Gender-related differences in chronic urticaria

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KEY WORDS: Chronic urticaria – Chronic spontaneous urticaria – Gender .... cold contact urticaria (65.9%) and dermographism (57.8%), while females suffered ...
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Gender-related differences in chronic urticaria Nicoletta CASSANO, Delia COLOMBO, Gilberto BELLIA, Emanuela ZAGNI, Gino Antonio VENA G Ital Dermatol Venereol 2015 Jun 19 [Epub ahead of print]

GIORNALE ITALIANO DI DERMATOLOGIA E VENEREOLOGIA Rivista di Dermatologia e Malattie Sessualmente Trasmesse pISSN 0392-0488 - eISSN 1827-1820 Article type: Review Article The online version of this article is located at http://www.minervamedica.it

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Gender-related differences in chronic urticaria Differenze legate al genere nell’orticaria cronica

Nicoletta Cassano,1 Delia Colombo,2 Gilberto Bellia,2 Emanuela Zagni,2 Gino A. Vena1

Dermatology and Venereology Private Practice, Bari and Barletta, Italy; 2 Novartis Farma,

1

Origgio, Varese, Italy

Corresponding author: Nicoletta Cassano; Dermatology and Venereology Private Practice, Bari and Barletta; E-mail: [email protected]

Word count: 4106 65 References 1 Table

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Summary Chronic urticaria (CU) is a common skin disorder with important repercussion on the quality of life and a relevant socioeconomic impact. CU is included among the skin diseases that exhibit a significant female preponderance, with an average female to male ratio of nearly 24/1. In recent years, an ever-growing interest in gender medicine has been registered and the assessment of gender differences has increasingly become an attractive issue in clinical research. Unfortunately, there are only limited data relative to the study of CU in the perspective of gender medicine. However, apart from the predilection for females, an in-depth evaluation of the available literature shows the existence of other interesting gender-related differences in CU. The aim of this article is to review the current knowledge on gender differences in CU under different points of view, including pathophysiology, epidemiology, clinical and prognostic features, association with comorbidities, psychological aspects and quality of life.

KEY WORDS: Chronic urticaria – Chronic spontaneous urticaria – Gender – Gender differences – Gender medicine - Epidemiology – Quality of life.

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Introduction Urticaria is a group of skin diseases characterized by pruritic wheals, angioedema or both. Chronic urticaria (CU) is defined on the basis of a duration of more than 6 weeks.1 Although usually without life-threatening consequences, CU is a disabling and frustrating disease that has substantial repercussions on the quality of life (QoL) and healthcare costs.2 Chronic spontaneous urticaria (CSU) is the most common type of non-acute urticaria, and consists in the spontaneous occurrence of clinical manifestations, that are not therefore evoked by physical and/or environmental factors as happens in physical and other inducible urticarias.3 Autoimmune pathomechanisms have been implicated in a relevant proportion of CSU patients, in whom histamine release has been attributed to circulating IgG antibodies specific for the high-affinity IgE receptor (Fc RI) expressed on the surface of mast cells and basophils.4 A screening test supportive of autoreactivity is the autologous serum skin test (ASST), whose positivity suggests the presence of circulating histamine-releasing factors of any type, and not only of functional autoantibodies.1 The frequent association with thyroid autoimmunity along with the predilection for women is believed to represent further indirect evidence of a possible autoimmune origin of CSU.4 CU is included among the skin diseases that exhibit a significant female predominance, with an overall female/male ratio of approximately 2-4/1.5 In recent years, an increasing interest in gender medicine has been acquired and the study of gender differences has progressively become an attractive issue in clinical research. The possibility of different clinical presentation of human diseases between the two genders may be due to differences in various factors, including anatomy, physiology, immunity, genetics, sociocultural aspects, with complex interactions among such factors. In this context, sex hormones play a fundamental role, bearing in mind that these hormones have a relevant influence on the immune and inflammatory responses, thus contributing to the pathogenesis

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of immune-mediated human diseases.5 The objective of this article is to review the current knowledge on gender differences in CU from various perspectives and with special emphasis on pathophysiology, epidemiology, clinical, prognostic and psychological aspects, as well as comorbidities and QoL.

