Rituximab hypersensitivity following re-exposure – A clinical paradox

INTRODUCTION

Rituximab, a chimeric monoclonal anti-CD20 antibody, has emerged as a highly effective therapeutic agent for pemphigus vulgaris (PV), offering sustained disease control and reducing dependence on long-term corticosteroids. Initially developed for B-cell malignancies, rituximab has now become a first-line therapy for PV, demonstrating significant efficacy in inducing and maintaining remission. However, its use is associated with a spectrum of infusion-related adverse events, including hypersensitivity reactions, which, although well-documented during the first infusion, are less frequently reported in subsequent doses. Herein, we present a case of rituximab-induced hypersensitivity occurring after the second infusion in a patient with PV, highlighting the need for vigilance in monitoring such reactions as rituximab is now widely being administered for PV patients; however, there is scarce literature regarding rituximab hypersensitivity reactions, particularly in PV patients.^[1]

CASE REPORT

A 48-year-old female, diagnosed with PV based on clinical, histopathological, and direct immunofluorescence findings, was initiated on the rheumatoid arthritis protocol (1000 mg) of rituximab following inadequate disease control with systemic corticosteroids and azathioprine. Premedication for both infusions included intravenous hydrocortisone 100 mg, pheniramine 45.5 mg, and paracetamol 1 g. The first infusion was uneventful.

However, during the second infusion with an infusion rate of 50 mg/h, approximately 30 minutes after initiation, she developed acute-onset dyspnea, perioral numbness, facial flushing, abdominal pain, and hypotension. The infusion was immediately halted, and she was administered intravenous corticosteroids, antihistamines, noradrenaline, and fluid resuscitation, leading to a rapid resolution of symptoms. No respiratory distress requiring intubation was observed. The grade of infusion-related reaction (IRR) was Grade 3 (severe) according to the Common Terminology Criteria for Adverse Events.

Further investigations revealed an elevated serum tryptase level: Peak tryptase: 32 μg/L (drawn 1 hour after reaction onset and baseline tryptase: 5 μg/L (drawn 48 hour post-event). Serum immunoglobulin E (IgE) and skin prick test showed wheal formation, indicating a positive response. A specific IgE assay was not performed. The temporal relationship between drug administration and symptom onset strongly suggested a hypersensitivity reaction rather than a cytokine-release syndrome (CRS), which is more common during the first infusion. Due to the severity of the reaction, rechallenging the patient with rituximab was not attempted. IRRs to rituximab are classified into CRS and hypersensitivity reactions. CRS results from rapid B-cell lysis and subsequent cytokine release, typically occurring during the first infusion. In contrast, hypersensitivity reactions can be IgE-mediated (true allergic reactions) or non-IgE-mediated, involving direct mast cell degranulation or complement activation. The occurrence of a severe reaction during the second infusion in our patient raises the possibility of immune sensitization during the first exposure, leading to a delayed onset hypersensitivity response.^[1]

While IgE-mediated anaphylaxis to rituximab is rare, the presence of hypotension and respiratory symptoms in our patient strongly suggested an allergic mechanism. The absence of symptoms during the first infusion and the abrupt onset of systemic manifestations with the second dose align with a sensitization pattern. Several reports have described similar reactions following second or third rituximab infusions in patients with autoimmune or oncologic conditions, although not in PV [Table 1], and they infer that delayed-onset rituximab hypersensitivity can occur due to antigenic epitope recognition following initial exposure.^[1-4]

From a mechanistic standpoint, rituximab hypersensitivity can result from IgE-mediated allergy in which sensitization occurs during initial exposure, leading to an anaphylactic response upon re-exposure, non-IgE-mediated mast cell degranulation in which direct activation of mast cells and basophils occurs without prior sensitization, and complement activation-related pseudoallergy, which involves rituximab-induced complement activation leading to pseudoallergic reactions.^[1]

The management of rituximab hypersensitivity remains challenging. While premedication with corticosteroids and antihistamines can mitigate IRRs, true hypersensitivity reactions may require desensitization protocols or switching to alternative B-cell-targeting agents. In cases where continued rituximab therapy is necessary, a desensitization protocol involving incremental dosing under close supervision can be considered. In addition, alternative CD20 inhibitors, such as ofatumumab or obinutuzumab, which have distinct antigen-binding properties, may serve as viable options for patients who develop hypersensitivity to rituximab.^[5]

CONCLUSION

This case underscores the potential for rituximab hypersensitivity even after an uneventful first infusion, emphasizing the importance of continuous monitoring during subsequent doses. As rituximab becomes increasingly integrated into the treatment paradigm for PV and other autoimmune disorders, clinicians must remain vigilant for late-onset hypersensitivity reactions. Further research is needed to identify predictive markers for rituximab hypersensitivity and to develop standardized desensitization protocols to ensure patient safety while optimizing therapeutic outcomes.