Rituximab bests MMF for pemphigus vulgaris

The humanized anti-CD20 monoclonal antibody rituximab was superior to mycophenolate mofetil (MMF) in terms of producing sustained complete remission* (CR) and a glucocorticoid-sparing effect in patients with moderate-to-severe pemphigus vulgaris, the PEMPHIX study has shown.

Although rituximab is a recommended first-line therapy for pemphigus, MMF – though not approved for this condition – is considered standard of care in treatment guidelines. [J Eur Acad Dermatol Venereol 2015;29:405-414; J Am Acad Dermatol 2020;82:575-585.e1; J Eur Acad Dermatol Venereol 2020;34:1900-1913] “[I]n many countries, MMF is used as a first-line glucocorticoid-sparing treatment. Therefore, we chose to compare MMF plus glucocorticoids with rituximab in the current trial,” said the researchers.

A total of 135 participants (median age 48 years, 47 percent male) were randomized 1:1 to receive IV rituximab** 1,000 mg or oral MMF** BID for 52 weeks. This was administered on top of an oral glucocorticoid*** regimen following a similar tapering schedule as the two study drugs, with the goal of discontinuing by week 24. [N Engl J Med 2021;384:2295-2305]

Week 52 saw more rituximab vs MMF recipients achieving sustained CR (40 percent vs 10 percent; difference, 31 percentage points; p<0.001).

Rituximab use also led to lower glucocorticoid use compared with MMF (mean cumulative dose, 3,545 vs 5,140 mg; difference, −1,595 mg; p<0.001). “Reduction of oral glucocorticoid use is a goal in the treatment of pemphigus vulgaris. [Our study shows that] more patients [on rituximab vs MMF] were able to discontinue glucocorticoids, and patients on rituximab had lower cumulative glucocorticoid exposure than those on MMF over 52 weeks,” said the researchers.

Mean change from baseline DLQI^# score was greater with rituximab vs MMF (−8.87 vs −6.00 points; difference, −2.87 points; p=0.001). On post hoc analysis, more rituximab vs MMF recipients had a DLQI score of 0 (62 percent vs 25 percent).

The incidence of disease flares was lower with rituximab vs MMF (n=6 vs 44; adjusted rate ratio, 0.12), as was the fraction of participants having at least one disease flare during the treatment phase (8 percent vs 41 percent; hazard ratio for disease flare, 0.15; p<0.001 for both). However, serious adverse event rate was higher with rituximab vs MMF (22 percent vs 15 percent).

Despite the occurrence of serious infections in six rituximab recipients, all resolved with treatment and none led to treatment withdrawal or dose modification. In the MMF arm, of the four who had serious infections, two discontinued treatment while two had dose interruptions.

Anti-Dsg3 autoantibodies

At week 8, median reductions from baseline anti-Desmoglein (Dsg)3 and anti-Dsg1 autoantibody titres were similar in both arms. The anti-Dsg1 curves remained essentially the same over time, but with anti-Dsg3, the reduction was greater in the rituximab vs the MMF arm through 52.

“Anti-Dsg3 autoantibodies are pathogenic in pemphigus vulgaris and correspond to disease activity,” the researchers explained. “[However,] no conclusions can be drawn from [these data owing to] the exploratory nature of the analyses.”

More studies needed

While the findings align with those seen in Ritux 3, the current results cannot be compared to its results owing to differences in study design, patient cohorts, rituximab administration schedule and dosing, glucocorticoid-tapering regimens, and treatment duration. [Lancet 2017;389:2031-2040]

“[In our study], both treatment arms followed the same prednisone-tapering dose and schedule,” they added. Moreover, rituximab recipients in Ritux 3 were allowed to receive rituximab again upon relapse and may be considered as having a response on primary analysis. “[In our study,] patients who received additional immunosuppressive treatment or had treatment failure during the 52-week treatment period were considered to have not had a response.”

Further exploration is thus warranted to ascertain the comparative efficacy and safety of rituximab and MMF beyond 52 weeks.