While treatments for patients with chronic spontaneous urticaria (CSU) have progressed significantly and have led to significant improvements for many over the last few decades, some patients may be refractory to several lines of therapy. Investigator clinicians at the 2024 Fall Clinical Dermatology Conference discussed treatment approaches that may be used in treatment-refractory patients to improve outcomes.

Following this presentation, featured expert Allen P. Kaplan, MD, was interviewed by Conference Reporter Associate Editor-in-Chief Christopher Ontiveros, PhD. Dr Kaplan’s clinical perspectives on these findings are presented here.

A presentation given by Brad P. Glick, DO, MPH, FAAD, David Lang, MD, FAAAAI, and Dawn L. Merritt, DO, FAAD, FAOCD, at the recent 2024 Fall Clinical Dermatology Conference focused on the evolution of treatment for CSU. Current guidelines speak to a stepwise approach to treatment, starting with the standard dose of a second-generation antihistamine. In patients who are unresponsive to the standard dose, the antihistamine can be updosed up to fourfold, although doing so is off-label. Even with dose escalation, however, refractoriness to antihistamines still occurs in about half of patients.

The next step of treatment is to add omalizumab to the antihistamine. Omalizumab is an excellent therapy that binds to circulating IgE and may also help counteract circulating IgG autoantibodies in patients with autoimmune CSU. Most of the patients who are antihistamine resistant respond to omalizumab when it is used optimally. Omalizumab is Food and Drug Administration (FDA) approved to be given at a dosage of 150 mg or 300 mg monthly (what is typically given). However, recent publications suggest that 300 mg can be given every 2 weeks or up to 600 mg monthly if patients are refractory or have a partial response. This is off-label but I think helps a lot of patients. A smaller number of people are refractory to both omalizumab and antihistamines. A subgroup of those who are refractory to omalizumab typically have low levels of IgE.

If someone is refractory to antihistamines in combination with omalizumab, the guidelines recommend stopping omalizumab and the off-label addition of the drug cyclosporine as the next step, and I agree with this completely. Cyclosporine is more difficult to handle, as it requires more patient monitoring because it has side effects, although it is also efficacious and many patients respond. If a patient is refractory to or has a partial response with cyclosporine, I would not alter the dose very much, and I do not exceed 3 mg/kg.

Refractoriness to second-generation antihistamines, omalizumab, and cyclosporine is uncommon and is more difficult to treat because we do not have any other reliable drugs to use if these fail. I may consider the off-label use of tacrolimus as an alternative to cyclosporine since its mechanism of action is so similar, but it has not been formally evaluated in a double-blinded placebo-controlled study in CSU. We tend not to use corticosteroids chronically the way we used to before omalizumab and cyclosporine were available. Corticosteroids are sometimes used for a few days for a particularly severe exacerbation of disease.

There are a lot of drugs on the horizon that I think could be helpful in treating refractory CSU, and several of these emerging therapies were discussed by Drs Glick, Lang, and Merritt during their presentation at the 2024 Fall Clinical Dermatology Conference. Dupilumab, which inhibits IL-4 and IL-13, may be close to being approved by the FDA. There is also the BTK inhibitor remibrutinib and the anti-KIT monoclonal antibody barzolvolimab, both of which act on mast cells and I think are promising.