pissn: 2288-0402 eissn: 2288-0410 1(2):151-156, June 2013 http://dx.doi.org/10.4168/aard.2013.1.2.151 ORIGINAL ARTICLE 갑상선자가항체와만성특발성두드러기의예후 이서영 1,2, 송우정 1,2, 정재우 3, 박흥우 1,2, 조상헌 1,2, 민경업 1,2, 강혜련 1,2 1 서울대학교의과대학내과학교실, 2 서울대학교의과대학알레르기임상면역학연구소, 3 중앙대학교의과대학내과학교실 Thyroid autoantibodies and the prognosis of chronic idiopathic urticaria Suh-Young Lee 1,2, Woo-Jung Song 1,2, Jae-Woo Jung 3, Heung-Woo Park 1,2, Sang-Heon Cho 1,2, Kyung-Up Min 1,2, Hye-Ryun Kang 1,2 1 Department of Internal Medicine, Seoul National University College of Medicine, Seoul; 2 Institute of Allergy and Clinical Immunology, Seoul National University Medical Research Center, Seoul; 3 Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul, Korea Purpose: Chronic urticaria is a common disease, but clinically, it is not easy to treat and predict the prognosis since the causes and pathophysiology of chronic urticaria remain unknown. Many studies have been done that defined the association between chronic urticaria and thyroid autoimmunity. However, the clinical role of antithyroid antibodies (ATAs) has not been fully evaluated. Methods: We retrospectively reviewed the medical records of patients with chronic urticaria and compared the duration of treatment, the frequency of steroid use, and the level of medications used in the treatment of urticaria according to the presence or absence of ATAs including the antithyroglobulin (anti-tg) antibody, antithyroid peroxidase antibody, and antithyrotropin-stimulating hormone receptor antibody. Results: A total of 194 patients with chronic urticaria was enrolled; of which, 108 patients were free of ATAs and 86 patients had at least one ATA. The treatment duration was significantly longer in the anti-tg antibody-positive patients compared to the patients without ATAs (39.6± 10.2 months/18.0± 3.4 months, P= 0.02). The patients with the anti-tg antibody also showed more frequent steroid use than that of the patients without the anti-tg antibody (2.1±0.4/1.1±0.3, P=0.05). The level of medications used to achieve control of urticaria tended to be higher in patients with the anti-tg antibody than in the ATA-negative patients group. Conclusion: From this study, we suggest that the evaluation of thyroid autoantibodies, especially the anti-tg antibody, can be a useful tool in predicting the prognosis and making decisions for the treatment strategy of patients with chronic urticaria. (Allergy Asthma Respir Dis 2013;1:151-156) Keywords: Urticaria, Thyroid gland, Autoimmunity, Autoantibodies 서론두드러기는다양한크기, 개수, 분포를보이는소양감을동반한 24시간이내소실되는일시적인팽진으로정의되는질환이다. 