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Urticaria

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• Published: 15 September 2022

Urticaria

• Pavel Kolkhir, 
• Ana M. Giménez-Arnau, 
• Kanokvalai Kulthanan, 
• Jonny Peter, 
• Martin Metz & 
• Marcus Maurer 

Nature Reviews Disease Primers volume 8, Article number: 61 (2022) Cite this article

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Abstract

Urticaria is an inflammatory skin disorder that affects up to 20% of the world population at some point during their life. It presents with wheals, angioedema or both due to activation and degranulation of skin mast cells and the release of histamine and other mediators. Most cases of urticaria are acute urticaria, which lasts ≤6 weeks and can be associated with infections or intake of drugs or foods. Chronic urticaria (CU) is either spontaneous or inducible, lasts >6 weeks and persists for >1 year in most patients. CU greatly affects patient quality of life, and is linked to psychiatric comorbidities and high healthcare costs. In contrast to chronic spontaneous urticaria (CSU), chronic inducible urticaria (CIndU) has definite and subtype-specific triggers that induce signs and symptoms. The pathogenesis of CSU consists of several interlinked events involving autoantibodies, complement and coagulation. The diagnosis of urticaria is clinical, but several tests can be performed to exclude differential diagnoses and identify underlying causes in CSU or triggers in CIndU. Current urticaria treatment aims at complete response, with a stepwise approach using second-generation H1 antihistamines, omalizumab and cyclosporine. Novel treatment approaches centre on targeting mediators, signalling pathways and receptors of mast cells and other immune cells. Further research should focus on defining disease endotypes and their biomarkers, identifying new treatment targets and developing improved therapies.

두드러기는 

전 세계 인구의 최대 20%가 일생 중 한 번쯤 경험하는 

염증성 피부 질환입니다. 

피부 비만 세포의 활성화 및 탈과립과 

히스타민 및 기타 매개체의 방출로 인해 

두드러기, 혈관 부종 또는 두 가지 증상이 모두 나타납니다. 

대부분의 두드러기는 

6주 이내로 지속되는 급성 두드러기이며 

감염이나 약물 또는 음식 섭취와 관련이 있을 수 있습니다. 

만성 두드러기(CU)는 

자연 발생하거나 

유발될 수 있으며, 

대부분의 환자에서 6주 이상 지속되고 

1년 이상 지속됩니다. 

Chronic urticaria (CU) is either spontaneous or inducible,

만성 두드러기는 

환자의 삶의 질에 큰 영향을 미치며, 

정신과적 동반 질환 및 높은 의료 비용과도 관련이 있습니다. 

만성 자발 두드러기(CSU)와 달리 

만성 유도성 두드러기(CIndU)는 

징후와 증상을 유발하는 명확한 하위 유형별 유발 요인이 있습니다. 

chronic spontaneous urticaria (CSU),

chronic inducible urticaria (CIndU)

CSU의 발병 기전은 

자가 항체, 

보체 및 응고와 관련된 여러 가지 상호 연관된 사건으로 구성됩니다. 

두드러기의 진단은 

임상적이지만, 

감별 진단을 배제하고 

CSU의 근본 원인 또는 CIndU의 유발 요인을 확인하기 위해 

몇 가지 검사를 수행할 수 있습니다. 

현재  을 통해 

완전한 반응을 목표로 합니다. 

새로운 치료 접근법은 

비만 세포 및 기타 면역 세포의 매개체, 

신호 전달 경로 및 수용체를 표적으로 하는 데 중점을 두고 있습니다. 

향후 연구는 질병의 내재형과 바이오마커를 정의하고, 

새로운 치료 표적을 식별하고, 

개선된 치료법을 개발하는 데 초점을 맞춰야 합니다.

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Introduction

Urticaria is a common and heterogeneous inflammatory skin disorder, with a lifetime preval‎ence of up to 20% worldwide1,2. The disease results from the activation and degranulation of skin mast cells, followed by the release of histamine and other mediators that lead to sensory nerve activation, vasodilatation, plasma extravasation and cellular recruitment3,4. This process causes the development of the disease-defining signs and symptoms, itchy wheals (hives) and angioedema or both (Fig. 1).

두드러기는 

흔하고 이질적인 염증성 피부 질환으로, 

전 세계적으로 평생 유병률이 최대 20%에 이르는 흔한 질환입니다1,2. 

이 질환은 

피부 비만 세포의 활성화와 탈과립에 이어 

히스타민 및 기타 매개체가 방출되어 

감각 신경 활성화, 

혈관 확장, 

혈장 유출 및 세포 모집으로 이어집니다3,4. 

이 과정에서 질병을 정의하는 

징후와 증상, 

가려운 발진(두드러기)과 

혈관 부종 또는 두 가지가 모두 나타납니다(그림 1).

Fig. 1: Typical presentation of urticaria.

a,b | Wheals. c,d | Angioedema.

Full size image

Urticaria is classified, first, based on its duration as acute urticaria (AU), lasting ≤6 weeks, or chronic urticaria (CU), lasting >6 weeks4. Urticaria is further divided into inducible and spontaneous forms. In inducible urticaria, the signs and symptoms are induced by a subtype-specific and definite trigger, for example cold in cold urticaria (ColdU). In spontaneous urticaria, the signs and symptoms appear unprompted, and there are no definite triggers, although stress, infections and other aggravators can increase disease activity in some patients. Spontaneous urticaria is more common than inducible urticaria and both can coexist in the same patient4,5,6 (Tables 1 and 2).

두드러기는 

먼저 지속 기간에 따라 6주 이하로 지속되는 급성 두드러기(AU) 또는 

6주 이상 지속되는 만성 두드러기(CU)로 분류합니다4. 

두드러기는 다시 

유도성 두드러기와 

자연 발생 두드러기로 나뉩니다. 

inducible and spontaneous forms.

유도성 두드러기의 경우, 

감기 두드러기(ColdU)와 같이 

아형에 특이적이고 

확실한 유발 요인에 의해 징후와 증상이 유발됩니다. 

자발성 두드러기의 경우 

징후와 증상이 예고 없이 나타나며 

스트레스, 

감염 및 

기타 악화 요인이 일부 환자에서 질병 활동을 증가시킬 수 있지만 

명확한 유발 요인은 없습니다. 

자연 두드러기는 

유발성 두드러기보다 더 흔하며 

같은 환자에서 두 가지가 공존할 수 있습니다4,5,6(표 1 및 2).

Table 1 Comparison of different types of urticaria

Table 2 Classification of chronic inducible urticaria4,106

Most cases of AU resolve within 1 week, and <40% of cases become chronic (see Supplementary Table 1). CU often lasts for several years before spontaneous remission occurs (see Supplementary Tables 2 and 3). AU is mostly spontaneous and of unknown cause, although infections and the intake of drugs or foods are thought to be relevant in some patients (see Supplementary Table 4). The underlying causes of chronic inducible urticaria (CIndU) remain unknown, whereas two causes of chronic spontaneous urticaria (CSU) (previously known as chronic idiopathic urticaria) are recognized: autoallergy (also called type I autoimmunity) with IgE autoantibody involvement, and type IIb autoimmunity with IgG autoantibody involvement7,8. These mast cell-activating autoantibodies along with cell infiltration, coagulation and complement activation are thought to be key drivers of the pathogenesis of CSU9,10.

