Comparative efficacy and safety of biologics and systemic immunomodulatory treatments for chronic urticaria: Systematic review and network meta-analysis

Alexandro W L Chu¹, Paul Oykhman¹, Xiajing Chu², Daniel G Rayner³, Sukhdeep Bhangal⁴, Andrew Dam⁵, Janice Xu⁶, Javed Sheikh⁷, Kathryn P Trayes⁸, Winfred T Frazier⁹, David M Lang¹⁰, Lisa A Beck¹¹, Sameer K Mathur¹², Susan Waserman¹³, Lehana Thabane¹⁴, Rachel N Asiniwasis¹⁵, Lauren Runyon¹⁶, Joseph Moellman¹⁷, Eric T Oliver¹⁸, Jeffrey Chan¹⁹, Emily F Cole²⁰, Diane R Baker²¹, David A Khan¹⁶, Moshe Ben-Shoshan²², Kathryn E Wheeler²³, Sanaz Eftekhari²⁴, Donna D Gardner²⁵, Tonya Winders²⁶, Maisie Flindall²⁷, Jamie Tattrie²⁷, Jonathan A Bernstein²⁸, Sarbjit S Saini¹⁸, Derek K Chu²⁹

Affiliations

¹ Department of Medicine, McMaster University, Hamilton, Ontario, Canada; Evidence in Allergy Group, McMaster University, Hamilton, Ontario, Canada.
² Evidence in Allergy Group, McMaster University, Hamilton, Ontario, Canada; Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada; Evidence-Based Medicine Center, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China.
³ Evidence in Allergy Group, McMaster University, Hamilton, Ontario, Canada; Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.
⁴ Michael G. DeGroote School of Medicine, McMaster University, Hamilton, Ontario, Canada.
⁵ Faculty of Health Sciences, Queen's University, Kingston, Ontario, Canada.
⁶ Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
⁷ Department of Clinical Immunology and Allergy, Southern California Permanente Medical Group, Los Angeles, Calif.
⁸ Department of Family and Community Medicine, Thomas Jefferson University Hospital, Philadelphia, Pa.
⁹ Department of Family Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pa.
¹⁰ Department of Allergy and Clinical Immunology, Cleveland Clinic, Cleveland, Ohio.
¹¹ Department of Dermatology, University of Rochester Medical Center, Rochester, NY.
¹² Department of Medicine, Division of Allergy, Pulmonary, and Critical Care, University of Wisconsin School of Medicine and Public Health, Madison, Wis.
¹³ Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
¹⁴ Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada.
¹⁵ Department of Medicine, Division of Dermatology, University of Saskatchewan, Regina, Canada.
¹⁶ Department of Internal Medicine, Division of Allergy and Immunology, The University of Texas Southwestern Medical Center, Dallas, Tex.
¹⁷ Department of Emergency Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio.
¹⁸ Department of Medicine, Division of Allergy and Clinical Immunology, Johns Hopkins University School of Medicine, Baltimore, Md.
¹⁹ Emergency Medicine, Southlake Regional Health Centre, Newmarket, Ontario, Canada.
²⁰ Department of Medicine, Division of Dermatology, Washington University School of Medicine, St Louis, Mo.
²¹ Department of Dermatology, Oregon Health and Sciences University, Portland, Ore.
²² Department of Pediatrics, Division of Allergy, Immunology, and Dermatology, McGill University, Montreal, Quebec, Canada.
²³ Department of Pediatrics, University of Florida, Gainesville, Fla.
²⁴ Asthma and Allergy Foundation of America, Arlington, Va.
²⁵ Allergy and Asthma Network, Fairfax, Va.
²⁶ Global Allergy and Airways Patient Platform, Vienna, Austria.
²⁷ patient partner.
²⁸ Department of Internal Medicine, Division of Rheumatology, Allergy, and Immunology, University of Cincinnati, Cincinnati, Ohio.
²⁹ Department of Medicine, McMaster University, Hamilton, Ontario, Canada; Evidence in Allergy Group, McMaster University, Hamilton, Ontario, Canada; Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada; The Research Institute of St Joe's Hamilton, St Joseph's Healthcare Hamilton, Hamilton, Ontario, Canada. Electronic address: chudk@mcmaster.ca.

PMID: 40663028
DOI: 10.1016/j.jaci.2025.06.004

Free article

Meta-Analysis

Comparative efficacy and safety of biologics and systemic immunomodulatory treatments for chronic urticaria: Systematic review and network meta-analysis

Alexandro W L Chu et al. J Allergy Clin Immunol. 2025 Oct.