두드러기가발생하는기전으로는면역성또는비면역성요인모두가능한데혈관확장, 혈류량증가, 혈관투과성증가와비만세포의활성화, 이에따른염증매개물질의분비가두드러기를일으킨다. 1) 두드러기가 6주이상지속되는경우만성두드러기라고정의하며, 유병률은 3% 까지보고되고있다. 2) 만성두드러기는원인에따라분류하기도하는데, 3) 물리적두드러기가만성두드러기의 20% 정도를차지하며 4) 음식물, 약물, 혈관염, 자가면역질환, 감염, 물리적자극등두드러기를유발하는원인을찾지못한경우특발성두 드러기로정의한다. 5) 만성특발성두드러기는전체만성두드러기환자의 75% 를차치한다는보고가있으며 6) 유병률이 0.5% 로드물지않게발생한다. 7) 만성특발성두드러기환자에서 IgE 또는 high-affinity IgE 수용체에대한자가항체의존재는잘알려져있다. 만성특발성두드러기환자의 45 55% 가 basophil activation test에서 FcεRI, FcεRII, IgE에대한자가항체측정에양성소견을보이며 8) 또한이결과는자가혈청피부반응검사의양성률과도밀접하게연관성을가지는것이밝혀졌다. 9) 또한여러연구에서만성두드러기환자에서의혈청갑상선자가항체증가가보고되어있다. 10-12) 그러나, 이들갑상선자가항체가만성두드러기환자의임상경과와어떤관계가있는지는잘알려져있지않다. Correspondence to: Hye-Ryun Kang Department of Internal Medicine, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul 110-799, Korea Tel: +82-2-2072-0820, Fax: +82-2-742-3291, E-mail: helenmed@snu.ac.kr Received: June 5, 2013 Revised: June 5, 2013 Accepted: June 7, 2013 151 2013 The Korean Academy of Pediatric Allergy and Respiratory Disease The Korean Academy of Asthma, Allergy and Clinical Immunology This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/). http://www.aard.or.kr
Lee SY, et al. Thyroid antibody in urticaria 이에본연구에서는만성특발성두드러기환자를대상으로시행한갑상선자가항체검사결과를확인하여양성을보이는환자들의검사결과와치료경과를자가항체음성환자와비교하여갑상선자가항체양성만성특발성두드러기환자의임상적인특징을알아보고자하였다. 대상및방법 1. 연구대상 2004년 1월부터 2010 년 12월까지서울대학교병원에서만성특발성두드러기로진단받은환자중갑상선자가항체에대한혈액검사에서양성소견을보인환자 86명과음성소견을보인환자 108명, 총 194명의환자가연구에포함되었다. 개별병변은 24시간내소실되는홍반성팽진이 6주이상지속되는경우만성두드러기로진단하였고, 병력청취에서음식물, 약물, 온도, 운동, 물리적인자극등두드러기의원인이알려진환자는연구에서제외하였다. 전자의무기록을통하여갑상선자가항체양성군과음성군의혈액검사소견과약물사용력, 급성악화로인한응급실내원횟수등의임상경과를후향적으로비교하였다. 2. 연구방법 1) 검사혈액검사를통하여혈청총 IgE, 혈중 T3, ft4, thyrotropin-stimulating hormone (TSH) 수치, antithyroglobulin antibody (anti- TG Ab), antimicrosome antibody (antithyroid peroxidase [TPO] Ab), anti-tsh receptor antibody (anti-tsh-r Ab) 수치를확인하였다. 갑상선자가항체유무에따라양성군과음성군으로구분하였고, 양성군에서는양성을보인자가항체별로재분류하였다. 알레르겐피부반응검사, 또는 Multiple Allergen Simultaneous Test (MAST) 를시행하여감작상태를확인하였다. 피부반응검사에서는항원에의한팽진의평균직경이히스타민에의한팽진의크기보다크거나 3 mm 이상인경우양성으로판단하였고 MAST 는 3+ 이상일때양성으로판단하였다. 자가혈청피부반응검사는환자의정맥혈을채취하여원심분리후혈청을추출하여 0.05 ml 주사한후 30분간관찰하여발생한팽진의평균직경이생리식염수주사후발생한팽진의직경보다 1.5 mm 이상큰경우양성으로판단하였다. 