Urticaria and comorbidities

INTRODUCTION

Urticaria is a mast cell (MC)-driven skin disease. Degranulation of these cells is triggered by the activation of several receptors on their surface. All MC express high-affinity immunoglobulin (Ig)E receptors (FcεRI) and, increasingly, the IgE-FcεRI complex appears to have role in the autoimmune etiology of chronic spontaneous urticaria (CSU), through the presence of IgG anti-FcεRI/anti-IgE or IgE against autoallergens.^[1,2]

Besides FcεRI-IgE complex, MC expresses numerous G protein-coupled receptors. Several drugs and other substances including antimicrobial host defense peptides, neuropeptides, and eosinophil peroxidase activate this type of receptor.^[3,4] MRGPRX2 receptor on MCs, basophils, and eosinophils associated with IgE-independent degranulation is highly expressed on cutaneous MCs in severe CSU.^[5]

MCs are multifunctional cells which play an important role in several diseases including allergic diseases, gastrointestinal disorders, certain malignancies, and cardiovascular diseases.^[5-8]

Comorbidities can add layers of complexity and often lead to a worse prognosis for the underlying disease. Management of comorbidities can be challenging as one condition may contribute or be linked to another and treatments can conflict with each other resulting in the modification of response to the drugs used to control diseases.^[9]

There are certain comorbidities, frequently associated with urticaria: Autoimmunity, infections, allergy, emotional stress, and metabolic syndrome with dietary factors that can aggravate chronic urticaria (CU).^[1,2,10-19] Some patients have more than one concomitant disease. These patients are older, have longer duration of urticaria, and are more resistant to antihistamines. The presence of such factors may be associated with worse prognosis. The progressive increase in the number of comorbidities in same patient may support the view that CU is a low-grade systemic inflammatory disease.^[20]

Netchiporouk et al. assessed comorbidities in children with CU, and they found that atopy was the most common comorbidity (28%); 4.32% of the patients was diagnosed as having autoimmunity; 20% had chronic inducible urticarial (CIndU); and almost 30% had at least one atopic condition.^[21]

Turk et al. identified four distinct subgroups of CU using machine learning algorithms. The first group (7%) included only patients with CIndU, this was the smallest group, with the highest age and the lowest total serum IgE. All patients in the second group (42%) presented CSU, with the higher total serum IgE levels and the lowest rate of autoantibodies (anti-TPO and/or ANA). The third group (38%) included 100% CSU, highest percentage of women, and highest rate of autoantibodies. Moreover, the forth group (13%), consisted only by CSU patients, had high frequency of comorbidities.^[22] According to this study, “CIndU cluster,” “high IgE cluster,” “autoimmune cluster,” and “high comorbidity” clusters were identified. The “high comorbidity cluster” included high rates of hypertension, diabetes mellitus, and hypothyroidism (correspondingly 74%, 62%, and 38%) each at least twice as high as in any other cluster.^[22]

We searched for original and review articles on CU and comorbidities in PUBMED, abstracts published in AAAAI and EAACI; all of them in English.

AUTOIMMUNITY

Indirect evidence that CU is an autoimmune disease is derived from its association with other autoimmune conditions, a strong association between serum functionality and the human leukocyte antigen-DR4 haplotype, and response to immunotherapies.^[23]

Many studies in different populations indicate that CSU is strongly linked to Hashimoto’s thyroiditis (HT), pernicious anemia, vitiligo, type 1 diabetes mellitus, Graves’ disease, celiac disease, rheumatoid arthritis, systemic lupus erythematosus, Sjögren syndrome, inflammatory bowel disease, HenochSchönlein purpura, and Kawasaki disease.^[2,24-29] Patients with CSU, especially adult women with family history of autoimmune disease, should undergo screening for common autoimmune conditions, especially HT and vitiligo.^[2,24] CSU often precedes the onset of other autoimmune diseases.^{[25,28,30-33]}

Based on two types of MC degranulating signals, two endotypes of CSU, that is, autoallergic and autoimmune are proposed [Table 1]. The first one is known as type I autoimmune CSU mediated by IgE autoantibodies (TIaiCSU) and the second – aiCSU, known as type IIb autoimmune CSU (TIIbaiCSU), in which IgG autoantibodies, and probably IgM and IgA, are responsible for direct activation of MC through binding to high-affinity IgE receptors.^[1,2,34,35] Thyroid peroxidase (TPO) is a common and relevant autoallergen in TIaiCSU, beyond TPO, there are IgE autoantibodies directed to another autoantigens: Thyroglobulin, tissue factor, and interleukin (IL)-24.^[1,32]

