When Hives Do Not Quit: A Practical Update on Chronic Spontaneous Urticaria

A 34-year-old teacher arrives in clinic exhausted. For the last 3 months, she has woken most nights with intensely pruritic wheals scattered across her trunk and extremities. The lesions rise, itch, and fade within a day, only to recur elsewhere. Twice a week, her lips and eyelids swell. She has tried rotating nondrowsy antihistamines at label doses with little relief and now avoids exercise and social plans because flare-ups feel inevitable. There is no obvious trigger, no new medications, and no history suggesting food allergy. She looks to you for an explanation and, more importantly, for control.

What Is Chronic Spontaneous Urticaria?

Chronic spontaneous urticaria (CSU) is defined by the unprompted appearance of wheals, angioedema, or both, on most days for at least 6 weeks, without a consistent external trigger. It is distinguished from chronic inducible urticaria (CIndU), in which physical or environmental stimuli such as pressure, cold, heat, or cholinergic stimuli reproducibly elicit lesions. The distinction matters: Many patients have both, but management and counseling for CIndU rely on identifying and minimizing specific triggers, whereas CSU management focuses on suppressing mast cell–driven activity and achieving durable control in the absence of a single culprit exposure.

Consensus guidelines emphasize a targeted history and examination to rule out mimics such as urticarial vasculitis, bradykinin-mediated angioedema, and autoinflammatory syndromes, with limited baseline laboratory tests in most patients.¹

How Common Is It?

Acute urticaria is common, but CSU is the chronic subset that erodes quality of life and productivity. Globally, CSU affects approximately 0.5% to 1% of the population at any given time, with variation across regions and study designs.² Recent US data suggest diagnosed prevalence to be roughly between 0.1% and 0.3% in claims-based cohorts, with higher estimates (~0.8%) when based on surveys or electronic health records, underscoring the mix of underdiagnosis and coding differences in routine care.^3,4 Regardless of method, CSU is more common in women and often affects adults in their working years.

Two Autoimmune Endotypes

The modern view recognizes CSU as a mast cell–driven disease with 2 overlapping autoimmune endotypes. Type I (autoallergic) CSU involves IgE antibodies directed against self-antigens that cross-link FcεRI via IgE. Type IIb (autoimmune) CSU involves IgG (or IgM) autoantibodies against FcεRI or IgE that directly activate mast cells and basophils. Patients with a type IIb endotype often have lower total IgE levels, higher rates of angioedema, and more severe or refractory disease, which can influence expectations and the pace of escalation. This endotype framing helps explain why therapies that lower IgE signaling or mast cell activation meaningfully change the course for many patients.⁵

Where Traditional Therapy Falls Short

Guidelines recommend a stepwise approach that starts with a modern, second-generation H₁ antihistamine at standard dose, titrating up to 4-fold if needed. This strategy is safe, but many patients remain symptomatic, particularly at night, and sedation risk increases when patients self-add first-generation agents. Leukotriene receptor antagonists and H₂ blockers offer modest benefit for a subset of patients, but evidence is limited. Short oral corticosteroid bursts may help an acute flare, but repeated or prolonged courses carry familiar systemic risks and are not disease modifying. For the teacher in our opening vignette, label-dose antihistamines were not enough, which is a common inflection point in CSU care.¹

Targeted and Advanced Therapies

Omalizumab (Xolair), an anti-IgE monoclonal antibody, transformed refractory CSU care and remains a bedrock second-line biologic after high-dose second-generation antihistamines. It is approved in patients 12 years and older who remain symptomatic despite H₁ antihistamines, with recommended dosing of 150 or 300 mg subcutaneously every 4 weeks. In clinical practice, many patients respond rapidly, and dose escalation strategies are supported by real-world experience for partial responders.⁶

In April 2025, dupilumab (Dupixent) became the first new targeted therapy for CSU in more than a decade, approved for patients 12 years and older who remain symptomatic on H₁ antihistamines. Dupilumab binds IL-4 receptor alpha to block IL-4 and IL-13 signaling, key drivers of type 2 inflammation. The label outlines induction and every-2-week maintenance dosing under the CUPID program, with phase 3 data demonstrating significant improvements in itch and urticaria activity by week 24 compared with placebo. For clinicians, dupilumab offers an additional nonsedating, home-injectable option with a safety profile familiar to its other indications.⁷