13) 2) 치료경과두드러기의증상조절을위해서약물투약내역을조사하였다. 항히스타민제를단독으로사용하였는지, 혹은증량하였는지, 다른항히스타민제제를추가하였는지, 두드러기증상조절을위하여항류코트리엔제제, 사이클로스포린, 전신스테로이드를사용하였 는지확인하였고, EAACI/GA(2)LEN/EDF/WAO 2009 Guideline 에따라약제사용의단계를나누었다. 14) 1 단계는 H1 항히스타민제 제로수주내에증상이조절되는경우, 2 단계는 1 단계약제로증상 이조절되지않아 H1 항히스타민제제의용량을 4 배까지증량한경 우, 3 단계는 2 단계약물로증상이지속되어항류코트리엔제제를 추가하거나다른 H1 히스타민제제로변경, 또는급성악화로전신 스테로이드를사용한경우, 4 단계는증상조절을위해 H2 항히스 타민제제나사이클로스포린 (cyclosporin, Cipol-N, Chong Gun Dang Pharmaceutical Co., Seoul, Korea), 오말리주맙 (omalizumab, Xolair, Novartis, Basel, Switzerland), 답손 (dapsone, Dapsone, Tai-Guk Pharm Co., Seoul, Korea) 을복용한경우로정의하였다. 치료중환자가두드러기증상악화로응급실을방문하였거나예 정되지않은외래를방문하였을경우급성악화로판단하였다. 조사 당시치료를종료한환자를대상으로총치료기간을조사하였다. 3) 통계분석 군간에연속변수비교를위해서는 Student t-test 를, 비연속변수 비교를위해서는 chi-square test 를이용하였다. P-value 가 0.05 보다 작을경우통계적으로유의하다고정의하였다. 통계분석은 SPSS ver. 17 (SPSS Inc., Chicago, IL, USA) 을이용하였다. 1. 대상환자의임상적특성 결과 전체환자의평균연령은 50.4 세였고갑상선자가항체음성군에 서는 49.6 세, 양성군에서는 54.4 세였다 (Table 1). 성별분포는전체 적으로는여성이 66.5% 를차지하였는데, 특히갑상선자가항체양 성군의경우여성의비율이 76.7% 로음성군 (58.3%) 에비하여유의 하게높았다 (P = 0.005). 항체의종류별로는 anti-tg Ab 와 anti- TPO Ab 에양성인경우여성의비율이 84.2%, 90.0% 로높게나타 났다. 갑상선자가항체에양성을보인만성두드러기환자의경우자가 Table 1. Baseline characteristics of antithyroid antibody (+) and antithyroid antibody (-) group Characteristic ATA (+) (n= 86) ATA (-) (n= 108) P-value Female sex (%) 76.7 58.3 0.005 Mean age (yr) 54.4 49.6 0.397 ASST positive (%) 51.6 18.4 0.005 Dermographism (%) 54.3 28.6 0.100 Atopy (%) 55.9 53.5 0.871 Total IgE (KU/L), mean± SD 357.4± 217.4 192.9± 47.7 0.409 TSH (μiu/ml), mean± SD 4.7± 1.9 1.9± 0.2 0.155 ATA, anti-thyroid antibody; ASST, autologous serum skin test; TSH, thyrotropin-stimulating hormone. 152 http://dx.doi.org/10.4168/aard.2013.1.2.151
이서영외 두드러기와갑상선항체 ATA (+) n=31 ASST (+) n=23 Anti-TG Ab (+) n=64 15 16 7 Fig. 1. The concordance rate of antithyroid antibody (ATA) (+) and autologous serum skin test (ASST) (+). A total of 16 patients represented double positivity to antithyroid antibody and autologous serum skin test among 54 patients who underwent both tests. 