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Murdaca, G.;  Paladin, F.;  Borro, M.;  Ricciardi, L.;  Gangemi, S. Autoimmune and Autoinflammatory Diseases in Chronic Urticaria. Encyclopedia. Available online: https://encyclopedia.pub/entry/41054 (accessed on 17 November 2024).
Murdaca G,  Paladin F,  Borro M,  Ricciardi L,  Gangemi S. Autoimmune and Autoinflammatory Diseases in Chronic Urticaria. Encyclopedia. Available at: https://encyclopedia.pub/entry/41054. Accessed November 17, 2024.
Murdaca, Giuseppe, Francesca Paladin, Matteo Borro, Luisa Ricciardi, Sebastiano Gangemi. "Autoimmune and Autoinflammatory Diseases in Chronic Urticaria" Encyclopedia, https://encyclopedia.pub/entry/41054 (accessed November 17, 2024).
Murdaca, G.,  Paladin, F.,  Borro, M.,  Ricciardi, L., & Gangemi, S. (2023, February 09). Autoimmune and Autoinflammatory Diseases in Chronic Urticaria. In Encyclopedia. https://encyclopedia.pub/entry/41054
Murdaca, Giuseppe, et al. "Autoimmune and Autoinflammatory Diseases in Chronic Urticaria." Encyclopedia. Web. 09 February, 2023.
Autoimmune and Autoinflammatory Diseases in Chronic Urticaria
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This entry is adapted from the peer-reviewed paper 10.3390/biomedicines11020410

Chronic spontaneous urticaria (CSU) is defined as the almost daily occurrence of widespread wheals, angioedema, or both, for more than 6 weeks. It affects 1–2% of the general population, with a higher prevalence in female patients, and is more frequent patients over 20 years of age. More than half of all cases of chronic idiopathic urticaria are thought to occur due to an autoimmune mechanism, specifically the production of autoantibodies against the high-affinity immunoglobulin E (IgE) receptor (FcεRI). The quality of life in these patients is often greatly compromised, also due to the onset of comorbidities represented by other autoimmune diseases, such as thyroid disease, rheumatoid arthritis, systemic lupus erythematosus, Sjögren’s syndrome, celiac disease, and type 1 diabetes, among others.

chronic spontaneous urticaria autoimmune diseases

1. Chronic Urticaria

Chronic spontaneous urticaria (CSU) is defined as the almost daily occurrence of widespread wheals, angioedema, or both for more than 6 weeks [1]. It affects 1–2% of the general population, and it is more frequent in women and in patients older than 20 years [2][3][4]. Quality of life is often highly compromised, with interference in daily routine and consequent onset of psychiatric comorbidities, such as depression and anxiety [5][6]. Symptoms of chronic urticaria comprehend hives, angioedema or both (in almost one-third of patients). Clinical manifestation may range in frequency and duration: about 50% of patients have symptoms for 3–6 months with a self-limiting evolution, whereas more than 10% of patients present symptoms for 5 years or more [2][7][8]. Classification of urticaria is made according to the triggers and patient-reported signs and symptoms, and it may be divided into spontaneous and inducible [1].

2. Associations with Other Autoimmune Diseases

Chronic urticaria has been always described with and correlated to the presence of various other pathologies, including autoimmune, psychiatric, and atopic diseases [1]. In particular, the prevalence of autoimmune diseases in CSU is increased, e.g., ≥1% in most studies compared to ≤1% in the general population [9]. Autoimmune diseases can be divided into organ-specific and non-organ-specific diseases [10][11]

2.1. Organ-Specific Autoimmune Disease and CSU

In a metanalysis on 60 studies, the prevalence of organ-specific autoimmune diseases in patients diagnosed with chronic spontaneous urticaria reached 27.5%. The most common organ-specific autoimmune disease in CSU were endocrine, especially Hashimoto thyroiditis, followed by hematological, like pernicious anemia, and skin, like vitiligo [9]. These results were then confirmed by the authors in a further retrospective study in 2021, with 28% of patients with urticaria that presented at least one autoimmune disease [12].

2.2. Type I Diabetes Mellitus

A study evaluating 12,778 patients with chronic urticaria showed that type I diabetes mellitus had an odds ratio of 7703 compared with that in control subjects. Dividing the study population into male and female, authors showed a higher odds ratio in female (12.92, 95% CI, 6.53–25.53; p < 0.0005) than in men (2.34; p = 0.015). The onset of type I diabetes mellitus was after years from CU diagnosis.
The systematic review performed by Kolkhir et al. [9] on five previous studies showed that prevalence of insulin-dependent diabetes mellitus is 0.5% in patients diagnosed with chronic spontaneous urticaria, ranging from 0.2 to 5.5%.

