Urticaria, with its characteristic pruritic weals and angioedema, can be frustrating for patients and a challenge for dermatologists to treat. No matter whether patients experience an acute or chronic case, urticaria can be a significant source of stress and decrease quality of life during a flare. However, a number of breakthroughs have been seen over the past few years, leading to satisfactory patient outcomes for chronic spontaneous urticaria (CSU).
Brian Berman, MD, PhD, is co-director of Center for Clinical and Cosmetic Research (Aventura, FL) and professor emeritus of dermatology and cutaneous surgery at University of Miami Miller School of Medicine. He is also the immediate past president of the American Dermatological Association as well as former vice president of the American Academy of Dermatology. He shared the critical information that dermatologists need to know about updates in the treatment and management of urticaria at the 2021 Winter Clinical Dermatology Conference.
What should dermatologists know about the latest updates in urticaria?
It is important to recognize that CSU, which is defined as at least 6 weeks of recurring or continuous bouts of urticarial lesions lasting less than 48 hours each, is associated with inducible urticarias, angioedema, and thyroid findings.
Approximately 40% of patients with CSU will have, in addition to their spontaneous hives, an inducible urticaria, including dermatographism, cholinergic, cold-induced, solar, aquagenic, exercise, or delayed pressure urticaria, the latter responding better to corticosteroids than antihistamines.
CSU is also associated with angioedema. In fact, in one study, two- thirds of patients with CSU had at least one episode of angioedema, primarily on the eyelids and lips, that was described as disturbing but never fatal. It is important to avoid angiotensin-converting enzyme (ACE) inhibitors in patients with CSU because ACE inhibitors can cause a nonallergic angioedema in up to 6% of patients. Angioedema develops because ACE inhibitors increase levels of bradykinin, a vasodilatory peptide causing tissue edema, by inhibiting its degradation. One should consider an alternate antihypertensive in these patients such as an angiotensin-receptor blocker.
Finally, approximately 25% of patients with CSU have thyroid findings including IgG antithyroglobulin and antithyroperoxidase, and there is an increased incidence of Hashimoto’s thyroiditis.
Is there anything in the pipeline for the management and treatment of urticaria that excites you?
More than half (52%) of patients with CSU treated every 4 weeks with 300-mg subcutaneous injection of omalizumab, which binds IgE, achieved complete clearance at 24 weeks.
Ligelizumab is the next generation, high-affinity, humanized monoclonal anti-IgE antibody. In a phase 2b, dose-finding trial, 382 patients with CSU were randomized to receive ligelizumab (24 mg, 72 mg, or 240 mg), omalizumab (300 mg), or placebo, administered subcutaneously every 4 weeks for a trial period of 20 weeks. Patients who received the highest dose of ligelizumab had about double the chance of achieving weekly hive severity, itch severity, and urticaria activity scores of zero compared with those treated with omalizumab. According to FDA guidelines, treatments that receive Breakthrough Therapy Designation must target a serious or life-threatening disease and demonstrate a potential substantial improvement over existing therapies on one or more significant clinical end points. Ligelizumab was granted an FDA Breakthrough Therapy Designation on January 14, 2021, for patients who have an inadequate response to H1 antihistamine treatment!
In a recent paper in New England Journal of Medicine, nine patients with CSU completed a 24-week study in which they received three monthly 30-mg subcutaneous injections of benralizumab (an anti–IL-5 receptor alpha antibody). Of these patients, five experienced a complete response (UAS7=0; no hives and no itch) and two had a partial response. There also was a sustained effect 8 weeks after the last dose of benralizumab. The further good news was that there were no drug-related adverse events.
Another new target against urticaria is Bruton tyrosine kinase (BTK), which is pivotally involved in activated IgE-FC receptor signal transduction, independent of how the FC receptor gets activated. In a controlled study, approximately 39% of patients with CSU had a complete response at the highest 200-mg twice a day dose of fenebrutinib. Potential treatment of various forms of urticaria with another BTK inhibitor, LOU064, is looking favorable as well.
What concerns, if any, are there regarding urticaria and COVID-19? Should dermatologists be on the lookout for these signs and symptoms?
