Urticaria, Itchy Rash, Hives: We offer Tests & Treatment
Mechanism
Chronic spontaneous urticaria is a common skin disorder that is characterised by recurrent itchy, usually raised rash (wheals) and pruritus, with or without angioedema, which can persist for ≥ 6 weeks
It is a heterogeneous mast cell-driven disorder manifesting as recurrent urticarial wheals, angioedema, or both, persisting for six weeks or longer. In the European and UK context, chronic urticaria is subdivided into chronic spontaneous urticaria (CSU) and chronic inducible urticaria (CIndU), with the majority being CSU.
The aetiology is multifactorial, involving autoimmune, idiopathic, and sometimes physical or environmental triggers. Autoimmunity is prominent, with subsets characterised by type IIb autoantibodies directed against the high-affinity IgE receptor (FcεRI) or, less commonly, IgE itself directed at autoantigens including interleukin 24, thyroid peroxidase (TPO), and double-stranded DNA (dsDNA). This produces two principal forms: type IIb autoimmune CSU and autoimmune CSU with IgE autoantibodies.
Angioedema may develop concurrently with or independently from urticaria, typically presenting as deeper dermal or submucosal swelling.
Some cases of angioedema are kinin-mediated, due to bradykinin rather than histamine, especially in hereditary or acquired forms, necessitating distinct diagnostic and therapeutic pathways.
Epidemiologically, urticaria prevalence varies by region, with incidence rates in Asia and Latin America exceeding those reported in Europe, though CSU and CIndU remain diagnosed widely across the UK. Notably, cholinergic urticaria is more frequently reported in East Asian populations, whereas studies in Europe emphasise higher rates of accompanying angioedema.
Solar urticaria in European cohorts is predominantly UV-induced, in contrast to the visible light predominance observed in Asian series. Recent multicentre studies recommend individualised photoprovocation and photoprotection advice tailored to regional patterns.
Central to CU pathophysiology is the activation and degranulation of dermal mast cells, resulting in histamine and other proinflammatory mediator release.
While antihistamines—particularly second-generation non-sedating agents—are standard first-line therapy, their efficacy is limited by histamine-independent pathways, especially at supraphysiological histamine concentrations that may evade receptor blockade.
The kinetic pattern of spontaneous versus histamine-induced wheals differs, highlighting the contribution of non-histaminergic factors, such as platelet-activating factor and leukotrienes.
Omalizumab, a monoclonal anti-IgE antibody, has demonstrated robust efficacy in CSU refractory to antihistamines, with response rates exceeding 80% in clinical trials conducted in Europe (e.g., AWARE and XTEND-CIU studies).
However, only around 60% of patients exhibit immunological evidence of autoimmunity, suggesting additional pathogenic mechanisms, including IgE autoreactivity and basophil dysregulation.
IgE antibodies in CSU often display unique glycosylation patterns influencing effector cell activation, and spontaneous basophil histamine release is notably elevated in CSU, partially mediated by interleukin-3 priming. Non-IgE-dependent mechanisms, such as complement activation and the involvement of vasoactive peptides, are also increasingly recognised.
Patients with CSU often demonstrate reduced peripheral blood basophil counts despite increased spontaneous histamine release, and basophil infiltration is frequently observed in lesional biopsies. Severe CSU correlates with elevated coagulation markers (D-dimer, fibrin degradation products [FDP]), which typically normalise following clinical remission.
Enhanced tissue factor expression on endothelial cells and monocytes may promote thrombogenic potential, but clinically significant thromboembolic events are rare. Coagulation activation is believed to require synergy between histamine (or vascular endothelial growth factor [VEGF]) and proinflammatory cytokines—most notably tumour necrosis factor alpha (TNF-α), interleukin-1 beta (IL-1β), and interleukin-33 (IL-33).
This leads to a cascade wherein activated coagulation factors and complement fragment C5a jointly induce robust mast cell and basophil degranulation.
Approved management of CSU in Europe and the UK begins with standard-dose second-generation H1-antihistamines, escalating to up to fourfold dosing where necessary and then to omalizumab for antihistamine-refractory cases. ciclosporin is recommended as third-line therapy, and off-label agents—including leukotriene receptor antagonists, immunosuppressants such as methotrexate or mycophenolate mofetil, and anticoagulants in select cases—may be considered for severe or recalcitrant courses.
Dupilumab, an anti-IL-4Rα monoclonal antibody, has shown emerging efficacy in both CSU and atopic comorbidities, acting by reducing total serum IgE and suppressing vascular adhesion molecule (VCAM-1) and basophil activation.
Data indicate that dupilumab may effectuate disease modification, with some patients demonstrating sustained remission and persistent IgE reduction beyond the duration of therapy.
The full immunological and clinical profiles of optimal dupilumab responders are under active investigation in ongoing European trials.
Cholinergic urticaria has distinctive clinical subphenotypes, often presenting in younger adults with pinpoint pruritic papules precipitated by exercise, heating, or emotional stress.
While classical forms respond well to antihistamines and omalizumab, non-atopic or hypohidrotic phenotypes—characterised by suppressed sweating, intense dermal pain, and male predominance—are more refractory and may require topical corticosteroids, transdermal neuromodulators, or tricyclic antidepressants.
An association with acquired idiopathic generalised anhidrosis (AIGA) is recognised, and certain patients benefit from treatments targeting nociceptive pathways or underlying sweat gland pathology. The role of sweat-derived histamine in symptom generation has been substantiated in contemporary European studies.