Sex-related pathophysiological peculiarities and role of sex hormones There are well-established differences between women and men in the structure and function of the skin, immune responses, and molecular biology, while no functional differences seem to exist in the cutaneous microvascular response to histamine.5 Significant gender differences have been detected in pruritogen-induced scratching behaviour in mice, with more intense scratching in females, 6 whereas similar aspects have not been explored in human beings. Serum IgE levels were shown to be much higher in allergic female mice compared to male mice.7 Female mice were also prone to develop more severe anaphylactic responses. This effect has been related to the estrogen-induced increased tissue expression of endothelial nitric oxide synthase and nitric oxide production, leading to vascular hyperpermeability.8 As concerns the immunological effects of sex hormones, it is known that androgens tend to have an immunosuppressive action through multiple mechanisms, and progesterone similarly seems to suppress immunity and inflammation. In contrast, estrogens can stimulate humoral immunity and antibody synthesis.5 The susceptibility of mast cells to the activity of sex hormones is highlighted by the expression of receptors for these hormones on their cell surface.7,9 Testosterone however proved unable to induce mast cell degranulation. 9,10 Experimental studies showed that estradiol may activate mast cells and enhance IgE-induced degranulation.11,12 Progesterone may preferentially act as a negative regulator of mast cell degranulation but it potentiates IgE formation.11,13,14

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The available data on the effect of sex hormones on CU disclose contradictory results. It has been reported that urticaria may be associated with some conditions characterized by hormonal changes, including endocrinopathy, menstrual cycle, menopause and hormonal contraceptives or hormone replacement therapy.15 Bork et al16 suggested however that any impact of oral contraceptives and hormone replacement therapy on CU worsening is probably very marginal. Urticaria/angioedema syndrome may appear or worsen in some pregnant women while it can improve during pregnancy in others.17 Hormonal fluctuations during the menstrual cycle are also thought to influence urticaria expression. Progesterone- or estrogen-dependent urticaria should be suspected in women who present with cyclic appearance of hives with each menses or CU lesions with periodic exacerbations.15 Hypersensitivity reactions to endogenous or exogenous female sex hormones have been implicated in the pathogenesis of these forms. Autoimmune progesterone dermatitis is a rare cyclic disease that can be characterized by premenstrual exacerbation of urticaria and angioedema. Urticaria typically appears at the end of the luteal phase and spontaneously disappears or improves a few days after menses. Estrogen-related urticaria shows an unremitting chronic course, with constant premenstrual peaks in disease activity. An association between wheals and menstruation was observed in 4.8% of the 1,113 female patients with CSU evaluated in the study of Zhong et al.18 A recent case report suggested the relationship between irregular menstrual cycle and CU symptoms, which resolved after commencement of oral contraceptive therapy.19 Dehydroepiandrosterone (DHEA) and its sulphate ester (DHEA-S) are secretory products of adrenal glands, that are converted to either androgens and estrogens in the periphery. DHEA may antagonize the production of Th2 cytokines.11 A reduced concentration of DHEA-S, likely to be the consequence of psychological distress, has been demonstrated in CU patients, regardless of their gender and response to ASST.20

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Epidemiological aspects CU is known to be more common among middle-aged women. In previous studies, with the exception of only isolated reports, most authors found male/female ratios of 1:2.21-25 In a representative cross-sectional survey of the population of the city of Berlin, 26 women were more likely than men to have CU (70.3% vs. 29.7%). In a population-based study among adults in Spain,27 the comparison between sexes disclosed a clear-cut female preponderance, with an odds ratio (OR) of 3.82. The age of onset followed the same profile in men as in women. A cross-sectional analysis using insurance claims in the United States showed that two-thirds of patients with claims consistent with CSU/chronic idiopathic urticaria were females.28 A descriptive prospective study carried out in Brazil enrolled a total of 125 patients with CU to obtain sociodemographic and clinical data.29 Of these patients, 76% were female, giving a male/female ratio of 1:3. Among the patients’ occupations, 52.8% were classified as inactive (32% housewives). In accordance with literature data, the authors noted that the predominance among females was between the ages of 30 and 40 years, whereas, among males, it was between 10 and 30 years. On the contrary, Helgreen and Hersle30 reported predominance among males between 30 and 40 years old. A Swedish study in 330 CU patients showed a different age distribution between women and men: in particular, most women were aged 24-38 years with a clear peak at age 29, while most of the men were aged 18–54 years with no peak in the age distribution at all.21 Another study suggested a somewhat later age of onset in men affected with CU as compared to female patients.31 Interestingly, a case series in CU elderly patients consisted of a lower proportion of females as compared to adult non-elderly subjects with CU (46.7% vs 69.2%).32 A prospective, cross-sectional, questionnaire-based epidemiologic investigation analyzed the

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clinical and laboratory features of 3,027 patients diagnosed with CU recruited at 19 tertiary referral hospitals in China over 9 months.18 Again, female preponderance was observed (female/male ratio, 1.46:1), although it was not seen in patients