Trial Finds Rituximab Is Superior to Mycophenolate Mofetil in Treating Pemphigus Vulgaris

A phase 3 trial explored which treatment option for pemphigus vulgaris, a rare skin disease, resulted in better outcomes after 52 weeks.

In patients with pemphigus vulgaris, rituximab was superior to mycophenolate mofetil in producing sustained complete remission after 52 weeks, according to study results published in The New England Journal of Medicine. However, serious adverse events occurred more frequently in the rituximab cohort.

Pemphigus vulgaris is a rare, autoimmune skin disease caused by cadherin desmoglein (Dsg)–specific autoantibodies that bind to epidermal desmosomes, resulting in blisters and erosions of the mucous membranes or skin or both, researchers explained.

Although rituximab is used to treat moderate-to-severe forms of the disease in the United States and Europe and is recommended as first-line treatment for patients with pemphigus, the treatment’s comparison with mycophenolate mofetil has not been extensively investigated.

Rituximab is a chimeric, humanized anti-CD20 monoclonal antibody, while mycophenolate mofetil is a first-line glucocorticoid-sparing agent, also used to treat pemphigus vulgaris.

To address this knowledge gap, the international, phase 3 PEMPHIX trial compared the 2 treatments, each in combination with a tapering glucocorticoid regimen (oral prednisone or equivalent), in individuals with pemphigus vulgaris for a total of 52 weeks. Patients were randomly assigned 1:1 to each treatment arm, with the glucocorticoid regimen discontinuing by week 24.

All participants were between the ages 18 and 75 and had a Pemphigus Disease Area Index (PDAI) score of 15 or more, indicating moderately to severely active disease.

“Patients in the rituximab group received 1000 mg of intravenous rituximab on days 1, 15, 168, and 182 plus twice-daily oral placebo,” authors wrote. “Patients in the mycophenolate mofetil group received mycophenolate mofetil orally twice daily, starting at 1 g per day in divided doses and adjusted to 2 g per day in divided doses by week 2, plus placebo infusions on days 1, 15, 168, and 182.”

Those in the mycophenolate mofetil group received saline solution intravenously prior to the placebo solution. Between weeks 12 to 52, patients reporting treatment failure could receive rescue therapy with another treatment or procedure based on investigators’ judgement. Investigators assessing safety and efficacy were unaware of treatment assignments.

A total of 135 patients underwent randomization between May 2015 and November 2017. The intention-to-treat population consisted of 62 patients in the rituximab group and 63 in the mycophenolate mofetil group while median PDAI activity scores at baseline were 22.7 and 18.3, respectively.

The primary endpoint of sustained complete remission was defined as the healing of lesions with no new active lesions, reflected by a PDAI score of 0 for at least 16 weeks without using a glucocorticoid.

Analyses revealed:

  • At week 52, sustained complete remission was observed in 25 patients (40%) in the rituximab group and in 6 (10%) in the mycophenolate mofetil group for a difference of 31 percentage points (95% CI, 15­-45; P <.001)
  • The hazard ratio for sustained complete remission with rituximab as compared with mycophenolate mofetil was 4.83 (95% CI, 1.97-11.81; P <.001)
  • Mean cumulative glucocorticoid dose during the 52-week treatment period was 3545 mg in the rituximab group and 5140 mg in the mycophenolate mofetil group for a difference of −1595 mg (95% CI, −2838 to −353; P <.001)
  • There were 6 disease flares in the rituximab group and 44 in the mycophenolate mofetil group (adjusted rate ratio 0.12; 95% CI, 0.05-0.29; P <.001)
  • Mean change in Dermatology Life Quality Index score was −8.87 points and −6 points, respectively, for a difference of −2.87 points (95% CI, −4.58 to −1.17; 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

Among the serious adverse events reported in the rituximab group, serious infections like pneumonia and upper respiratory tract infections, occurred in 6 patients compared with 4 patients in the mycophenolate mofetil group. All infection cases resolved.

In addition, “1 patient (1%) in the rituximab group and 5 (7%) in the mycophenolate mofetil group had a glucocorticoid-related adverse event of grade 3 or higher, as assessed by the investigator,” authors wrote.

The small number of participants with severe or recalcitrant pemphigus and the short duration of follow-up after glucocorticoid discontinuation mark limitations to the current study. “Further trials are needed to determine the comparative efficacy and safety of these drugs beyond 52 weeks of treatment,” researchers concluded.


Werth VP, Joly P, Mimouni D, et al. Rituximab versus mycophenolate mofetil in patients with pemphigus vulgaris. N Enlg J Med. Published online May 19, 2021. doi:10.1056/NEJMoa2028564

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