Simultaneous Immediate and Delayed Hypersensitivity to Galcanezumab—Case Report

We report the first case of delayed hypersensitivity to galcanezumab demonstrated by skin tests and molecular analysis. Galcanezumab, a calcitonin gene-related peptide (CGRP) antagonist, is a subcutaneous effective treatment for migraine prevention [1, 2]. No delayed-type hypersensitivity reactions have been reported following this treatment [3]. A 41-year-old woman with a 20-year history of severe migraines and a background of atopy started galcanezumab. The treatment effectively controled her migraines. However, within an hour of the first injection, she developed an erythematous, pruritic plaque at the injection site that progressively enlarged within 5 days (Figure 1) before disappearing on day 8. She reported no other adverse drug reactions. The patient did not discontinue galcanezumab due to its high efficacy, despite a progressive increase in her skin reaction after each injection over a 6-month period. A 24-h slow infusion via subcutaneous pump was attempted but triggered the same reaction. Full-dose antihistamine premedication (3 days before and after injections) was ineffective, while topical corticosteroids partially reduced swelling, duration, plaque size and pruritus. An allergy investigation was initiated with the patient's consent. A skin prick test for galcanezumab (120 mg/mL) was negative. However, intradermal testing (IDT) showed immediate positive reactions at all dilutions (from undiluted to 1/1000). These reactions persisted for 48 h. A control test with paracetamol was negative. Polysorbate 80 (PS80), the galcanezumab's main excipient, was also tested. A skin prick test for picloxydine dihydrochloride eye drops (containing PS80) was negative. However, IDT was positive for PS80 at 1:10 dilution (8x8 mm), while lower dilution (1:100 and 1:1000) were negative. A basophil activation test (BAT) was performed for both galcanezumab and PS80. The BAT for galcanezumab was positive at 52% and 7% at the concentrations of 12 000 μg/mL and 240 μg/mL respectively. BAT for PS80 was negative for all tested concentrations. To further investigate, a skin biopsy was performed on the positive galcanezumab IDT area after 48 h, with a control biopsy from healthy skin (performed on the opposite shoulder). Histology of the IDT area showed pericapillaritis with superficial infiltration of lymphocytes and eosinophils. Reverse transcription-quantitative polymerase chain reaction analysis [4] revealed a clear signature of type IV hypersensitivity with increased expression of CD8, interleukin-5, HLA-DRA in the positive test area compared to the healthy skin (Figure 2). Clinical trials and case reports have reported that galcanezumab induces an inflammatory reaction at the injection site, such as erythema, swelling or pruritus [1, 3, 5, 6]. Recently, two cases of delayed hypersensitivity reactions have been reported without allergological investigation: one presenting as a fixed drug eruption-like reaction [6], and the other as an ecchymotic rash at the injection site [5]. This is the first reported case of both immediate and delayed allergic reactions to galcanezumab, confirmed by BAT, skin testing, cellular and molecular analysis. Delayed-type hypersensitivity reactions have been reported with other CGRP antagonists [7, 8], but not with galcanezumab until now. The immediate reaction after the first injection raises the possibility of cross-reactivity or an initial reaction against PS80, although BAT results suggest galcanezumab was the primary allergen. The initial reaction to PS80 could also have resulted from an irritation phenomenon, as similar reactions have been observed in healthy controls at our centre. The patient's history of atopy could have also contributed to the development of this reaction [5]. The patient discontinued galcanezumab for 1 year. After discontinuation, there was no increase in migraine frequency and no further testing with other CGRP antagonists was needed [3]. Peter Refki: (1) made substantial contributions to acquisition of data, analysis and interpretation of data; (2) drafted the article; (3) given final approval of the version to be published; and (4) agreed to be accountable for all aspects of the work. Aude Belbézier: (1) made substantial contributions to interpretation of data; (2) drafted the article; (3) given final approval of the version to be published; and (4) agreed to be accountable for all aspects of the work. Marine-Alexia Lefevre: (1) made substantial contributions to acquisition of data, analysis of data; (2) reviewed the article critically for important intellectual content; (3) given final approval of the version to be published; and (4) agreed to be accountable for all aspects of the work. Marc Vocanson: (1) made substantial contributions to acquisition of data, analysis of data; (2) reviewed the article critically for important intellectual content; (3) given final approval of the version to be published; and (4) agreed to be accountable for all aspects of the work. Amandine Mosnier: (1) made substantial contributions to interpretation of data; (2) reviewed the article critically for important intellectual content; (3) given final approval of the version to be published; and (4) agreed to be accountable for all aspects of the work. Marie Tauber: (1) made substantial contributions to interpretation of data; (2) reviewed the article critically for important intellectual content; (3) given final approval of the version to be published; and (4) agreed to be accountable for all aspects of the work. Martine Pernollet: (1) made substantial contributions to acquisition of data, analysis and interpretation of data; (2) reviewed the article critically for important intellectual content; (3) given final approval of the version to be published; and (4) agreed to be accountable for all aspects of the work. Pauline Pralong: (1) made substantial contributions to conception and design, acquisition of data, analysis and interpretation of data; (2) reviewed the article critically for important intellectual content; (3) given final approval of the version to be published; and (4) agreed to be accountable for all aspects of the work. The authors have nothing to report. The authors declare no conflicts of interest. No sources were used to fund this work.