CONTINUING EDUCATION COLUMN J Korean Med Assoc 2019 January; 62(1):37-46 pissn / eissn 만

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1 CONTINUING EDUCATION COLUMN pissn / eissn 만성두드러기의최신치료가이드라인 노주영 가천대학교의과대학길병원피부과학교실 Updated treatment guideline of chronic spontaneous urticaria Joo Young Roh, MD Department of Dermatology, Gil Medical Center, Gachon University School of Medicine, Incheon, Korea Chronic spontaneous urticaria (CSU), also known as chronic idiopathic urticaria, is a common chronic inflammatory skin disorder that has a prevalence of 0.5% to 1% in the general population. It affects daily normal life and work productivity, with significant impacts on quality of life. Generally, the management of CSU uses a step-wise approach. Although second-generation H1 antihistamines are an effective mainstay of CSU, approximately 20% of patients are resistant to conventional antihistamine monotherapy. Evidence-based and expert consensus-based treatment guidelines of CSU can be a useful resource for primary care physicians and specialists. This review presents diverse information to support decision-making for individualized treatment plans in this special population. Several major therapeutic advances have occurred in recent years. Omalizumab, an immunoglobulin G humanized monoclonal anti-immunoglobulin E antibody that prevents binding of immunoglobulin E to the high-affinity immunoglobulin E receptor has shown safety and efficacy in patients with intractable CSU. In well-controlled clinical trials in patients with refractory CSU who received add-on therapy with subcutaneous omalizumab (300 mg every 4 weeks for 12 or 24 weeks), the rates of complete response were significantly higher in the omalizumab group (relative risk, 4.55; P<0.0001). The introduction of omalizumab as an add-on therapy to H1 antihistamines as a management option has markedly improved the therapeutic possibilities for CSU and the quality of life of CSU patients. Nevertheless, many patients still do not tolerate or benefit from existing therapies, including omalizumab. There are ongoing studies investigating the treatment potential of novel therapeutic targets in CSU. Key Words: Urticaria; Antihistamine; Omalizumab 서론 두드러기는평생에걸쳐 5 명에한명꼴로나타나는비교 적흔한피부질환으로발생후대부분수시간내에사라지 는팽진과가려움증을특징으로한다. 급성두드러기는대부 Received: December 19, 2018 Accepted: January 8, 2019 Corresponding author: Joo Young Roh jyroh1@gilhospital.com Korean Medical Association This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. 분 1주일에서 1달이내에완전히치유되나, 6주이상두드러기가지속되는경우만성두드러기라한다 [1]. 만성두드러기는환자들의일상생활과수면에지대한영향을미칠뿐아니라수시로재발하는양상을보여오래지속될경우불안, 우울, 대인기피증을보여삶의질에지대한영향을미친다. 만성두드러기는원인을특정할수없는만성자발성두드러기 (chronic spontaneous urticaria, CSU) 와마찰, 압박, 온도등물리적자극등에의해유발되는만성유발성두드러기로분류할수있다. 만성특발성두드러기는만성자가면역성두드러기를포함하는용어지만, 일반적으로 CSU와동의어로사용된다. CSU는만성두드러기의약 2/3를차지한다. 만성두드러기의치료지침 37

2 우리나라에서의유병률은 2,256.5명 /100,000명/ 년으로보고된바있으며, 2010년부터 2014년까지매년증가하는추세를보였다 [2]. 2006년에서 2014년까지건강보험심사평가원의자료를토대로분석한결과 20세이상의성인에서만성두드러기의유병률은 % 로발병률은약 명 /1,000명 / 년이고, 여자에서더높은발병률을보였다 [3]. 4세에서 13세소아에서의만성두드러기유병률은 1.8% 로나타났다 [4]. 성인과만성두드러기의경과는 2003년에서 2007년사이에건강보험심사평가원에만성두드러기로등록된환자들을 2013년까지 10년간추적하여분석한결과, 1년, 2년, 3년, 4년, 5년째완전관해율은각기 21.5%, 33.0%, 38.9%, 42.6%, 44.6% 였고, 65세이상의남자의경우첫진단후 1년이내에관해되는비율이낮아나쁜예후를보였다 [5]. CSU의병리기전은명확히밝혀지지는않았으나, 비만세포와호염구, 히스타민, 화학적매개물질들이중요한역할을하는것으로알려져있다 [6]. 비만세포의세포막의탈과립현상이일어난후히스타민과염증성화학매개물질들이분비되어팽진을야기한다. 이를근거로 H1 항히스타민제가 CSU 의주요한일차치료제로사용되고있다. 한편비만세포나호염구의세포막을자극하여탈과립현상을야기하는데중심적인역할을하는인자로면역글로불린 E (immunoglobulin E, IgE) 와 IgE 와결합하는 high affinity receptor (FcɛR1) 에대한연구가진행되면서 IgE를표적으로하는오말리주맙 (omalizumab) 과같은새로운표적치료제가개발되었다 [7]. 