Rituximab Bests Mycophenolate Mofetil for Pemphigus

In patients with moderate-to-severe pemphigus vulgaris, rituximab was superior to mycophenolate mofetil in effecting sustained complete remission at 52 weeks and brought about greater reductions in glucocorticoid use but more serious adverse events, according to results from the PEMPHIX trial.

“Mycophenolate mofetil is commonly used as a first-line glucocorticoid-sparing agent for the treatment of moderate-to-severe pemphigus vulgaris and is recommended in treatment guidelines. Rituximab has been approved for the treatment of pemphigus vulgaris in the United States and in Europe on the basis of the results of the Ritux 3 trial,” wrote Victoria P. Werth, MD, of the Perelman School of Medicine, University of Pennsylvania and the Corporal Michael J. Crescenz Veterans Affairs Medical Center, Philadelphia, and fellow researchers of the PEMPHIX Study Group. They published their results in The New England Journal of Medicine to coincide with their presentation at the International Society for Pharmacoeconomics and Outcomes (ISPOR) 2021 Annual Meeting.

Rituximab is a chimeric monoclonal anti-CD20 antibody and is also approved for the treatment of non-Hodgkin’s lymphoma, chronic lymphocytic leukemia, rheumatoid arthritis, and granulomatosis with polyangiitis.

For this international, phase III, double-blind, double-dummy, randomized, controlled trial, Werth et al randomized 125 patients (median age: 48.0 years; 53% women; 73% White) with moderate-to-severe pemphigus vulgaris to treatment with rituximab (1,000 mg on days 1, 15, 168, and 182) or oral mycophenolate mofetil (2 g/d), plus an oral glucocorticoid administered according to an identical tapering schedule. Mean duration of pemphigus vulgaris was 5.0 months, and 74% of patients were newly diagnosed.

Lesions were graded using the Pemphigus Disease Area Index (PDAI) activity score (scale: 0-250, with higher scores indicative of greater disease severity). At baseline, median PDAI activity score was 22.7 in rituximab patients, versus 18.3 in the mycophenolate mofetil group.

The primary efficacy end point of the study was sustained complete remission at week 52, as defined by lesion healing with no new active lesions for at least 16 weeks without glucocorticoid treatment.

By week 52, 40% of patients treated with rituximab demonstrated complete remission, compared with 10% in the mycophenolate mofetil group (difference: 31 percentage points; 95% CI: 15-45; P<0.001). Over the 52 weeks, patients treated with rituximab had a lower mean cumulative glucocorticoid dose compared with those in the mycophenolate mofetil group (3,545 versus 5,140, respectively; difference: −1,595 mg; 95% CI: −2838 to −353; P<0.001).

Patients treated with rituximab also had significantly fewer disease flares compare to the mycophenolate mofetil group (6 versus 44, respectively; adjusted rate ratio: 0.12; 95% CI: 0.05-0.29; P˂0.001).

Significant between-group differences were also seen in mean changes in the Dermatology Life Quality Index (DLQI) scores, which range from 0 to 30, with higher scores indicating greater impairment. In patients treated with rituximab, the mean change in DLQI score was −8.87, compared with −6.00 in those treated with mycophenolate mofetil (difference: −2.87 points; 95% CI: −4.58 to −1.17; P=0.001).

Finally, the incidence of adverse events was similar in the two groups (85% in rituximab versus 88% in mycophenolate mofetil groups), with the most common in the rituximab group including infusion-related reactions (22%), headache (15%), lymphopenia (12%), and upper respiratory tract infections (10%). In the mycophenolate mofetil group, the most frequent events were diarrhea (15%) and nasopharyngitis (12%).

Serious adverse events occurred significantly more often in the rituximab group compared with the mycophenolate mofetil group (22% versus 15%, respectively), with serious infections in 9% and 6%. Treatment was discontinued because of these in two patients in the mycophenolate mofetil group, compared with no patients in the rituximab group.

“Anti-Dsg3 autoantibodies are pathogenic in pemphigus vulgaris and correspond to disease activity,” noted researchers, who found that 32% of patients treated with rituximab tested positive for anti-drug antibodies, of which 19 were deemed to be treatment-induced and 1, treatment-enhanced.

“Reduction of oral glucocorticoid use is a goal in the treatment of pemphigus vulgaris. In this trial, more patients in the rituximab group than in the mycophenolate mofetil group were able to discontinue glucocorticoids, and patients in the rituximab group had lower cumulative glucocorticoid exposure than those in the mycophenolate mofetil group over 52 weeks. As is consistent with the greater use of glucocorticoids in the mycophenolate mofetil group, more grade 3 or higher glucocorticoid-related adverse events occurred in the mycophenolate mofetil group than in the rituximab group,” concluded Werth and colleagues, adding that further studies are needed. to assess the efficacy and safety of treatment beyond 52 weeks.

Study limitations include the small number of patients with severe or recalcitrant pemphigus, and the short duration of follow-up after glucocorticoid discontinuation, and imbalance between the two groups caused by patients who did not complete the 52-week trial period.

1. Rituximab was superior to mycophenolate mofetil in producing sustained complete remission at 52 weeks in patients with pemphigus vulgaris.

2. Treatment with rituximab resulted in a greater reduction in glucocorticoid use than mycophenolate mofetil, but more patients had serious adverse events.

Liz Meszaros, Deputy Managing Editor, BreakingMED™

Cat ID: 105

Topic ID: 75,105,730,105,192,923,925