Rituximab hypersensitivity following re-exposure – A clinical paradox

Rituximab, an anti-CD20 monoclonal antibody, is widely used in pemphigus vulgaris (PV) for inducing and maintaining remission. While infusion-related reactions are well recognized during the first administration, hypersensitivity reactions on re-exposure are uncommon and underreported in PV. We describe a 48-year-old woman with PV, unresponsive to corticosteroids and azathioprine, who was started on rituximab (rheumatoid arthritis protocol, 1000 mg). The first infusion was uneventful under standard premedication. However, 30 minutes into the second infusion, she developed acute dyspnea, perioral numbness, flushing, abdominal pain, and hypotension. The infusion was stopped and managed with intravenous corticosteroids, antihistamines, fluids, and inotropes, with rapid symptom resolution. Serum tryptase and immunoglobulin E (IgE) were elevated, and a skin prick test was positive, supporting IgE-mediated hypersensitivity. This likely represented sensitization from the first exposure, triggering an allergic reaction upon re-exposure. Due to the severity, rituximab was not re-challenged. Management options for such cases include desensitization protocols or alternative CD20-targeting agents (ofatumumab and obinutuzumab). This case underscores the need for vigilance during subsequent rituximab infusions, even after a well-tolerated initial dose. Clinicians should be aware of delayed-onset hypersensitivity and consider predictive markers and standardized desensitization strategies to optimize patient safety and treatment continuity.