The burden of CU for patients and society is substantial. CU manifestations have a strong effect on health-related quality of life, including sleep impairment, diminished physical and emotional well-being and poor performance at school and work11,12. Current treatment options are still limited and are not effective in around one-third of patients with CU. Novel targeted treatments are needed, and several promising drugs are already under development13.

In this Primer, we discuss the current knowledge of urticaria epidemiology, diagnosis, screening, management and quality of life, and highlight recent advances in the understanding of disease pathogenesis and targeted treatment. Other pathophysiologically and clinically distinct conditions that present with wheals and/or angioedema, for example urticarial vasculitis, autoinflammatory syndromes and bradykinin-mediated angioedema, are briefly discussed as differential diagnoses. Detailed tables of study findings relating to epidemiology and diagnosis, with accompanying references, can be found in the Supplementary information.

대부분의 AU 사례는 1주일 이내에 해결되며, 

40% 미만의 사례는 만성화됩니다(보충 표 1 참조). 

CU는 

자연 관해가 일어나기 전까지 

수년간 지속되는 경우가 많습니다(보충 표 2 및 3 참조). 

일부 환자에서 

감염과 약물 또는 

음식 섭취가 관련이 있는 것으로 생각되기는 하지만, 

대부분 자연적으로 발생하며 원인을 알 수 없습니다(보충 표 4 참조). 

만성 유도성 두드러기(CIndU)의 

근본 원인은 

아직 밝혀지지 않은 반면, 

만성 자발성 두드러기(CSU)(이전의 만성 특발성 두드러기)의 원인은 

IgE 자가 항체가 관여하는 

자가 알레르기(제1형 자가 면역이라고도 함)와 

IgG 자가 항체가 관여하는 제2b형 자가 면역7,8)의 두 가지로 알려져 있습니다. 

이러한 

비만세포 활성화 자가항체는 

세포 침윤, 

응고 및 보체 활성화와 함께 

CSU 발병의 주요 원인으로 생각됩니다9,10.



CU로 

인한 환자와 사회의 부담은 상당합니다. 

CU 증상은 

수면 장애, 

신체적, 정서적 안녕감 저하, 

학교 및 업무 수행 능력 저하 등 

건강 관련 삶의 질에 큰 영향을 미칩니다11,12. 

현재 치료 옵션은 

여전히 제한적이며, 

CU 환자의 약 1/3에게는 효과가 없습니다. 

새로운 표적 치료법이 필요하며 

이미 몇 가지 유망한 약물이 개발 중입니다13.

이 입문서에서는 

두드러기 역학, 

진단, 검사, 

관리 및 삶의 질에 대한 현재 지식을 논의하고 

질병 발병 기전 및 표적 치료에 대한 최근의 진전을 강조합니다. 

두드러기 혈관염, 

자가염증 증후군, 

브라디키닌 매개 혈관 부종 등 

두드러기 및/또는 혈관 부종을 동반하는 

다른 병리 생리학적 및 임상적으로 구별되는 질환을 감별 진단으로 간략하게 논의합니다. 

역학 및 진단과 관련된 자세한 연구 결과 표와 함께 참고 문헌은 보충 정보에서 확인할 수 있습니다.

Epidemiology

Preval‎ence and incidence

For 2017, the preval‎ence of urticaria was estimated at 86 million cases and the annual incidence at 160 million cases globally14. However, each urticaria subtype has its own preval‎ence within different populations. The preval‎ence of AU is highest in children <5 years of age14,15,16, whereas CU, especially CSU, is most preval‎ent in women >30 years old6,17,18,19,20,21. Adult patients with CSU are older than adult patients with CIndU (average age ~30–70 years versus ~20–40 years) and have older age of disease onset (~30–50 years versus ~20–35 years). In adults, all types of urticaria are more preval‎ent in women than in men, except for cholinergic urticaria (CholU), which is more prominent in both male adults and children; female predominance is absent or is less prominent in younger children21 (Table 1; see Supplementary Tables 2 and 3).

All ethnicities are affected; however, the preval‎ence of AU and CU was higher in non-white patients in some studies15,19,22 but not all23. The lifetime preval‎ence of all types of urticaria and AU is 3–22% and 6–19%, respectively (see Supplementary Table 5). The overall lifetime preval‎ence of CU is 4.4%22, and the point preval‎ence of CU (1-year preval‎ence in most studies) ranges from ≤1.5% in the USA and Europe to 3–4% in Mexico, Korea and China (Fig. 2; see Supplementary Table 5).

유병률 및 발병률

2017년 두드러기 유병률은 

전 세계적으로 8,600만 건, 

연간 발생 건수는 1억 6천만 건으로 추정됩니다14. 

그러나 

각 두드러기 아형은 

인구 집단마다 유병률이 다릅니다. 

AU의 유병률은 

5세 미만의 어린이14,15,16에서 가장 높은 반면, 

CU, 특히 CSU는 

30세 이상의 여성6,17,18,19,20,21에서 가장 많이 발생합니다. 

CSU를 앓는 성인 환자는 

CIndU를 앓는 성인 환자보다 나이가 많고(평균 연령 ~30-70세 대 ~20-40세), 

질병 발병 연령도 더 높습니다(~30-50세 대 ~20-35세). 

성인에서는 

모든 유형의 두드러기가 

남성보다 여성에서 더 많이 발생하지만, 

남성 성인과 소아 모두에서 더 두드러지는 콜린성 두드러기(CholU)를 제외하고는 

여성 우세가 없거나 어린 소아에서는 덜 두드러집니다21(표 1, 보충 표 2 및 3 참조).

모든 인종이 영향을 받지만 

일부 연구15,19,22에서는 

비백인 환자에서 AU 및 CU의 유병률이 더 높았으나 전부는 아닙니다23. 

모든 유형의 두드러기와 

AU의 평생 유병률은 각각 3-22%, 6-19%입니다(보충 표 5 참조). 

CU의 전체 평생 유병률은 4.4%22이며, 

CU의 점 유병률(대부분의 연구에서 1년 유병률)은 

미국과 유럽에서 ≤1.5%에서 멕시코, 

한국 및 중국에서 3~4%입니다(그림 2, 보충 표 5 참조).

Fig. 2: Global preval‎ence of chronic urticaria.

A point preval‎ence of chronic urticaria (CU) in children, adults and/or both is presented where available. The lowest preval‎ence rates were observed in the USA and Europe, whereas the highest rates were reported in Mexico, China and Korea. Detailed information can be found in Supplementary Table 5. CIndU, chronic inducible urticaria; CSU, chronic spontaneous urticaria.

