Urticaria is a condition characterized by the development of itchy wheals (hives). Chronic urticaria (CU) is a condition characterized by the development of itchy wheals (hives), angioedema, or both, with reoccurring symptoms for more than six weeks.
1. Characteristics and Epidemiology of Chronic Urticaria
Chronic urticaria (CU) is a condition characterized by the development of itchy wheals (hives), angioedema, or both, with reoccurring symptoms for more than six weeks
[1]. The lifetime prevalence of all types of urticaria is usually below 10% according to different reports, whereas CU develops only in approximately one-fourth of these individuals. Of the total CU patients, one-third suffer from both hives and angioedema, 30–40% present isolated hives, and approximately 10% show isolated angioedema. The natural history of the disease has a very wide range. Approximately half of the patients follow a three-month self-limited evolution, and within a year the disease resolves in almost 80% of them. However, in more than 10% of the patients, a disease duration of 5 years or longer is expected. Females are affected at least twice as often as males, and most patients are over 20 years of age. In children, the prevalence varies from less than 1% to almost 5%, largely depending on the methodology employed by the researchers
[2].
2. Current Insight into the CSU Mechanism
The pathomechanism of chronic spontaneous urticaria (CSU) is not well established. It is suggested that there is no dominant and independent mechanism of CSU; however, there are different immunological and non-immunological abnormalities that act mutually or/and follow each other resulting in clinical symptoms of CSU
[3]. Undoubtedly, for all types of urticaria, the major players of the disease and wheal formulation are mast cells (MCs) and mediators released from these cells. Still, antihistamines constitute the first-line therapy in CSU; however, they are not equally effective in all cases
[4]. Light and electron microscopy revealed degranulated MCs in the dermis following wheal appearance. According to some reports, increased numbers of skin MCs are detected in lesional and non-lesional skin in CSU and other types of urticaria; however, the results concerning the disposition of dermal MCs in urticarial patients are somewhat conflicting
[3][5][3,5]. The activation of dermal MCs leads to immediate cell degranulation and the release of preformed mediators stored in granules, such as histamine, heparin, serotonin, chymase, tryptase tumor necrosis factor-α (TNF-α), nerve growth factor (NGF), and many others. Activated MCs also secrete de novo synthetized arachidonic acid metabolites including leukotrienes (LTs), prostaglandins (PGs), and a platelet activation factor (PAF) into the tissue. A wide range of cytokines and chemotactic agents including interleukins (ILs) such as IL-1, IL-4, IL-5, IL-6, IL-8, IL-10, IL-31, IL-33, macrophage inflammatory protein-1 (MIP-1), granulocyte–macrophage colony-stimulating factor (GM-CSF), transforming growth factor β (TGF-β), vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), TNF-α, and C–C chemokine ligand 2 and 5 (CCL2 and CCL5) are also released upon the MCs’ activation
[5][6][7][8][5,6,7,8]. The vasoactive properties of the MCs’ mediators induce increased vasodilatation, an up-regulation of adhesion molecule expression, higher vascular permeability, and plasma extravasation. As a consequence, inflammatory cell/protein accumulation is observed in the affected skin. Importantly, some of the MCs’ mediators including substance P (SP), NGF, and vasoactive intestinal peptide (VIP) can interact with peripheral nerve endings and activate sensory nerves. Cross-talk between MCs and neuronal tissue is the fundamental point of the stress-induced skin neurogenic inflammation further discussed below. The abundance of neutrophils, eosinophils, basophils, CD4+ lymphocytes, as well as monocytes is detected in urticarial wheal. Furthermore, alternations in serum circulating T cell subtypes and their activities were observed in CSU vs. healthy subjects (imbalance in the proinflammatory Th17 cells and Treg cells). Skin biopsies revealed a higher expression of IL-4, IL-5, IL-25, IL-33, and thymic stromal lymphopoietin (TSLP) in urticarial wheal and non-lesional skin. These cytokines can promote a Th2-related response as well as amplify chronic inflammation and angiogenesis. On the other hand, an elevated expression of interferon γ (IFN-γ) in affected skin was detected, indicating a mixed Th1- and Th2-skewed polarization of skin immune response in CSU
[3][4][5][9][10][11][3,4,5,9,10,11].
