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ANALELE UNIVERSITĂŢII “DUNĂREA DE JOS” GALAŢI MEDICINĂ FASCICULA XVII, no 1, 2012 ORIGINAL STUDY ASSOCIATION BETWEEN CHRONIC AUTOIMMUNE URTICARIA AND THYROID AUTOIMMUNITY Adriana Mihaela Tudose1, Florin-Dan Popescu1, Mariana Vieru1 ,Florica Popescu2 1 Department of Allergology, “Carol Davila” University of Medicine and Pharmacy Bucharest, Romania 2 Department of Pharmacology, University of Medicine and Pharmacy Craiova, Romania [email protected] ABSTRACT A subset of chronic idiopathic urticaria has been classified as autoimmune (presence of anti-IgE receptor antibodies). The link between chronic urticaria(CU) and thyroid disease has been discussed. We evaluated the association between urticaria and thyroiditis in romanian patients. From adult patients with CU(≥ 6-week duration), presented during one-year period, we selected a group poorly controlled with high doses of H1 antihistamines and we performed autologous serum skin test (ASST) and screening levels for anti-thyroid peroxidase(anti-TPO) antibodies, suggestive for Hashimoto tyroiditis, thyroid-stimulating hormone(TSH) and thyroid hormones. Urticaria activity score(UAS) was used for monitoring disease activity, ASST and screening for HIV-1 and -2, HBV and HCV serological markers were also performed in all patients, with written informed consent obtained. From 238 patients with CU, 133 patients (55.88%) had positive ASST. 63 of them had elevated levels of anti-TPO antibodies, 34 had Hashimoto's thyroiditis with euthyroid status, 20 had subclinical hypothyroidism and 9 patients had clinical manifestations of hypothyroidism.. 105 patients had negative ASST and of these only 5had elevated anti-TPO antibodies levels and only one had subclinical hypotiroidism. Conclusion. In patients with autoimmune chronic urticaria, our data suggested that the frequency of thyroid autoantibodies is significantly higher. KEYWORDS: autoimmune urticaria, Hashimoto thyroiditis In the last years a relationship between chronic 1. Introduction urticaria and thyroid disease was frequently discussed. Chronic urticaria (CU) appears not to have Urticaria is defined as a heterogeneous group a direct link with atopic dermatitis or allergic rhinitis. of disorders with a distinct characteristic, urticarial IgE levels are usually within normal limits. No lesion, with edema and vasodilation in the superficial external allergen is involved in the initiation of the dermis, papule of varying sizes surrounded by a reflex pathomechanisms of urticarial lesions. A subset of erythema, associated with itching or sometimes CU patients had recently been classified as having burning sensation, with or without angioedema. autoimmune urticaria on the basis of two main Urticarial papule appears rapidly and resolves within findings: association with thyroid autoimmunity and 1-24 hours without residual lesions [1]. with anti-IgE and/or anti-IgE receptor antibodies [1]. 133 ANALELE UNIVERSITĂŢII “DUNĂREA DE JOS” GALAŢI In recent guidelines, the incidence FASCICULA XVII of antihistamines and we performed autologous serum autoimmune urticaria is about 30–50% of CU and skin test (ASST) and screening for anti-thyroid may be associated with other autoimmune conditions, peroxidase (anti-TPO) antibodies, suggestive for especially autoimmune thyroiditis. Hashimoto thyroiditis. Thyroid-stimulating hormone At least one-third of all cases of CU are (TSH) and thyroid hormones levels were also autoimmune, with the possible association of thyroid autoimmunity with or without determined in these patients. clinically ASST was performed task force according consensus to manifestations of hypothyroidism. In addition to the EAACI/GA2LEN report presence of antithyroid antibodies (more frequent guidelines [9]. Autologous serum was obtained by than in the general population), these patients may centrifugation from venous blood (cubital vein) in have IgG antibodies targeted against circulating IgE sterile Vacuette® serum tubes without clotting or (much more often) against the epsilon subunit of accelerator, allowed to clot for 30 min. A samples 50 the IgE high-affinity receptor (FcεR-I). The presence μL autologous serum and 0.9% saline (from sterile of such autoreactivity can be evaluated by skin testing individual vials) separately was injected intradermally with autologous serum, the intradermal autologous into volar forearm exposed upward, with the 29- serum skin test (ASST) [2]. gauge needle, at 15-degree angle at least 3-5 cm apart. Early studies on the association of autoimmune H1 antihistamines were withdrawn at least two days thyroiditis with chronic urticaria have shown higher and systemic corticosteroids for two months. If the frequency of Hashimoto thyroiditis [3, 4]. The average diameter of the autologous serum-induced incidence of abnormal thyroid function, either wheal was >1.5 mm of the saline-induced wheal, the increased or decreased values of thyroxine levels, or ASST was considered positive. ASST was