Total IgE is a valuable marker to distinguish between TIaiCSU and TIIbaiCSU.^[1,34] High levels of total IgE may suggest TIaiCSU. These patients may have high disease activity, longer disease duration, and high likelihood of response to omalizumab but rapid relapse after its discontinuation, while the likelihood of response to ciclosporin is lower.^[34] On another hand, markedly low IgE may indicate to TIIbaiCSU that accounts 8% of patients with CSU,^[30] which have lesser chance of response to omalizumab and a better chance of response to cyclosporine treatment.^[34] These patients have higher rates of eosinopenia and basopenia,^[1] highly expressed MRGPRX2 receptor on cutaneous MC, especially in patients with severe CSU.^[5]

The high IgE levels are seen in atopic patients with CSU,^[32] CSU with gastroesophageal reflux disorder,^[13] and CSU with high IL-33 serum levels.^[36] These results suggest that the presence of atopy and concomitant disorders may affect serum total IgE levels in patients with CSU.^[33] Scientific data indicate that in approximately 50% of patients with CSU, total serum IgE levels were >100 IU/mL, whereas IgE-low (<30 IU/mL) and very low levels (<2 IU/mL) levels were seen in 25% and 10% of patients, respectively.^[34] Schoepke et al. recommended to use the ratio of IgG anti-TPO to total IgE, as marker for TIIbaiCSU.^[30] In another study was suggested to use anti-TPO↑IgE↓ as a diagnostic marker for this type of aiCSU and indicator of low response to antihistamine than patients without aTPO↑IgE↓.^[31]

Recent scientific data indicate that, 28% of patients with CSU had at least one autoimmune disease, mostly HT (≥21%) and vitiligo (2%). A total of 2% of CSU patients had ≥2 autoimmune comorbidities. In patients with autoimmune CSU type IIb, autoimmune disease markers: Antinuclear antibodies and/or IgG antithyroid antibodies have been associated with non-response to omalizumab therapy.^[2]

A systematic analysis of autoimmune comorbidity, in CSU revealed that the rates of comorbidity were ≥2% for Graves’ disease, ≥3% for vitiligo, and ≥5% for pernicious anemia and HT.^[24] More than 15% of CSU patients had family history for autoimmune diseases.^[2,28] The prevalence of hives in AIDS patients was noted in more than 1% of most studies.^[24] In regard to thyroid dysfunction, hypothyroidism and HT are more common than hyperthyroidism and Graves’ disease in patients with CSU; likewise, elevated levels of IgG against thyroid peroxidase (TPO) are often observed in those patients.^[25,28]

INFECTIOUS DISEASES

Helicobacter pylori (HP) affects a high percentage of patients with CSU; eradication of HP is associated with a remission of urticaria, suggesting role in CSU pathogenesis.^[37,38] The effectiveness of eradication of HP in suppressing CSU symptoms was evident;^[39] however, resolution of CSU was not associated with successful eradication HP. Significant higher CSU remission with or without HP eradication was seen in CSU with antibiotic therapy for HP eradication.^[39]

Some parasites, Toxocara, F asciola, Ancylostoma, Strongyloides, Filaria, etc., have been associated with acute urticarial.^[39] A nisakis simplex can also cause urticaria after eating of contaminated sushi fish with the parasites.^[40]

Epidemiological studies and case reports suggest that some bacterial, fungal, and viral infections might be associated with the CSU, they are as follows: Streptococcus, Staphylococcus, Mycoplasma pneumoniae, Salmonella, Brucella, Borrelia, Chlamydia pneumoniae, Yersinia enterocolitica, Herpesviridae, Parvoviridae, Caliciviridae, Flaviviridae, Hepadnaviridae, etc.^[41,42]

Chronic hepatitis B virus and hepatitis C virus are also reported to be comorbidities in patients with CSU. About <5% and 2% of patients with CSU have markers of hepatitis B and C. Urticarial rash including CSU occurs in ≤3% of patients with hepatitis C.^[43]

The routine screening of infections in CU is not recommended, however, testing for certain infections can be done on case-to-case basis according to patients characteristics.^[44]

The COVID-19 pandemic is significantly disrupting health-care systems around the world. Skin manifestations predominate and can sometimes be the first symptom of a COVID-19.^[45] It is noted that acral lesions and vesicular rash are the most common types of rash that precede non-cutaneous symptoms of COVID-19; however in rare cases, urticarial rash can also appear before other non-cutaneous symptoms of COVID-19.^[45]

A cross-sectional, international, and questionnaire-based study by Kocatürk et al., 2021, evaluated impact of the pandemic on CU and its management.^[46] It was concluded that the COVID-19 pandemic severely impairs CU patient care resulting in <50% reduction of numbers of weekly treated patients, due to restricted patients’ referrals in clinics and decreased clinic hours. This study showed that CU does not affect the COVID-19, but COVID-19 may exacerbate CU.^[46]

