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Among patients with systemic lupus erythematosus (SLE) managed successfully with mycophenolate mofetil (MMF), rates of disease flare were not massively greater when the drug was withdrawn over several months versus kept at their regular doses, a small randomized trial showed.

"Clinically significant" disease reactivation occurred within 5 years in 18% of the withdrawal group, compared with 10% of those staying on MMF, according to Judith A. James, MD, PhD, of the Oklahoma Medical Research Foundation in Oklahoma City, and colleagues.

Although the researchers calculated that patients stopping MMF faced a 7-percentage point increase in risk for lupus flare than those on maintenance, they concluded in that weaning "is not significantly inferior" to continued maintenance treatment, especially since infections were less frequent during follow-up in the withdrawal group.

An accompanying echoed that conclusion. The findings "demonstrate the feasibility of weaning selected patients off immunosuppression after a few years of treatment and reaching disease quiescence," wrote Noémie Jourde-Chiche, MD, PhD, of Aix-Marseille University, and Laurent Chiche, MD, of Hôpital Européen de Marseille, in France.

As well, the pair added, the study provides a basis for "a quantified risk assessment" that clinicians can use in deciding whether to recommend MMF tapering and withdrawal to their SLE patients.

While active SLE leads to significant risk for irreversible organ damage, immunosuppressants such as MMF have their own downsides when used long-term. Both James's group and the commentary authors noted that, until now, clinical opinion has favored keeping patients on their medications indefinitely after lupus is brought under control, believing their adverse effects were outweighed by the risks from disease reactivation. Studies have shown that corticosteroids (another mainstay of SLE therapy) can be tapered without severely jeopardizing disease control. Researchers have thus wondered whether the same could work for other common lupus medications.

An , led by Jourde-Chiche, was not promising. Patients with lupus nephritis who were weaned off maintenance immunosuppressants (azathioprine or MMF) showed much higher rates of relapse than those kept on their regular doses. But patients in that trial had been on maintenance therapy for substantially less time than those in the new study (2-3 years, versus a mean of nearly 7 years), suggesting that perhaps disease control had not been as fully established and thus patients were more susceptible to reactivation.

For the current trial, James and colleagues recruited adult SLE patients from 19 U.S. clinics with "quiescent" disease, defined as SLE Disease Activity Index (SLEDAI) scores less than 4. MMF treatment had to have been kept stable or decreased over the previous year (2 years if given for renal issues). Patients also received hydroxychloroquine (HCQ) and stayed on it through the 5-year trial; prednisone at no more than 10 mg/day was allowed as well. Patients on high prednisone doses or with indications of kidney impairment were excluded.

A total of 102 were randomized 1:1 to MMF withdrawal or continued maintenance. Withdrawal was conducted in steps over 3 months. "Clinically significant disease reactivation" was the primary endpoint, defined as a need for increased steroid doses, resumed or increased MMF dosing, or use of a new immunosuppressant.

More than 80% of patients were women; about 40% were white and 40% were Black. Mean age was 42, with disease duration averaging about 13 years. MMF doses averaged 1.6 g/day, with just under half taking 2 g/day or more. Mean SLEDAI score at baseline was about 2.2; the median was 2.0 (despite eligibility restricted to those with scores less than 4 at initial screening, some participants had values as high as 8 in baseline testing).

After certain adjustments, James and colleagues calculated that the risk for clinically significant reactivation was 18% with withdrawal (95% CI 10%-32%) versus 11% with continued maintenance (95% CI 5%-24%). With such overlap in the confidence intervals -- relatively broad because of the small group sizes -- the researchers felt justified in determining that withdrawal was not inferior to maintenance.

Still, they acknowledged that the withdrawal strategy appeared to convey increased risk, and this was supported by secondary endpoints such as flares defined by increases in SLEDAI or other disease activity scores during follow-up. Between-group differences were not statistically significant, but they all trended toward greater risk of increased disease activity in the withdrawal group.

But this was counterbalanced by the lower frequency of adverse events unrelated to lupus: 40% in the maintenance group versus 27% with withdrawal. Five severe events (including those from lupus) were counted in the withdrawal group compared with seven in the maintenance patients.

Infections showed the greatest difference, affecting 64% of the maintenance group versus 46% stopping MMF. Four patients staying on the drug had grade 3 infections, as opposed to just one in the withdrawal group.

Jourde-Chiche and Chiche said that future studies should look at whether "more gradual weaning" might reduce the flare risk with withdrawal, and also at the extent to which suboptimal HCQ compliance compromises the strategy. They also suggested that renal biopsy might be a good idea, "to verify histological remission before weaning." And tracking patients with biomarkers in addition to clinical symptoms could be useful in monitoring patients' risk, they wrote.

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