10 24 Anti-TPO Ab (+) n=34 38 2 12 Anti-TSH-R Ab (+) n=14 Fig. 2. Diagram exhibiting distribution of each antithyroid antibody (ATA) among patients who showed positivity to at least one ATA. Anti-TG Ab, antithyroglobulin antibody; antithyroid peroxidase (TPO) Ab, antimicro some antibody. Table 2. Baseline characteristics of autologous serum skin test (+) and autologous serum skin test (-) group Characteristic ASST (+) (n= 23) ASST (-) (n= 46) P-value Female (%) 73.9 56.5 0.195 Mean age (yr), mean± SD 53.0± 2.8 46.0± 2.5 0.069 ATA positive (%) 69.6 32.6 0.005 Anti-TG antibody 60.9 23.9 0.004 Anti-TPO antibody 33.3 11.4 0.064 Anti-TSH-R antibody 27.8 11.4 0.137 Anti-TG and TPO 16.7 6.8 0.344 Dermographism (%) 21.7 13.0 0.416 Atopy (%) 63.6 48.8 0.301 Total IgE (KU/L), mean± SD 192.3± 61.9 245.2± 97.7 0.683 TSH (μiu/ml), mean± SD 3.1± 1.0 2.1± 0.3 0.324 ASST, autologous serum skin test; ATA, antithyroid antibody; Anti-TG, antithyroglobulin; Antithyroid peroxidase (TPO), antimicrosome; Anti-TSH-R, antithyrotro pinstimulating hormone receptor. 혈청피부반응검사양성비율이 51.6% 로음성인환자 (18.4%) 에비 해약세배가량높았다 (P = 0.005). 갑상선자가항체에양성군에서 피부묘기증동반비율도높았으나 (54.3% vs. 28.6%) 통계적으로유 의하지는않았다. 현증갑상선기증저하나항진으로치료중인환 자는없었다. 자가혈청피부반응검사를시행한 69 명의환자중 23 명의환자에 서양성을보였다. 자가혈청피부반응검사결과양성여부에따른 특징을비교하여보았을때양성군에서여성의비율이높고평균 연령이높은경향을보였다. 자가혈청피부반응검사에서양성을보 인 23 명의환자중갑상선자가항체에양성을보인환자는 16 명 (69.6%) 이었는데 (Fig. 1), 특히 anti-tg Ab 양성이 60.9% 로음성군 에비해유의하게많았다 (Table 2). 2. 검사실소견 혈청총 IgE 수치는갑상선자가항체양성군과음성군에서각각 357.4±217.4 KU/L, 192.9±47.7 KU/L 이었으며두군간에통계적 인차이는없었다. 피부반응검사와 MAST 를통해조사된아토피 유무또한양군간에차이를보이지않았다. 갑상선자가항체양성 군과음성군의혈중 T3 수치는각각 116.4±8.4 ng/dl 와 170.9± 35.2 ng/dl, free T4 수치는각각 1.2±0.0 ng/dl와 1.4±0.2 ng/dl, TSH 수치는각각 4.7±1.9 μiu/ml 와 1.9±0.2 μiu/ml 로양군간에유의한차이는없었다. 갑상선자가항체에양성을보인환자 86명중 anti-tg Ab, anti- TPO Ab, anti-tsh receptor Ab 각각에단독으로양성을보인환자는각각 38명, 10명, 12명이었고, anti-tg Ab와 anti-tpo Ab에동시에양성을보인환자가 24명, anti-tg Ab와 anti-tsh receptor Ab 에동시에양성을보인환자는 2명이었다 (Fig. 2). 3. 갑상선자가항체에따른두드러기치료경과 1) 두드러기치료기간연구시점에서두드러기치료가종료된환자중갑상선자가항체음성인환자의평균치료기간은 18.0±3.4 개월이었음에반해, 갑상선자가항체양성인환자의평균치료기간은 32.2±5.4개월로나타났다. 특히 anti-tg Ab 양성인환자군의경우치료기간은 39.6±10.2 개월로가장길었으며, 갑상선자가항체음성인군과비교하였을때유의한차이를보였다 (Table 3) (P = 0.02). Anti-TPO Ab와 anti-tsh receptor Ab에양성인환자를자가항체음성인환자군과각각비교하였을때에는통계적으로유의한치료기간의차이를보이지않았다. 2) 두드러기증상조절을위한약제사용증상조절을위해서동시에사용한항히스타민제의개수는갑상선자가항체는양성군에서는 1.5±0.1개, 음성군에서는 1.6±0.1 개로차이가없었다. 양성을보인갑상선자가항체종류에따라비교하였을때에는 anti-tpo Ab 양성군에서는평균 1.4±0.2 개, anti-tg Ab 양성군에서는평균 1.5±0.7 개, anti-tsh receptor Ab 양성군에서는평균 1.5±0.2개였으며, 통계적차이는없었다. 항류코트리엔제제의사용에도유의한차이를보이지않았다. 반면갑상선자가항체에따른스테로이드사용횟수는 anti-tg Ab 양성군에서유의하게많았고 (Fig. 3), 반면 anti-tsh receptor Ab에양성인환자군에서는스테로이드사용이한명도없었다. 두드러기증상조절을위해사용한약제의단계를 EAACI/ http://dx.doi.org/10.4168/aard.2013.1.2.151 153