The literature review by Algaadi assessed English-language studies and case reports that focused on urticaria in patients with COVID-19. A total of 30 papers met the inclusion criteria for the review, and among these publications, 202 patients had COVID- 19-associated urticaria. Patients were between the ages of 2 months and 84 years, and the majority of patients (64%) were women.
Approximately 55% of patients with a determined onset of COVID-19 had rash that preceded or occurred concurrently with classic COVID-19 symptoms. Urticarial rash was either generalized or found on the trunk. All reported cases with urticaria and COVID-19 responded favorably to antihistamines, as well as systemic and topical steroids.
A 73-patient study found that 66% (n=48) of patients with urticaria and COVID-19 had cough and 41% (n=30) had dyspnea. Another study of 27 patients with urticaria and COVID-19 reported that 59% of patients had cough and 41% had dyspnea. In additional studies consisting of 123 patients, 71% (n=88) had fever during the course of their disease.
References
1. Coutinho IA, Soares Regateiro F, et al. Refractory chronic urticaria in adults: clinical characterization and predictors of severity. Allergy Asthma Clin Immunol. Published online November 11, 2020. doi:10.1186/s13223-020-00496-0
2. Sánchez J, Amaya E, Acevedo A, Celis A, Caraballo D, Cardona R. Prevalence of inducible urticaria in patients with chronic spontaneous urticaria: associated risk factors. J Allergy Clin Immunol Pract. 2017;5(2):464-470. doi:10.1016/j.jaip.2016.09.029
3. Hon KL, Leung AKC, Ng WGG, Loo SK. Chronic urticaria: an overview of treatment and recent patents. Recent Pat Inflamm Allergy Drug Discov. 2019;13(1):27-37. doi:10.2174/1872213X13666190328164931.
4. Maurer M, Weller K, Bindslev-Jensen C, et al. Unmet clinical needs in chronic spontaneous urticaria. A GA²LEN task force report. Allergy. 2011;66(3):317-330. doi:10.1111/j.1398-9995.2010.02496.x.
5. Powell RJ, Leech SC, Till S, Huber PAJ, Nasser SM, Clark AT. BSACI guideline for the management of chronic urticaria and angioedema. Clin Exp Allergy. 2015;45(3):547-565. doi:10.1111/cea.12494
6. Kanani A, Betschel SD, Warrington R. Urticaria and angioedema. Allergy Asthma Clin Immunol. 2018;14(Suppl 2):59. doi:10.1186/s13223-018-0288-z
7. Kolkhir P, Metz M, Altrichter S, Maurer M. Comorbidity of chronic spontaneous urticaria and autoimmune thyroid diseases: a systematic review. Allergy. 2017;72(10):1440-1460. doi:10.1111/all.13182
8. Casale TB, Win PH, Bernstein JA, et al. Omalizumab response in patients with chronic idiopathic urticaria: insights from the XTEND-CIU study. J Am Acad Dermatol. 2018;78(4):793-795. doi:10.1016/j.jaad.2017.10.010
9. Maurer M, Giménez-Arnau A, Sussman G, et al. Ligelizumab for chronic spontaneous urticaria. New Engl J Med. 2019;381(14):1321-1332. doi:10.1056/NEJMoa1900408
10. Ligelizumab receives FDA breakthrough therapy designation. The Dermatologist. Accessed January 19, 2021. https://www.the-dermatologist.com/news/ligelizumab-receives-fda-breakthrough-therapy-designation
11. Bernstein JA, Singh U, Rao MB, Berendts K, Zhang X, Mutasim D. Benralizumab for chronic spontaneous urticaria. New Engl J Med. 2020;383(14):1389-1391. doi:10.1056/NEJMc2016395
12. Kolkhir P, Altrichter S, Munoz M, Hawro T, Maurer M. New treatments for chronic urticaria. Ann Allergy Asthma Immunol. 2020;124(1):2-12. doi:10.1016/j.anai.2019.08.014
13. Algaadi SA. Urticaria and COVID-19: a review. Dermatol Ther. 2020;33(6):e14290. doi:10.1111/dth.14290