유럽, 미국, 일본에서무작위조절시험을포함한근거중심의의학적보고들과전문가들의협의과정을거친 CSU의치료지침들을중심으로고찰하고자한다. 국내에서는대한천식알레르기학회와대한피부면역학회가공동으로한국의만성특발성 ( 자발성 ) 두드러기진료지침을개발하였으며, 공청회와일련의외부검토작업을거쳐 2019년에공포할예정이다. 만성자발성두드러기의치료 만성두드러기의치료목표는증상의완전소실이다. 약물 치료외에일반적인치료지침으로는가능한원인을찾아원인인자를제거하고, 악화나유발요인을회피하거나, 내성을유도하면서약물치료를통해두드러기발생에관여하는비만세포나호염구의탈과립화, 화학매개물질의분비를억제하는것이다. 1. 유발인자제거및악화요인회피만성두드러기에서정확한원인을찾아이를제외시키는것은필수선행요건이나대부분경우에서원인을찾기는어렵다. 이중맹검유발검사로의심이되는원인또는유발인자를제거했을때증상이사라지고, 다시투여했을때증상이재발하는경우원인으로확진할수있다. 1) 약물약제가유발유인으로의심되는경우에는약제를중단하거나다른계통의약제로대체해야한다. 비알레르기성과민반응을일으키는약제 ( 예 : 소염진통제나아스피린등 ) 는두드러기를유발할뿐아니라기존의만성두드러기를악화시킬수있으므로이를중단해야만증상을완화시킬수있다 [8]. 2) 감염인자제거및염증반응의치료 CSU는다양한염증성또는감염성질환과연관되어발생하기도한다. 위장의 Helicobacter pylori나비인두의세균감염이있는경우이를먼저치료하는것이 CSU의치료에도움이될수있다 [9]. 장관의기생충감염도연관이있는경우가있어, 필요한경우이를먼저제거해야한다. 3) 물리적, 감정적스트레스요인감소육체적감정적스트레스와 CSU와의연관성은명확히밝혀지진않았으나, 증상의발현과중증도와의상관성이있는경우도있다 [10]. 4) 기능성자가면역항체감소기능성자가면역항체양성인 CSU 환자에서일반적치료에반응하지않는경우, 자가면역항체를감소시키는혈장치환술이일시적으로도움이되는경우도있으나 [11], 고비용과적은치료경험에비추어제한적으로고려할수있다. 5) 식이요법 CSU 환자에서식품알레르기가원인이되는경우는매우드물다. 간혹 IgE가관여하지않고천연식품성분이나첨가물 38 대한의사협회지

3 Roh JY Treatment guideline of chronic spontaneous urticaria Table 1. Second generation H1 antihistamines Family Substance Mechanism of action Dose Side effects Piperidine Mizolastine Neutrophil recruitment 5-lipooxigenase, VEGF, TNF Terfenadine Eosinophil chemotaxis Eosinophil adherence Superoxide synthesis IL-6, IL-8, TNF, GM-CSF 10 mg/24 hr Prolongation of the QT interval, gastrointestinal disturbances, dryness of the mouth, somnolence, headache mg/ 24 hr Cardiotoxicity, headache, vertigo, increased sweating, digestive disturbances, sedation, dryness of the mouth Fexofenadine 180 mg/ 24 hr Headache, dizziness, somnolence, fatigue, dryness of the mouth, nausea Loratadine Eosinophil chemotaxis IL-8, RANTES, ICAM-1 10 mg/ 24 hr Somnolence/insomnia, headache, increased appetite Desloratadine Alkylamine Acrivastine Eosinophil chemotaxis Superoxide production TNF, IL-1, IL-6, IL-8, IL-13 P-selectin, ICAM-1 Eosinophil apoptosis NK-kB cell activation 5 mg/24 hr Tiredness, dryness of the mouth, headache Rupatadine PAF, TNF 10 mg/24 hr Somnolence, headache, fatigue Ebastine Antihistamine Antiallergic mg/24 hr Headache, somnolence, fatigue, dryness of the mouth, rhinitis, pharyngitis Piperazine Cetirizine Eosinophil adhesion, Eosinophil & neutrophil chemotaxis T-cell & monocyte chemotaxis, IL-8, MCP1/RANTES, NF-kB 19, ICAM-1, LTC4 Levocetirizine mg/24 hr 10 mg/24 hr Headache, somnolence, fatigue, dryness of the mouth, gastrointestinal disturbances 5 mg/24 hr Adapted from Curto-Barredo L, et al. Actas Dermosifiliogr 2014;105: [13]. VEGF, vascular endothelial growth factor; TNF, tumor necrosis factor; IL-8, interleukin-8; GM-CSF, granulocyte-macrophage colony-stimulating factor; RANTES, regulated upon activation, normal T cell expressed, and secreted; ICAM, intercellular adhesion molecule; NF-kB, nuclear factor kappa light chain enhancer of activated B cells; PAF, platelet-activating factor; MCP1, monocyte chemoattractant protein-1; LTC4, leukotriene C4. 등에가성알레르기반응을일으켜 CSU가악화또는유발되는경우도있다. 이경우가성알레르겐을포함하는식품이나히스타민이적은식이요법을최소 2-3주간지속할경우증상이호전되는경우도있으나실생활에서적용하기가매우어렵고식이요법의효과에대해서는아직도논란의여지가있다 [12]. 타민제는중추신경계에대한영향과항콜린성효과로졸음, 어지럼증을유발하고인지능력과정신운동신경을저하시켜수행능력에영향을미치므로고령층이나정신집중을요하는기계공, 항공기조정사, 운동선수등의특수한직업군에서는처방시주의해야한다 [14]. 따라서유럽치료지침에서는 일차치료제로중추신경계에대한영향이적은이세대항히 2. 약물치료 1) H1 항히스타민제항히스타민제는 1950년대부터 CSU의치료에사용되었던주된치료제이다. 항히스타민제는혈관내피세포에존재하는 H1 수용체에작용하여팽진의발생을감소시키고피부의 C 신경섬유에작용하여가려움증을줄여준다. 대부분의항히스타민제는사이토카인과접착분자의생성을감소시켜항염작용을가지는데이는비만세포와호염구의세포막을안정화시키고, 세포내전사인자인 nuclear factor kappa B (NF-kB) 를억제함으로써작용한다 [13]. 일반적으로일세대와이세대항히스타민제중, 특히이세대항히스타민제를일차치료제로권고하고있다 (Tables 1,2) [13]. 일세대항히스 스타민제를사용하도록권고하고일세대항히스타민제는치료지침에서제외시켰다. 하지만미국알레르기학회에서는일세대항히스타민제의수면효과가 CSU의치료에도움이될수있어이세대항히스타민제로충분한반응을보이지않을경우, 일세대항히스타민제를취침전에추가처방하는것이도움이될수있다고권고하고있다 (Figure 1) [15]. 항히스타민제를사용한무작위배정조절연구들에서이세대항히스타민제의안전성과효능, 내약성등이입증된바있다 [16]. 복용방법은필요시마다복용하는것보다매일규칙적으로복용하는것이임상반응을높이고삶의질을높이는데더효과적이다 [17]. 50% 이상의환자들은허가된용량의항히스타민제에반응하지않는데, 이경우허가용량의 2-4배를증 만성두드러기의치료지침 39

