Options exist to manage immune-mediated adverse reactions to insulin
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Key takeaways:
- The four patients with insulin allergy had type 1 diabetes.
- These patients also had positive anti-insulin antibody levels.
- Reactions included urticaria and panniculitis.
ANAHEIM, Calif. — Patients with insulin allergy were treated successfully with omalizumab, rituximab and/or mycophenolate, according to a presentation at the American College of Allergy, Asthma & Immunology Annual Scientific Meeting.
These treatments addressed immediate-type IgE reactions such as urticaria and delayed-type IgG reactions such as panniculitis alike, Irene Yuan, MD, clinical fellow at Vanderbilt University Medical Center, said during her presentation.
The study’s impetus
Yuan told Healio that she and her colleagues occasionally get referrals for evaluation of “insulin allergy” at their drug allergy clinic.
“Usually, the patients have been on a variety of insulins and/or other medications, such as antihistamines, before coming to see us, and nothing has helped much,” Yuan said.
These patients are reacting every day to life-sustaining medication, she continued, which is very frustrating for both them and their providers.
“These reactions also contribute to insulin resistance and decreased treatment efficacy,” Yuan said. “It is a rare but serious problem.”
As a first-year fellow-in-training, Yuan evaluated a case with her mentor, Cosby A. Stone Jr., MD, MPH, assistant professor in the division of allergy, pulmonary and critical care medicine at Vanderbilt University, that she said left an impression.
The patient was a woman, aged 25 years, with type 1 diabetes who was coming to the clinic with daily itching and pain at her insulin injection sites, which often became painfully indurated nodules and sterile abscesses requiring numerous incisions and drainages.
Describing this patient as “very miserable,” Yuan also said that she had previously tried many things that did not work, including insulin desensitization at another hospital. Yuan and her colleagues tested this patient with insulin skin testing and anti-insulin antibody levels.
Based on the patient’s positive results and reaction phenotype, Yuan said that she and her colleagues were able to successfully improve her symptoms with anti-IgE omalizumab (Xolair; Genentech, Novartis) treatment.
“She is now much more comfortable and has been able to decrease her basal insulin requirement,” Yuan said. “It seems like she has less inflammation when she injects her medicine.”
These cases of insulin hypersensitivity are very uncommon, Yuan continued, so there are no standardized guidelines for evaluation and treatment. However, the clinic had previously evaluated and treated similar cases.
“So, we decided to perform a chart review study to better characterize these patients and share what we learned from that experience,” Yuan said.
The chart review
A review of “insulin allergy” labels included in a drug allergy clinic’s Redcap database between October 2015 and May 2023 yielded 21 cases. Fourteen of these patients had insulin skin testing, with four positive results indicating hypersensitivity.
Yuan called insulin allergy very rare, with some studies estimating allergies in less than 3% of all patients on insulin.
“We suspect that immune-mediated reactions might be underrecognized,” Yuan said. “Reactions are likely underreported, because many are mild enough to be managed by antihistamines or a change in insulin formulation and are not being referred to allergy clinic.”
Seven of the 10 patients who had negative skin testing possibly had dermatographic urticaria that contributed to local reactions, the researchers said, whereas the other three probably had nonallergic side effects.
The four patients identified in this study all had type 1 diabetes and positive human anti-insulin antibody levels, including IgE and/or IgG.
The first patient with positive skin testing was a woman aged 40 years whose reaction history included local swelling, burning and erythema at pump sites as well as subcutaneous bruising, nodule formation and atrophy that all appeared dose dependent.
Intradermal testing was positive for Humalog (insulin lispro injection, Lilly). Anti-insulin IgG testing included 156 kUA/L in July 2017 and 122 kUA/L in November 2017. In October 2017, the patient began taking 375 mg/m2 of rituximab (Rituxan, Genentech) every 4 weeks.
The patient experienced 18 months of relief before symptom recurrence, and rituximab was repeated along with 200 mg of hydroxychloroquine twice a day for a year for neuropathic pain. The researchers reported no following recurrence of symptoms.
The second patient was a woman aged 30 years with a history of local urticaria at pen injection sites that spread to her trunk and upper legs. Symptoms improved with an insulin pump, although dose-dependent breakthrough urticaria and itching persisted.
