How do I identify and treat Chronic Spontaneous Urticaria?
Medically reviewed on 5.1.2025 by Nick Brownstone, MD
Update since this article was written: On 4/18/25 the US FDA approved dupilumab for the treatment of chronic spontaneous urticaria in patients aged 12 years and older who have not previously reached controlled disease status with H1 antihistamine treatment.
Chronic spontaneous urticaria is defined as the occurrence of wheals and/or angioedema for a total duration of 6 weeks or more. The female to male ration is 2:1 and peak onset is between 20 to 40 years of age. Chronic spontaneous urticaria (CSU) and chronic inducible urticaria (CIU) affect somewhere between 0.5-1% of the population, so this is something you likely see in your dermatology practice.
The good news is 45-55% of patients will go into remission within the first 12 months, but 11% will have symptoms for > 5 years. And even those who have CSU for a year or two can suffer immensely during that time with itch and lack of sleep.
CSU is a clinical diagnosis. An individual wheal should resolve within 24 hours. If a patient is unsure how long their individual hives are lasting, circle a lesion during your exam and have them monitor and time its disappearance. If an individual wheal lasts > 24 hours you should consider urticarial vasculitis and do a couple punch biopsies including a DIF. Also consider autoinflammatory disorders like cryopyrin-associated periodic syndromes, which present in childhood, and Schnitzler syndrome in adult patients who exclusively get wheals (but not angioedema) by asking about recurrent unexplained fevers, joint/bone pain, and malaise.
In patients who exclusively get angioedema, ask about ACE inhibitor treatment. The patient’s ACE-inhibitor medication could still be the cause even if they were on it for many years prior to the angioedema starting. Also ask about age of onset or family history of angioedema since hereditary angioedema will typically present in childhood and usually other family members will also have HAE. Are the hives inducible by heat? Cold? The sun? Exercise? If so, they may have a chronic inducible urticaria.
Although the international EAACI/GA²LEN/EuroGuiDerm/APAAACI guideline recommends (but doesn’t require) ordering a CBC w/ diff, ESR and/or CRP, IgG anti-TPO and total IgE, many leading dermatology experts in urticaria treatment don’t find these tests necessary in establishing the diagnosis of CSU and getting the patient started on effective treatments as long as a good history and exam are performed.
By the time many of these patients present in your office, they are usually already on a 2nd generation antihistamine like cetirizine or fexofenadine. But only 40% of CSU patients will get control of their symptoms with just once daily dosing. What the above guideline recommends is quickly up-dosing to QID. But since most patients have a hard time complying with taking a pill four times a day, many of us just have our patients take two pills in the morning and two in the evening. If within a week or two the patient still isn’t getting good control of their hives on this regimen, I am quick to initiate omalizumab (Xolair) injections which were approved in 2014 for CSU and therefore have some great data behind them. I start at 300mg a month, and if good control is not achieved by 3 months, the guideline now recommends up-titrating to up to 600mg q2 weeks. I would start by up-titrating to 600mg monthly for three months first. Typically, patients with higher IgE levels will respond quickest to omalizumab. Those with lower IgE levels may need a higher dose to get control of their hives.
The package insert recommends the first three doses of omalizumab be given in the provider’s office, but after that the patient can do their injections at home. Many experts recommend watching the patient for 2 hours after their first injection, then 30 minutes after their second and third injections as your office should have an epi pen on hand. The anaphylaxis rate in the trials was quite low, however, at just 0.2% of patients.
If after 6 months the patient is completely clear, taper down their antihistamine dose. If the hives come back then return to the antihistamine dose where they last had it under control. If a patient becomes well-controlled on just one antihistamine a day, you may then be able to taper them off their omalizumab as well.
A good way to measure if the patient is having a good response is by administering the urticaria control test in your office. This is a survey of four simple questions: 1) How much have you suffered from the physical symptoms of the urticaria (itch, hives, and/or swelling) in the last four weeks? 2) How much was your quality of life affected by the urticaria in the last four weeks? 3) How often was the treatment for your urticaria in the last four weeks not enough to control your urticaria symptoms? 4) Overall, how well have you had your urticaria under control in the last four weeks? They answer these questions as either 1) not at all 2) a little 3) well or 4) very well.
Although omalizumab is off-label for the inducible urticarias (such as the cholinergic, cold, heat, pressure, sunlight and vibrational-induced urticarias as well as dermatographism), it has been shown in a systematic review of published evidence to be helpful for CIU as well.
Coming down the pipeline there will be some other potential treatments for CSU. One is dupilumab, which I’m sure many of us are already familiar with for its use in atopic dermatitis and prurigo nodularis. Another is remibrutinib, an oral BTK inhibitor which has an intracellular mechanism of action which means a patient’s IgE levels won’t influence its effectiveness to block mast cell activation and prevent histamine release.
References:
Zuberbier T, Maurer, M. The international EAACI/GA2LEN/EuroGuiDerm/APAAACI guideline for the definition, classification, diagnosis, and management of urticaria. Allergy. September 2021, 77 (3) 734-766; DOI https://doi.org/10.1111/all.15090
Maurer M et al. Dupilumab in patients with chronic spontaneous urticaria (LIBERTY-CSU CUPID): Two randomized, double-blind, placebo-controlled, phase 3 trials. J Allergy Clin Immunol. 2024 July.
Maurer M et al. Remibrutinib, a novel BTK inhibitor, demonstrates promising efficacy and safety in chronic spontaneous urticaria. J Allergy Clin Immunol. 2022 Dec.
Marcus Maurer et al. Omalizumab treatment in patients with chronic inducible urticaria: A systematic review of published evidence. J Allergy Clin Immunol. 2018 Feb.
Antia C et al. Urticaria: A comprehensive review: Epidemiology, diagnosis, and work-up. J Am Acad Dermatol. 2018 Oct.
Maurer M et al. Unmet clinical needs in chronic spontaneous urticaria. A GA2LEN task force report. Allergy. 2011 March.
