time to BILAG A flares by treatment allocation. D: Time to achieve a BILAG A or B flare by treatment allocation. Numbers indicate the number of patients who did not meet the endpoint while numbers in parenthesis indicate the number of censored patients.

Figure 3:

Risks of clinically significant disease reactivation (CSDR) and flare endpoints at week 60 with MMF withdrawal. A. Kaplan-Meier estimated risks at week 60 with 95% CI in the mITT population (n=100). B. Observed increase in risk with MMF withdrawal (black star) and one-sided, upper 75, 85, and 95% confidence limits (flat end of the arrow) in the mITT population. C. Kaplan-Meier estimated risks at week 60 with 95% CI in the subset with a history of renal disease (n=76). D. Observed increase in risk with MMF withdrawal (black star) and one-sided, upper 75, 85, and 95% confidence limits (flat end of the arrow) in the subset with a history of renal disease.