Mycophenolate mofetil, commonly used as a first-line corticosteroid-sparing agent for moderate to severe cases of the autoimmune blistering skin condition pemphigus vulgaris, has been found to be inferior to the biologic agent rituximab.
Dr. Victoria P. Werth
Mycophenolate mofetil is widely accepted as a first-in-line corticosteroid-sparing agent for pemphigus vulgaris, but few studies have compared the effectiveness of the two treatments for pemphigus vulgaris. The European Academy of Dermatology and Venereology recommends rituximab (Rituxan), a CD20 inhibitor, as first-line treatment for patients with new-onset cases of moderate to severe intensity or for patients who fail to achieve clinical remission with systemic corticosteroids with or without other immunosuppressive treatments.
In the current study, published online on May 19, 2021, in the New England Journal of Medicine, researchers led by Victoria P. Werth, MD, professor of dermatology at the University of Pennsylvania, Philadelphia, conducted a randomized, controlled trial of 135 patients (mean age, 48 years; 53% women) with moderate to severe pemphigus vulgaris with 67 receiving rituximab and 68 receiving mycophenolate mofetil (99% of patients in the rituximab group and 85% of patients in the mycophenolate mofetil group completed the trial).
Patients in the rituximab group received 1,000 mg of IV rituximab on days 1, 15, 168, and 182 of the study, plus twice-daily oral placebo. Intravenous methylprednisolone at 100 mg was administered before each rituximab infusion to reduce infusion-related reactions. Patients in the second group were given mycophenolate mofetil orally twice daily, starting at 1 g/day in divided doses and adjusted to 2 g/day in divided doses by week 2. They also received placebo infusions on days 1, 15, 168, and 182 of the study.
Patients in both groups received oral glucocorticoids throughout the course of the trial: an average of 3,545 mg for the rituximab treatment group and a cumulative dose of 5,140 mg for the group treated with mycophenolate mofetil, a statistically significant difference (P < .001). Outcomes based on 62 patients treated with rituximab and 63 on MMF, a modified intention-to-treat group.
By week 52, 25 patients (40%) who were treated with rituximab experienced complete sustained remission (the primary endpoint), compared with 6 patients (10%) in the mycophenolate mofetil group (95% confidence interval, 15-45, P < .001).
Only six patients in the rituximab group experienced a disease flare as compared with 44 patients in the mycophenolate mofetil group (adjusted rate ratio, 0.12; 95% CI, 0.05-0.29; P < .001). Serious adverse events occurred in 15 of 67 patients (22%) in the rituximab group and in 10 of 68 (15%) in the mycophenolate mofetil group with 3 patients in the rituximab group and 26 in the mycophenolate mofetil receiving rescue therapy.
Second to remission, the goal of treatment for pemphigus vulgaris is to reduce the use of glucocorticoids, Dr. Werth and colleagues wrote, adding: “The results of this trial showed that rituximab was superior to mycophenolate mofetil in producing sustained complete remission over 52 weeks among patients with moderate to severe pemphigus vulgaris. Rituximab had a greater glucocorticoid-sparing effect than mycophenolate mofetil, but more patients in this group had serious adverse events.”
Most adverse events in the rituximab group were limited to infusion-related reactions, but serious adverse events occurred in 15 patients (including pneumonia and upper respiratory tract infection, cellulitis and acute pyelonephritis, viral pneumonia, and skin infection). Ten patients in the mycophenolate mofetil group experienced serious adverse events (pneumonia and influenza, cellulitis and sepsis, herpes zoster, and pyelonephritis).
The current study had several limitations, primarily its small size. Plus, the authors noted a short follow-up period after glucocorticoids were stopped.
Mycophenolate mofetil, along with immunosuppressants, is approved in the United States as a treatment for organ rejection in patients who have received kidney, heart or liver transplants. But it is also used off label for pemphigus vulgaris and in rheumatology as a treatment for lupus, rheumatoid arthritis, vasculitis, inflammatory bowel disease (Crohn’s disease), inflammatory eye disease (uveitis) as well as kidney and skin disorders.
In the 2018 treatment guidelines for pemphigus by the European Dermatology Forum and the EADV, mycophenolate mofetil is recommended as a first-line corticosteroid sparing agent for pemphigus vulgaris.
Rituximab was approved in 2018 as the first biologic therapy for patients with pemphigus vulgaris and is currently recommended as a treatment for patients with pemphigus. But how well it works in comparison with the long-established mycophenolate mofetil hasn’t been extensively studied.
Other smaller studies show that mycophenolate mofetil has a treatment effect, but those studies were small. The Ritux 3 trial, published in The Lancet showed that rituximab plus glucocorticoids as opposed to glucocorticoids alone was beneficial in treating pemphigus.
“Rituximab has moved toward first-line therapy for moderate to severe pemphigus as recommended by an international panel of experts,” Dr. Werth said in an interview.
In her practice, Dr. Werth said that she has observed similar outcomes in clinical practice for patients prescribed oral mycophenolate mofetil. “Patients take a long time to get to remission and frequently end up staying on prednisone and long-term mycophenolate mofetil,” she said. She uses mycophenolate mofetil less often since rituximab has been shown to be effective for many patients, but mycophenolate mofetil “still has a place for patients who don’t want, or can’t tolerate, rituximab, or for cases in which rituximab doesn’t work.”
This study was supported by a grant from Hoffmann–La Roche. Dr. Werth disclosed having served as a consultant to Genentech on pemphigus, and that the University of Pennsylvania has received a grant/contract to perform a rituximab–mycophenolate mofetil trial for pemphigus vulgaris.