Itching for Therapy: Alpha-Gal Syndrome as a Cause of Anaphylaxis to Ustekinumab

Background:
A 48-year-old man with a history of alpha-gal syndrome and ulcerative colitis (UC) was admitted for acute severe UC and initiated on combination therapy of infliximab and 6-mercaptopurine. He had resolution of symptoms after completion of induction therapy; however, after the fourth infliximab infusion, he developed significant itching, nausea, and dyspepsia that improved after IV diphenhydramine. The patient did not want to re-challenge with infliximab and therapy was changed to vedolizumab. Unfortunately, he was a primary non-responder after 7 months of therapy and was switched to ustekinumab.
Methods:
Twenty minutes into the induction infusion, he developed urticaria on his back and abdomen. The infusion was stopped, and he was treated with IV diphenhydramine and IV famotidine. One hour later, his symptoms progressed to lip swelling. Given concern for anaphylaxis, IM epinephrine was administered and symptoms resolved. Of note, the patient’s alpha-gal syndrome was diagnosed by serology 10 years prior after he reported urticaria and abdominal pain temporally related to meat ingestion. Alpha-gal syndrome is an IgE mediated hypersensitivity reaction to galactose-a-1,3- galactose (alpha-gal). Sensitization to alpha-gal occurs following a tick bite. The syndrome can cause delayed allergic reactions, typically hours after eating mammalian meat, but can also cause more immediate reactions to infused medications. Chimeric mouse-human monoclonal antibodies, notably cetuximab, contain alpha-gal glycosylation in the Fab and Fc domains and severe hypersensitivity reactions to cetuximab have been associated with IgE antibodies against alpha-gal. Like cetuximab, infliximab and ustekinumab are expressed in the murine mouse myeloma sp2/0 cell line, allowing for the alpha-gal glycosylation, though only in the Fc domain. Hypersensitivity reactions to infliximab have been hypothesized to occur due to alpha-gal syndrome. Conversely, vedolizumab is produced in Chinese hamster ovary cells which lack the ability to synthesize glycoproteins with alpha-gal antigens.
Results:
We posit that our patient’s anaphylaxis was due to IgE-mediated hypersensitivity reaction against alpha gal present on ustekinumab, a fully humanized monoclonal antibody expressed through the same murine cell line as cetuximab and infliximab. Although our patient’s mild infliximab reaction may also be explained by the same mechanism, there are too many confounding variables to establish a potential link including the use of high dose oral steroids during induction as well as infusion pretreatment with cetirizine and IV methylprednisolone. Of note, he did not receive steroids prior to his ustekinumab infusion.
Conclusions:
More research about alpha-gal syndrome and its implication in hypersensitivity drug reactions is needed so that high risk medications and at-risk patients can be identified.