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Urticaria

Nature Reviews Disease Primers volume 8, Article number: 61 (2022) Cite this article

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Abstract

Urticaria is an inflammatory skin disorder that affects up to 20% of the world population at some point during their life. It presents with wheals, angioedema or both due to activation and degranulation of skin mast cells and the release of histamine and other mediators. Most cases of urticaria are acute urticaria, which lasts ≤6 weeks and can be associated with infections or intake of drugs or foods. Chronic urticaria (CU) is either spontaneous or inducible, lasts >6 weeks and persists for >1 year in most patients. CU greatly affects patient quality of life, and is linked to psychiatric comorbidities and high healthcare costs. In contrast to chronic spontaneous urticaria (CSU), chronic inducible urticaria (CIndU) has definite and subtype-specific triggers that induce signs and symptoms. The pathogenesis of CSU consists of several interlinked events involving autoantibodies, complement and coagulation. The diagnosis of urticaria is clinical, but several tests can be performed to exclude differential diagnoses and identify underlying causes in CSU or triggers in CIndU. Current urticaria treatment aims at complete response, with a stepwise approach using second-generation H1 antihistamines, omalizumab and cyclosporine. Novel treatment approaches centre on targeting mediators, signalling pathways and receptors of mast cells and other immune cells. Further research should focus on defining disease endotypes and their biomarkers, identifying new treatment targets and developing improved therapies.

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Fig. 1: Typical presentation of urticaria.
Fig. 2: Global prevalence of chronic urticaria.
Fig. 3: Key pathways of urticaria pathogenesis including current and future therapeutic targets.
Fig. 4: Clinical manifestations of urticaria.
Fig. 5: Differential diagnosis of urticaria.
Fig. 6: Algorithm of chronic urticaria treatment.

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Acknowledgements

The authors thank H. Bonnekoh, K. Brockow, T. Buttgereit, L. Ensina, M. Hide, T. Jacob, A. Kasperska-Zając, L. Kiefer, E. Kocatürk, O. M. E. Calderón LLosa and P. Pyatilova for providing clinical pictures during the writing of this publication.

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Authors and Affiliations

  1. Urticaria Center of Reference and Excellence (UCARE), Institute of Allergology, Charité — Universitätsmedizin Berlin, Berlin, Germany

    Pavel Kolkhir, Martin Metz & Marcus Maurer

  2. Allergology and Immunology, Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Berlin, Germany

    Pavel Kolkhir, Martin Metz & Marcus Maurer

  3. Urticaria Center of Reference and Excellence (UCARE), Department of Dermatology, Hospital del Mar, Institut Mar d’Investigacions Mediques, Universitat Autònoma, Barcelona, Spain

    Ana M. Giménez-Arnau

  4. Urticaria Center of Reference and Excellence (UCARE), Department of Dermatology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand

    Kanokvalai Kulthanan

  5. Urticaria Center of Reference and Excellence (UCARE), Division of Allergy and Clinical Immunology, Department of Medicine, University of Cape Town, Cape Town, South Africa

    Jonny Peter

  6. Urticaria Center of Reference and Excellence (UCARE), Allergy and Immunology Unit, University of Cape Town, Lung Institute, Cape Town, South Africa

    Jonny Peter

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  1. Pavel Kolkhir
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Contributions

Introduction (P.K., A.M.G.-A., K.K., M. Maurer); Epidemiology (P.K., K.K., M. Maurer); Mechanisms/pathophysiology (P.K., M. Metz, M. Maurer); Diagnosis/screening/prevention (P.K., A.M.G.-A., K.K., M. Maurer); Management (P.K., A.M.G.-A., J.P., M. Maurer); Quality of life (P.K., M. Metz, M. Maurer); Outlook (P.K., A.M.G.-A., J.P., M. Maurer); Overview of the Primer (P.K., M. Maurer).

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Correspondence to Pavel Kolkhir or Marcus Maurer.