4 Table 2. Pharmacolkinetics of H1 antihistamines H1 antihistamine tmax(h) t1/2 (hr) Onset of action (hr) Duration of action (hr) Common adult doses for urticaria First generation Hydroxyzine mg 3-4 times daily or mg at bedtime Conditions that might require dose adjustment Hepatic impairment Second generation Cetirizine mg/day Renal and hepatic impairment Desloratadine mg/day Renal and hepatic impairment Fexofenadine mg/day Renal impairment Levocetirizine mg/day Renal and hepatic impairment Loratadine mg/day Hepatic impairment t max, time to reach maximum plasma concentration; t 1/2, time taken for maximum concentration to drop in half. 량하는경우반응도를높일수있다. 항히스타민제증량시증상의호전은약 2.27배개선될수있다. 표준용량의항히스타민제불응성의환자의약 2/3가용량증량시호전되었으며, 가려움증은현저히호전되나팽진의감소에는영향을미치지못했다 [18]. 2) H2 항히스타민제 H2 히스타민수용체는위장관의 parietal cell 세포막에존재한다. H1 항히스타민제에반응이불충분할경우 cimetidine이나 ranitidine과같은 H2 항히스타민제를추가로복용할경우효 sgah If inadequate control: after 2-4 weeks or earlier, if symptoms are intolerable Step 1 Monotherapy with second generation antihistamine Avoidance of triggers (e.g., NSAIDs) and relevant physical factors if physical uticaria/ angioedema syndrome is present 과를보인다는보고가있다. Cimetidine 이 H1 항히스타민제의반감기를늘려 H1 항히스타민제의작용을증가시킨다고추정한다 [19]. 하지만 CSU에서 H2 항히스타민제의효과에대해서는근거 Increase sgah dose (up to 4x) Add-on to sgah: omalizumab If inadequate control: after 2-4 weeks or earlier, if symptoms are intolerable If inadequate control: within 6 months or earlier, if symptoms are intolerable Step 2 One or more of the following: Dose advancement of second generation antihistamine used in Step 1 Add another second generation antihistamine Add H2 antagonist Add leukotriene-modifying agent Add first-generation antihistamine to be taken in bedtime Step 3 Dose advancement of sedating firstgeneration antihistamine (e.g., hydroxyzine or doxepin) as tolerated 가부족하고전문가들의이견이많아, 유럽알레르기학회치료지침에서는 H2 항히스타민제의추가처방을권고하지않으나, 미국알레르기학회에서는복합처방을허용하고있다 (Figure 1) [15]. 3) 전신스테로이드제전신스테로이드제는대규모의무작위조절연구가없는데도불구하고항히스타민제불응성 CSU환자에서흔히사용되는약제이다. 최근의보고에따르면전신스테로이드제는만성두드러기환자의 54.7% 에서처방되었 Add-on to sgah: cyclosporine Step 4 Add an alternative agent: Omalizumab or cyclosporine Other anti-inflammatory agents, immunosuppressants, or biologics Figure 1. Chronic urticaria treatment algorithm. (A) EAACI/GA2LEN/EDF/WAO international guidelines and (B) the US practice parameters for the diagnosis and management of chronic urticaria. sgah, second-generation H1 antihistamine; NSAID, non-steroidal anti-inflammatory drugs. Adapted from Beck LA, et al. Acta Derm Venereol 2017;97: [15]. 다 [20]. 일반적으로전문가그룹합의안에서는장기간의스테로이드사용을금하고있다. 만성두드러기환자에서단기간 (10일이내 ) 전신스테로이드제의유용성을확인하기위해 750 명의만성두드러기환자치료를후향적 40 대한의사협회지

5 Roh JY Treatment guideline of chronic spontaneous urticaria 으로분석한연구에서는만성두드러기환자중 88%(660명 ) 는항히스타민제에반응하였으며, 항히스타민제에반응하지않는만성두드러기환자중 47% 는 1회의단기간 (3일) 스테로이드제추가후항히스타민제단독으로조절되었고, 스테로이드를재투여시 9% 가추가반응을보였으나, 약 15% 의환자에서는스테로이드에도반응을보이지않았다 [21]. CSU환자에서초기치료단계부터항히스타민제와전신스테로이드제를병행한경우항히스타민제단독치료한환자군과비교할때장기적으로안정적으로조절하는데필요한시간에유의한차이가없는것을보여전신스테로이드제가 CSU의질환의경과에는영향을미치지못하는것을확인하였다 [22]. 4) 류코트리엔수용체길항제류코트리엔수용체길항제 (leukotriene receptor antagonist) 도만성두드러기의치료에효과가있다는보고가있다 [14]. 하지만, 무작위배정시험결과가보고에따라상반된결과를보여아직까지권고할만한근거가부족하나 [23] 기존항히스타민제치료에반응하지않는환자의경우제한적으로사용을고려해볼수는있다. 특히아스피린이나식품첨가제에불내성이있거나자가혈청피부반응에서양성을보인 CSU 환자에서류코트리엔수용체길항제의효과를기대해볼수있다 [24]. 5) 면역억제제 (1) Ciclosporin Ciclosporin 은비만세포와호염구에서히스타민의분비를감소시키고 T세포의기능에영향을미치는것으로알려져있다. 