INVOLVEMENT OF PSYCHOLOGICAL FACTORS IN CHRONIC URTICARIA

INTRODUCTION
Urticaria is an immuno-allergic reaction caused by multiple factors, characterised by the appearance of an eruption consisting of erythematous-edematous, pruritic, rapidly fading papules and plaques affecting the dermis and the subcutaneous tissue. At least 1 out of 6 persons develops one or more episodes of urticaria during lifetime; women are more predisposed than men; urticaria can appear at any age, with an incidence peak between 20 and 40 years (1). Regarding the evolution, urticaria is usually dedivde into acute urticaria (the episode lasts for less than 6 weeks), chronic urticaria (the episode lasts for more than 6 weeks) and chronic intermittent or episodic urticaria (acute episodes which reoccur after more than 6 weeks) (1, 2).
While in acute urticarias the cause can be easily detected and the aetiologic trigger removed from the environment or diet, in chronic urticarias (CU) avoidable triggers can only be identified in 10-20% of the cases (3, 4).
Regarding the etiopathogeny of CU, there have been incriminated physical agents (35%) consisting of thermal and/or mechanic factors, ultraviolet radiation , autoimmune diseases (25%)- autoimmune thyroid disease, systemic lupus erythematous, cryoglobulinemia, neoplasms- vasculitic conditions (5%)- especially leukocytoclastic vasculitis- and various infectious agents (2%)- H. pylori, Streptococcus, Mycoplasma, various parasitic infestations; an important percentage of the CU cases (approximately 30%) are considered idiopathic (5). Many of these apparently idiopathic cases are assumed to be associated with autoimmune conditions or psychological factors.

PSYCHOLOGICAL FACTORS INVOLVEMENT IN CU – NEUROHUMORAL HYPOTHESES Psychological factors are, by nature, difficult to objectify, thus proving their involvement in various conditions being extremely troublesome; the responsibility of demonstrating the connections between psychological factors and cutaneous conditions is subject of psychodermatology, which developed as an interface branch between dermatology and psychiatry. Most studies focus on proving an association between the depression or anxiety level of the patient and the presence and severity of the cutaneous manifestations of CU, on proving the impact of CU on the quality of life and on searching for a marker which would chemically characterise CU and would proportionally correlate with the measured level of stress, depression or anxiety.
The mechanisms through which psychological factors affect cutaneous immunity and influence the appearance and evolution of CU are incompletely elucidated; yet, there are numerous hypotheses which could explain, at least partially, the involvement of psychological factors in CU.
Stress and psychological factors can influence immunity by altering the cytokine panel that assures intercellular cooperation within the immune response. Thus, acute stress determines an immunological switch towards the stimulation of T helper 2 lymphocytes (LTh2) and the synthesis of IgE; moreover, it can alter the ratio between stress hormones, by diverting the adrenal gland secretion from the production of mineralocorticoids and epinephrine towards the synthesis of glucocorticoids, as an adaptive mechanism (6). The polymorphism of the gene encoding PTPN22 (Protein tyrosine phosphatase- 22), a protein involved in B and T lymphocytes responsivity to various stimuli, plays an important role in the pathogenesis of CU; mutations in this gene are involved in several autoimmune disorders, such as type I diabetes mellitus, systemic lupus erythematous or Basedow-Graves disease (7).
An important link connecting the nervous system and u r t i c a r i a l i n f l a m m a t i o n i s r e p r e s e n t e d b y dehidroepiandrosterone (DHEA) and its sulfate derivate, dehydroepiandrosterone sulfate (DHEA-S). In chronic urticaria, the levels of DHEA and DHEA-S are low (6, 8). DHEA-S plays an important role in the immune system homeostasis; since the level of DHEA-S depends on the action of the nervous system on the adrenal gland and because its action is also exerted in the CNS through the modulation of GABAA and NDMA receptors, DHEA-S plays an important role by linking the nervous system, endocrine system and immune response altogether (9, 10). DHEA-S is synthesised in the adrenal cortex and represents a metabolic intermediate in the synthesis of androgens and estrogens. After reaching the skin through systemic circulation, it is converted to androstendiol and then andronstentriol, a process which only appears in skin (11). DHEA-S has an important role in regulating antiviral, antibacterial and antiparasitic immunity, fact proven by Loria and Padgett who obtained, by subcutaneously injecting DHEA in mice, a significant growth of the resistance against herpes virus type 2, Coxsackievirus B4, Pseudomonas aeruginosa and Trypanosoma cruzi (11, 12); moreover, DHEA increases the level of Th1 cytokines (IL-2, IL-3, IFN) and plays an important role in maintaining the Th1/Th2 ratio (13).