It is not entirely understood (i) what is the major stimulator of MC activation in the onset of CSU and (ii) which MC receptors are mainly involved in CSU-related activation. The proposed hypothesis points at MCs’ activation via autoantibodies, i.e., IgE specific to self-antigen (autoallergic mechanism) or IgG1/IgG3/IgM specific to IgE or its high-affinity receptor FcεRI (autoimmune mechanism). The autoimmune nature of the disease is supported by a deficit in T regulatory cell (Treg) activity in CSU. Tregs are generally responsible for suppressing the autoreactive immune response. It is worth remembering that FcεRI-mediated stimulation is not the only possible mechanism of MC activation considering the varied repertoire of MCs’ receptors. According to the stress-induced reaction in the skin, MC receptors specific to neuropeptides, neurotransmitters, and hormones are of special importance. There is a growing body of research on the potential role of other factors in CSU pathological cascade reaction, i.e., mediators other than histamine recruited inflammatory cells (e.g., basophils, neutrophils, and eosinophils) and skin-related cells, especially keratinocytes as a source of proinflammatory cytokines and activation of the coagulation system. The genetic background of CSU was also confirmed (alternations in HLA-DR4 and HLA-DQ8 gene expression)
[3][4][12][3,4,12]. Interestingly, the urticarial lesion was reported to be the second most common skin-related symptom of COVID-19, which could also indicate the potential role of infectious agents in the course of CSU
[13].
3. Urticaria Affects the Quality of Life and Psychological Functioning
CSU is a stress-modulated condition in which the outcome of conventional treatment is often suboptimal. A bio–psycho–social approach including psychological support and patient education seems to be as important as traditional pharmacotherapy. It facilitates effective control and a prolonged remission time of the disease. During the COVID-19 pandemic and massive isolation, excessive fear, stress, and anxiety among people were reported. Patients suffering from chronic conditions, such as CSU, additionally experienced insufficient control of the disease. Beyaz et al.
[14] have documented that urticarial activity score 7 (UAS7) during the pandemic time was higher compared to the pre-pandemic period. Furthermore, authors have observed that UAS7 was positively correlated with the Fear of COVID–19 Scale (FCV-19), depression, anxiety, and stress subscale score.
The association with psychological stress indicates the potential role of the neuroendocrine system in the etiopathogenesis of urticaria. However, it is still poorly understood how psychological stress interferes with the skin immune system in CSU. Although the role of psychological factors in development and aggravation is not fully confirmed, the psychosocial impact of CSU is widely accepted
[15][16][17][18][19][20][21][22][15,16,17,18,19,20,21,22]. The struggle of chronic disease, prolonged treatment, and multiple consultations with different practitioners (often resulting in fatigue, work absence, or lowered school performance)
[16][17][16,17] leads to a deterioration in psychological functioning. Patients suffering from urticaria manifest significantly higher scores in somatization, obsessive–compulsive disorder, interpersonal sensitivity and depression, anxiety, and stress levels
[18][19][20][21][18,19,20,21]. A positive correlation between the severity of the disease and poor psychological wellness or lower quality of life is also frequently reported
[22].
The wellbeing and quality of life of CSU patients is also affected by their quality of sleep. Subjective symptoms such as itching and pain can have a significant impact on sleep quality in patients with chronic skin diseases
[23]. At the same time, sleep alterations (i.e., shortening of sleep; frequent awakenings during the night) lead to further deterioration in quality of life together with fatigue and frustration. In addition, patients with CSU are more likely to suffer from sleep disorders such as obstructive sleep apnea syndrome or sleep-disordered breathing
[24][25][24,25]. As a consequence, there is an even greater psychological burden on the patient and, as a consequence, a higher risk of an exacerbation of CSU symptoms.