만성두드러기환자에서 ciclosporin의안전성과효능에대한무작위배정조절연구에서는 ciclosporin 이양호한효과를보이는것을나타났다. 위약군에비해 ciclosporine을복용한만성두드러기환자군에서 8, 16주후에현저하게두드러기증상의수치가감소하는결과를보였다 [25]. Ciclosporin의용량은일반적으로 4 mg/kg/day나 200 mg/day을처방하고, 사용시혈압과신장기능검사혈중지질검사를정기적으로시행해야한다. Ciclosporin의부작용을고려하여유럽알레르기학회는만성두드러기환자에서 ciclosporin의사용을낮은수준으로권고하고있으며최근 에개정된 2018년도만성두드러기치료지침권고안에서는 ciclosporin의부작용측면을고려하여 ciclosporin 보다오말리주맙을먼저사용하도록권고하고있다 [1]. (2) Methotrexate Methotrexate는경험적으로항히스타민제불응성 CSU 환자에서스테로이드대체제로유용하게사용해왔던약제이다. 용량은 mg/wk로사용한다. 면역억제효과보다는항염효과가더주요한역할을하는것으로여겨진다 [26]. 하지만 CSU 환자를대상으로한무작위조절연구에서는 15 mg/wk 용량으로 3개월간사용후효과를비교하였을때 H1 항히스타민제에추가적으로유효한효과는보이지않았다 [27]. (3) Mycophenolate mofetil Mycophenolate mofetil은림프구에서 DNA합성을억제하는면역조절제로서만성두드러기에서는 high affinity IgE 수용체에대한항체나 IgE의생성을억제한다. 그외에도혈관내피세포에서부착분자의발현을감소시키고림프구가피부로이동하는것을방해한다. Mycophenolate mofetil 은자가면역성두드러기나특발성두드러기에서효과를보였는데가려움증과팽진의수, 두드러기의발현기간과횟수를감소시키는것으로알려져있다. 후향적연구에따르면용량은 1 g/day을사용하여 90% 의환자에서호전되었고 14주째에 60% 의환자에서조절되었다. 일반적으로심각한부작용이나검사실수치이상은없었으며, 20-50% 의환자에서위장관증상을호소하였으나서서히호전되었다 [28]. (4) Azathioprine Azathioprine도만성두드러기의치료에사용할수있는데, 자가혈청피부반응양성환자에서 azathioprine 50 mg/day 을 8주간복용하였을때위장관증세외에특이한부작용없이두드러기가호전되는결과를보였다 [29]. (5) Cyclophosphamide Cyclophosphamide 주사제또는경구복용도만성두드러기환자에서항히스타민제보다좋은효과를보이는것으로보고된증례들이있다. 용량은 500 mg-1,500 mg/iv을 2-4주마다주사하거나또는 mg/day을경구복용한다 [30]. 만성두드러기의치료지침 41

6 Table 3. The potential pharmacologic mechanisms of omalizumab in patients with chronic spontaneous urticaria Binding of omalizumab to IgE Mechanism Free IgE concentration in blood and interstitial space FcεRI on mast cells and basophils IgE-FcεRI engagement Potentiating of mast cells Secretion of cytokines (without degranulation) Mast cell pool Immune complexes of IgE-omalizumab Trapping of autologous antigens (e.g., TPO) Trapping of IgE-specific IgG autoantibodies Binding of omalizumab to membrane-bound IgE on B lymphocytes Continual synthesis of IgE in extended periods IgE pool in the immune system Overall effects Release thresholds for mast cells for various degranulators Degranulation of mast cells Secretion of mediators, cytokines, and chemokines Recruitment of T cells, macrophages, and eosinophils Inflammatory manifestation in skin Vasopermeability, wheal, edema, itch, and erythema Effects Adapted from Chang TW, et al. J Allergy Clin Immunol 2015;135: [7]. IgE, immunoglobulin E; TPO, thyroperoxidase. Reduction in weekly ISS between baseline and week 12 (%) Asteria Asteria Glacial -26% -67% -36% -71% -26% -62% Placebo Omalizumab (300 mg) Figure 2. Percentage of reduction in weekly ISS (itch severity score) at week 12 with omalizumab (300 mg/mo) vs. placebo. Adapted from Kaplan A, et al. J Allergy Clin Immunol 2016;137: [33]. 가어느정도조절되는부분관해를보였다 (Figure 3) [33]. 치료효과는오말리주맙피하주사후평균 1 주일부터나타 나기시작했다. 오말리주맙의치료효과에인종적차이있는 지를확인하기위해한국인과일본인에서시행한위약대조 무작위배정 3 상시험의결과도기존의 3 상시험결과들과비 슷한양상을보였고, 심각한부작용이나아나필락시스반응 을보인경우는없었다 (Figure 4) [34]. 실제임상에서의치 료효과를메타분석한결과에서는완전관해가 72.2% (95% confidence interval [CI], %; P<0.001; 45 종 6) 오말리주맙오말리주맙은원래심한천식치료제로승인받은 IgG1 인간재조합단클론항체로서혈중 IgE와결합하여 IgE가 high affinity IgE 수용체인 FcɛR1에결합하는것을방해하는항체이다. H1 항히스타민제불응성의 CSU에대한치료효과가인정되어 2016년에 CSU 치료제로미국식품의약국의승인을받았다. 오말리주맙은혈중 IgE를감소시킬뿐만아니라, 비만세포와호염구의 IgE 수용체를감소시켜서사이토카인이나두드러기의활성매개체의분비를억제한다 (Table 3) [7]. 항히스타민제불응성의심한만성두드러기환자를대상으로한세종류의주요한무작위배정위약대조군 3상임상시험 (ASTERIA I, ASTERIA II, GLACIAL) 결과에서만족할만한효과와안전성이입증된바있다 (Figure 2) [31-33]. 3상임상시험결과를종합하여분석한결과 150 mg/mo 보다 300 mg/mo 피하주사에서가장좋은효과를보였다. 치료 12주차에 35-40% 의환자에서두드러기의완전관해를보였고, 3-6개월치료후나머지 30% 는두드러기증세 의연구, 환자 1,158명 ), 부분관해 17.8% (95% CI, %; P<0.001; 37종의연구, 환자 908명 ) 를보였고, 부작용의평균빈도는 4.0% (95% CI, %; P<0.001; 47종연구, 환자 1,314명 ) 를보여유용성과안전성을고려할때임상시험결과보다더뛰어난효과를보였다 [35]. 7) 대체치료제 (1) Dapsone Dapsone은 sulfone계항균계로호중구성피부질환에사용한다. 만성두드러기에서는 leukotriene B4와 prostaglandin E2의합성을감소시키고 CD11b의억제작용이있다 [35]. 2개의무작위배정조절연구에따르면, CSU 환자에서 25 mg/day 또는 mg/day 용량으로위약군에비해유효한치료효과를보였다. 치료효과는빠르면 1주후부터나타나기시작하나평균 3-4주후부터호전을보인다. 부작용은약 50% 에서나타나며이중 5.5% 는치료를중단할정도이고 2.7% 에서심각한부작용이발생할수있다 [36]. 흔한부작용으로는헤모글로빈감소, 간기능수치이상, 두통, 42 대한의사협회지

