Daijiworld Media Network - New Delhi
New Delhi, Oct 12: Emerging therapies could offer new treatment options for patients with pemphigus vulgaris who fail to respond to rituximab or experience a relapse after treatment, according to a review of developing approaches targeting the autoimmune disorder.
Rituximab has transformed the treatment of pemphigus vulgaris, a condition in which the immune system attacks proteins responsible for keeping skin and mucosal cells attached. The treatment achieves complete remission off therapy in 70% to 90% of patients. However, around 20% to 30% either do not respond adequately or experience a relapse, highlighting the need for alternative strategies.
Several biological mechanisms may contribute to treatment resistance or recurrence. Following rituximab treatment, B cells can repopulate as levels of B-cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL) rise. Meanwhile, long-lived plasma cells can continue producing disease-causing antibodies because they do not express CD20, the protein targeted by rituximab.
Other possible contributors include IgG4-dominant autoantibodies, activation of the innate immune system, antibodies that neutralise rituximab and persistent immune activity within the skin and mucosal tissues.
These findings have prompted researchers to investigate therapies that target different stages of the disease process.
Next-generation anti-CD20 treatments, including ofatumumab, ocrelizumab, obinutuzumab and veltuzumab, aim to improve B-cell depletion while potentially reducing immune reactions against the drugs themselves. Ofatumumab currently has the strongest evidence for pemphigus among these therapies, although the available findings are largely based on patient cohorts and case reports.
Another approach involves blocking BAFF and APRIL, signalling molecules that support B-cell recovery and plasma-cell survival. Although these treatments remain experimental for pemphigus, researchers are investigating their potential to prevent relapses following B-cell depletion.
Bruton tyrosine kinase (BTK) inhibitors offer a different strategy by interfering with B-cell and Fc receptor signalling without directly eliminating B cells. Rilzabrutinib demonstrated rapid disease control and reduced corticosteroid requirements in Phase II testing. However, its Phase III trial failed to meet the primary endpoint.
FcRn antagonists represent another potential treatment option. These drugs accelerate the removal of circulating immunoglobulin G (IgG), including disease-causing antibodies. Efgartigimod substantially reduced IgG levels and produced rapid disease control in Phase II testing, but it also failed to meet its primary endpoint in Phase III.
Researchers are also exploring DSG3-CAAR T-cell therapy, a targeted approach designed to eliminate desmoglein 3-specific pathogenic B cells while preserving the broader B-cell population. Human efficacy data for this strategy are still awaited.
Rather than pointing to a single replacement for rituximab, the review highlights the potential of combining therapies that act through complementary mechanisms. Combining B-cell depletion with FcRn blockade could help eliminate existing disease-causing antibodies while limiting their continued production. Similarly, blocking BAFF and APRIL could potentially reduce B-cell repopulation after rituximab treatment.
Although these approaches remain investigational, they reflect a growing focus on tailoring treatment to the biological mechanisms responsible for persistent or recurring pemphigus vulgaris. Further clinical research will be necessary to establish their safety, effectiveness and role in routine patient care.