2.3. Celiac Disease

A study conducted on 12,778 patients with a diagnosis of CU and 10,714 control subjects, spread over 17 years, showed a certain association between CU and celiac disease [13]. Specifically, in patients diagnosed with CU when compared to controls, the odds of having celiac disease was 26.96 overall (CI 6.6–110.17). When analyzing by sex, women presented higher odds: 57.83 CI 7.99–418.29 for women and 3.90 0.50–30.27 for men. Moreover, the authors found that celiac disease was diagnosed mostly after CU: 17.2% and 82.2%, respectively.
A systematic review showed that celiac disease is the third autoimmune disease in order of overall prevalence associated with CU, after rheumatoid arthritis and Hashimoto’s thyroiditis [9]. The papers evaluated by the authors were dated from 1992 to 2015 and the prevalence of celiac disease in association with CU ranges from 0.5 to 9.3. The calculated mean prevalence for celiac disease among CU diagnosis has been estimated to be 0.7%.

2.4. Vitiligo

In the systematic review performed by Kolkhir et al., vitiligo has been classified as the sixth more frequent autoimmune disease associated with chronic urticaria. Among nine different studies analyzed, the prevalence of vitiligo in patient diagnosed with CSU has been estimated to be 0.6–9.8 [9]. The prevalence of urticarial rush in patients diagnosed with vitiligo has been estimated to be 0.5–1 among three different studies [9]. In 2021, a retrospective study on 1199 CSU patients found that vitiligo was the second most frequently associated condition with CUS among autoimmune diseases, after autoimmune thyroiditis. The estimated prevalence has been reported to be 2.3% [12]. Moreover, some case reports and a case series described the concomitant presence of vitiligo and urticaria in patients [14][15][16].

2.5. Pernicious Anemia

Magen et al. [17], Mete et al. [18], and Leznoff and Sussman [19] demonstrated a certain association between low levels of vitamin B12 caused by autoimmune production of antibodies and chronic urticaria, with a prevalence of 5.4, 6.1, and 5.5, respectively. The overall prevalence of Pernicious Anemia has been calculated to be 0.2% [9].

3. Non-Organ Specific Autoimmune Diseases and CU

Taking together all systemic autoimmune diseases, the most frequent correlation with urticaria has been seen in connective tissue diseases, with rheumatoid arthritis placed first [9]. The onset of a systemic autoimmune disease has been demonstrated with a higher incidence in female patients with urticaria, especially for rheumatoid arthritis (RA), Sjögren’s syndrome (SS), and systemic lupus erythematosus (SLE). Moreover, the presence of a positive rheumatoid factor and antinuclear antibodies were significantly more frequent in patients with chronic urticaria [13]. Ghazanfar et al. [20] have in fact highlighted how the increased general inflammatory state caused by CU correlates significantly with the increased prevalence of rheumatoid arthritis in women affected by CU (HR = 1.8), as a consequence of mast cell destabilization. In addition, UC has been shown to have a genetic association with the human leukocyte antigen (HLA)-DR4 and HLA-DQ8 alleles, of which the former is strongly associated with rheumatoid arthritis [21]. A cross-sectional study of 390 CSU patients reported a higher prevalence of connective tissue diseases (CTDs) such as RA, SS, and SLE in UC patients than in the normal population, with a prevalence of 1.8% for RA and of 0.3% for SLE [22]. Chiu et al. have deepened the biochemical correlation existing between CU and SLE, recognizing a fundamental role of autoantibodies, complement activation, and the coagulation cascade. CU and SLE were in fact both characterized by a higher prevalence of autoantibodies against FceRI and IgE. The appearance of urticaria in patients with active SLE is due to immune complex deposition and complement activation; this could indicate the key role of SLE in the etiopathogenesis of UC. Furthermore, an increased risk of SLE with UC was confirmed only in women, particularly in those aged between 20 and 59 years [23][24][25]. CSU can also be triggered by drugs routinely used to treat lupus, especially nonsteroidal anti-inflammatory drugs, with a predominance of constitutional, mucocutaneous, and musculoskeletal involvement, without a high frequency of manifestations of severe lupus [26].