7 Roh JY Treatment guideline of chronic spontaneous urticaria Proportion of patients achieved response (%) 10.6 Placebo Omalizubab 75 mg Omalizubab 150 mg Omalizubab 300 mg N= Asteria Asteria Glacial Figure 3. Proportion of patients achieved complete response at week 12. Adapted from Kaplan A, et al. J Allergy Clin Immunol 2016;137: [33] 여매주 500 mg씩증량하여 4 g까지사용할수있다. 치료효과는 1개월경부터나타나며용량이 2 g/day 이상일경우부작용의빈도도높고부가적인치료효과는없는것으로알려져있다 [37]. 일부증례보고와후향적연구만있어치료효능에대한평가는제한적이다. 한연구에서는항히스타민제불응성환자들에서 sulfasalazine을 3년간사용하였으며심각한정도는아니나 37% 의환자에서부 작용이나타났다. 흔한부작용으로는오 Omalizubab 300 mg Omalizubab 150 mg Placebo 심, 설사, 위장장애, 복통, 식욕부진, 두 Proportion of patients (%) P< P= Proportion of patients (%) P< P= 통, 근육통, 독감증상등이있다. 혈액이나간기능이상, 신장기능이상, 혈액기능장애가있는환자에서는금기이다. (3) Hydroxychloroquine Hydroxychloroquine은 major histocompatibility complex class II 항원의발현을억제하는면역조절기능이 0 Week 4 Week 8 Week 12 0 Week 4 Week 8 Week 12 있는데만성두드러기에서정확한작용 A B 기전은아직밝혀지지않았다. 소규모 Figure 4. Proportion of patients achieved (A) partial (UAS7 6) and (B) complete response (UAS7=0) at week 12 in Korean and Japanese chronic spontaneous urticaria patients. UAS7, weekly urticaria activity score. Adapted from Hide M, et al. J Dermatol Sci 2017;87:70-78 [34]. 의조절연구와증례보고들만있으나, hydroxychloroquine 사용시만성두드 러기환자의삶의질이호전되는결과 혈액이상질환, 무증상의 methemoglobinemia 등이있다. 심각한혈액용혈의위험성을배제하기위해 glucose-6- phosphate dehydrogenase 검사와혈액검사, 간기능검사를시행하고정기적으로검사하도록권하고있다. 서양에비해한국에서는 glucose-6-phosphate dehydrogenase 효소결핍환자는드물어, 심각한혈액이상반응은흔하지않다. (2) Sulfasalazine Sulfasalazine은항염효과가있는 5-aminosalicylic acid 유도체로서만성두드러기에서는 prostaglandin 생성을억제하고 IgE에의한비만세포탈과립화현상을억제하여히스타민의분비를감소시키고 B 림프구의증식을억제하는작용이도움이되리라추정한다 [37]. 용량은 500 mg/day 로시작하 를보였다. 용량은 200 mg을하루 2회복용하고, 2-3개월후치료효과가나타난다. 비교적안전한약제로알려져있으나 16% 에서부작용이발생하고이중 7% 는부작용으로인해투약을중단한다. 흔한부작용은설사, 복통, 오심, 시력변화, 두통이있다. 망막병증은 5년이상사용시나타나며불가역적반응이므로정기적인안과진찰이필요하다. 특히기존의망막병증이있는환자에서는망막부작용이더흔히나타날수있다 [38]. (4) Colchicine 만성두드러기환자에서 colchicine의효과는제한적이나호중구성침윤을보이거나두드러기성혈관염이있는경우효과가있다. Colchicine은호중구의화학주성을억제하고 만성두드러기의치료지침 43

8 접착분자를감소시켜항염효과가있는것으로알려져있다. 또한히스타민과 interleukin-1의분비를억제하는능력이있다 [39]. 용량은 mg을하루 2회복용한다. 최근의후향적연구에서는항히스타민제와류코트리엔수용체길항제에반응을보이지않는만성두드러기환자의 18% 에서완전관해를보였다. 흔한부작용은설사, 오심구토, 복통등의위장관증상으로용량에비례하며, 매우드물게백혈구감소증, 혈소판감소증, 골수억제, 간기능이상, 근신경증등이보고되었다. (5) 자외선치료자외선을이용한광선치료는비만세포에서히스타민의분비를감소시키는효과가있다고추정한다. Broad-band ultraviolet B와 narrow-band ultraviolet B (NB-UVB) 를이용한광선치료는효과적인것으로보고되었다. NB-UVB와 levocetirizine을이용한무작위배정연구에서는 levocetirizine만복용한군과 NB-UVB를추가한군, 모두에서두드러기활성지수가유의미하게감소하였으나, NB-UVB 치료를추가한군에서두드러기가 3개월이상조절되는양상을보였다 [40]. 3. 특수환자군의치료 1) 소아소아에서는일세대의중추신경계에대한수면효과부작용때문에이세대항히스타민제를우선적으로권고한다. 2세이상의소아의경우 cetirizine, loratadine과 desloratadine 을사용할수있고, 12세이상의소아에서는모든항히스타민제를사용할수있다 [13]. 전신스테로이드제는성장에미치는영향을고려하여사용하지않도록권고하며항히스타민제불응성두드러기에서급성악화기에조절이필요한경우에단기간 (10일이하 ) 사용할수도있다 [1,41]. 2) 임산부와수유부임산부나수유부의경우에는이세대 H1 항히스타민제를권고한다. H1 항히스타민제를최소유효용량으로사용하고, 가능한짧은기간사용하도록권고한다 [41]. 항히스타민제의태아에대한영향이나유즙에분비될경우미치는반응은아직정확히알려진바가없다. H1 항히스타민제는모 두유즙에분비되므로수유부의경우에는유아에서진정효과를보일수있는일세대항히스타민제는사용하지않도록권고한다. 미국식품의약국에서는 cetirizine, loratadine, levocetirizine을 category B로분류하였고, desloratadine 과 fexofenadine은 category C로분류하였다 [42]. 임산부에서 loratadine을사용한전향적무작위배정연구에서는대조군에비해선천기형의위험율이증가하지않았다. 임산부에서항히스타민제불응성의만성두드러기가있는경우, 오말리주맙의사용을고려해볼수있다. 오말리주맙은 category B로분류되어있으며, 10년이상등록된환자들에서태아의선천기형보고가없는안전한약제로알려져있다 [1]. 