EMERGING therapies could reshape pemphigus vulgaris treatment for patients who relapse or remain refractory after rituximab.
Rituximab has transformed treatment of the autoimmune blistering disorder, achieving complete remission off therapy in 70% to 90% of patients. However, approximately 20% to 30% either fail to respond or experience relapse, creating a need for treatments that address mechanisms not fully controlled by conventional B-cell depletion.
Why Pemphigus Vulgaris Relapses After Rituximab
Several processes may contribute to refractory pemphigus vulgaris. B cells can repopulate after rituximab as levels of B-cell activating factor (BAFF) and a proliferation inducing ligand (APRIL) rise. Long lived plasma cells may also continue producing pathogenic antibodies because they do not express CD20 and therefore escape rituximab.
Other proposed drivers include IgG4 dominant autoantibodies, innate immune activation, anti-drug antibodies that neutralize rituximab, and localized immune activity within skin and mucosal tissue.
These mechanisms have prompted investigation of targeted therapies acting at different stages of disease.
Targeted Therapies Address Different Disease Pathways
Next generation anti-CD20 therapies, including ofatumumab, ocrelizumab, obinutuzumab, and veltuzumab, aim to improve B-cell depletion while reducing immunogenicity. Ofatumumab currently has the strongest pemphigus evidence within this group, although available data remain largely limited to cohorts and case reports.
BAFF and APRIL inhibitors offer another approach by targeting signals that support B-cell repopulation and plasma-cell survival. These agents remain experimental in pemphigus but may ultimately be suited to preventing relapse after B-cell depletion.
Bruton tyrosine kinase inhibitors can interfere with B-cell and Fc receptor signaling without directly depleting B cells. Rilzabrutinib produced rapid disease control and corticosteroid sparing in Phase II testing, although its Phase III trial failed to meet the primary endpoint.
FcRn antagonists instead accelerate removal of circulating pathogenic IgG. Efgartigimod reduced IgG substantially and produced rapid disease control in Phase II testing, but also missed its Phase III primary endpoint.
Could Combination Therapy Change Pemphigus Care?
DSG3-CAAR T-cell therapy represents a more precise strategy, designed to eliminate desmoglein 3 specific pathogenic B cells while preserving the wider B-cell population. Human efficacy data, however, remain awaited.
Rather than identifying one replacement for rituximab, the review points toward rational combinations. Pairing B-cell depletion with FcRn blockade could remove existing pathogenic antibodies while limiting new production, while BAFF/APRIL blockade may help prevent post-rituximab repopulation.
For clinicians, these approaches remain investigational, but they illustrate a shift toward targeting the specific biological mechanisms sustaining refractory pemphigus vulgaris.
Reference
Ahuja R et al. Targeted therapies in pemphigus vulgaris: Emerging horizons beyond rituximab. J Eur Acad Dermatol Venereol. 2026;DOI:10.1111/jdv.70773.
Featured Image: DC Studio on Adobe Stock.
Featured Image: DC Studio on Adobe Stock.
- Author:
