Unraveling the Complexity of Chronic Spontaneous Urticaria
Urticaria, an inflammatory skin disorder affecting up to 20% of the global population, manifests as the development of pruritic wheals (commonly known as hives), angioedema, or a combination of both; these symptoms are triggered by the release of histamine and other mediators from mast cells in the skin.1 Among the range of urticarial presentations, chronic spontaneous urticaria (CSU) is a particularly distressing skin condition characterized by recurrent, intensely itchy wheals; angioedema; or the coexistence of both symptoms.2 CSU can be challenging because of its spontaneous nature and lack of an identifiable cause; it may persist for more than 6 weeks and profoundly reduce quality of life (QOL) among affected patients.3 Whereas many individuals endure daily or near-daily symptoms for years, other individuals experience multiple episodes interspersed with brief symptom-free intervals.2,4
A prominent feature of CSU is its association with angioedema, observed in approximately 40% to 50% of patients with CSU; around 10% of patients primarily experience angioedema as the main symptom. However, the diagnosis of CSU is complex because it commonly involves both wheals and angioedema.4 Furthermore, discrepancies often arise between physician and patient reports of angioedema: approximately 40% of patients with inadequately controlled CSU report angioedema, even when their physician does not concur with this assessment.5
These diagnostic challenges underscore the need for a comprehensive and nuanced approach to the identification and management of this prevalent and vexing skin condition. This article unravels the complex diagnostic aspects of CSU by providing insights into its clinical manifestations, testing modalities, differential diagnoses, and the underlying mechanisms that involve mast cells and immunoglobulin E (IgE).
Epidemiology
CSU occurs in approximately 1% of the global population; its prevalence is increasing.2 Global estimates for urticaria in 2017 indicated that there were approximately 86 million existing cases, with an annual occurrence of about 160 million new cases.1 In the United States, around half a million individuals are affected by chronic urticaria, constituting a prevalence of 0.23%.6
In children, the estimated prevalence of CSU is 1.4%, whereas it is 0.9% in adults. This prevalence exhibits geographical disparities, such that rates are higher in Latin America and Asia than in Europe and North America.3 The epidemiology of CSU displays a degree of diversity similar to the affected populations. CSU tends to occur in women aged 30 years and older; it is most prevalent in this population. Furthermore, disparate prevalences have been noted among various ethnicities, emphasizing the importance of a nuanced diagnostic approach that considers demographic differences.1 Figure 1 illustrates the prevalence and impact of CSU.1-5
QOL Implications
In addition to the statistical considerations, it is important to recognize the profound impact of CSU on QOL among adult and pediatric patients, as well as their families. The relentless cycle of daily or near-daily episodes of hives and angioedema, accompanied by intense itching, results in decreased productivity and an increased burden of psychological comorbidities. More than 20% of patients with CSU miss at least 1 hour of work per week, leading to a 27% loss of overall productivity. The economic and humanistic burdens of CSU reverberate throughout healthcare systems, affecting patients, their families, and their partners. Consequently, there is an increasingly urgent need to enhance diagnostic precision and develop improved treatment options for individuals affected by the complexities of CSU.2
Mast Cells and IgE in CSU
These seemingly innocuous symptoms of CSU belie its complex underlying pathogenesis. The onset of wheals and angioedema results from a cascade of events triggered by mast cell degranulation,1 leading to sensory nerve activation, vasodilation, and increased vascular permeability.4 This process culminates in the pruritic, raised, and erythematous skin lesions that characterize CSU.1,4
Mast cells and IgE antibodies play pivotal roles in CSU development. Mast cells (ie, immune cells) in the skin initiate inflammation when activated through various receptors, including high-affinity IgE receptor (FcεRI), mas-related G protein-coupled receptor-X2 (MRGPRX2), complement 5a receptor (C5aR), protease-activated receptor 1 (PAR1), protease-activated receptor 2 (PAR2), chemoattractant receptor-homologous molecule expressed on T helper 2 cells (CRTh2), and cytokine receptors. The interaction between stem cell factor (SCF) and its receptor KIT (CD117) drives mast cell differentiation and proliferation. The activation of FcεRI involves multiple cytoplasmic signaling proteins, leading to mast cell activation and the release of histamine and other mediators, which ultimately cause CSU symptoms.1
Further complicating the clinical picture, CSU is associated with the infiltration of various immune cells at wheal sites. These cellular infiltrates include basophils, eosinophils, neutrophils, monocytes, and T lymphocytes, similar to a late-phase cutaneous reaction. The cytokine profile within these infiltrates is biased toward a T helper 2 (Th2) immune response, but it also involves Th1 and Th17 cells and their associated cytokines. Eosinophils interact with mast cells by secreting SCF in response to mast cell activation, thereby promoting mast cell proliferation and differentiation. Eosinophil movement from the blood to the skin involves chemokines, which are potential therapeutic targets. The intricate crosstalk between eosinophils and mast cells, combined with the involvement of the coagulation cascade, adds complexity to CSU pathogenesis.4
CSU involves dermal mast cell activation and the release of inflammatory mediators; IgE contributes to these processes in direct and indirect ways. The direct effect is attributed to the presence of autoantigen-specific IgE, which is known as type I autoimmunity. The indirect effect is associated with low levels of IgE due to IgE-specific IgG, which is known as type IIb autoimmunity.7 The identification of these antibodies helps to diagnose autoimmune CSU, a process that can be complicated by the existence of overlapping endotypes.1
In addition to IgE-dependent pathways, IgE-independent mast cell activation has a crucial role in CSU.1 Mast cells can be activated by various ligands including C5a, neuropeptides, and cytokines, providing multiple pathways for eventual mast cell degranulation.4 These intricate interactions highlight the complexity of CSU pathogenesis.