Full size image

No significant changes in the global preval‎ence, incidence and the years of life lived with disability were seen for urticaria between 1990 and 2017 (ref.14). The consistent increase in CU preval‎ence in South Korea21,24, Italy25,26 and Taiwan27 may be linked to country-specific demographic, environmental and behavioural factors and changes.

CIndU is less preval‎ent than CSU6,28. The pooled rate of all CIndU subtypes was 13%29 and that of CSU was ~60–90% across all cases of CU (see Supplementary Table 6). The most preval‎ent types of CIndU are symptomatic dermographism, CholU and ColdU, in both adults and children21,30, whereas aquagenic urticaria, solar urticaria, heat urticaria, vibratory angioedema and contact urticaria are rare, that is, are seen in <2–3% of all CU cases (Table 2; see Supplementary Table 6). Delayed pressure urticaria is rarely seen as an isolated disorder but present in combination with CSU in up to 36% of patients with CU (Table 2; see Supplementary Table 6).

1990년과 2017년 사이에 두드러기의 전 세계 유병률, 발병률, 장애 수명에 큰 변화가 나타나지 않았습니다(참고 14). 한국21,24, 이탈리아25,26, 대만27에서 CU 유병률이 지속적으로 증가하는 것은 국가별 인구통계학적, 환경적, 행동적 요인 및 변화와 관련이 있을 수 있습니다.

CIndU는 CSU보다 유병률이 낮습니다6,28. 모든 CIndU 하위 유형의 풀링 비율은 13%29였으며, CSU는 모든 CU 사례에서 약 60~90%였습니다(보충 표 6 참조). 성인과 소아 모두에서 가장 흔한 CIndU 유형은 증상성 피부 두드러기, 콜드U 및 콜드U이며21,30 수양성 두드러기, 태양 두드러기, 열 두드러기, 진동성 혈관부종 및 접촉 두드러기는 전체 CU 사례의 2/3 미만에서 드물게 나타납니다(표 2, 보충 표 6 참조). 지연성 두드러기는 단독 질환으로 나타나는 경우는 드물지만 CU 환자의 최대 36%에서 CSU와 함께 나타납니다(표 2, 보충 표 6 참조).

Natural course

The average duration of AU is ≤1 week. The rates of progression of AU to CU are between 5% and 39% in most studies (see Supplementary Table 1). CSU is of shorter duration than CIndU, with a mean or median disease duration of ~1–4 years in most studies (see Supplementary Table 2), and the cumulative weighted average estimates for spontaneous remission at 1, 5 and 20 years are 17%, 45% and 73%, respectively31. CSU relapses in 6–31% of patients (see Supplementary Table 2). The mean or median duration of CIndU and its three most common subtypes (symptomatic dermographism, CholU and ColdU) was 2–12 years, 2–5 years, 3–8 years and 2–9 years, respectively. Remission of CIndU within 5 years occurs in only around one-third of patients, with the highest rates in symptomatic dermographism and the lowest in CholU and ColdU30 (see Supplementary Table 3). Various factors and markers have been found to be associated with urticaria natural course, phenotypes, endotypes, clinical and laboratory characteristics and response to treatment (see Supplementary Box 1).

AU의 평균 지속 기간은 

1주일 이내입니다. 

대부분의 연구에서 

AU에서 CU로 진행되는 비율은 

5%에서 39% 사이입니다(보충 표 1 참조). 

CSU는 

대부분의 연구에서 질병 지속 기간의 평균 또는 중앙값이 

1~4년으로 CIndU보다 더 짧으며(보충 표 2 참조), 

1년, 5년, 20년째의 자연 관해에 대한 누적 가중 평균 추정치는 각각 17%, 45%, 73%입니다31. 

CSU는 

환자의 6~31%에서 재발합니다(보충 표 2 참조). 

CIndU와 가장 흔한 세 가지 하위 유형(증상성 피부 촬영증, 콜드유, 콜드유)의 평균 또는 

중앙값은 각각 2-12년, 2-5년, 3-8년, 2-9년이었습니다. 

5년 내 CIndU의 관해는 환자의 약 1/3에서만 발생하며, 증상성 피부 촬영증에서 가장 높은 비율을 보였고 CholU와 ColdU에서 가장 낮았습니다30(보충 표 3 참조). 두드러기의 자연 경과, 표현형, 내형, 임상 및 실험실 특성, 치료에 대한 반응과 관련된 다양한 인자 및 마커가 밝혀졌습니다(보충 자료 1 참조).

Risk factors

Risk factors reported for AU include high population density15 and personal32 and parental history of allergic diseases2,33. Higher preval‎ence and/or higher risk of having AU may be associated with poverty and lower socio-economic status14,15, whereas risk for CU was linked to high income and socio-economic status in some studies2,23,34 but not all35,36. In studies involving twins, genetic factors could partly explain susceptibility to urticaria32. The role of polymorphisms of several genes, including TNFRS11A, TBXA2R and PLA2G4A37, has been suggested in susceptibility to AU and/or angioedema induced by multiple NSAIDs.

Genetic predisposition to CU has been associated with gene polymorphisms of IFNγ, IL-6, IL-17RA, IL-10, TGFβ, IL-6, tumour necrosis factor (TNF), PTPN22, IL-1, IL-2 and HLA class I and II alleles38. Some of these genes, such as PTPN22, and HLA alleles, for example HLA-DR4 allele, are also responsible for susceptibility to various autoimmune disorders. For example, HLA-DR4 was strongly associated with autoimmune CSU defined by a positive basophil histamine release assay (BHRA)39 and other autoimmune diseases, for example rheumatoid arthritis and type 1 diabetes mellitus. CSU, especially in middle-aged women with autoimmune CSU40, is associated with an increased risk of developing autoimmune disease within 10 years after the diagnosis of CSU41. For example, women with CSU were 23 and 20 times more likely to also have hypothyroidism and rheumatoid arthritis, respectively, compared with the control group41. Diagnosis of CSU was made in ~80% and ~20% of patients before and after diagnosis of autoimmune diseases, respectively, including rheumatoid arthritis, systemic lupus erythematosus, type I diabetes mellitus and coeliac disease41. Patients with autoimmune thyroid diseases, especially female patients, had a considerably higher risk of CSU development42. Up to 25% of patients with CSU, especially those with positive markers of autoimmune urticaria43,44,45, had a family history of CSU (see Supplementary Table 7). In addition, female patients with peptic ulcer disease46 and abnormal uterine bleeding47 have been shown to have a higher CU risk.

Geographical differences in frequency of CholU and ColdU were reported suggesting that some environmental factors, for example temperature and altitude, might increase the risk of developing CIndU48.

AU의 위험 요인으로는 

높은 인구 밀도15 및 

개인32, 부모의 알레르기 질환 병력2,33 등이 보고되었습니다. 