3) 고령자고령의환자에서는동반질환들로여러가지약제를복용하거나각기관의기능저하가있어여러가지요인을고려해야한다. 일세대항히스타민제는혈액뇌장벽을통과하며, 항콜린성, 항세로토닌성, 항도파민성효과가있어뇨정체현상, 부정맥, 말초혈관확장, 기립성저혈압, 빈맥, 산동현상이나타날수있다. 따라서혈액뇌장벽을통과하지않는이세대항히스타민제를처방하는것을권고한다. 또한신기능, 간기능이상이있는경우용량을조절해야한다. Levocetirizine은신기능이상이있는경우용량조절이필요하며, mizolastine은간기능이상이있거나 azole계의항진균제, macrolide계통의항생제를복용하고있는경우에는금기이다. Ebastine은심각한간기능장애가있는경우에는금기이며중등도의간부전환자에서는 10 mg/day 이상의용량을사용하지않도록주의해야한다 [43]. 결론 만성두드러기는복합적인요인에의해발생하므로다양한원인과개인적인특성에따라통합적인치료와관리와교육이필요하다. 기존의유럽치료지침에따라 6개월간치료하면약 58% 의환자에서 H1 항히스타민제의표준용량에반응을보이고, 18% 는항히스타민제의증량이필요하며약 15% 의환자에서는오말리주맙이나사이클로스포린추가 44 대한의사협회지

9 Roh JY Treatment guideline of chronic spontaneous urticaria 치료로조절될수있다. 이치료제들에도반응이없을경우 dapsone, colchicines, mycophenolate mofetil, azathioprine 등을고려해볼수있다. 두드러기의병인에관한연구 가활발히진행되면서새로운표적치료제들이개발되어임 상시험을진행하고있어, 보다효과적이고근원적인치료제 로기대를모으고있다. 찾아보기말 : 두드러기 ; 항히스타민제 ; 오말리주맙 ORCID Joo Young Roh, REFERENCES 1. Zuberbier T, Aberer W, Asero R, Abdul Latiff AH, Baker D, Ballmer-Weber B, Bernstein JA, Bindslev-Jensen C, Brzoza Z, Buense Bedrikow R, Canonica GW, Church MK, Craig T, Danilycheva IV, Dressler C, Ensina LF, Gimenez-Arnau A, Godse K, Gonçalo M, Grattan C, Hebert J, Hide M, Kaplan A, Kapp A, Katelaris CH, Kocaturk E, Kulthanan K, Larenas- Linnemann D, Leslie TA, Magerl M, Mathelier-Fusade P, Meshkova RY, Metz M, Nast A, Nettis E, Oude-Elberink H, Rosumeck S, Saini SS, Sanchez-Borges M, Schmid- Grendelmeier P, Staubach P, Sussman G, Toubi E, Vena GA, Vestergaard C, Wedi B, Werner RN, Zhao Z, Maurer M; Endorsed by the following societies: AAAAI, AAD, AAIITO, ACAAI, AEDV, APAAACI, ASBAI, ASCIA, BAD, BSACI, CDA, CMICA, CSACI, DDG, DDS, DGAKI, DSA, DST, EAACI, EIAS, EDF, EMBRN, ESCD, GA²LEN, IAACI, IADVL, JDA, NVvA, MSAI, ÖGDV, PSA, RAACI, SBD, SFD, SGAI, SGDV, SIAAIC, SIDeMaST, SPDV, TSD, UNBB, UNEV and WAO. The EAACI/GA²LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria. Allergy 2018;73: Lee N, Lee JD, Lee HY, Kang DR, Ye YM. Epidemiology of chronic urticaria in Korea using the Korean health insurance database, Allergy Asthma Immunol Res 2017;9: Kim YS, Park SH, Han K, Bang CH, Lee JH, Park YM. Prevalence and incidence of chronic spontaneous urticaria in the entire Korean adult population. Br J Dermatol 2018;178: Lee SJ, Ha EK, Jee HM, Lee KS, Lee SW, Kim MA, Kim DH, Jung YH, Sheen YH, Sung MS, Han MY. Prevalence and risk factors of urticaria with a focus on chronic urticaria in children. Allergy Asthma Immunol Res 2017;9: Kim YS, Park SH, Han K, Lee JH, Kim NI, Roh JY, Seo SJ, Song HJ, Lee MG, Choi JH, Park YM. Clinical course of chronic spontaneous urticaria in the Korean adult population. Allergy Asthma Immunol Res 2018;10: Jacques P, Lavoie A, Bédard PM, Brunet C, Hebert J. Chronic idiopathic urticaria: profiles of skin mast cell histamine release during active disease and remission. J Allergy Clin Immunol 1992;89: Chang TW, Chen C, Lin CJ, Metz M, Church MK, Maurer M. The potential pharmacologic mechanisms of omalizumab in patients with chronic spontaneous urticaria. J Allergy Clin Immunol 2015;135: Kowalski ML, Woessner K, Sanak M. Approaches to the diagnosis and management of patients with a history of nonsteroidal anti-inflammatory drug-related urticaria and angioedema. J Allergy Clin Immunol 2015;136: Shakouri A, Compalati E, Lang DM, Khan DA. Effectiveness of Helicobacter pylori eradication in chronic urticaria: evidence-based analysis using the Grading of Recommendations Assessment, Development, and Evaluation system. Curr Opin Allergy Clin Immunol 2010;10: Varghese R, Rajappa M, Chandrashekar L, Kattimani S, Archana M, Munisamy M, Revathy G, Thappa DM. Association among stress, hypocortisolism, systemic