POTENTIAL BIOCHEMICAL MARKERS IN CU
Usual laboratory findings in patients with chronic urticaria fail to offer crucial data that could significantly either modify patient management or influence their treatment (14). Therefore, discovering serological markers associated with CU able to would vary according to the severity of the episodes represents a goal of paramount importance in CU researches. Various markers have been proposed as candidates in this respect over time, but until now, no ideal biomarker for CU has been reported.
-autoimmune thyroid disease biomarkers. Missaka et. al showed a close association between idiopathic chronic urticaria and the presence of autoimmune thyroid disease marker antibodies, also proving that patients with CU that present these antibodies have a higher risk of evolution towards angioedema (15). The idiopathic CU- autoimmune thyroid disease association can be encuntered in 27-30% of the patients suffering from CU and appears without clinically manifest thyroid dysfunction (16, 17).
-eotaxin- a β-chemokine receptor agonist with the role of attracting eosinophils to the inflammatory spot, eotaxin is present in the serum of CU patients at higher doses than in healthy patients; its levels are more increased in patients with severe forms of CU; in some patients, the level of eotaxin varies depending on the course of the disease (18).
-dehydroepiandrosterone sulfate (DHEA-S) – its level is low in patients suffering from CU and its decrease can be correlated to the level of depression and anxiety in these patients; Brzoza et al showed in 2008 in a study that included 54 patients suffering from CU and 59 healthy subjects that the level of DHEA-S is low in patients with CU, as compared to the healthy control group (6, 19). DHEA-S and the DHEA-S/cortisol ratio are modulated by various psychological factors (20). In depression, the level of DHEA-S is also low (21, 22). DHEA-S is considered to have an important role in the efficient stress accommodation and the decrease in its level could signal the decrease in stress resilience (10). It has been observed that DHEA administration in patients suffering from h e r e d i t a r y a n g i o e d e m a , i n w h o m t h e a l l e rg i c manifestations are due to the absence of the C1q inhibitor of the complement (C1INH), suppresses the development of angioedema, which could constitute a clue favouring the hypothesis according to which the decrease of DHEA, encountered in CU, would contribute to the activation of inflammation or the maintenance of a high status of inflammatory activity (9).
-prolactine. The prolactine level is particularly high in patients with CU in which the autologous serum skin test is positive; however, no correlation between the level of prolactine and DHEA-S has been observed (23).
-procalcitonine and C-reactive protein. These two proteins show higher levels in patients with severe CU than in the ones with mild CU or healthy individuals. Yet, they most likely reflect the inflammatory systemic response and do not present any real utility in the management of patients suffering from CU (24).
-other markers: the tryptase can be a useful marker in CU (25), as well as BAFF (B-cell activating factor), which is high in patients with CU and is positively correlated to the severity of the disease (26).

STUDIES ASSERTING THE INVOLVEMENT OF PSYCHOLOGICAL FACTORS IN CU
Stress and psychological factors are frequently involved in numerous dermatological conditions, some authors considering that psychological factors play an important role in 30% of the cutaneous disorders (27). Of these cutaneous conditions, a study performed on 1073 patients suffering from dermatological disorders found the highest rate of psychiatric comorbidities in patients diagnosed with CU (28).
Psychic stress can trigger or exacerbate CU; in a cohort of
50 patients with CU, Malhorta et al noticed the existence of a major stressful event during the year before the debut or acutisation of the CU in 16% of the patients; the most frequently incriminated events were the decease of a family member and financial or sexual difficulties (29). Also, in a smaller study performed on a cohort of 30 patients with CU, Berrino et al showed that patients with CU faced a major stressful event during the last 6 months p r i o r t o t h e o n s e t o f t h e d i s e a s e ( 3 0 ) . Depression and anxiety are frequently encountered in patients with CU. Brzoza et al showed that patients with CU have higher anxiety and depression levels and consider that these could be epiphenomena which accompany CU, interpreting them as consequences rather that causes of CU. Moreover, in patients with CU the level of DHEA-S is low; this DHEA-S decrease can raise CU patients predisposition towards developing mood disorders (6).
Psychiatric comorbidities are not only encountered in adults. A study published in 2011 and performed on 27 children suffering from CU and 27 children as controls showed higher anxiety and depression levels in the first group, as compared to the second one (31).
Alexithymia, a personality feature characterised by difficulties in differentiating and describing emotions, is associated with many dermatological conditions, one of them being chronic urticaria (32). A study published in 2011 performed on 55 individuals with CU revealed alexithymic features in 56.9% of the patients included in the study (33).
P a t i e n t s s u f f e r i n g f r o m C U s h a r e c e r t a i n psychobehavioural characteristics; according to a study performed on 59 patients with CU who answered the Minnesota multiphasic personality inventory, these patients are more likely to be depressive, touchy, hysteric, suspicious and hypochondriac persons; also, they are individuals with attitudes towards perfectionism and have a high need for attachment (34).
On the other hand, CU alters patients’ quality of life. A study published by Engin et al in 2008 revealed an important quality of life decrease in patients suffering from CU; also, high anxiety and depression levels were observed among them (35). Other studies also reported similar results, especially significant reductions in the fields of social and emotional state functioning (36).
The pruritus accompanying chronic urticaria can also be modulated by the pre-existence of depression; thus, on a group of 252 patients diagnosed with psoriasis (77 patients), atopic dermatitis (143 patients) and urticaria (32 patients), Grupta et al demonstrated that the perception of pruritus is higher among patients who have a higher score on the Carroll Rating Scale for Depression (CRSD) (37). The involvement of psychological factors can also be demonstrated through the encouraging results obtained in the treatment of chronic urticaria with doxepin, a tricyclic antidepressant with H1 antihistamine activity (2). The association of doxepin to a treatment comprising a sedative with anti-H1 activity type clorfeniramin proved to be more efficient than other therapeutic regimens in the treatment of CU (38).
Olff et al showed that psychotherapy can produce increases in the level of DHEA-S, which could suggest that patients with chronic urticaria, in which DHEA-S serum level is low, could benefit from psychotherapy (39).

CONCLUSIONS
Psychological factors play a significant role in triggering or exacerbating dermatological diseases. The numerous studies existing so far in literature prove the existence of a strong association between psychological factors and dermatological disorders in general, and those and CU in particular. The relationship between psychological factors and CU is biunivoque, because on one hand, stressful events can trigger the debut or aggravation of CU, and on the other hand, CU, through the discomfort it produces, increases the level of stress and alters the mood, acting as anxiety and/or depression and affecting the quality of life of these patients. Establishing a panel of biomarkers which would correlate with the severity of the disease and the stress level could decisively contribute to a better management of the patients with CU in the dermatological practice. Interdisciplinary cooperation between the dermatologist and the psychiatrist or the psychologist is of a paramount importance in the treatment of chronic urticaria.

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