4. CU and Other Immune-Mediated Diseases

A recent study by Magen et al. highlighted a high prevalence of UC in patients affected by alopecia areata (AA), recognizing in the IgG-anti-IgE autoantibodies and RI anti-Fc (high affinity IgE receptor) the possible physiopathological correlation factors [27]. The presence of such functional FceRIa-Ab anti-IgE antibodies in UC patients is responsible for the release of histamine by activating the complement system. The same immunological mechanism is also found in subjects affected by myasthenia gravis (MG), an autoimmune disease that causes weakness of striated muscles mediated by the AChR-Abs antibody, responsible for the degradation of the neuromuscular junction by activation of the complement system. Although the pathogenic link between these two autoimmune diseases remains unclear, complement activation plays an important pathophysiological role in both diseases, being able to represent their possible link [28][29].
The international EAACI/GA2LEN/EuroGuiDerm/APAAACI guideline for the definition, classification, diagnosis, and management of urticaria [30], published in March 2022, reports that it is well known that causes of CSU include autoimmunity type I (CSU)aiTI, or “autoallergic CSU”; with IgE autoantibodies against autoantigens and type IIb autoimmunity (CSU)aiTIIb; with activating autoantibodies directed by mast cells. In the diagnostic process, the patient’s history and a physical exam can provide clues to the underlying causes. For this purpose, the execution of basic tests, such as CRP (more often elevated) and the dosage of eosinophils and basophils (more often reduced in CSUaiTIIb), is of primary importance. Testing for TPO-IgG and total IgE should also be performed in CSU patients in specialist care, as they are useful for diagnostic purposes. CSUaiTIIb patients are more likely to have low or very low total IgE and elevated anti-TPO IgG levels, and a high ratio of anti-TPO IgG to total IgE is currently the best surrogate marker for CSUaiTIIb. Other underlying causes include active thyroid disease, infections, inflammatory processes, food and medications. In CSU, the most common comorbidities are CIndUs, autoimmune diseases, and allergies. Findings from the patient’s medical history, a physical exam, or baseline tests that indicate a comorbidity or consequence of CSU should prompt further investigation, such as screening for specific diseases by means of questionnaires, provocation tests, further laboratory tests, or referral to a specialist.

5. CSU and Autoinflammatory Diseases

Autoinflammatory diseases (Cryopyrin-Associated Periodic Syndrome (CAPS), Familial Mediterranean Fever (FMF), Schnitzler Syndrome (SchS), Adult Still’s Disease (AOSD)) represent a group of chronic disabling diseases characterized by a condition of direct self-inflammation, mediated by disturbances in innate immune signalling pathways [31]. Specifically, an excessive secretion of cytokines by innate immune cells (such as macrophages, monocytes) is observed, among which the researchers mention the group of interleukin (IL)-1, which, accumulating at the level of different tissues and systems, lead to the clinical development of disease. The latter includes recurrent fever attacks, musculoskeletal, gastrointestinal, and neurological involvement. The integumentary system is also a frequent site of autoinflammatory disease, with typical symptoms including urticaria, pustular and ulcerative lesions [32].
The urticarial rash in patients with autoinflammatory syndromes is often grossly indistinguishable from that in patients with CSU. However, it is possible to observe, in these cases, a wider spectrum of lesions than true urticaria, i.e., flat wheals that can, at first sight, resemble erythematous patches, but also more solid and stable lesions. The distribution of this type of urticarial rash is also slightly different, being distributed rather symmetrically over the trunk and/or extremities, usually sparing the head [33].
Considering the great clinical similarity between these two diseases, the need arises, where an autoinflammatory disease is suspected, to perform specific tests, including dosage for elevated inflammatory markers; serum protein electrophoresis to rule out monoclonal gammopathy in adults; urinalysis to screen for proteinuria from secondary renal amyloidosis; and skin biopsy to look for neutrophil-rich infiltrates. If an inherited autoinflammatory disease is suspected, testing for mutations in the relevant genes should be performed [34].
Within the broad spectrum of autoinflammatory diseases, two are those that present most frequently clinically with urticarial lesions that enter into the differential diagnosis with CSU: urticarial vasculitis (UV) and Schnitzler Syndrome (SchS).
If a form of UV is suspected, the differential diagnosis with CSU [35] is based on testing for skin histopathology, as well as specific laboratory tests, such as complete blood count, serum creatinine, C-reactive protein (C-RP), rate of erythrocyte sedimentation (ESR), urinalysis, complement studies (C1q, C3, C4), and anti-C1q antibody analysis underlying connective tissue disease or viral infection [35][36].
As for SchS, a member of the family of autoinflammatory syndromes, this too often manifests itself with chronic recurrent, nonpruritic and confluent plaques. These urticarial plaques can persist for up to 24 h and then resolve without residual pigmentation. Characteristic of SchS is the presence of monoclonal paraproteinemia, typically IgM, with neutrophil-dominated cellular infiltrates and upregulation of cytokines and inflammasome components in lesional skin, supporting them as potential biomarkers to differentiate SchS from CSU [37]. IL-1-related cytokines and inflammasome components are upregulated in skin biopsy specimens from SchS patients, resulting in products from mast cells (IL-1β, IL-6) and neutrophils (IL-6, IL-18). In view of these immunohistochemical features, it is recommended to apply a panel of skin biomarkers, including MPO, IL-1β, IL-6, IL-18, as well as ASC and caspase-1, to differentiate SchS from CSU [36].

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Subjects: Immunology
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Giuseppe Murdaca
,
Francesca Paladin
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Matteo Borro
,
Luisa Ricciardi
,
Sebastiano Gangemi
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Update Date: 10 Feb 2023
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