Lee SY, et al. Thyroid antibody in urticaria Table 3. Treatment course according to the presence and the type of anti-thyroid antibody 3 P=0.05 No. of patients Treatment duration (mo), mean± SD Steroid use (%) ER visit (%) ATA (-) 108 18.0± 3.4 26.9 3.7 ATA (+) 86 32.2± 5.1 32.6 3.5 Anti-TG 64 39.6± 10.2* 42.1 5.3 Anti-TPO 34 20.9± 8.3 0 10.0 Anti-TSH-R 14 29.3± 10.1 33.3 0.0 Steroid use 2 1 The number of patients who had both anti-tg Ab and anti-tpo Ab was 24; the number of patients who had both anti-tg Ab and anti-tsh receptor Ab was 2. ER, emergency room; ATA, antithyroid antibody; Anti-TG, antithyroglobulin; Antithyroid peroxidase (TPO), antimicrosome; Anti-TSH-R, antithyrotropin-stimulating hormone receptor. *P= 0.02 between anti-tg and ATA (-). 0 Anti-TG (-) Anti-TG (+) Fig. 3. The number of steroid use was higher in anti-thyroglobulin (anti-tg) antibody positive group than negative group. GA(2)LEN/EDF/WAO 2009 Guideline 에따라나누었을때 3단계이상의약제를사용한비율은 anti-tg Ab 양성군에서 70.0% 로갑상선자가항체음성군의 54.6% 에비하여높은경향을보였다 (P = 0.066). 3) 응급실방문두드러기치료기간중두드러기증상악화로인하여응급실방문을한환자의비율은갑상선자가항체음성군에서는 4명 (3.7%), anti-tg Ab 양성군에서는 2명 (5%), anti-tpo Ab 양성군에서는 1 명 (10%) 이었으며군간에유의한차이는없었다. 고찰만성두드러기는비교적흔히발생하는질환으로일단발생하면이환기간이길뿐만아니라삶의질을저하시키며장기간의치료를필요로하는경우가대부분이다. 원인인자를알수없는 특발성 으로진단되는경우가 75% 정도로많은부분을차지하여환자에따라서다양한경과를나타내는데아직만성특발성두드러기의예후인자에대해서는명확히알려진바가없다. 일부만성두드러기환자에서자가혈장이나혈청을피내주사하였을때팽진과발적반응이확인되어자가항체가만성두드러기의발생에관여할가능성을시사하였다. 15) 만성두드러기환자의 45% 에서 55% 에서 IgE 또는비만세포나호염기구의 high afficity IgE 수용체 (FcεRI) 에대한자가항체를가지며 8) 만성두드러기의병인에있어서 Anti-FcεRI Ab는 C5a의생성을촉진하여보체를활성화시킴으로써비만세포와호염기구의활성화를돕는역할을한다고알려져있다. 16) 이러한자가항체는호염기구히스타민유리검사 (basophil histamine release test) 나호염기구활성화검사 (basophil activation test) 를이용해볼수있지만, 임상에서는자가혈청피부반응검사를통해간접적으로항체의존재를확인해볼수있다. 많 게는 76.5% 의만성두드러기환자에서자가혈청피부반응검사양성을보인다. 13) 본연구에서갑상선자가항체양성군은음성군에비하여여성의비율이더높았고 (76.7% vs. 58.3%), 자가혈청피부반응검사양성율도유의하게높았는데이는갑상선질환의유병률이남성보다여성에서더높은데따른결과로생각할수있다. 자가혈청피부반응검사는환자의혈청을분리하여피내에주입하는것으로 Anti-FcεRI Ab의존재를예측하는데에사용되고있으나, 사실이는특정한항체가아닌다양한팽진유발물질의혈청내존재를알려주는검사로 anti-fcεri Ab 뿐만아니라갑상선자가항체, 그리고알려지지않은다른자가항체에대해서도반응을할것이라예상된다. 또한갑상선자가항체양성자에서도자가혈청피부반응검사에음성을보인일부환자도있어이검사방법이언제나자가항체의유무와일치하는것은아니라는것을알수있었다. 1980년대초반 Leznoff 등 17) 에의해서만성특발성두드러기의발생에관여하는자가면역기전일부로, 갑상선자가항체의역할이대두되었다. TPO ( 갑상선과산화효소, thyroid peroxidase) 는 heme prosthetic group을가진세포막에붙은당단백효소로미크로솜에존재한다. Anti-TPO Ab는정상인의 12 14% 에서검출되고갑상선질환이없는다른종류의자가면역질환환자에서는이보다더높은빈도로나타난다. 