더 높은 유병률 및/또는 

더 높은 AU 위험은 빈곤 및 낮은 사회경제적 지위와 관련이 있을 수 있으며14,15, 

CU의 위험은 일부 연구에서 고소득 및 사회경제적 지위와 관련이 있는 반면2,23,34 

전부는 아니었지만35,36. 

쌍둥이를 대상으로 한 연구에서는 

유전적 요인이 두드러기에 대한 감수성을 부분적으로 설명할 수 있다고 합니다32. 

여러 NSAID에 의해 유발되는 

AU 및/또는 혈관부종에 대한 감수성에서 

TNFRS11A, TBXA2R 및 PLA2G4A37를 포함한 여러 유전자의 다형성의 역할이 제안되었습니다.



CU에 대한 유전적 소인은 

IFNγ, IL-6, IL-17RA, IL-10, TGFβ, IL-6, 종양괴사인자(TNF), 

PTPN22, IL-1, IL-2 및 HLA 클래스 I 및 II 대립유전자38의 유전자 다형성과 관련이 있는 것으로 알려져 있습니다. 

PTPN22와 같은 일부 유전자와 HLA 대립유전자(예: HLA-DR4 대립유전자)는 다양한 자가면역질환에 대한 감수성을 유발하기도 합니다. 

예를 들어, HLA-DR4는 양성 호염기구 히스타민 방출 분석(BHRA)39으로 정의되는 자가면역성 CSU 및 류마티스 관절염, 제1형 당뇨병과 같은 기타 자가면역 질환과 밀접한 관련이 있습니다. 특히 자가면역성 CSU40를 앓고 있는 중년 여성의 경우, CSU 진단 후 10년 이내에 자가면역 질환이 발병할 위험이 높아지는 것과 관련이 있습니다41. 예를 들어, CSU를 가진 여성은 대조군에 비해 갑상선 기능 저하증과 류마티스 관절염을 앓을 가능성이 각각 23배, 20배 더 높았습니다41. 류마티스 관절염, 전신성 홍반성 루푸스, 제1형 당뇨병, 체강 질병 등 자가면역 질환 진단 전후에 각각 약 80%와 약 20%의 환자에서 CSU가 진단되었습니다41. 자가면역성 갑상선 질환 환자, 특히 여성 환자의 경우 CSU 발병 위험이 상당히 높았습니다42. 특히 자가면역 두드러기 마커가 양성인 환자의 최대 25%43,44,45가 CSU 가족력이 있는 것으로 나타났습니다(보충 표 7 참조). 또한 소화성 궤양 질환46 및 비정상 자궁 출혈47이 있는 여성 환자의 경우 CU 위험이 더 높은 것으로 나타났습니다.

온도 및 고도와 같은 일부 환경적 요인이 CIndU 발병 위험을 증가시킬 수 있음을 시사하는 CholU 및 ColdU 빈도의 지리적 차이가 보고되었습니다48.

Healthcare use and annual treatment costs

Urticaria, especially CU, is associated with considerable healthcare utilization and economic burden, including both regular and unanticipated healthcare visits, costs due to laboratory expenses and indirect costs due to the absence from work or reduced efficiency11,49. Patients with CU, especially those with angioedema, more frequently visit physicians, mostly family doctors, allergists and dermatologists, and emergency rooms, and are more frequently hospitalized than individuals without urticaria12,49,50. Patients with CIndU were more often hospitalized than patients with CSU (paediatric, 15.5% versus 9.9%; adult, 7.8% versus 4.6%; respectively)6. Average annual economic costs for a patient with CSU ranged from PPP$907 (purchasing power parity dollars) in Italy to PPP$2,984 in France, mostly due to therapies and inpatient visits12.

두드러기, 

특히 CU는 정기 및 예기치 않은 의료기관 방문, 

검사 비용으로 인한 비용, 

결근 또는 효율성 저하로 인한 간접 비용 등 

상당한 의료 이용 및 경제적 부담과 관련이 있습니다11,49. 

CU 환자, 

특히 혈관부종 환자는 주로 가정의학과, 알레르기내과, 피부과, 응급실 등 

의사를 더 자주 방문하며, 

두드러기가 없는 사람보다 더 자주 입원하는 것으로 나타났습니다12,49,50. 

CIndU 환자는 

CSU 환자보다 더 자주 입원했습니다(소아, 15.5% 대 9.9%, 성인, 7.8% 대 4.6%, 각각)6. 

CSU 환자의 연평균 경제적 비용은 이탈리아에서 PPP$907(구매력 평가 달러)에서 프랑스에서 PPP$2,984까지 다양했으며, 대부분 치료와 입원 방문으로 인해 발생했습니다12.

Mechanisms/pathophysiology

Skin mast cells have a central role in urticaria pathogenesis and are found in the upper papillary dermis as well as the deep dermis and subcutis, mostly around cutaneous blood vessels and sensory nerves. Their activation with subsequent degranulation drives the development of itchy wheals and/or angioedema3.

피부 비만 세포는 

두드러기 발병의 중심 역할을 하며, 

주로 피부 혈관과 감각 신경 주변의 심부 진피와 피하층뿐만 아니라 

상부 유두 진피에서도 발견됩니다. 

이후 탈과립화와 함께 활성화되면 

가려움증 및/또는 혈관 부종이 발생하게 됩니다3.

Acute urticaria

The pathogenesis of AU is poorly investigated. Acute spontaneous urticaria, as well as wheals and/or angioedema in patients with anaphylaxis, have been described to result from type I hypersensitivity reactions to foods, drugs and other allergens51. Type I hypersensitivity, also known as an immediate IgE-mediated reaction, describes interaction between exoallergen and a pre-existing complex of an IgE antibody bound to its high-affinity receptor, FcεRI, on mast cells and basophils that leads to cell activation and degranulation52. NSAID‐induced urticaria and/or angioedema is IgE-mediated or T cell-mediated, or due to the pharmacological inhibition of cyclooxygenase 1 (COX1) and increased levels of cysteinyl leukotrienes53. Acute contact urticaria can develop in response to direct contact with allergens with previous sensitization54 and urticariogenic substances without prior sensitization, for example after touching stinging nettles4.

아나필락시스의 발병 기전은 제대로 밝혀지지 않았습니다. 아나필락시스 환자의 급성 자연 두드러기 및/또는 혈관 부종은 음식, 약물 및 기타 알레르겐에 대한 제1형 과민 반응으로 인해 발생하는 것으로 설명되어 있습니다51. 즉각적인 IgE 매개 반응이라고도 하는 제1형 과민증은 외알레르겐과 비만세포 및 호염기구의 고친화성 수용체인 FcεRI에 결합된 기존 IgE 항체 복합체 간의 상호작용으로 세포 활성화 및 탈과립화를 유발하는 것으로 설명됩니다52. NSAID로 인한 두드러기 및/또는 혈관 부종은 IgE 매개 또는 T 세포 매개, 또는 시클로옥시게나제 1(COX1)의 약리학적 억제와 시스테인 류코트리엔 수치 증가로 인해 발생합니다53. 급성 접촉 두드러기는 이전에 감작이 있었던 알레르겐54과 감작이 없는 두드러기 유발 물질과의 직접 접촉에 반응하여 발생할 수 있으며, 예를 들어 쏘는 쐐기풀을 만진 후4에 발생할 수 있습니다.