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Competing interests

P.K. received speakers fees, honoraria or travel support from Novartis and Roche. A.M.G.-A. is/was a medical adviser for Uriach Pharma/Neucor, Genentech, Novartis, FAES, GSK, Sanofi–Regeneron, Amgen, Thermo Fisher Scientific, Almirall, Celldex and LEO Pharma; received research grants supported by Uriach Pharma, Novartis and Instituto Carlos III — FEDER; and participated in educational activities for Uriach Pharma, Novartis, Genentech, Menarini, LEO Pharma, GSK, MSD, Almirall, Sanofi and Avene. K.K. received grants/research support from Novartis and honoraria or consultation fees from Novartis, Menarini and Sanofi. J.P. received speakers fees, honoraria or travel support from Takeda, CSL Behring, Janssen, Novartis and Sanofi and Pharming, and educational research grants from Takeda and Novartis. M. Metz has received honoraria (advisory board, speaker) from Amgen, ArgenX, Celldex, Moxie, Novartis, Roche and Sanofi. M. Maurer is or recently was a speaker and/or adviser for and/or has received research funding from Astria, Allakos, Alnylam, Amgen, Aralez, ArgenX, AstraZeneca, BioCryst, Blueprint, Celldex, Centogene, CSL Behring, Dyax, FAES, Genentech, GIInnovation, GSK, Innate Pharma, Kalvista, Kyowa Kirin, LEO Pharma, Lilly, Menarini, Moxie, Novartis, Pfizer, Pharming, Pharvaris, Roche, Sanofi/Regeneron, Shire/Takeda, Third Harmonic Bio, UCB and Uriach.

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Nature Reviews Disease Primers thanks Y. M. Ye, Z. K. Brzoza, A. Marzano, K. V. Godse and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Supplementary information

Glossary

Degranulation

The process by which cytoplasmic granules (originating from mast cells or other granulocytes) release their contents including preformed mediators such as histamine.

Wheals

Intermittent, circumscribed, superficial, central swellings, often surrounded by reflex erythema, that cause itching or burning sensations.

Angioedema

An intermittent, localized and self-limiting swelling of the subcutaneous or submucosal tissue, due to a temporary increase in vascular permeability, causing tingling, burning, tightness and, sometimes, pain.

Mast cells

Immune cells of the myeloid lineage that contain many granules rich in histamine and other mediators and are present in connective tissues throughout the body, especially skin, near blood vessels, lungs and intestines.

Cysteinyl leukotrienes

A family of inflammatory lipid mediators synthesized from arachidonic acid by various cells including mast cells, eosinophils and basophils.

Eotaxins

A CC chemokine subfamily of potent eosinophil chemoattractants including CCL11 (eotaxin 1), CCL24 (eotaxin 2) and CCL26 (eotaxin 3).

Autologous serum skin test

(ASST). Intradermal injection of autologous serum to assess autoreactivity associated with autoantibodies and other histamine-releasing factors; defined as a serum-induced wheal response with a diameter ≥1.5 mm compared with that of the saline-induced response.

Tissue factor

The high-affinity receptor expressed on eosinophils, epithelial cells and other cell types, and cofactor for factor VII (FVII)/FVIIa important for initiation of blood coagulation.

Oral drug provocation testing

The gold standard for diagnosis of NSAID-mediated reactions including identification of a culprit drug, confirming or excluding cross-reactivity, and finding the most likely tolerated alternative drug.

Provocation testing

A method to confirm the diagnosis of chronic inducible urticaria (CIndU) using established protocols.

GRADE methodologies

(Grading of Recommendations Assessment, Development and Evaluation methodologies). A transparent framework for rating the quality of evidence and grading the strength of recommendations.

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Kolkhir, P., Giménez-Arnau, A.M., Kulthanan, K. et al. Urticaria. Nat Rev Dis Primers 8, 61 (2022). https://doi.org/10.1038/s41572-022-00389-z

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