Recent European and UK case series also underscore the importance of metabolic and environmental cofactors in CSU pathogenesis, with emerging links to vitamin D deficiency, iron homeostasis, and reduced physical activity.
While definitive causal relationships require further research, assessment and correction of these factors may benefit symptom control in selected populations. The role of Bruton’s tyrosine kinase (BTK) inhibitors and their impact on iron metabolism remains experimental, with limited but promising results from Phase II studies.
Overall, a multidimensional, pathomechanistic understanding of chronic urticaria is recommended for European and UK clinicians, with ongoing research set to further clarify immunological endotypes, the contribution of comorbidities, and optimise individualised therapy.
References:
- Zuberbier T, et al. The EAACI/GA²LEN/EDF/WAO Guideline for the definition, classification, diagnosis, and management of urticaria. Allergy. 2022;77(3):734-766.
- Kolkhir P, et al. Autoimmune chronic spontaneous urticaria: What we know and what we do not know. J Allergy Clin Immunol. 2022;149(1):163-178.e3.
- Maurer M, et al. Omalizumab for the treatment of chronic urticaria. N Engl J Med. 2013;368(10):924-935.
- Sánchez-Borges M, et al. Cholinergic urticaria, clinical presentation, pathogenesis, and management. J Eur Acad Dermatol Venereol. 2021;35(9):1787-1799.
- Deja, et al. Emerging molecules in the treatment of chronic urticaria. J Allergy Clin Immunol Pract. 2021;9(8):3157-3168.
Bernstein JA, et al. Treatment of chronic urticaria: an updated international guideline. Ann Allergy Asthma Immunol. 2023;130(2):125-135. - Palacios T, et al. Basophil biology and function in chronic urticaria. Curr Opin Allergy Clin Immunol. 2021;21(5):525-534.
- Vestergaard C, et al. Management of chronic urticaria: influence of sex and comorbid atopic dermatitis. Br J Dermatol. 2020;183(5):883-892.
London Allergy and Immunology Centre is UCARE and ACARE accredited centre of excellence
London Allergy and Immunology Centre is the first UK certified Urticaria and Angioedema Centre of Reference and Excellence
Why do you need to see a doctor?
Doctor will do a number of blood test that will help to find out what is causing your symptoms
-urticaria can be related to more severe autoimmune condition.
-urticaria can have allergic nature and simple avoidance can help a lot.
-urticaria can be related to physical factors (temperature, pressure…)
-urticaria can be induced by exercise.
-sometimes it is not possible to find what causes the symptoms, but than doctor can advice how to achieve better control.
What blood tests are recommended?
New HR-Urticaria test -Histamine release (CURT)
This test can help to diagnose a subgroup of chronic urticaria related to circulating histamine releasing auto antibodies.
Identifying this subgroup of patients has practical implications for their treatment.
Other tests: (Full blood count, liver and thyroid function, autoimmune antibodies, total specific IgE and some others)
Occasionally screening for allergens (food and airborne) are used if doctor suspects it to be of allergic nature.
References:
Carsten Bindslev-Jensen, Aldo Finzi, Malcolm Greaves, Jose Camarasa, Jean-Paul Ortonne. Chronic urticaria: diagnostic recommendations. JEADV (2000)14,175-180.
M.H.Platzer, C.E.H.Grattan, L.K.Poulsen, P.S.Skov. Validation of basophil histamine release against the autologous serum skin test and outcome of serum-induced basophil histamine release studies in a large population of chronic urticaria patients. Allergy 2005: 60: 1152-1156.
High prevalence of autoimmune urticaria in children with chronic urticaria. Luigia Brunetti, Ruggiero Francavilla, Vito L. Miniello, Michael H. Platzer, Domenica Rizzi, Maria Letizia Lospalluti, Lars K. Poulsen, Lucio Armenio, Per Stahl Skov. J. Allergy Clin Immunol; October 2004: 922-927
Se also information in our Allergy blog:
Chronic urticaria 4 Nov 2011 07:03
Informa Healthcare – Expert Opinion on Pharmacotherapy – 0(0):1 – Summaryinformahealthcare.comChronic urticaria: a comparison of management guidelinesJean-Paul Ortonne MD Posted online on October 29, 2011. (doi …
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What Causes Exercise Urticaria? 20 Feb 2012 08:43
Allergic to Exercise? What Causes Exercise Urticaria? From @DermdocDo you break out in an itchy rash or develop itchy pink welts when you exercise? If so, you might have …
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Selective COX-2 inhibitors may be unsafe 8 Oct 2011 00:55
Response to a selective COX-2 inhibitor in patients with urticaria/angioedema induced by nonsteroidal anti-inflammatory drugsonlinelibrary.wiley.com Doña I, Blanca-López N, Jagemann LR, Torres MJ …
Allergy Blog Allergy News Information for Patients GPs and Health Professionals > Selective COX-2 inhibitors may be unsafe
Novel antihistamine 23 Oct 2011 10:58
Bilastine in allergic rhinoconjunctivitis and urticariaC. Bachert1, P. Kuna2 & T. Zuberbier3Allergy Volume 65, Issue Supplement s93, Article first published online: 19 MAY 2010… Given its pharmacodynamic profile, which …
Allergy Blog Allergy News Information for Patients GPs and Health Professionals > Novel antihistamine