18) Anti-TPO Ab는자가면역성갑상선질환진단에서가장예민한검사법으로거의모든하시모토갑상선염, 위축성갑상선염, 산후갑상선염환자, 그리고그레이브스병환자의 70 80% 에서검출된다. 19,20) TG는갑상선여포세포에서합성되는두개의동일한폴리팹티드로구성된요오드당단백으로여포강안에저장되며, 갑상선호르몬의전구물질에해당한다. Anti-TG Ab는자가면역성갑상선질환환자에서 anti-tpo Ab와같이나타나는경우가많은데, anti-tg Ab만단독으로검출되는사람은 TSH에이상이없어현재까지 anti-tg Ab 단독으로검출되는경우의임상적의의는아직뚜렷하지않다. 20) TSH receptor 는갑상선세 154 http://dx.doi.org/10.4168/aard.2013.1.2.151
이서영외 두드러기와갑상선항체 포표면에표출되는당단백으로그레이브스병과일차성점액부종의원인이되는자가항체의표적이다. Anti-TSH receptor Ab는갑상선기능항진증환자에서그레이브스병과다른원인에의한갑상선중독증의감별에도움이되는검사이다. 이러한갑상선자가항체가두드러기의임상경과에미치는영향은잘알려져있지않으며, 자가면역갑상선질환과만성두드러기와의관련을두가지다른자가면역상태의교차반응성으로설명하려는가설이있었으나, 결과적으로두가지항체사이에항원결정부 (epitope) 을공유하지않는것으로알려져있다. 21) 과거여러연구에서만성두드러기와자가면역갑상선질환과의관련성이논의되었고, 만성특발성환자에서의갑상선자가항체양성률은다양하게보고되고있으나최근에발표된연구일수록양성률이보다높게나타나는경향을보인다. 22) 만성특발성두드러기환자에서정상인대조군에비하여갑상선자가항체가증가되어있다는것은여러연구를통해잘밝혀져있으며, 12,17,22-27) 갑상선호르몬치료를통하여만성두드러기의경과를호전시킨결과가보고된바있으나, 28) 갑상선자가항체의증가를보이는만성특발성두드러기환자의특징에대해서는아직연구가부족하며특히양성을보인갑상선자가항체의종류에따라임상양상을분석한연구는전세계적으로아직없어본연구가의미를가질것으로판단된다. 본연구는만성특발성두드러기환자에서갑상선자가항체여부에따른환자의임상적특징을분석하고자가항체의종류에따른치료경과의차이를보고자하였다. 연구에포함된감상선자가항체양성환자 86명중약절반에가까운 40명에서 anti-tg Ab에양성을보는데, anti-tg 양성환자군은갑상선자가항체음성군에비하여여성의비율이높았고혈청총 IgE, T3, ft4, TSH 등검사실소견에서는유의한차이를보이지않았지만, 유의하게갑상선자가항체음성군에비하여통계적으로유의하게긴치료기간을보였고, 3 단계이상의약물사용을한환자의비율이높아 anti-tg Ab 양성환자에서두드러기의경과가더심한양상을보일가능성을시사하였다. 이전의연구에서갑상선자가항체가만성두드러기의경과에미치는영향은연구된바가없어본연구의결과가향후심한만성두드러기환자의평가와치료에새로운방향을제시할수있겠다. 또한이전의연구와같이 29) T3, ft4, TSH 등의갑상선기능검사에서는갑상선자가항체양성군과음성군의차이를보이지않았는데이는만성특발성두드러기환자에서갑상선질환과관련된원인을감별하기위해서갑상선기능검사뿐만아니라갑상선자가항체검사를포함시켜시행하여야하는근거가된다. 본연구에서는갑상선자가항체에양성을보이는만성특발성두드러기환자의특성, 검사실소견, 치료경과등의특징을음성군과비교하여알아보고자하였고, 갑상선자가항체중 anti-tg Ab 양성군에서의치료기간이길고증상조절을위한약제사용을더많이필요로함을알수있었다. 이연구는갑상선자가항체의평가가 조절이어려운만성특발성두드러기환자의예후예측과치료방 침의결정에유용한도구가될수있음을밝혔으며갑상선세부자 가항체종류에따라임상소견을비교한첫번째연구라는점에서 그의의가있다고판단된다. REFERENCES 1. Zuberbier T, Asero R, Bindslev-Jensen C, Walter Canonica G, Church MK, Gimenez-Arnau A, et al. EAACI/GA(2)LEN/EDF/WAO guideline: definition, classification and diagnosis of urticaria. Allergy 2009;64:1417-26. 2. Najib U, Sheikh J. The spectrum of chronic urticaria. Allergy Asthma Proc 2009;30:1-10. 3. Grattan CE, Humphreys F; British Association of Dermatologists Therapy Guidelines and Audit Subcommittee. Guidelines for evaluation and management of urticaria in adults and children. Br J Dermatol 2007;157: 1116-23. 4. Fernando S, Broadfoot A. Chronic urticaria: assessment and treatment. Aust Fam Physician 2010;39:135-8. 