MMF forever? Stopping appears safe for some with lupus



Patients with quiescent systemic lupus erythematosus who are taking mycophenolate mofetil (MMF) need not continue this therapy forever, a multicenter, phase 2, randomized, controlled trial suggests.

“Long-term use of MMF is associated with adverse events, pregnancy risks, drug monitoring, and increased cost,” noted the investigators, who were led by Eliza Chakravarty, MD, an associate member of the Arthritis & Clinical Immunology Research Program at the Oklahoma Medical Research Foundation in Oklahoma City.

“Current management continues therapy indefinitely,” they added. “Whether immunosuppression may be safely withdrawn or whether risks of withdrawal outweigh the benefits of continuation is unknown.”

The investigators enrolled in the trial 102 patients with quiescent systemic lupus erythematosus (SLE) taking MMF long term and randomized them evenly to drug withdrawal using a 12-week taper or drug maintenance (1,000-3,000 mg per day), each with continuation of background antimalarial therapy and, for at least 36 weeks, any steroid therapy.

After 60 weeks of follow-up, fewer than 20% of patients in each group had experienced a serious flare, with no significant difference in the probability of this outcome or the time to its occurrence, according to study results reported at the annual European Congress of Rheumatology. Meanwhile, the incidences of drug-related adverse events and infections were lower in the group stopping the drug.

“In this cohort of quiescent SLE subjects on long-term MMF therapy, few serious flares occurred in either group, and all-flare rates overlapped between groups as did the time to flare,” Dr. Chakravarty and coinvestigators summarized. “Our overall conclusion is that withdrawal of MMF may be safely considered in the majority of lupus patients with prolonged quiescent disease.”


An important question

“I commend the authors for adding to the literature and providing data to help answer an important question relevant to clinicians and patients,” commented Rosalind Ramsey-Goldman, MD, the Solovy/Arthritis Research Society Research Professor and professor of medicine (rheumatology) at Northwestern University, Chicago.

“All immunosuppressive drugs have the potential for toxicity, and MMF is no exception,” she said in an interview. “The goal of therapy is to control disease and minimize side effects, which can occur early or late during the disease course.”

Dr. Rosalind Ramsey-Goldman


Findings of the study may not be generalizable to patients who have been taking MMF for a shorter duration, and the lack of blinding and statistical power calculations were limitations, Dr. Ramsey-Goldman noted.

“However, it supports other data in the literature (Arthritis Care Res. 2019 Jun;71[6]:822-8) where patients with long-term disease with low-level disease activity can do well, suggesting the possibility of gradually decreasing their immunosuppressive medications and possibly discontinuing them completely, albeit still needing close follow-up for a flare,” she concluded.


Study details

On average, the trial patients had been diagnosed with lupus for 12.9 years, and more than three-fourths had a history of lupus nephritis. They had been taking MMF for a mean of 6.6 years, and their mean Safety of Estrogen in Lupus National Assessment–Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) score was 2.2.

The trial definition of clinically significant disease reactivation required both of two criteria: a mild/moderate or severe flare according to SELENA-SLEDAI criteria plus increased immunosuppressive therapy on a sustained basis.

After 60 weeks, the Kaplan-Meier estimated probability of clinically significant disease reactivation according to intention to treat did not differ significantly, at 0.18 with MMF withdrawal and 0.11 with MMF maintenance (difference, 0.07; 95% CI, –0.068 to 0.214). The mean time to disease reactivation was also statistically indistinguishable, at 38.5 weeks in the withdrawal group and 38.0 weeks in the continuation group.

Findings were similar when considering all flares meeting SELENA-SLEDAI criteria (difference, 0.08; 95% CI, –0.116 to 0.279), and when instead using British Isles Lupus Assessment Group A disease activity (difference, 0.06; 95% CI, –0.028 to 0.149) or BILAG A or B disease activity (difference, 0.06; 95% CI, –0.140 to 0.256).

Relative to the MMF maintenance group, the MMF withdrawal group was less likely to experience MMF-related adverse events (40.4% vs. 70.0%) and infections (46.2% vs. 64.0%), more likely to experience adverse events related to lupus (61.5% vs. 50.0%), and similarly likely to experience any adverse events (88.5% vs. 90.0%).

Dr. Chakravarty disclosed that she had no conflicts of interest. The study was sponsored by the Autoimmunity Centers of Excellence at the National Institute of Allergy and Infectious Diseases’s Division of Allergy, Immunology, and Transplantation. Dr. Ramsey-Goldman disclosed that she had no relevant conflicts of interest.