inflammation, and disease severity in chronic urticaria. Ann Allergy Asthma Immunol 2016;116: Grattan CE, Francis DM, Slater NG, Barlow RJ, Greaves MW. Plasmapheresis for severe, unremitting, chronic urticaria. Lancet 1992;339: Wagner N, Dirk D, Peveling-Oberhag A, Reese I, Rady-Pizarro U, Mitzel H, Staubach P. A popular myth: low-histamine diet improves chronic spontaneous urticaria. Fact or fiction? J Eur Acad Dermatol Venereol 2017;31: Curto-Barredo L, Silvestre JF, Gimenez-Arnau AM. Update on the treatment of chronic urticaria. Actas Dermosifiliogr 2014;105: Bernstein JA, Lang DM, Khan DA, Craig T, Dreyfus D, Hsieh F, Sheikh J, Weldon D, Zuraw B, Bernstein DI, Blessing-Moore J, Cox L, Nicklas RA, Oppenheimer J, Portnoy JM, Randolph CR, Schuller DE, Spector SL, Tilles SA, Wallace D. The diagnosis and management of acute and chronic urticaria: 2014 update. J Allergy Clin Immunol 2014;133: Beck LA, Bernstein JA, Maurer M. A review of international recommendations for the diagnosis and management of chronic urticaria. Acta Derm Venereol 2017;97: Kapp A, Pichler WJ. Levocetirizine is an effective treatment in patients suffering from chronic idiopathic urticaria: a randomized, double-blind, placebo-controlled, parallel, multicenter study. Int J Dermatol 2006;45: Grob JJ, Auquier P, Dreyfus I, Ortonne JP. How to prescribe antihistamines for chronic idiopathic urticaria: desloratadine daily vs PRN and quality of life. Allergy 2009;64: Guillen-Aguinaga S, Jauregui Presa I, Aguinaga-Ontoso E, Guillen-Grima F, Ferrer M. Updosing nonsedating antihistamines in patients with chronic spontaneous urticaria: a systematic review and meta-analysis. Br J Dermatol 2016;175: Simons FE, Sussman GL, Simons KJ. Effect of the H2-antagonist cimetidine on the pharmacokinetics and pharmacodynamics of the H1-antagonists hydroxyzine and cetirizine in patients with chronic urticaria. J Allergy Clin Immunol 1995;95: Broder MS, Raimundo K, Antonova E, Chang E. Resource use and costs in an insured population of patients with chronic idiopathic/spontaneous urticaria. Am J Clin Dermatol 2015; 16: 만성두드러기의치료지침 45

10 21. Asero R, Tedeschi A. Usefulness of a short course of oral prednisone in antihistamine-resistant chronic urticaria: a retrospective analysis. J Investig Allergol Clin Immunol 2010; 20: Kim S, Baek S, Shin B, Yoon SY, Park SY, Lee T, Lee YS, Bae YJ, Kwon HS, Cho YS, Moon HB, Kim TB. Influence of initial treatment modality on long-term control of chronic idiopathic urticaria. PLoS One 2013;8:e de Silva NL, Damayanthi H, Rajapakse AC, Rodrigo C, Rajapakse S. Leukotriene receptor antagonists for chronic urticaria: a systematic review. Allergy Asthma Clin Immunol 2014;10: Bagenstose SE, Levin L, Bernstein JA. The addition of zafirlukast to cetirizine improves the treatment of chronic urticaria in patients with positive autologous serum skin test results. J Allergy Clin Immunol 2004;113: Vena GA, Cassano N, Colombo D, Peruzzi E, Pigatto P; Neo- I-30 Study Group. Cyclosporine in chronic idiopathic urticaria: a double-blind, randomized, placebo-controlled trial. J Am Acad Dermatol 2006;55: Sagi L, Solomon M, Baum S, Lyakhovitsky A, Trau H, Barzilai A. Evidence for methotrexate as a useful treatment for steroid-dependent chronic urticaria. Acta Derm Venereol 2011; 91: Sharma VK, Singh S, Ramam M, Kumawat M, Kumar R. A randomized placebo-controlled double-blind pilot study of methotrexate in the treatment of H1 antihistamine-resistant chronic spontaneous urticaria. Indian J Dermatol Venereol Leprol 2014;80: Zimmerman AB, Berger EM, Elmariah SB, Soter NA. The use of mycophenolate mofetil