5. Posthumus J, Tinana A, Mozena JD, Steinke JW, Borish L. Autoimmune mechanisms in chronic idiopathic urticaria. J Allergy Clin Immunol 2012; 130:814-6.e4. 6. Kulthanan K, Jiamton S, Thumpimukvatana N, Pinkaew S. Chronic idiopathic urticaria: prevalence and clinical course. J Dermatol 2007;34:294-301. 7. Charlesworth EN. Urticaria and angioedema.allergy Asthma Proc 2002; 23:341-5. 8. Eckman JA, Hamilton RG, Gober LM, Sterba PM, Saini SS. Basophil phenotypes in chronic idiopathic urticaria in relation to disease activity and autoantibodies. J Invest Dermatol 2008;128:1956-63. 9. Sabroe RA, Grattan CE, Francis DM, Barr RM, Kobza Black A, Greaves MW. The autologous serum skin test: a screening test for autoantibodies in chronic idiopathic urticaria. Br J Dermatol 1999;140:446-52. 10. Levy Y, Segal N, Weintrob N, Danon YL. Chronic urticaria: association with thyroid autoimmunity. Arch Dis Child 2003;88:517-9. 11. Verneuil L, Leconte C, Ballet JJ, Coffin C, Laroche D, Izard JP, et al. Association between chronic urticaria and thyroid autoimmunity: a prospective study involving 99 patients. Dermatology 2004;208:98-103. 12. Palma-Carlos AG, Palma-Carlos ML. Chronic urticaria and thyroid auto-immunity. Eur Ann Allergy Clin Immunol 2005;37:143-6. 13. Konstantinou GN, Asero R, Maurer M, Sabroe RA, Schmid-Grendelmeier P, Grattan CE. EAACI/GA(2)LEN task force consensus report: the autologous serum skin test in urticaria. Allergy 2009;64:1256-68. 14. Zuberbier T, Asero R, Bindslev-Jensen C, Walter Canonica G, Church MK, Giménez-Arnau AM, et al. EAACI/GA(2)LEN/EDF/WAO guideline: management of urticaria. Allergy 2009;64:1427-43. 15. Hide M, Francis DM, Grattan CE, Barr RM, Winkelmann RK, Greaves MW. The pathogenesis of chronic idiopathic urticaria: new evidence suggests an auto-immune basis and implications for treatment. Clin Exp Allergy 1994;24:624-7. 16. Kaplan AP. Chronic urticaria: pathogenesis and treatment. J Allergy Clin Immunol 2004;114:465-74. 17. Leznoff A, Josse RG, Denburg J, Dolovich J. Association of chronic urticaria and angioedema with thyroid autoimmunity. Arch Dermatol 1983;119: 636-40. 18. Hollowell JG, Staehling NW, Flanders WD, Hannon WH, Gunter EW, http://dx.doi.org/10.4168/aard.2013.1.2.151 155
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