Chronic spontaneous urticariaMast cells

The development of wheals and angioedema in CSU is dependent on mast cell-activating signals and receptors, signalling pathways, inhibitory receptors and mediators, which are targets of current and future therapy3,10,13 (Fig. 3). Mast cells express many activating receptors including FcεRI, MRGPRX2, C5aR, PAR1, PAR2, chemoattractant receptor-homologous molecule expressed on T helper 2 cells (TH2 cells) (CRTh2) and cytokine receptors, which can be activated by various signals13. Interaction of stem cell factor (SCF), produced by fibroblasts, endothelial cells and mast cells, with its receptor KIT (CD117) on mast cells is a major driver of mast cell differentiation, migration, proliferation, survival and apoptosis55. Activation of FcεRI involves several cytoplasmic signalling proteins, for example. LYN, spleen tyrosine kinase (SYK) and Bruton’s tyrosine kinase (BTK), which phosphorylate downstream signalling targets and induce mast cell activation and degranulation56 The first step in FcεRI-mediated signalling is the phosphorylation of the FcεRI β-chain and γ-chain by LYN followed by activation of SYK and BTK. The cytosolic tyrosine kinase BTK is the central positive regulator of FcεRI-mediated mast activation and cytokine production56,57. In addition to its role in mast cell activation, BTK is also required for B cell receptor (BCR) signalling56,57. In addition to activating receptors, mast cells express a few inhibitory receptors, such as sialic acid-binding immunoglobulin-like lectin 8 (Siglec 8), CD200R, CD300a and FcγRIIb58, which can silence mast cells and block mast cell activation upon interaction with their ligands.

CSU에서 수포와 혈관 부종의 발생은 

비만 세포 활성화 신호 및 수용체, 신호 경로, 억제 수용체 및 매개체에 의존하며, 

이는 현재 및 향후 치료의 표적입니다3,10,13(그림 3). 

비만세포는 

다양한 신호에 의해 활성화될 수 있는 

FcεRI, MRGPRX2, C5aR, PAR1, PAR2, T 헬퍼 2 세포(TH2 세포)에 발현되는 

화학 유인 수용체 상동 분자(CRTh2) 및 

사이토카인 수용체를 포함한 

많은 활성화 수용체를 발현합니다13. 

섬유아세포, 

내피세포 및 비만세포에서 생성되는 

줄기세포 인자(SCF)와 

비만세포의 수용체 KIT(CD117)의 상호작용은 

비만세포 분화, 이동, 증식, 생존 및 

아포토시스55의 주요 동인입니다. 

FcεRI의 활성화에는 

다음과 같은 여러 세포질 신호 단백질이 관여합니다. 

LYN, 비장 티로신 키나제(SYK) 및 브루톤 티로신 키나제(BTK)는 하류 신호 표적을 인산화하고 비만 세포 활성화 및 탈과립화를 유도합니다56 FcεRI 매개 신호의 첫 번째 단계는 LYN에 의한 FcεRI β사슬 및 γ사슬의 인산화 후 SYK 및 BTK의 활성화입니다. 세포질 티로신 키나아제 BTK는 FcεRI 매개 비만 활성화 및 사이토카인 생산의 핵심적인 양성 조절인자입니다56,57. 비만 세포 활성화에 대한 역할 외에도 BTK는 B 세포 수용체(BCR) 신호에도 필요합니다56,57. 비만 세포는 활성화 수용체 외에도 시알산 결합 면역 글로불린 유사 렉틴 8(Siglec 8), CD200R, CD300a 및 FcγRIIb58와 같은 몇 가지 억제 수용체를 발현하여 비만 세포를 침묵시키고 리간드와의 상호작용 시 비만 세포 활성화를 차단할 수 있습니다.

Fig. 3: Key pathways of urticaria pathogenesis including current and future therapeutic targets.

Activation and degranulation of mast cells leads to the development of signs and symptoms of urticaria due to the release of histamine and other mediators, which activate sensory skin nerves (itch), dilate skin blood vessels (erythema) and induce plasma extravasation (oedema and influx of other immune cells). In allergic urticaria, release of alarmins, TSLP, IL-33 and IL-25, by the epithelium, activation of skin-resident group 2 innate lymphoid cells (ILC2), polarization of T cells (mostly T helper 2 cells (TH2 cells)) with release of TH2 cytokines, for example IL-4, IL-5 and IL-13, and allergen-specific IgE production by B cells enable subsequent cross-linking of IgE–FcεRI complexes on the surface of mast cells by allergens, which triggers mast cell activation. Chronic spontaneous urticaria (CSU) can appear due to a chain of complex multistep interlinked events including cell infiltration (mostly eosinophils, basophils, neutrophils and T cells), autoimmunity (for example, IgE/IgG histamine-releasing autoantibodies), neurogenic inflammation (via histamine-dependent and histamine-independent itch signalling pathways mediated by cutaneous pruriceptive sensory nerves), activation of the complement cascade (for example, via production of anaphylatoxin C5a) and activation of tissue factor-initiated extrinsic pathway of the coagulation cascade. Here, receptors (for example, FcεRI, C5aR, MRGPRX2, Siglec 8, KIT and IL-4Rα), signalling pathways (for example, BTK and SYK) and mediators (for example, histamine, tryptase, IL-5, IL-17 and IL-31) of mast cells, eosinophils, basophils and/or other immune cells involved in urticaria, as well as activating signals (for example, IgE anti-autoallergens), are the targets for current therapy and drugs in development. In chronic inducible urticaria (CIndU), similar mechanisms of mast cell activation including autoallergy and/or autoimmunity may have a role.

비만 세포의 활성화 및 탈과립은 

히스타민 및 기타 매개체의 방출로 인해 

두드러기의 징후와 증상을 유발하여 

감각 피부 신경(가려움증)을 활성화하고 

피부 혈관을 확장하며 혈장 유출(부종 및 다른 면역 세포의 유입)을 유도합니다. 

