Daratumumab as a therapeutic option for rituximab-recalcitrant pemphigus

Rituximab combined with short-term corticosteroids is the standard first-line treatment for pemphigus, but a subset of patients remains refractory, with limited effective alternatives. Daratumumab, an anti-CD38 mAb targeting plasma cells, has emerged as a potential option in severe autoimmune diseases. We report 2 cases of life-threatening pemphigus refractory to rituximab and alternative therapies that were successfully treated with daratumumab, with longitudinal clinical and immunological monitoring of antidesmoglein responses. Rituximab failure was associated with incomplete B-cell depletion, with the persistence of memory B cells and plasmablasts. Daratumumab induced rapid clinical improvement, depletion of CD38⁺ plasma cells, and a reduction of antidesmoglein antibodies. In 1 patient, relapse occurred after daratumumab discontinuation, with subsequent rituximab inefficacy due to antirituximab antibodies; combined daratumumab and belimumab led to sustained complete remission, likely through complementary targeting of plasma cells and the prevention of autoreactive B-cell reconstitution. In the second patient, remission induced by daratumumab was consolidated with additional rituximab. No treatment-related adverse events were observed. These findings suggest that daratumumab, alone or in combination with B-cell-targeting agents, may represent a promising therapeutic strategy for rituximab-refractory pemphigus.