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

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.

Informations de copyright

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Déclaration de conflit d'intérêts

Declaration of interests AS received consulting fees from AstraZeneca, AbbVie, GSK, Kezar Life Sciences, Eli Lilly, Bristol Myers Squibb and lecture fees from Astra Zeneca, Rheumatologic Dermatology Society, and Lupus Therapeutics. GC was a member of independent data monitoring boards of clinical trials by Roche and VERA therapeutics. BHR received consulting payments from Roche/Genentech, Aurinia, Novartis, Alexion, GSK, Kyverna, Kezar, HI-Bio, and Tome and served on the Board of Directors for NephroNet and the Scientific or Medical Advisory Board for the Lupus Foundation of America and Lupus Accelerating Breakthroughs Consortium/Lupus Research Alliance. RJL received support for the present manuscript as part of the Autoimmunity Centers of Excellence grant. DE received grants or contracts from the American College of Rheumatology and European Alliance of Associations for Rheumatology, NIH, GSK, and Exagen; royalties or licenses from UptoDate; consulting fees from Chugai, AbbVie, and Argenx; and lecture fees from GSK and Aurinia. JM is an employee of DAIT/NIAID, the sponsor and funding agency of this trial. CA received a grant or contract from GSK; consulting fees from GSK, AstraZeneca, Bristol Myers Squibb, and AbbVie; and served on a data safety monitoring or advisory board for Alumis. LKE serves as a consultant for Rho Federal Division. All other authors declare no competing interests.