Calling All Derms! Chronic Spontaneous Urticaria Is For You!

At the 2024 ODAC Dermatology, Aesthetic & Surgical Conference, we were lucky to learn about the management of chronic spontaneous urticaria (CSU) from the renowned researcher and clinician, Dr. Adam J. Friedman, Professor and Chair of Dermatology at The George Washington University School of Medicine and Health Sciences. CSU can be a frustrating, exhausting condition for patients to endure, with no identifiable triggers and a relapsing disease course. Caring for CSU requires particularly strong patient-provider trust, given that symptoms are often absent during the clinical visit and that adjustments to the regimen can often be required to minimize breakthrough symptoms. Dr. Friedman emphasized a call to action for dermatologists to take ownership of managing patients with CSU, sharing his expertise about clinching the diagnosis, the current treatment options, and the future landscape of promising therapies.

Diagnosis

Urticaria is frequently misdiagnosed, with average time to diagnosis up to 2 years! Patients tend to describe a wide range of skin findings as “hives,” so clarifying follow-up questions can be key to pinpointing true urticaria. Dr. Friedman noted that the quality of the pruritus is classically a burning itch, with each single lesion “moving” to different locations on the body and never persisting in one area for more than 24 hours. Distinguishing between acute urticaria with episodes lasting less than 6 weeks and chronic urticaria with episodes lasting longer is important because triggers are more likely to be identified with acute urticaria. Common triggers can be broken down into the categories of food, bug, or drug. Specific foods associated include milk, egg, peanut, wheat, soy, and red and yellow food dye. Exposure to common viruses such as mycoplasma, adenovirus, enterovirus, and respiratory syncytial virus has been implicated, particularly in children. Medications, such as opiates, muscle relaxants, salicylates, and sympathomimetics, can cause urticaria through direct mast cell activation. Separately, chronic urticaria can be broken down into subtypes, such as physical urticaria secondary to heat, exercise, cold, water, pressure, vibration, and sun exposure.

Dr. Friedman recommends patients keep a diary and snap photos before the first medical visit and in between follow-up visits. In the office, provocative tests, such as an ice cube to the skin or a set of jumping jacks, can help explore common physical urticarias, such as cold-induced or exercise-induced urticaria. Consensus guidelines advise against a barrage of lab tests for CSU.^1-3 If angioedema is present, screening with C3 and C4 levels is reasonable. If suspicion is high for a specific allergen, allergy testing such as patch testing can be considered. The transient nature of active lesions limits the utility of a biopsy, but a biopsy should be considered if individual lesions are lasting more than 48 hours, are atypical, and have been refractory to therapy.

Management

Various consensus guidelines have been published by different medical expert groups, but common themes run throughout each of them. Treatment should be escalated quickly to achieve clearance, followed by stepping up or stepping down to the minimum amount of medication needed to sustain symptom remission.^1-3 Monotherapy with H1 antihistamines is first-line, with the option to safely escalate to fourfold the standard dose.^1-3 Dr. Friedman noted that he tends to opt for the non-sedating second-generation antihistamines for most patients to minimize the risk of drowsiness with increased doses.  He emphasized that monotherapy with antihistamines can be highly effective for many patients, with a double-blinded randomized clinical trial showing that the addition of prednisone 40mg daily for 4 days to levocetirizine 5mg daily for 5 days did not improve the symptomatic and clinical response of acute urticaria without angioedema.⁴

Targeting free IgE with subcutaneous omalizumab is 2^nd-line therapy for CSU.^1-3 Pre-treatment IgE level and weight no longer dictate the dosing, with up to 300mg every 4 weeks approved by the United States Food and Drug Administration for CSU.⁵ Beyond-label doses of 450mg or 600mg every 4 weeks can be considered in cases of partial response.^6,7 Omalizumab should be administered in a medical office with an epinephrine autoinjector available for the first 3 doses, and subsequent doses can be self-administered if no concerns for anaphylaxis from the initial doses.⁵ Cyclosporin and mycophenolate mofetil are third-line options in cases of minimal response to antihistamines and anti-IgE monoclonal antibody or coverage exclusions. Oral modified cyclosporin 3-5mg/kg/day shows efficacy for recalcitrant CSU.⁸ Mycophenolate mofetil can be a long-term option that can be gradually titrated up and down for symptom control.⁹ Notably, the European consensus guidelines no longer recommend H2 and leukotriene antagonists due to insufficient evidence.¹

