Allergy & Immunology

Chronic Spontaneous Urticaria

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The Role of Immunosuppressive Therapy in the Treatment of Chronic Spontaneous Urticaria

clinical topic updates by Allen P. Kaplan, MD
Overview

Most patients with chronic spontaneous urticaria (CSU) will respond to recommended first- or second-line therapies; however, those who do not respond to standard therapies have limited options. For those hard-to-treat patients, other immunosuppressive medications may be considered, although robust data supporting the consistent efficacy of these drugs are lacking.

Expert Commentary
“I really believe that the CSU therapies of the future will be drugs that target the inhibition of mast cell secretion.”
— Allen P. Kaplan, MD

Nearly half of patients with CSU can be treated successfully with antihistamines. Approximately 70% of patients who do not respond to antihistamines will respond to omalizumab, and, of those who do not respond to an antihistamine or to omalizumab, approximately 70% will respond to cyclosporine. Individuals who do not respond to any of these 3 therapies account for probably less than 10% of patients with CSU.

 

For these patients, there is not good evidence that methotrexate will work, and mycophenolate has also not been properly studied. Mycophenolate is a favorite drug for the treatment of a lot of autoimmune diseases, and some health care providers like trying it in patients with CSU because it has a little less toxicity and is therefore easier to use than cyclosporine. You may try it in somebody who has failed everything else, but data showing that mycophenolate works specifically in those with CSU do not exist. So, most treatments that have been tried in patients with CSU are ineffective. In fact, in 50 years, we really have only found 3 treatments that work well.

 

Cyclophosphamide is efficacious in CSU; however, given its side-effect profile, new, effective, and less toxic agents would be welcome. Rituximab may work, although there is currently not any high-quality evidence to support its use in CSU. In addition, in my opinion, it is too toxic to be seriously considered. Further, as bad as the morbidity associated with CSU is, the mortality rate is 0. Drugs such as cyclophosphamide or rituximab are appropriate for other autoimmune diseases that have substantial mortality associated with them, such as systemic lupus erythematosus.

 

I do occasionally use tacrolimus in patients who fail recommended therapies. Like mycophenolate, it has never been properly studied in CSU, but tacrolimus is very much like cyclosporine. Mechanistically, they overlap, and tacrolimus is probably a little easier to use, and its side-effect profile is a little bit better than that of cyclosporine.

 

Bear in mind, mycophenolate acts on T lymphocytes, as does cyclosporine, but cyclosporine inhibits secretion by mast cells and basophils. Tacrolimus shares this effect with cyclosporine, whereas none of the other immunosuppressive agents affect mast cells and basophils. That may relate to their lack of efficacy.

 

I really believe that the CSU therapies of the future will be drugs that target the inhibition of mast cell secretion. There are several agents that are being studied. The investigational therapy barzolvolimab is one such agent that has shown promise in early studies in both CSU and chronic inducible urticaria. Barzolvolimab inhibits the activity of KIT, a receptor required for mast cell survival and function, and one effect is to actually deplete mast cells. Another category of therapies that is being investigated are inhibitors of BTK, which is an enzyme required for mast cell function. By inhibiting BTK, mast cells become less responsive to activating stimuli. In short, rather than solely relying on our current standard immunosuppressive therapies for CSU, I would say that targeted, mast cell–suppressive agents are the way of the future.

References

Dai A, Kim SJ. Systemic calcineurin inhibitors tacrolimus and voclosporin: a review of off-label dermatologic uses. J Am Acad Dermatol. 2024;90(2):358-367. doi:10.1016/j.jaad.2023.05.074

 

Kaplan AP. Treatment of urticaria: a clinical and mechanistic approach. Curr Opin Allergy Clin Immunol. 2019;19(4):387-392. doi:10.1097/ACI.0000000000000538

 

Maurer M, Berger W, Giménez-Arnau, et al. Remibrutinib, a novel BTK inhibitor, demonstrates promising efficacy and safety in chronic spontaneous urticaria [published correction appears in J Allergy Clin Immunol. 2023;151(2):579]. J Allergy Clin Immunol. 2022;150(6):1498-1506.e2. doi:10.1016/j.jaci.2022.08.027

 

Tauber PA, Pickl WF. Pharmacological targeting of allergen-specific T lymphocytes. Immunol Lett. 2017;189:27-39. doi:10.1016/j.imlet.2017.03.010

 

Terhorst-Molawi D, Hawro T, Grekowitz E, et al. Anti-KIT antibody, barzolvolimab, reduces skin mast cells and disease activity in chronic inducible urticaria. Allergy. 2023;78(5):1269-1279. doi:10.1111/all.15585

 

Zuberbier T, Abdul Latiff AH, Abuzakouk M, et al. The international EAACI/GA²LEN/EuroGuiDerm/APAAACI guideline for the definition, classification, diagnosis, and management of urticaria. Allergy. 2022;77(3):734-766. doi:10.1111/all.15090

Allen P. Kaplan, MD

    Professor
    Department of Medicine
    Medical University of South Carolina
    Charleston, SC
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