In September 2025, remibrutinib (Rhapsido), an oral Bruton tyrosine kinase (BTK) inhibitor, received FDA approval for CSU inadequately controlled on standard therapies. BTK, a TEC kinase family member, integrates proximal signaling downstream of FcεRI on mast cells and basophils. Given this central mechanism of BTK, remibrutinib has demonstrated consistent and broad clinical efficacy across CSU endotypes (ie, IgE high, IgE low). In late-stage trials, remibrutinib produced early and meaningful reductions in itch and hives. With a convenient twice-daily oral regimen and without routine laboratory monitoring requirements, remibrutinib offers a targeted, safe, noninjectable alternative that will likely expand access for patients who prefer pills over injections.⁸

Clinicians and patients with CSU alike want to know: How fast can remibrutinib work? For some patients in the phase 3 REMIX-1 (NCT05030311) and REMIX-2 (NCT05032157) trials, it was like a race car, with significant reductions in UAS7 scores (ie, Urticaria Activity Scores over 7 days) as early as week 1. I have witnessed this already in my clinic, when a patient who had inadequate response to prior biologics saw her hives and itch disappear within 90 minutes after her first dose. Her words: “Is this real? Can it really be true?”

Cyclosporine remains an available third-line option in guidelines, particularly in severe disease or when biologics are unavailable, but monitoring and adverse events profiles limit its long-term use for many. Intravenous immunoglobulin and other immunomodulators have been studied in small series and are not routine. The expanding set of targeted therapies makes it increasingly feasible to avoid chronic corticosteroids, which should remain short, sparing interventions.

A Practical, Patient-Centered Sequence

For our teacher, I would confirm the diagnosis with a focused history and exam, screen for red flags that suggest alternative diagnoses, and keep baseline laboratory tests lean. If she is on a standard-dose second-generation H₁ antihistamine such as cetirizine (Zyrtec), fexofenadine (Allegra), or loratadine (Claritin), I would escalate to up to 4-fold daily dosing for 2 to 4 weeks, taken consistently. If control remains inadequate, I would introduce a targeted therapy.

Choice among advanced therapies should account for comorbidities, patient preference for route of administration, speed of onset, insurance realities, and pregnancy plans. Omalizumab has the longest CSU track record and every-4-week dosing. Dupilumab offers every-2-week dosing with broad experience across dermatologic and respiratory diseases. Remibrutinib brings a convenient oral mast cell–centric option with rapid symptom relief in trials.⁸ Shared decision-making that honestly addresses practical trade-offs will improve adherence, satisfaction, and outcomes.

I also counsel patients that CSU is often self-limited over years but that relapsing courses occur. The goal is full control: Urticaria Control Test scores should guide us toward zero itch and zero hives, not mere “tolerable” disease. I set a tight follow-up to judge response at 2 to 4 weeks after any step change. If we choose a biologic or BTK inhibitor, I plan reassessments at 3 and 6 months, with a long-term view toward maintaining control for a symptom-free life and tapering when appropriate.

Closing Thoughts

CSU is a quality-of-life emergency masquerading as a rash. It interrupts sleep, erodes concentration, and isolates patients socially. Fortunately, the toolbox has expanded for dermatology providers, equipping us with all the therapies we need to care for patients with CSU in our dermatology clinics. High-dose modern antihistamines are still the first rung, but we should not linger there long when patients remain symptomatic. With omalizumab, dupilumab, and now oral remibrutinib, we can tailor therapy to biology and patient preference while avoiding the harms of chronic corticosteroids.

The message to our patients with CSU can be simple and hopeful: There is a path to complete control, and we will take it.

References

1. 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

2. 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

3. Geissbühler Y, Balp MM, McConnon A, et al. Incidence and prevalence of chronic spontaneous urticaria among adult and pediatric populations in the United States. Adv Ther. 2025;42(6):2808-2820. doi:10.1007/s12325-025-03172-0

4. Soong W, Patil D, Rodrigues J, et al. Clinical profile, prevalence, and burden of chronic spontaneous urticaria in the United States. World Allergy Organ J. 2025;18(8):101081. doi:10.1016/j.waojou.2025.101081

5. Kolkhir P, Muñoz M, Asero R, et al. Autoimmune chronic spontaneous urticaria. J Allergy Clin Immunol. 2022;149(6):1819-1831. doi:10.1016/j.jaci.2022.04.010

6. Xolair. Prescribing information. Genentech Inc; 2024. Accessed November 10, 2025. www.gene.com/download/pdf/xolair_prescribing.pdf

7. Dupixent. Prescribing information. Regeneron Pharmaceuticals Inc; 2025. Accessed November 10, 2025. www.accessdata.fda.gov/drugsatfda_docs/label/2025/761055s051lbl.pdf

8. Rhapsido. Prescribing information. Novartis Pharmaceuticals Corporation; 2025. Accessed November 10, 2025. www.novartis.com/us-en/sites/novartis_us/files/rhapsido.pdf.