Free article

. 2025 Oct;156(4):1008-1023.

doi: 10.1016/j.jaci.2025.06.004. Epub 2025 Jul 15.

Authors

Affiliations

¹ Department of Medicine, McMaster University, Hamilton, Ontario, Canada; Evidence in Allergy Group, McMaster University, Hamilton, Ontario, Canada.
² Evidence in Allergy Group, McMaster University, Hamilton, Ontario, Canada; Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada; Evidence-Based Medicine Center, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China.
³ Evidence in Allergy Group, McMaster University, Hamilton, Ontario, Canada; Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.
⁴ Michael G. DeGroote School of Medicine, McMaster University, Hamilton, Ontario, Canada.
⁵ Faculty of Health Sciences, Queen's University, Kingston, Ontario, Canada.
⁶ Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
⁷ Department of Clinical Immunology and Allergy, Southern California Permanente Medical Group, Los Angeles, Calif.
⁸ Department of Family and Community Medicine, Thomas Jefferson University Hospital, Philadelphia, Pa.
⁹ Department of Family Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pa.
¹⁰ Department of Allergy and Clinical Immunology, Cleveland Clinic, Cleveland, Ohio.
¹¹ Department of Dermatology, University of Rochester Medical Center, Rochester, NY.
¹² Department of Medicine, Division of Allergy, Pulmonary, and Critical Care, University of Wisconsin School of Medicine and Public Health, Madison, Wis.
¹³ Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
¹⁴ Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada.
¹⁵ Department of Medicine, Division of Dermatology, University of Saskatchewan, Regina, Canada.
¹⁶ Department of Internal Medicine, Division of Allergy and Immunology, The University of Texas Southwestern Medical Center, Dallas, Tex.
¹⁷ Department of Emergency Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio.
¹⁸ Department of Medicine, Division of Allergy and Clinical Immunology, Johns Hopkins University School of Medicine, Baltimore, Md.
¹⁹ Emergency Medicine, Southlake Regional Health Centre, Newmarket, Ontario, Canada.
²⁰ Department of Medicine, Division of Dermatology, Washington University School of Medicine, St Louis, Mo.
²¹ Department of Dermatology, Oregon Health and Sciences University, Portland, Ore.
²² Department of Pediatrics, Division of Allergy, Immunology, and Dermatology, McGill University, Montreal, Quebec, Canada.
²³ Department of Pediatrics, University of Florida, Gainesville, Fla.
²⁴ Asthma and Allergy Foundation of America, Arlington, Va.
²⁵ Allergy and Asthma Network, Fairfax, Va.
²⁶ Global Allergy and Airways Patient Platform, Vienna, Austria.
²⁷ patient partner.
²⁸ Department of Internal Medicine, Division of Rheumatology, Allergy, and Immunology, University of Cincinnati, Cincinnati, Ohio.
²⁹ Department of Medicine, McMaster University, Hamilton, Ontario, Canada; Evidence in Allergy Group, McMaster University, Hamilton, Ontario, Canada; Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada; The Research Institute of St Joe's Hamilton, St Joseph's Healthcare Hamilton, Hamilton, Ontario, Canada. Electronic address: chudk@mcmaster.ca.

PMID: 40663028
DOI: 10.1016/j.jaci.2025.06.004

Abstract

Background: Chronic urticaria is a common skin condition characterized by itchy wheals (hives), angioedema, or both, lasting for 6 weeks or more. Beyond antihistamines, multiple systemic treatments are available, but there is uncertainty regarding their comparative effects on chronic urticaria outcomes.

Objective: We systematically synthesized the comparative benefits and harms of systemic treatments for chronic urticaria.

Methods: As part of updating the AAAAI/ACAAI JTFPP chronic urticaria guidelines, we searched Medline, Embase, Central, Chinese Biomedical Databases (CBM), China National Knowledge Infrastructure (CNKI), Chinese Scientific Journal Database (VIP), and Wanfang from inception to February 4, 2025, for randomized trials addressing systemic immunomodulatory treatments, including phototherapy, for chronic urticaria. Paired reviewers screened records, extracted data, and assessed risk of bias. Random effects Bayesian network meta-analyses addressed urticaria activity (comprising itch and wheal scores), angioedema activity, health-related quality of life, and adverse events. The GRADE approach informed certainty-of-evidence ratings (PROSPERO: CRD42023429819).

