Evaluation of Pharmacologic Treatments for H1 Antihistamine–Refractory Chronic Spontaneous Urticaria: A Systematic Review and Network Meta-analysis | Allergy and Clinical Immunology | JN Learning | AMA Ed Hub [Skip to Content]
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Evaluation of Pharmacologic Treatments for H1 Antihistamine–Refractory Chronic Spontaneous UrticariaA Systematic Review and Network Meta-analysis

Educational Objective
To describe the evidence regarding treatment options for refractory chronic spontaneous urticaria
1 Credit CME
Key Points

Question  What are the comparative benefits and harms of all available pharmacologic treatments for H1 antihistamine–refractory chronic spontaneous urticaria?

Findings  In this network meta-analysis of 23 randomized clinical trials including 2480 participants, the biologic agents ligelizumab, 72 or 240 mg (large beneficial effect), and omalizumab, 300 or 600 mg (moderate beneficial effect), appeared to be effective treatments for H1 antihistamine–refractory chronic spontaneous urticaria. Alternative treatments with small beneficial effects, namely, dapsone, hydroxychloroquine, cyclosporine, and zafirlukast, can be used.

Meaning  The findings of this meta-analysis may inform international guidelines for the management of chronic spontaneous urticaria that is inadequately controlled with H1 antihistamines and further research in this clinical setting.

Abstract

Importance  The comparative benefits and harms of all available treatments for H1 antihistamine–refractory chronic spontaneous urticaria (CSU) have not been established.

Objective  To evaluate different treatment effects of pharmacologic treatments among patients with H1 antihistamine–refractory CSU.

Data Sources  Searches were conducted of MEDLINE, Embase, PubMed, Cochrane Library, Web of Science, Scopus, and CINAHL from inception to April 19, 2021, with no language restrictions. Gray literature from Google Scholar, ongoing trial registers, and preprint reports was added to the searches of electronic databases.

Study Selection  Randomized clinical trials using validated measurement tools that investigated the benefits and harms of pharmacologic treatments among adolescent or adult patients with CSU who had an inadequate response to H1 antihistamines were screened for inclusion independently by 2 investigators.

Data Extraction and Synthesis  Two investigators independently extracted study data according to the predefined list of interests. A random-effects model was used to calculate the network estimates reported as standardized mean differences and odds ratios with corresponding 95% CIs.

Main Outcomes and Measures  The primary outcomes that reflect the patient’s perspective included changes in urticaria symptoms from baseline and unacceptability of treatment (all-cause dropouts).

Results  Twenty-three randomized clinical trials with 2480 participants that compared 18 different interventions or dosages and placebo were included. The standardized mean differences for change in urticaria symptoms were −1.05 (95% CI, −1.37 to −0.73) for ligelizumab, 72 mg; −1.07 (95% CI, −1.39 to −0.75) for ligelizumab, 240 mg; −0.77 (95% CI, −0.91 to −0.63) for omalizumab, 300 mg; and −0.59 (95% CI, −1.10 to −0.08) for omalizumab, 600 mg. No significant differences in treatment unacceptability were observed. With respect to benefits and harms, the network estimates illustrated that the most efficacious treatments were achieved with ligelizumab, 72 or 240 mg (large beneficial effect) and omalizumab, 300 or 600 mg (moderate beneficial effect).

Conclusions and Relevance  The findings in this meta-analysis suggest that the biologic agents ligelizumab, 72 or 240 mg, and omalizumab, 300 or 600 mg, can be recommended as effective treatments for patients with CSU who have had an inadequate response to H1 antihistamines. Head-to-head trials with high methodologic quality and harmonized design and outcome definitions are needed to help inform subsequent international guidelines for the management of CSU.

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CME Disclosure Statement: Unless noted, all individuals in control of content reported no relevant financial relationships. If applicable, all relevant financial relationships have been mitigated.

Article Information

Accepted for Publication: July 7, 2021.

Published Online: August 25, 2021. doi:10.1001/jamadermatol.2021.3237

Corresponding Authors: Surapon Nochaiwong, PharmD, Department of Pharmaceutical Care, Faculty of Pharmacy, Chiang Mai University, Chiang Mai 50200, Thailand (surapon.nochaiwong@gmail.com); Mati Chuamanochan, MD, Division of Dermatology, Department of Internal Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand (mati.c@cmu.ac.th).

Author Contributions: Drs Nochaiwong and Chuamanochan had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Nochaiwong and Chuamanochan contributed equally to this study.

Concept and design: Nochaiwong, Chuamanochan.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Nochaiwong, Chuamanochan.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Nochaiwong, Chuamanochan.

Obtained funding: Nochaiwong, Chuamanochan.

Administrative, technical, or material support: Nochaiwong, Chuamanochan.

Supervision: Nochaiwong, Chuamanochan.

Conflict of Interest Disclosures: None reported.

Funding/Support: This work was supported by a grant from the Pharmacoepidemiology and Statistics Research Center through Chiang Mai University. This work was also partially supported by grant 077/2564 from the Faculty of Medicine, Chiang Mai University, Thailand.

Role of the Funder/Sponsor: The funding organizations had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Additional Contributions: We thank the research assistants and all staff of the Pharmacoepidemiology and Statistics Research Center, Chiang Mai, Thailand, as well as the following authors for their support in providing information: Nico Janssens and Mohammad Fahad Haroon (Novartis Pharma AG), Jonathan A. Bernstein, University of Cincinnati Medical Center, Cincinnati, Ohio), Burhan Engin (Istanbul University-Cerrahpaşa, Turkey) Marcus Maurer and Markus Magerl (Charité-Universitätsmedizin Berlin, Germany), Tadech Boonpiyathad (Phramongkutklao Hospital, Thailand), Lukas Jörg (University of Bern, Switzerland), Jorge Sánchez (University of Antioquia, Colombia), Sophie Leducq (University of Tours, France), and Clive Grattan (St John's Institute of Dermatology, Guy's Hospital, London, UK). No compensation was received.

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