Skin prick testing to Novolog (insulin aspart injection, Novo Nordisk) and intradermal testing to Humalog and Humulin (insulin human injection, Lilly) were positive, and intradermal testing to metacresol was negative. Anti-insulin IgE testing included 1.02 kUA/L in November 2021. The patient began taking 300 mg of omalizumab every 4 weeks in November 2021.
Four months later, the patient reported “50% improvement,” although there was localized pus and urticaria once or twice a week. Clinicians increased the omalizumab frequency to every other week, and full improvement followed.
The third patient was a woman aged 40 years with a history of urticaria around the insulin pump injection site that progressed to induration and abscess formation. These reactions began within a few months of initiating treatment.
SPT with various insulins produced large positive wheals and flares, the researchers said, although testing for metacresol was negative. Anti-insulin levels included 0.27 kUA/L for IgE and 67 kUA/L for IgG.
The patient began taking 1 g of rituximab twice a day in May 2022 and had faster injection site healing 2 months later, although indurations and pus persisted. In July 2022, the patient began 500 mg of mycophenolate twice a day, which increased to 1,000 mg twice a day and was joined by 300 mg of omalizumab every 4 weeks in October 2022.
There were improvements in inflammatory plaques by December 2022, and the patient was able to decrease her insulin requirement by 50% for the first time in years. Treatment with monthly omalizumab and daily mycophenolate continued.
The fourth patient was the woman aged 25 years who prompted the review. Her history included local urticaria, itching and pain with injections, in addition to pain and indurations that became sterile abscesses a few years after initiating pump treatment.
Positive intradermal testing included Humalog, Humulin, neutral protamine Hagedorn insulin and insulin glargine. Anti-insulin IgG testing yielded a result of 147 kUA/L, with a total IgE of 9 kUA/L. The patient began doses of 300 mg of omalizumab every 4 weeks in May 2023.
The patient has since reported less itching and burning at injection sites. Also, she has been able to decrease her basal insulin dose. She and her physicians are planning on repeating skin testing in 3 to 4 months.
Conclusions, next steps
Approximately 20% of the patients who presented to the clinic with “insulin allergy” labels had true immune-mediated insulin reactions, Yuan said.
“True reactions were supported by positive skin testing and positive anti-insulin antibodies, either IgG or IgE, on top of consistent clinical symptoms,” Yuan said.
Led by Robert G. Hamilton, PhD, MS, the Dermatology, Allergy and Clinical Immunology Reference Laboratory at Johns Hopkins Medicine can perform this testing, Yuan noted.
Among these four patients, Yuan continued, clinical symptoms fell into two categories: immediate-type IgE-mediated reactions such as urticaria, angioedema and erythema, and delayed-type IgG-mediated reactions that also might have inflammatory T cells, including lipodystrophy, thickened subcutaneous plaque or nodules.
Patients with the immediate phenotype responded well to anti-IgE therapy such as omalizumab, and those with delayed phenotype responded to anti-IgG therapy including rituximab and mycophenolate, Yuan said, adding that patients with a mixed phenotype benefited from treatment with both therapies.
“Previous studies have not provided such a framework for treatment. Most were case studies on the efficacy of singular agents,” Yuan said. “Our work adds some valuable information on how confirmation of the actual reaction phenotype guides proper management.”
Yuan also said that she and her colleagues hope that their work sheds light on insulin hypersensitivities, because these patients do exist and are struggling with daily reactions that affect their quality of life.
“From our clinical work, we know that there is no need for them to suffer. Diagnostic testing exists, and treatment works,” she said. “We hope our study enables better recognition of insulin hypersensitivities as an entity and provides a framework for guiding evaluation and treatment.”
Further, Yuan noted that many patients who present with “insulin allergy” really have dermatographic urticaria at baseline. Their skin has an underlying propensity for turning red and itchy when scratched or injected or when pressure is applied, she explained.
“This is likely the reason they are having problems with their insulin injections,” Yuan said. “This scenario may be more common than we realize and can be easily mitigated with the consistent use of antihistamines.”
Yuan and her colleagues plan on following these patients over time to monitor their treatment response. They also expect to continue using a consistent approach for evaluating future insulin allergy labels that present to their clinic.
“Each additional patient will help expand our knowledge on this rare condition,” Yuan said. “Over time, we hope to accumulate a larger patient panel and refine our diagnostic and treatment strategies.”