Results: We included 93 studies (n = 11,398; mostly adult and adolescent participants across 83 randomized trials and 10 nonrandomized studies) that evaluated 42 interventions. With high certainty, standard-dose omalizumab (300 mg every 4 weeks) and remibrutinib are among the most effective for improving multiple patient-important outcomes. The safety profile of remibrutinib, however, is less certain. Dupilumab improved urticaria activity, but its impact on quality of life is uncertain, and no dupilumab trials addressed angioedema activity. Cyclosporine may be among the most effective for improving urticaria activity but may be among the most harmful in increasing the frequency of any adverse events. Azathioprine, dapsone, hydroxychloroquine, mycophenolate, sulfasalazine, and vitamin D may improve outcomes, while benralizumab, quilizumab, and tezepelumab may not differ from placebo, though the evidence is uncertain. Findings were consistent across age groups and baseline severity, and were robust to subgroup analyses.

Conclusions: Among individuals with chronic urticaria refractory to antihistamines, standard-dose omalizumab and remibrutinib are among the most effective drugs across multiple patient-important outcomes with a favorable safety profile across the studied duration. Cyclosporine may be effective but may be among the most harmful. Dupilumab improves itch and wheals, but it is uncertain whether it improves angioedema or quality of life. Lower doses of omalizumab are of intermediate effectiveness and favorable safety. The net benefit of conventional immunosuppressants is uncertain.

Keywords: Chronic urticaria; GRADE; biologics; comparative effectiveness; efficacy; hives; immunosuppressant; itch; network meta-analysis; safety.

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Conflict of interest statement

Disclosure statement This study was commissioned by the American Academy of Allergy, Asthma & Immunology and the American College of Allergy, Asthma & Immunology through the Joint Task Force on Practice Parameters for Chronic Urticaria. The funder contributed to defining the scope of the review but otherwise had no role in the study design, data collection, data synthesis, or data interpretation. The review team had the opportunity, but not obligation, to incorporate Joint Task Force feedback. The first and corresponding authors had full access to all the data in the study and had full responsibility for the decision to submit the report for publication. Disclosure of potential conflict of interest: D. M. Lang reports having carried out clinical research with or received honoraria from and/or serving as a consultant for AstraZeneca, Blueprint, Celldex, Genentech, Novartis, and Sanofi-Regeneron. L. A. Beck reports serving as a consultant for AbbVie, Allakos, Amgen, Arcutis, Arena Pharmaceuticals, AstraZeneca, Astria Therapeutics, Belharra Therapeutics, Celldex Therapeutics, Dermavent, Eli Lilly and Company, Escient Pharma, Galderma, GlaxoSmithKline, Invea Therapeutics, Janssen, LEO Pharma, Merck, Nektar Therapeutics, Novartis, Numab Therapeutics, Pfizer, Rapt Therapeutics, Regeneron Pharmaceuticals, ResVitaBio, Ribon Therapeutics, Sanofi-Aventis/Genzyme, Sitryx Therapeutics, Stealth BioTherapeutics, TRex Bio, Triveni Bio, UCB Pharma, Union Therapeutics, and Xencor; and as an investigator for AbbVie, AstraZeneca, Pfizer, Regeneron Pharmaceuticals, and Sanofi. S. Waserman reports contracts with Medexus, Mivaro Health, Novartis, and Sanofi. J. Moellman reports educational grants from RealCME/AstraZeneca; clinical research grants from Pharmin. E. T. Oliver reports consulting fees from Novartis and Sanofi/Regeneron. M. Ben-Shoshan reports contracts from Novartis and Sanofi; and consulting and board participation with ALK, Novartis, and Sanofi. J. A. Bernstein reports grants or contracts from Allakos, Areteia, AstraZeneca, Astria, Celldex, Evoimmune, Genentech, Incyte/Escient, Intellia, IONIS, Jasper, Novartis, Pharvaris, Springer, TLL, and Yuhan; royalties from Amgen, Cogent Pharmaceuticals, CRC Press, and UpToDate; consulting fees from Advanced Medical, Areteia, AstraZeneca, Astria, Best Doctor/Teledoc, BMJ, Celldex, DBV, Eli Lilly, Elsevier, Escient, Evoimmune, Genentech, Guidepoint, GUF, Imedics, Incyte/Escient, INEOS, Intellia, IONIS, Jasper, Kenvue, Novartis, Pharvaris, Telios, TEVA, and Yuhan; and speaking fees from Jasper. The rest of the authors declare that they have no relevant conflicts of interest.

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Comparative efficacy and safety of biologics and systemic immunomodulatory treatments for chronic urticaria: Systematic review and network meta-analysis

Affiliations

Comparative efficacy and safety of biologics and systemic immunomodulatory treatments for chronic urticaria: Systematic review and network meta-analysis

Authors

Affiliations

Abstract

Conflict of interest statement

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