Chronic Spontaneous Urticaria: Evidence-Based Management Update

A recent clinical management review on chronic spontaneous urticaria (CSU) highlighted ongoing challenges in optimizing treatment due to variable triggers, heterogeneous treatment responses, and limited data for special populations. CSU is defined by spontaneous wheals, angioedema, or both lasting more than 6 weeks, affecting up to 1% of the population and significantly impairing quality of life.¹ Two autoimmune mechanisms have been proposed: type 1 (autoallergic CSU) involving IgE autoantibodies against self-antigens, and type 2b (autoimmune CSU) with IgG autoantibodies against FcεRI or IgE, leading to mast cell activation.²

Trigger Avoidance

The review emphasized a stepwise, personalized approach consistent with updated international guidelines. Nonpharmacologic strategies remain key. Common exacerbating factors include NSAIDs, opioids, alcohol, stress, sleep deprivation, sex hormones, infections, and physical stimuli. NSAID sensitivity occurs in up to one-third of patients, though reproducible reactions are seen in ~20%.³ Selective COX-2 inhibitors or low-dose aspirin may be tolerated; avoidance or careful challenge is recommended for suspected NSAID-induced flares.⁴ Evidence for dietary triggers, histamine-rich foods, or alcohol is limited, but patient education and symptom monitoring are essential. Digital tools like the CRUSE app can assist in tracking triggers and disease activity.

First-Line Therapy: Second-Generation H1-Antihistamines (sgAHs)

Second-generation H1-antihistamines remain the cornerstone of first-line therapy.¹ They act as inverse agonists at H1 receptors, stabilizing mast cells. Common agents include cetirizine, fexofenadine, loratadine, desloratadine, bilastine, levocetirizine, rupatadine, and ebastine. Approximately 50% of patients respond to standard doses; dose escalation up to 4-fold is safe and recommended for persistent symptoms.⁴ Combination therapy of multiple antihistamines does not offer additional benefit over high-dose monotherapy. Disease activity should be assessed with validated tools such as UAS7 and UCT to guide dose adjustments and monitor response.

Second-Line Therapy: Omalizumab

For antihistamine-refractory CSU, omalizumab is the cornerstone biologic. It is a humanized anti-IgE monoclonal antibody that prevents mast cell and basophil activation. Recommended dosing is 300 mg every four weeks, achieving minimal disease activity in ~65% of patients within three months; real-world effectiveness can reach 85%, with 57% achieving complete response.⁵ Response patterns vary: fast (1–4 weeks, 60–70%), slow (3–6 months, 15–20%), and nonresponse (5–10%).⁶ Insufficient control may warrant off-label dose escalation to 450–600 mg or shortening intervals.⁴ Discontinuation should involve gradual interval tapering; 40–50% relapse within 3–6 months, with retreatment highly effective.⁴ Predictors of response include higher baseline IgE and FcεRI overexpression, whereas low IgE, autoimmune markers, and elevated CRP or D-dimer suggest poorer outcomes.

Third-Line Therapy: Cyclosporine A (CsA)

CsA is indicated for refractory disease, especially autoimmune CSU. It inhibits T-cell activation and IgE-mediated mast cell activity. Low to moderate doses (1–5 mg/kg/day, typically starting at 3 mg/kg/day) are effective, with dose-related adverse events including hypertension and nephrotoxicity.⁷ Response is rapid, often within weeks, with sustained remission possible. Tapering involves reducing the dose by 1 mg/kg every 2 weeks once disease control is achieved.⁷ Predictors of favorable response include positive basophil activation or histamine release assays, elevated D-dimer, and low total IgE.

Special Populations

Tailored approaches are required for pediatric, pregnant, and elderly patients. Pediatric CSU shows lower angioedema rates and higher remission; standard sgAHs remain first-line, with up-dosing and omalizumab for refractory cases.⁴ CsA is used cautiously in older children. In pregnancy, loratadine, cetirizine, levocetirizine, desloratadine, and fexofenadine are preferred; omalizumab may be considered for refractory disease, and CsA is reserved for severe cases under supervision.⁴ Elderly patients are more susceptible to antihistamine side effects, polypharmacy, and comorbidities; sgAH stepwise therapy is standard, with biologics and CsA reserved for refractory cases.⁴

Conclusion

The review reinforces the importance of early, stepwise, and personalized management of CSU. Trigger avoidance, judicious use of sgAHs, timely escalation to omalizumab, and careful use of CsA in refractory cases provide a framework for optimal care. Regular disease activity monitoring and individualized adjustments remain critical, particularly in special populations. Continued research is needed to refine biomarkers, dosing strategies, and discontinuation protocols.

Isabella J. Tan is a third-year medical student at Rutgers Robert Wood Johnson Medical School in New Brunswick, New Jersey.

References

1. Bernstein JA, Lang DM, Khan DA, et al. The diagnosis and management of acute and chronic urticaria: 2014 update. J Allergy Clin Immunol. 2014;133(5):1270-1277. doi:10.1016/j.jaci.2014.02.036
2. Zuberbier T, Ensina LF, Giménez-Arnau A, et al. Chronic urticaria: unmet needs, emerging drugs, and new perspectives on personalised treatment. Lancet. 2024;404(10450):393-404. doi:10.1016/S0140-6736(24)00852-3
3. Li L, Bensko J, Buchheit K, Saff RR, Laidlaw TM. Safety, outcomes, and recommendations for two-step outpatient nonsteroidal anti-inflammatory drug challenges. J Allergy Clin Immunol Pract. 2022;10(5):1286-1292.e2. doi:10.1016/j.jaip.2021.11.006
4. Kocatürk E, Chu DK, Türk M, et al. Management of chronic spontaneous urticaria made practical: What every clinician should know. J Allergy Clin Immunol Pract. Published online July 21, 2025. doi:10.1016/j.jaip.2025.07.021
5. Maurer M, Rosén K, Hsieh HJ, et al. Omalizumab for the treatment of chronic idiopathic or spontaneous urticaria. N Engl J Med. 2013;368(10):924-935. doi:10.1056/NEJMoa1215372
6. Mosnaim G, Casale TB, Holden M, Trzaskoma B, Bernstein JA. Characteristics of patients with chronic spontaneous urticaria who are late-responders to omalizumab. J Allergy Clin Immunol Pract. 2024;12(9):2537-2539. doi:10.1016/j.jaip.2024.05.043
7. 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(2):586-599. doi:10.1016/j.jaip.2017.07.017