알레르기 두드러기에서는 

상피에 의한 알라닌, 

TSLP, IL-33 및 IL-25의 방출, 

피부 상주 그룹 2 선천성 림프구 세포(ILC2)의 활성화, 

TH2 사이토카인의 방출과 함께 

T 세포(주로 T 헬퍼 2 세포(TH2 세포))의 분극화 등이 나타납니다, 

예를 들어 IL-4, IL-5 및 IL-13, B 세포에 의한 알레르겐 특이 IgE 생산은 알레르기 항원에 의해 비만 세포 표면에서 IgE-FcεRI 복합체가 가교 결합하여 비만 세포 활성화를 유발합니다. 만성 자발 두드러기(CSU)는 세포 침윤(주로 호산구, 호염기구, 호중구 및 T 세포), 자가 면역(예: IgE/IgG 히스타민 방출 자가 항체)을 포함한 복잡한 다단계 상호 연결 사건의 연쇄로 인해 나타날 수 있습니다, 신경성 염증(피부 가려움증 감각 신경에 의해 매개되는 히스타민 의존성 및 히스타민 독립성 가려움증 신호 경로), 보체 캐스케이드의 활성화(예: 아나필라톡신 C5a 생성) 및 응고 캐스케이드의 조직 인자 개시 외인성 경로의 활성화. 여기에는 비만 세포의 수용체(예: FcεRI, C5aR, MRGPRX2, Siglec 8, KIT 및 IL-4Rα), 신호 경로(예: BTK 및 SYK) 및 매개체(예: 히스타민, 트립타제, IL-5, IL-17 및 IL-31)가 포함됩니다, 호산구, 호염기구 및/또는 두드러기와 관련된 기타 면역 세포 및 활성화 신호(예: IgE 항알레르기 항원)는 현재 개발 중인 치료법 및 약물의 표적입니다. 만성 유도성 두드러기(CIndU)의 경우 자가 알레르기 및/또는 자가 면역을 포함한 유사한 비만 세포 활성화 메커니즘이 작용할 수 있습니다.

AR, alarmin receptors; BCR, B cell receptor; BTK, Bruton’s tyrosine kinase; CGRP, calcitonin gene-related peptide; CRTh2, chemoattractant receptor-homologous molecule expressed on TH2 cells; EPO, eosinophil peroxidase; FDP, fibrin degradation products; FXa, factor Xa; GM-CSF, granulocyte–macrophage colony-stimulating factor; HR, histamine receptors; MBP, major basic protein; MPO, myeloperoxidase; MRGPRX2, Mas-related G-protein-coupled receptor X2; PAF, platelet-activating factor; PAR, protease-activated receptor; PGD2, prostaglandin D2; SCF, stem cell factor; Siglec 8, sialic acid-binding immunoglobulin-like lectin 8; SYK, spleen tyrosine kinase; TNF, tumour necrosis factor; TSLP, thymic stromal lymphopoietin; VEGF, vascular endothelial growth factor.

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CSU symptoms occur mainly due to the release of histamine, but also by a broad range of other produced and secreted mediators, including tryptase, prostaglandin D2 (PGD2), TNF, IL-4, IL-5, IL-13, IL-17 and IL-31, which can exert effects on resident skin cells and other recruited target cells, for example T cells, eosinophils and basophils3,13.

CSU 증상은 

주로 히스타민의 방출로 인해 발생하지만 

트립타제, 프로스타글란딘 D2(PGD2), 

TNF, IL-4, IL-5, IL-13, IL-17 및 IL-31을 포함한 

광범위한 기타 생성 및 분비 매개체에 의해서도 발생하며, 

이는 상주 피부 세포 및 기타 모집 대상 세포(예: T 세포, 호산구 및 호염기구3,13)에 효과를 발휘할 수 있습니다.

Cell infiltrate

In CSU, perivascular and interstitial inflammatory cellular infiltrates, resembling an allergic late-phase reaction, include eosinophils, neutrophils, lymphocytes and basophils9,59,60,61. Infiltrating cells are thought to migrate from the blood into the skin in response to chemotactic factors, for example eotaxins, MCP3, RANTES, IL-5, C3a, C5a, TNF, IL-17 and platelet-activating factor (PAF), released by mast cells, activated endothelial cells, TH2 cells, dermal fibroblasts and other cells9. Cell adhesion molecules, for example P-selectin, E-selectin, ICAM, VCAM and PECAM, are upregulated on the surface of endothelial cells in the lesional skin of patients with CSU due to action of histamine, thrombin, TNF and other factors9.

Blood basopenia and eosinopenia that are observed in ~10–15% of patients with CSU may reflect the transport of cells into the skin, and are associated with CSU activity, presence of autoantibodies and poor response to H1 antihistamines (H1-AH) and omalizumab62,63. Perivascular eosinophils and neutrophils appeared in wheals 30 min after intradermal injection of autologous serum and, along with T lymphocytes, increased in numbers over the following 2 h with a decrease by 48 h (neutrophils) or later (eosinophils and lymphocytes)64. Blood and skin-migrated basophils can contribute to the CSU pathogenesis by releasing histamine, leukotrienes and cytokines via activation of FcεRI and C5aR65,66. Eosinophil granule proteins such as major basic protein (MBP) were detected in the wheals of patients with CSU67,68. MBP was able to induce mast cell activation and degranulation, representing a putative mechanism of crosstalk between eosinophils and mast cells in CSU67. Activation of eosinophils can occur due to mast cell mediators, namely IL-5, TNF, PAF and eotaxin, and also IgG autoantibodies to the low-affinity IgE receptor69. Activated eosinophils can also release SCF, a growth factor for mast cells. Finally, eosinophils might be key players in activation of the coagulation cascade and of Mas-related G-protein-coupled receptor X2 (MRGPRX2) on mast cells via expression‎ of tissue factor and release of MRGPRX2 agonists, respectively67,69.

TH2 cells are a predominant type of lymphocyte in CSU skin biopsy samples but TH1 cells and TH17 cells are also present9. TH2 cells are highly involved in allergic diseases, releasing a broad range of cytokines, stimulating IgE production and mast cell, basophil and eosinophil activation. In patients with CSU, cytokine levels and/or expression‎ were increased in the blood and/or lesional skin, for example IFNγ, TNF, TGFβ, IL-1β, IL-3, IL-4, IL-5, IL-6, IL-13, IL-17, IL-23, IL-24, IL-31 and IL-33, and correlated with disease activity, for example TNF, IL-6, IL-17, IL-23 and IL-24, and autologous serum skin test (ASST) positivity, for example IL-17 (ref.9).

CSU에서 

알레르기 후기 반응과 유사한 혈관 주위 및 간질성 염증성 세포 침윤에는 

호산구, 호중구, 림프구 및 호염기구9,59,60,61가 포함됩니다. 

침윤 세포는 

비만 세포, 

활성화된 내피 세포, 

TH2 세포, 

피부 섬유아세포 및 기타 세포에서 방출되는 

화학 주성 인자(예: 이오탁신, MCP3, RANTES, IL-5, C3a, C5a, TNF, IL-17 및 혈소판 활성화 인자(PAF)에 반응하여 혈액에서 피부로 이동하는 것으로 생각됩니다9. 

세포 부착 분자(예: P-셀렉틴, E-셀렉틴, ICAM, VCAM 및 PECAM)는 

히스타민, 트롬빈, TNF 및 기타 인자의 작용으로 인해 

CSU 환자의 병변 피부에서 내피 세포 표면에서 상향 조절됩니다9.