considered increased or decreased thyroid-stimulating hormone strongly positive if the erythematous papule diameter levels, or both, was estimated 12 ± 19% [5, 6]. A was at least 5 mm higher than the control test at 30 detailed study of autoantibodies present in patients min. Due to ethical reasons, screening for HIV-1 and with CU revealed that antibodies against thyroid -2, HBV and HCV serological markers were peroxidase are significantly more common in urticaria performed in all patients, with written informed (20%) than in controls (0%), but broad non-specific consent obtained. autoimmunity seems not to be detected [7]. Many patients with CU have Clinical monitoring of disease activity was positive performed by using urticaria activity score (UAS) of autologous skin test [8]. The aim of our study was to 0-6 points, depending on the daily number of wheals evaluate the association between autoimmune CU and (none=0; <20=1; 21-50=2; >50/large, confluent=3) autoimmune thyroid disease. and the intensity of pruritus (none=0; mild=1; moderate=2; intense=3) [1]. Patients who were included in the study were 2. Material and methods assessed to have normal test results, such as complete blood From subjects referred to our clinic, during a counts, erythrocyte sedimentation rate, 12-month period, for evaluation of chronic urticaria urinalysis, stool examination, hepatitis serology (CU defined as urticaria with a more than six-week negative duration), we selected the group poorly controlled patients were selected if values for rheumatoid factor with high doses of oral second-generation H1 (RF) (immunonephelometery), anti-double-stranded 134 (immunochromatography). In addition, ANALELE UNIVERSITĂŢII “DUNĂREA DE JOS” GALAŢI FASCICULA XVII DNA antibody (anti-dsDNA, latex agglutination), detected sixty-three patients (47.36 %) having Complement C3 and C4 (immmunonephelometery) increased levels of anti-TPO antibodies (Figure 4). were normal. In both groups, ASST+ and ASST-, free thyroxine (FT4) levels (normal, 0.7-1.48 ng/dL) and thyroid-stimulating hormone (TSH) levels were measured by chemiluminescent immunometric assays. The normal reference range for TSH was 0.35-4.94 μg/dL. Anti-thyroid peroxidase (anti-TPO) antibodies Figure 1. Sex ratio of patients with CU (n=238) screened during one year-period (green = 29.84 % males; blue = 70.16% females) were determined by chemiluminescent immunometric assay. The presence of anti-TPO antibodies and, in addition thyroid dysfunction, were considered criteria to meet the status of autoimmune thyroid disease. The diagnosis of hypothyroidism was made by clinical and laboratory criteria of FT4 < 0.7 ng/dL, TSH > 4.94 μg/dL. Patients were classified having subclinical hypothyroidism if they were clinically euthyroid with normal FT4 levels, but had significantly elevated TSH levels. The diagnosis of hyperthyroidism has been based on the detection of Figure 2. Percentage of patients with positive ASST (n=133 patients from a total of 238 patients) low serum TSH values (< 0.35 μg/dL) and elevated serum levels of FT4 (> 1.48 ng/dL). All patients with thyroid disease were examined by an endocrinologist. 3. Results We screened 238 adult subjects with CU with a mean age of 43.19 ± 15.4 years (limits 18; 82 years), 70.16% females (Figure 1). The group with CU was selected from patients with no detected etiology. No collagen tissue disease was suspected in this group using clinical and immunological tests. The mean duration of urticaria was 30.35 ± 24.11 months, and patients were treated with standard or high doses of oral nonsedating H1 antihistamines. 133 patients (55.88%) were evaluated having a UAS score greater Figure 3. Strong positive autologous serum skin test (ASST) than 3 points during pharmacotherapy and strong From the group of one hundred and thirty-three positive ASST (Figures 2 and 3), from which we patients with positive ASST sixty-three had elevated 135 ANALELE UNIVERSITĂŢII “DUNĂREA DE JOS” GALAŢI FASCICULA XVII levels of anti-TPO antibodies (47.36%), thirty-four greater than in the control group (4.76%), suggesting had Hashimoto's thyroiditis with euthyroid status a statistical correlation between autoimmune CU and (25.56%), twenty had subclinical hypothyroidism antithyroid antibodies. (15,03%) and nine patients had clinical manifestations of hypothyroidism (6,76%) (Figure 5). One hundred and five patients had negative ASST. Only five patients (4,76%) from this subgroup had elevated anti-TPO antibodies levels (Figure 6) and only one subject had subclinical hypotiroidism (0.95%). Figure 6. Percentage of patients with increased ATPO levels in the group of ASST-negative CU Confidence interval calculated proved statistical significance (47.36+/-8%). Risk of developing autoimmune thyroiditis in those with positive autolougus skin prick test was 47% while those with Figure 4. Percentage of patients with increased ATPO levels in the group with ASST-positive CU ASST negative was 4%. Relative risk was 11.75. Odds ratio was 18. Thyroid