Diagnosis and Clinical Presentation
The diagnosis of CSU is a complex process, primarily based on the exclusion of other potential causes. It begins with a comprehensive patient history and physical examination, focusing on details such as symptom patterns, triggers, medication use, allergies, family history, and associations with angioedema. The subsequent diagnostic journey may involve various tests, including a complete blood count (CBC), erythrocyte sedimentation rate (ESR) assessment, and measurements of the levels of C-reactive protein (CRP), liver enzymes, and thyroid-stimulating hormone (TSH). The scope of testing may vary depending on a particular patient’s clinical indications.3
Additional evaluations may include skin biopsies, physical challenge tests, complement component (C3 and C4) measurements, stool analyses, urinalysis, chest radiography, autoantibody assays, and serum protein electrophoresis. Infection-related investigations may be considered if clinically warranted, such as tests for Helicobacter pylori (H pylori), hepatitis B, hepatitis C, or malignancy. In some cases, investigational assays (eg, autologous serum skin tests and the detection of antibodies to the IgE receptor or Fc region of IgE) may offer insights into the mechanisms underlying CSU pathogenesis. Notably, there is no correlation between the number of tests performed and the likelihood of determining the underlying pathogenesis.3
CSU requires the exclusion of other conditions with similar presentations. Key differential diagnoses include physical urticarias, such as symptomatic dermographism, cholinergic urticaria, and cold urticaria, which often exhibit distinct clinical features and triggers.1 Careful analysis, symptom evaluation, and diagnostic testing are essential to distinguish these conditions from CSU. Table 1 details various characteristics of CSU.1
Conclusion
CSU is a multifaceted condition with clinical manifestations that extend far beyond the skin surface. The central role of mast cells and the intricate interactions with IgE add layers of complexity to the understanding of CSU pathogenesis. Mast cells can be activated through IgE-dependent or independent mechanisms, leading to the release of histamine, cytokines, and other mediators responsible for the characteristic symptoms of CSU.
As the understanding of CSU improves, researchers seek to refine diagnosis and treatment strategies, which will ultimately alleviate the burden of this particularly distressing skin condition. These collective efforts hold the promise of personalized care and improved QOL for patients with CSU, offering hope for a symptom-free future.
References
1. Kolkhir P, Giménez-Arnau AM, Kulthanan K, Peter J, Metz M, Maurer M. Urticaria. Nat Rev Dis Primers. 2022;8(1):61. doi:10.1038/s41572-022-00389-z
2. Kolkhir P, Muñoz M, Asero R, et al. Autoimmune chronic spontaneous urticaria. J Allergy Clin Immunol. 2022;149(6):1819-1831. doi:10.1016/j.jaci.2022.04.010
3. Greiner B, Nicks S, Adame M, McCracken J. Pathophysiology, diagnosis, and management of chronic spontaneous urticaria: a literature review. Clin Rev Allergy Immunol. 2022;63(3):381-389. doi:10.1007/s12016-022-08952-y
4. Kaplan A, Lebwohl M, Giménez-Arnau AM, Hide M, Armstrong AW, Maurer M. Chronic spontaneous urticaria: focus on pathophysiology to unlock treatment advances. Allergy. 2023;78(2):389-401. doi:10.1111/all.15603
5. Metz M, Vadasz Z, Kocatürk E, Giménez-Arnau AM. Omalizumab updosing in chronic spontaneous urticaria: an overview of real-world evidence. Clin Rev Allergy Immunol. 2020;59(1):38-45. doi:10.1007/s12016-020-08794-6
6. Lang DM. Chronic urticaria. N Engl J Med. 2022;387(9):824-831. doi:10.1056/NEJMra2120166
7. Maurer M, Kolkhir P, Moñino-Romero S, Metz M. The crucial role of IgE as a predictor of treatment response to omalizumab in chronic spontaneous urticaria. J Allergy Clin Immunol Pract. 2023;11(8):2390-2391. doi:10.1016/j.jaip.2023.06.026
Posted by Haymarket’s Clinical Content Hub. The editorial staff of MPR played no role in this content’s preparation.
Reviewed November 2023