CSU 환자의 약 10~15%에서 관찰되는 혈구 감소증 및 호산구 감소증은 세포가 피부로 이동하는 것을 반영할 수 있으며, CSU 활성, 자가 항체의 존재 및 H1 항히스타민제(H1-AH) 및 오말리주맙62,63에 대한 반응 저하와 관련이 있을 수 있습니다. 혈관 주위 호산구와 호중구는 자가 혈청 피내 주사 후 30분 후에 호산구와 호중구에서 나타났으며, T 림프구와 함께 다음 2시간 동안 그 수가 증가하여 48시간(호중구) 또는 그 이후(호산구 및 림프구)64에 감소했습니다. 혈액 및 피부로 이동한 호염기구는 FcεRI 및 C5aR65,66의 활성화를 통해 히스타민, 류코트리엔 및 사이토카인을 방출하여 CSU 발병에 기여할 수 있습니다. 주요 염기성 단백질(MBP)과 같은 호산구 과립 단백질이 CSU 환자의 휠에서 검출되었습니다67,68. MBP는 비만 세포 활성화와 탈과립화를 유도할 수 있었으며, 이는 CSU67에서 호산구와 비만 세포 간의 교란 메커니즘을 추정할 수 있는 것으로 나타났습니다. 호산구의 활성화는 비만 세포 매개체, 즉 IL-5, TNF, PAF 및 e오탁신과 저친화성 IgE 수용체에 대한 IgG 자가 항체69로 인해 발생할 수 있습니다. 활성화된 호산구는 비만 세포의 성장 인자인 SCF를 방출할 수도 있습니다. 마지막으로, 호산구는 조직 인자의 발현과 MRGPRX2 작용제의 방출을 통해 비만 세포에서 응고 캐스케이드와 Mas 관련 G 단백질 결합 수용체 X2(MRGPRX2)의 활성화에 핵심적인 역할을 할 수 있습니다67,69.

TH2 세포는 CSU 피부 생검 샘플에서 우세한 유형의 림프구이지만 TH1 세포와 TH17 세포도 존재합니다9. TH2 세포는 광범위한 사이토카인을 방출하고 IgE 생산과 비만 세포, 호염기구 및 호산구 활성화를 자극하여 알레르기 질환에 크게 관여합니다. CSU 환자의 경우 혈액 및/또는 병변 피부에서 사이토카인 수치 및/또는 발현이 증가했으며(예: IFNγ, TNF, TGFβ, IL-1β, IL-3, IL-4, IL-5, IL-6, IL-13, IL-17, IL-23, IL-24, IL-31 및 IL-33), 질병 활성도와 상관관계가 있으며(예: TNF, IL-6, IL-17, IL-23 및 IL-24) 자가 혈청 피부 검사(ASST) 양성과도 상관관계가 있습니다(참조9).

Coagulation cascade and complement

Eosinophils and dermal microvascular endothelial cells can express a large amount of tissue factor on their surface in response to tissue factor inducers, for example histamine, vascular endothelial growth factor (VEGF), LPS, TNF, IL-6, IL-33 and IL-1β70. Tissue factor can activate the extrinsic coagulation cascade leading to the production of activated coagulation factors, such as factor Xa (FXa) and FIIa (thrombin)71,72.

Coagulation factors, histamine, VEGF73, bradykinin, PAF and/or other molecules can lead to gap formation between vascular endothelial cells via protease-activated receptor 1 (PAR1), other specific receptors and/or a direct action on endothelial cells9. This results in the leakage of plasma that can contain autoantibodies to IgE or FcεRI, and/or autoantigens for specific IgE bound to mast cells in the skin with subsequent activation of mast cells and wheal and flare formation9. In addition, thrombin and FXa may induce mast cell degranulation via action on PAR1 and PAR2, respectively10,74. Furthermore, complement component C5a is thought to be produced following the activation of extrinsic coagulation, fibrinolysis and/or binding of IgG anti-FcεRI to FcεRI on mast cells and basophils10. Activated coagulation factors (FXa and FIIa) and plasmin can produce C5a and C5b from C5, and/or C3a and C3b from C3. C3a and C5a in leaked plasma can activate mast cells and basophils via C3aR and C5aR, respectively10,75. Finally, functional specific IgE antibodies to tissue factor were reported to release leukotriene C4 by tissue factor-stimulated peripheral basophils76.

Activation of coagulation and fibrinolysis in patients with CSU is reflected in increased mean platelet volume, levels of D-dimer, fibrin and fibrinogen degradation products, prothrombin fragment 1 + 2, FVIIa and other molecules41,71. An increase in blood markers of thrombin generation and fibrinolysis, for example D-dimer, was linked to severe CSU and a decrease was observed during CSU remission77. Although activation of the coagulation cascade happens in CSU, it is considered mostly a local process with active fibrinolysis without increased risk for thrombotic events71.

In patients with CSU, increased C-reactive protein (CRP) levels correlated with increased D-dimer, IL-6, C3 and C4 levels as well as CSU activity and ASST positivity78,79. This finding supports a close link between autoimmunity, inflammation, complement and coagulation activation pathways in CSU pathogenesis that may lead to maintenance and amplification of urticarial inflammation.

호산구와 피부 미세 혈관 내피 세포는 

히스타민, 혈관 내피 성장 인자(VEGF), LPS, TNF, IL-6, IL-33 및 IL-1β70과 

같은 조직 인자 유도제에 반응하여 표면에 다량의 조직 인자를 발현할 수 있습니다. 

조직 인자는 

외인성 응고 캐스케이드를 활성화하여 

응고 인자 Xa(FXa) 및 FIIa(트롬빈)71,72와 같은 활성화된 응고 인자의 생성을 유도할 수 있습니다.



응고 인자, 히스타민, VEGF73, 브라디키닌, PAF 및/또는 기타 분자는 프로테아제 활성화 수용체 1(PAR1), 기타 특정 수용체 및/또는 내피 세포에 직접 작용하여 혈관 내피 세포 사이에 간극을 형성할 수 있습니다9. 이로 인해 피부의 비만 세포에 결합된 특정 IgE에 대한 자가 항체 또는 FcεRI 및/또는 자가 항원을 포함하는 혈장이 누출되어 비만 세포가 활성화되고 발진 및 발적이 형성됩니다9. 또한 트롬빈과 FXa는 각각 PAR1과 PAR2에 작용하여 비만 세포 탈과립화를 유도할 수 있습니다10,74. 또한 보체 성분 C5a는 비만세포와 호염기구에서 외인성 응고, 섬유소 용해 및/또는 IgG 항-FcεRI와 FcεRI의 결합이 활성화된 후 생성되는 것으로 생각됩니다10. 활성화된 응고 인자(FXa 및 FIIa)와 플라스민은 C5에서 C5a 및 C5b를 생성하고, C3에서 C3a 및 C3b를 생성할 수 있습니다. 누출된 혈장의 C3a 및 C5a는 각각 C3aR 및 C5aR을 통해 비만 세포와 호염기구를 활성화할 수 있습니다10,75. 마지막으로, 조직 인자에 대한 기능적 특이 IgE 항체는 조직 인자 자극 말초 호염기구에 의해 류코트리엔 C4를 방출하는 것으로 보고되었습니다76.