Future Directions

Our understanding of the underlying pathophysiology of CSU is evolving, with experts now postulating a role for the TH2 inflammatory pathway rather than simply a process driven by mast cells and histamine release. About 20% of CSU patients do not respond to increased doses of H1 antihistamines, and about half of these patients eligible for omalizumab either do not respond¹⁰ or experience a significant delay in therapy. Dr. Friedman declared, “The future is flaring,” recognizing the ongoing clinical trials for medications targeting IL-5, IgE production through IL-4 and IL-13, JAK-1, and Bruton’s tyrosine kinase. These promising therapies can help address the unmet needs for a large subset of patients with CSU. Some of these medications are already used in dermatology for other indications, highlighting the opportunity for dermatologists to be an integral part of CSU management.

In conclusion, CSU can have debilitating effects on quality of life, with persistence beyond 5 years for about 20% of patients.¹¹ Patients’ history, along with their notes and photos, can clinch the diagnosis and identify plausible triggers. Consensus guidelines from multiple expert groups can help climb the therapeutic ladder to aim for symptom clearance.

References

1. 1. Zuberbier T, Abdul Latiff AH, Abuzakouk M, et al. The international EACI/GA²LEN/EuroGuiDerm/APAAACI guideline for the definition, classification, diagnosis, and management of urticaria. Allergy. 2022 Mar;77(3):734-766. PMID: 34536239.
   2. Bernstein JA, Lang DM, Khan DA, et al. The diagnosis and management of acute and chronic urticaria: 2014 update. J Allergy Clin Immunol. 2014 May;133(5):1270-7. PMID: 24766875.
   3. Sabroe RA, Lawlor F, Grattan CEH, et al; British Association of Dermatologists’ Clinical Standards Unit. British Association of Dermatologists guidelines for the management of people with chronic urticaria 2021. Br J Dermatol. 2022 Mar;186(3):398-413. Epub 2022 Jan 27. PMID: 34773650.
   4. Barniol C, Dehours E, Mallet J, et al. Levocetirizine and prednisone are not superior to levocetirizine alone for the treatment of acute urticaria: a randomized double-blind clinical trial. Ann Emerg Med. 2018 Jan;71(1):125-131.e1. PMID: 28476259.
   5. XOLAIR [prescribing information]. Genentech USA, Inc. and Novartis Pharmaceuticals Corporation; 2021. Accessed April 20, 2024.
   6. Al-Shaikhly T, Rosenthal JA, Ayars AG, Petroni DH. Omalizumab for chronic urticaria in children younger than 12 years. Ann Allergy Asthma Immunol. 2019 Aug;123(2):208-210.e2. PMID: 31082483.
   7. Sussman G, Hébert J, Gulliver W, et al. Omalizumab re-treatment and step-up in patients with chronic spontaneous urticaria: OPTIMA trial. J Allergy Clin Immunol Pract. 2020 Jul-Aug;8(7):2372-2378.e5.
   8. Kulthanan K, Chaweekulrat P, Komoltri C, et al. Cyclosporine for chronic spontaneous urticaria: a meta-analysis and systematic review. J Allergy Clin Immunol Pract. 2018;6:586–99. PMID: 28916431.
   9. Zimmerman AB, Berger EM, Elmariah SB, Soter NA. The use of mycophenolate mofetil for the treatment of autoimmune and chronic idiopathic urticaria: experience in 19 patients. J Am Acad Dermatol. 2012 May;66(5):767-70. PMID: 21783274.
   10. Ertas R, Ozyurt K, Atasoy M, Hawro T, Maurer M. The clinical response to omalizumab in chronic spontaneous urticaria patients is linked to and predicted by IgE levels and their change. Allergy. 2018 Mar;73(3):705-712. PMID: 29083482.
   11. Weller K, Siebenhaar F, Hawro T, et al. Clinical measures of chronic urticaria. Immunol Allergy Clin North Am. 2017 Feb;37(1):35-49. PMID: 27886909.

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“Chronic spontaneous urticaria” by Allergyresearch is licensed under CC BY 4.0.

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