for the treatment of autoimmune and chronic idiopathic urticaria: experience in 19 patients. J Am Acad Dermatol 2012;66: Bhanja DC, Ghoshal L, Das S, Das S, Roy AK. Azathioprine in autologous serum skin test positive chronic urticaria: a case-control study in a tertiary care hospital of eastern India. Indian Dermatol Online J 2015;6: Asero R. Oral cyclophosphamide in a case of cyclosporin and steroid-resistant chronic urticaria showing autoreactivity on autologous serum skin testing. Clin Exp Dermatol 2005; 30: Maurer M, Rosén K, Hsieh HJ, Saini S, Grattan C, Gimenez- Arnau A, Agarwal S, Doyle R, Canvin J, Kaplan A, Casale T. Omalizumab for the treatment of chronic idiopathic or spontaneous urticaria. N Engl J Med 2013;368: Kaplan A, Ledford D, Ashby M, Canvin J, Zazzali JL, Conner E, Veith J, Kamath N, Staubach P, Jakob T, Stirling RG, Kuna P, Berger W, Maurer M, Rosen K. Omalizumab in patients with symptomatic chronic idiopathic/spontaneous urticaria despite standard combination therapy. J Allergy Clin Immunol 2013; 132: Kaplan A, Ferrer M, Bernstein JA, Antonova E, Trzaskoma B, Raimundo K, Rosen K, Omachi TA, Khalil S, Zazzali JL. Timing and duration of omalizumab response in patients with chronic idiopathic/spontaneous urticaria. J Allergy Clin Immunol 2016;137: Hide M, Park HS, Igarashi A, Ye YM, Kim TB, Yagami A, Roh J, Lee JH, Chinuki Y, Youn SW, Lee SK, Inomata N, Choi JH, Fukunaga A, Wang J, Matsushima S, Greenberg S, Khalil S. Efficacy and safety of omalizumab in Japanese and Korean patients with refractory chronic spontaneous urticaria. J Dermatol Sci 2017;87: Tharp MD, Bernstein JA, Kavati A, Ortiz B, MacDonald K, Denhaerynck K, Abraham I, Lee CS. Benefits and harms of omalizumab treatment in adolescent and adult patients with chronic idiopathic (spontaneous) urticaria: a meta-analysis of real-world evidence. JAMA Dermatol 2018 Nov 14 [Epub] Engin B, Ozdemir M. Prospective randomized non-blinded clinical trial on the use of dapsone plus antihistamine vs. antihistamine in patients with chronic idiopathic urticaria. J Eur Acad Dermatol Venereol 2008;22: Orden RA, Timble H, Saini SS. Efficacy and safety of sulfasalazine in patients with chronic idiopathic urticaria. Ann Allergy Asthma Immunol 2014;112: Marmor MF, Kellner U, Lai TY, Lyons JS, Mieler WF; American Academy of Ophthalmology. Revised recommendations on screening for chloroquine and hydroxychloroquine retinopathy. Ophthalmology 2011;118: Pho LN, Eliason MJ, Regruto M, Hull CM, Powell DL. Treatment of chronic urticaria with colchicine. J Drugs Dermatol 2011;10: Engin B, Ozdemir M, Balevi A, Mevlitoglu I. Treatment of chronic urticaria with narrowband ultraviolet B phototherapy: a randomized controlled trial. Acta Derm Venereol 2008;88: Antia C, Baquerizo K, Korman A, Alikhan A, Bernstein JA. Urticaria: a comprehensive review: treatment of chronic urticaria, special populations, and disease outcomes. J Am Acad Dermatol 2018;79: Kar S, Krishnan A, Preetha K, Mohankar A. A review of antihistamines used during pregnancy. J Pharmacol Pharmacother 2012;3: Ventura MT, Cassano N, Romita P, Vestita M, Foti C, Vena GA. Management of chronic spontaneous urticaria in the elderly. Drugs Aging 2015;32: Peer Reviewers Commentary 이논문은최근대한피부면역학회와대한천식및알레르기학회에 서공동으로작업중인만성두드러기의치료지침을바탕으로최 신치료가이드라인을소개해주고있다. 만성두드러기는복합적 인요인에의해발생하므로다양한원인과개인적인특성에따 라통합적인치료및관리와함께교육이필요하다. H1 항히스타 민제의표준용량에반응을보이지않는환자에서항히스타민제 의증량이나오말리주맙이나사이클로스포린등의추가치료나 광선치료등대체치료의적응증이나치료용량에대해서도자세 히소개해주고있다. 또한, 소아, 임산부및수유부, 고령자등의 특수환자군의치료시고려해야할사항도기술해주고있다. 이 논문은기존의미국, 일본, 유럽의치료지침과비교하여국내현 실에맞게정리한것으로임상의사의만성두드러기진료에큰도 움이될것으로판단된다. [ 정리 : 편집위원회 ] 46 대한의사협회지