Impact of mycophenolate mofetil discontinuation in patients with SLE

Mycophenolate mofetil (MMF) is a commonly used immunosuppressant to treat systemic lupus erythematosus (SLE) and lupus nephritis. However, long-term treatment with MMF increases the risk of adverse events, including infections and malignancies, requiring withdrawal following disease quiescence. Furthermore, the risks of MMF withdrawal are unclear.

Chakravarty et al. published an article in The Lancet Rheumatology,¹ assessing the risks associated with MMF discontinuation vs maintenance in patients with quiescent SLE on long-term MMF. Here, we summarize the key findings.

Methods¹

• This was an open-label, multicenter, randomized controlled trial (NCT01946880).
• Patients were randomly allocated 1:1 to MMF maintenance and withdrawal groups.
• The primary endpoint was the probability of clinically significant disease reactivation by Week 60.
• To evaluate non-inferiority, an estimation-based approach was used to calculate absolute increases in risk associated with MMF withdrawal, with one-sided upper 75%, 85%, and 95% confidence limits.

Key findings¹

• A total of 49 patients in the maintenance group and 51 patients in the withdrawal group were included in the modified intent-to-treat population.
  • Mean age was 42 years, 84% of patients were women, average MMF treatment duration was 6.6 years, and 76% of patients had a history of lupus nephritis.
• MMF withdrawal led to a non-significant 7% increase in the risk of clinically significant disease reactivation by Week 60 (Figure 1A).
  • Mean time to clinically significant disease reactivation was 38 weeks for the MMF maintenance group and 38.5 weeks for the MMF withdrawal group.
• Risk estimates for all other disease measures overlapped between maintenance and withdrawal groups (Figure 1A).
• In the subgroup of patients with renal disease, point estimates and one-sided confidence limits for increases in risk with MMF withdrawal were higher compared with the modified intention-to-treat group (Figure 1B).

BILAG, British Isles Lupus Assessment Group; MMF, mycophenolate mofetil; SELENA-SLEDAI, Safety of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index.
*Data from Chakravarty, et al.¹

Safety

• Adverse events were similar between groups; however, the MMF maintenance group reported more frequent infections and a shorter time to first infection compared with the withdrawal group (Table 1).
• One pregnancy happened nine months post complete MMF withdrawal, with a full-term healthy infant.
• No deaths were reported.

Table 1. AEs in the safety population*

AE, adverse event, SLE, systemic lupus erythematosus. *Data from Chakravarty, et al.1
Events, %	Maintenance cohort (n = 50)	Withdrawal cohort (n = 52)
Serious AEs	14	10
Total AEs	90	88
Related to SLE	50	62
AE by severity
Grade 1	0	2
Grade 2	90	87
Grade 3	20	21
Grade 4	4	0
Total infections	64	46
Infections by severity
Grade 2	60	46
Grade 3	8	2
Grade 4	0	0

Key learnings

MMF withdrawal is well tolerated and is not significantly inferior to MMF maintenance in patients with stable SLE. However, patients and clinicians should be informed of the slight increase in flare risk. The risk estimates with 75%, 85%, and 95% confidence limits will facilitate informed decision making on MMF discontinuation. Larger studies with a longer follow-up are needed.