DRUGS

Type I immediate IgE-mediated allergic reactions often involve acute urticaria, which is usually seen within minutes to 2 h of exposure to the allergen (food and food additives, insect venoms, etc.). These causes include also medications: Beta-lactams/penicillins, cephalosporins, and other drugs, latex, blood products, and rarely – vaccines. Allergic reactions may be presented by the skin manifestations or maybe a part of a systemic allergic reaction (e.g., anaphylaxis). Generalized urticaria/angioedema after exposure to an allergen should be considered as a systemic reaction with a potential risk of anaphylaxis after subsequent exposure.^[47]

Certain drugs (narcotics, muscle relaxants, vancomycin, and radiocontrast media), and plants (stinging nettle – Urtica dioica), as well as some food (tomatoes, strawberries, etc.) can cause urticaria due to MC degranulation through a nonIgE-mediated mechanism.^[48]

Nonsteroidal anti-inflammatory drugs (NSAIDs) can trigger urticaria and/or angioedema by two distinct mechanisms: Due to underlying abnormalities in arachidonic acid metabolism (aspirin exacerbated cutaneous/or respiratory disease) and allergic reactions to NSAIDs that may be both very severe.^[49]

IgE-mediated Type I allergic reactions are extremely rare causes of CSU, on the another hand, pseudo-allergic to NSAIDs or food may be more relevant for CSU.^[1,49]

ATOPIC DISEASES

The association between CU and atopic diseases (asthma, atopic dermatitis, and allergic rhinoconjunctivitis) was investigated through a cross-sectional study and observed significantly higher frequency of atopic diseases in patients with CU compared than control group.^[50]

The significant associations between CU and atopic and autoimmune diseases was observed in a retrospective cohort study suggesting important role of autoimmunity in CU pathogenesis and possibility of sharing common genetic components and etiological pathways by CU and comorbid atopic and autoimmune diseases.^[26]

METABOLIC SYNDROME (METS)

MetS is associated with cardiovascular disease including the increased risk for coronary heart disease and other cardiovascular atherosclerotic diseases. MetS includes glucose intolerance, dyslipidemia, hypertension, and central obesity.^[14] Thirty percent of patients with CU also had MetS, and this comorbidity was associated with a more severe and uncontrolled CU.^[18]

In a literature review, authors showed that MetS is becoming increasingly valued in patients with autoimmune skin diseases, including CU. Chronic inflammation may explain the link between autoimmune disease and MetS.^[16]

The association between CU and MetS was investigated through a cross-sectional study that included 11261 patients with CU and matched 67216 controls.^[19] In this study, patients were predominantly young women. The authors found that CU was significantly associated with MetS and its components: Diabetes, obesity, hyperlipidemia, and hypertension. These data are in agreement with the growing concept that CU is a chronic, low-grade inflammatory condition, indicating importance of the early detection and treatment of MetS or its components in CU to prevent further complications. From Public Health perspective, it is important to screen CU patients for MetS in the appropriate clinical settings.^[19]

EMOTIONAL STRESS

In CSU, recurrence of symptoms several times a week or even daily has a strong impact on quality of life (QoL) and psychological state. CU belongs to the group of psychodermatological disorders, the disease itself due to itching, can worsen the QoL of patients.^[51-53] There is a neuroimmune interaction that involves the secretion of neurohormones and neuropeptides. Emotional stress is an important trigger and risk factor for psychiatric disorders, which account for more than 30% of patients with CSU. Screening for mental health problems among patients with CSU should be a necessity.^[51]

A comprehensive neuro-immunocutaneous model including multiple neuropeptides and neurokinins, inflammatory mediators and cells, hypothalamic-pituitary-adrenal, and skin hormones may explain the underlying pathophysiological mechanisms in urticaria. In addition, increased levels of psychological stress, strongly associated with CSU/chronic idiopathic urticaria (CIU), may be related to imbalances or disturbances in this neuro-immunocutaneous circuit. It is still not clear, whether any psychological stress leads to CSU/CIU in addition to pre-existing neuroimmune dysregulation.^[51]

The depression and anxiety were evident in nearly half of the 50 CSU patients and both measures significantly positively correlated with the urticaria activity score.^[52] Patients with CSU often experience sleep disturbances (SDs) due to pruritus. However, SDs may also contribute to CSU development.^[54]

Investigation of the effects of stress and pruritus on the QoL of women with CU revealed that in these patients the stress level was significantly higher than in the control group.^[53] With regard to the overall pruritus score, all parameters of the Urticaria QoL questionnaire (CU-Q2oL) were affected, with the exception of the edema/mental status subscale.^[53]

CONCLUSION

CU is considered a heterogeneous disease with distinct clinical and pathophysiologic features. It is worth remembering that CU should not be considered just a skin disease and, in addition to the systemic symptoms, associated comorbidities could worsen CU evolution [Table 2]. The complete control of CU could minimize a worse clinical outcome for patients. Further investigations are required to determine sensitive biomarkers that can predict course of development of CU and its comorbidities associated with various phenotypes, or clusters of CU and overall effective response to adequate therapy.