hormone levels and autoimmune thyroiditis status in patients with increased levels of anti-TPO antibodies varied for thyroid hormone free T4 between 0.42 and 1,44 ng/dL, for TSH ranged between 1.33 and 5.6 microUI/mL. 4. Discussions Figure 5. Percentage of patients with autoimmune thyroid disease from patients with ASST-positive CU The significative high prevalence of females and the prevalence of the ASST positivity were The values of anti-TPO antibodies ranged consistent with results of similar studies [10, 11]. It is between 8 UI/mL and 1000 UI/mL. RF and anti-ds well known that autoimmune conditions have a higher DNA antibodies were found to be negative in all prevalence in females. The most striking sex patients. Because patients were age-and sex-matched differences are observed in Sjogren’s syndrome, with control group (the group with ASST negative) systemic lupus erythematosus, autoimmune thyroid there was no statistical difference between the disease (Hashimoto’s thyroiditis and well as Graves’ controls and the patients with respect to age and sex. disease) and scleroderma, which represent a spectrum Our study revealed that, in patients with of diseases, in which women population is greater autoimmune CU, the frequency of high thyroid than 80% [12]. autoantibodies levels (47.36%) was significantly 136 ANALELE UNIVERSITĂŢII “DUNĂREA DE JOS” GALAŢI FASCICULA XVII The prevalence of the positive ASST in in patients with thyroid autoimmunity is even less patients with comorbidity urticaria-thyroiditis was well established. There are conflicting reports on the lower to than the one reported in a previous study results of such hormonal therapy [6, 19]. Treatment (56%) [18], but higher than that reported by other with thyroxine was reported to alleviate the symptoms authors (25%) [13]. of urticaria in some cases, with a concomitant The association of CU with thyroid decrease in anti-thyroglobulin antibodies. Some autoimmunity has been known for two decades, but reports also advocated that patients with CU should its frequency seems to vary in different reports. The be screened for evidence of thyroid autoimmunity and prevalence in series ranges from 12% to 33% [14, that a trial of levothyroxine therapy for those who 15]. More recently, some studies have suggested that have thyroid autoimmunity can contribute to clinical there may be a link between CU and thyroid improvement by the suppression of chronic thyroid autoimmunity [3-5, 16, 17]. stimulation [20]. Our study revealed a higher frequency of Finally, we consider that our data are autoimmune thyroiditis in the group of patients with consistent with the new European guidelines for positive ASST, compared to those with CU, but with patients with CU, that recommend evaluation for negative ASST, thus suggesting a connection between autoimmune thyroiditis [1], and underline the role of the two conditions and explaining why the response performing ASST in selected CU patients [21]. This to systemic glucocorticosteroids seems to be better. study offers original data for Romanian patients We detected thyroid autoantibodies in 47.36% presenting this association of autoimmune disorders, of patients with autoimmune CU and this may be having in mind that genetic predisposition also plays considered an important role in such immune dysregulation a relatively high percentage. The frequency of thyroid antibodies in the control group conditions [22-25]. was 4.76%, when comparing with the previous studies (0-5.6%) [18]. 5. Conclusions In our study, TSH levels were increased in 21.80% of patients with ASST-positive CU or The recognition of functional autoantibodies in autoimmune CU, compared to the group having a group of CU patients developed a new concept of negative ASST (0.95%). autoimmune urticaria , therefore there is an important Thyroid function tests are not sufficient to rule role of autoimmune testing in CU. ASST remains a out thyroid disease, and thyroid antibody tests should baseline be carried out in all patients with autoimmune CU. diagnostic test for autoimmune CU. Screening for thyroid autoimmunity and thyroid Our study revealed a high incidence of the present of function is advisable in all patients with chronic anti-TPO antibodies in patients with autoimmune CU, urticaria presenting positive ASST or autoimmune compared to those who had negative ASST. We CU for an early identification of patients requiring consider that often it's just a matter of time before specific treatment of underlying thyroid dysfunction, thyroid dysfunction will have a clinical manifestation, for a better control of CU and for a proper follow-up . and more studies are required regarding this aspect. References While the association of CU and thyroid autoimmunity is not completely understood, the 1. Leznoff A, Josse RG, Denberg J, et al. Association of chronic urticaria and angioedema with thyroid autoimmunity. Arch Dermatol 1983; 119: 636-40. 2. Leznoff A, Sussman GL. 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