Suspected hypersensitivity to tirzepatide
Question:
8/6/2024
I have a patient who is a 42-year-old lady, was started on Tirzepatide (Mounjaro) 5 mg sc every week for obesity for one month, it was interrupted and stopped for three months. She then resumed it with a 5 mg sc and after 24 hours she developed large localized reaction (redness, swelling, itchy) and within few hours developed generalized urticaria with lip swelling, she was managed by antihistamines but did not improve and started to have sob but vitally were stable. She was managed with prednisolone and high dose antihistamines but her generalized urticaria rash improved for few hours then recurred again which lasted for four days on/off. Skin biopsy confirmed urticaria. I gave her one dose of omalizumab because I assumed Tirzepatide levels is going to be high unless we block her IgE this may alleviate her reaction, surprisingly, her rash disappeared within 24 hours.
After five weeks, I skin tested her with Tirzepatide: histamine was +6 mm, negative prick 1 mm, Tirzepatide neat prick was 1 mm. ID for 1:100 was 2 mm and 1:10 was 1 mm, neat was negative. After 24 hours ID became more positive 1:100 was 2mm, 1:10 was 3 mm and neat was 5 mm. She still wishes to continue Tirzepatide, but I am hesitant with her skin testing to challenge especially her symptoms started after 24 hours of her dose, would you consider this delayed immediate reaction? And are there any desensitization protocol for subcutaneous medication?
Answer:
The evaluation of potential hypersensitivity to glucagon-like peptide 1 receptor agonists was addressed in "Ask The Expert" on 4/1/2024.
Tirzepatide is a 39 amino acid linear polypeptide conjugated to a C20 fatty diacid moiety by a linker connected to the lysine20 residue. It has a molecular weight of only 4814 Daltons, lower than the 8000+ Daltons in most clinically significant antigens. The delayed onset of symptoms relative to the last exposure make an IgE-mediated allergy unlikely. The negative immediate type hypersensitivity skin testing also makes an IgE-mediated allergy unlikely. The clinical symptoms described are most compatible with an episode of acute idiopathic urticaria. Given the symptoms described, a clinically significant, T-cell mediated hypersensitivity to tirzepatide is very unlikely.
Desensitization is not possible for delayed onset hypersensitivities, independent of the underlying pathophysiology.
Given the relatively benign nature of the symptoms described and the patient's desire to continue glucagon-like peptide 1 receptor agonist therapy, the use of an alternative agent, such as semaglutide, exenatide, lixisenatide, or dulaglutide, would be my first recommendation.
If only tirzepatide therapy is optimal, then a rechallenge, with shared decision-making, with at least two days of observation, would be a reasonable way to proceed.
Eric Macy, MD, MS, FAAAAI