CSU 환자의 응고 및 섬유소 용해 활성화는 평균 혈소판 부피, D-이합체, 섬유소 및 섬유소원 분해 산물, 프로트롬빈 단편 1 + 2, FVIIa 및 기타 분자의 수준 증가41,71에 반영됩니다. 트롬빈 생성 및 섬유소 분해의 혈액 마커(예: D-이합체)의 증가는 중증 CSU와 관련이 있으며, CSU 관해 기간 동안 감소가 관찰되었습니다77. 응고 캐스케이드의 활성화는 CSU에서 발생하지만, 대부분 혈전 발생 위험 증가 없이 섬유소 용해가 활발하게 일어나는 국소적인 과정으로 간주됩니다71.

CSU 환자에서 C 반응성 단백질(CRP) 수치 증가는 D-이합체, IL-6, C3 및 C4 수치 증가, CSU 활동 및 ASST 양성78,79과 상관관계가 있습니다. 이 발견은 두드러기 염증의 유지 및 증폭으로 이어질 수 있는 CSU 발병에서 자가 면역, 염증, 보체 및 응고 활성화 경로 사이의 밀접한 연관성을 뒷받침합니다.

Autoantibodies

Antibodies of IgE, IgA, IgM and IgG classes are thought to be critically involved in the pathogenesis of CSU80,81,82. IgE binds to the α-subunit of its high-affinity receptor, FcɛRI, on mast cells and basophils and, if present at high concentrations, can activate these cells regardless of the specific antigen83. In addition, the cross-linking of IgE by their respective allergens, autoallergens and IgG anti-IgE antibodies can lead to mast cell and basophil activation and mediator release in allergic, autoallergic and autoimmune urticaria, respectively8,82,84,85.

Clinically relevant allergy as a cause of CSU is rare84,86. IgE antibodies to autoantigens, for example thyroid peroxidase (TPO), eosinophil peroxidase (EPO), double-stranded DNA, tissue factor, ECP, FcεRI, thyroglobulin and IL-24, are found in up to two-thirds of patients with CSU and some of these antibodies, for example IgE anti-IL-24 and IgE anti-TPO, were shown to activate mast cells and/or basophils in vitro8,87. Furthermore, evidence in support of IgE autoantibodies as a driver of CSU includes high rates of positive skin prick tests with TPO in patients with CSU with increased levels of IgE anti-TPO and successful experiments of passive transfer of IgE anti-TPO88. Cross-reactivity between proteins, for example between TPO (not present in the skin) and EPO (present in the skin)89, and expression‎ of autoallergens in the skin, for example IL-24, might explain why IgE–autoallergen interaction leads to activation of mast cells in skin rather than in other organs90.

IgG autoantibodies to IgE and FcɛRI were the first autoantibodies described in the context of autoimmune CSU. Most studies report that 20–50% of patients with CSU have these autoantibodies91. Since 2013, when a taskforce position paper was published, autoimmune CSU associated with these autoantibodies is defined by triple positivity for presence of IgG autoantibodies by immunoassay, functionality of autoantibodies assessed by basophil tests (basophil activation test and/or BHRA) and skin autoreactivity assessed by ASST92. If these strict criteria are applied, only 8% of patients with CSU are diagnosed with autoimmune CSU7.

It is still a matter of debate whether clearly defined and distinct auto-IgE and auto-IgG endotypes exist. Although real overlap rates are still unknown, there is growing evidence of co-expression‎ of IgG autoantibodies and other types of autoantibodies, specifically IgE, IgM and IgA autoantibodies, in the same patient80,81. IgE autoantibodies might appear in blood first, followed by other types of autoantibodies over the course of the disease.

IgE, IgA, IgM 및 IgG 계열의 항체는 CSU80,81,82의 발병에 결정적으로 관여하는 것으로 생각됩니다. IgE는 비만 세포와 호염기구에 있는 고친화성 수용체인 FcɛRI의 α-소분자에 결합하며, 고농도로 존재하는 경우 특정 항원에 관계없이 이들 세포를 활성화할 수 있습니다83. 또한 각각의 알레르겐, 자가 알레르겐 및 IgG 항-IgE 항체에 의한 IgE의 교차 결합은 각각 알레르기, 자가 알레르기 및 자가 면역 두드러기에서 비만 세포와 호염기구 활성화 및 매개체 방출로 이어질 수 있습니다8,82,84,85.

CSU의 원인으로 임상적으로 관련된 알레르기는 드뭅니다84,86. 갑상선 퍼옥시다제(TPO), 호산구 퍼옥시다제(EPO), 이중 가닥 DNA, 조직 인자, ECP, FcεRI, 티로글로불린 및 IL-24와 같은 자가 항원에 대한 IgE 항체는 CSU 환자의 최대 2/3에서 발견되며 이러한 항체 중 일부(예: IgE 항IL-24 및 IgE 항TPO)는 시험관 내에서 비만 세포 및 호염기구를 활성화시키는 것으로 나타났습니다8,87. 또한, IgE 자가항체가 CSU의 원인임을 뒷받침하는 증거로는 IgE 항-TPO 수치가 높은 CSU 환자에서 TPO를 이용한 피부 단자 검사 양성률이 높고, IgE 항-TPO의 수동 전달 실험에 성공했다는 점 등이 있습니다88. 단백질 간의 교차 반응성(예: 피부에 존재하지 않는 TPO와 피부에 존재하는 EPO)89 및 피부 내 자가 알레르겐(예: IL-24)의 발현은 IgE-자가 알레르겐 상호작용이 다른 기관이 아닌 피부에서 비만 세포의 활성화를 유발하는 이유를 설명할 수 있습니다90.

자가면역성 CSU의 맥락에서 설명된 최초의 자가항체는 IgE 및 FcɛRI에 대한 IgG 자가항체였습니다. 대부분의 연구에 따르면 CSU 환자의 20~50%가 이러한 자가항체를 가지고 있다고 합니다91. 2013년 태스크포스 입장 논문이 발표된 이후, 이러한 자가항체와 관련된 자가면역성 CSU는 면역 분석에 의한 IgG 자가항체의 존재, 호염기구 검사(호염기구 활성화 검사 또는 BHRA)로 평가한 자가항체의 기능 및 ASST로 평가한 피부 자가반응성에 대한 삼중 양성으로 정의됩니다92. 이러한 엄격한 기준을 적용할 경우, CSU 환자의 8%만이 자가면역성 CSU로 진단됩니다7.

명확하게 정의되고 구별되는 자가 IgE 및 자가 IgG 내형이 존재하는지는 여전히 논쟁의 여지가 있습니다. 실제 중복 비율은 아직 알려지지 않았지만, 동일한 환자에서 IgG 자가항체와 다른 유형의 자가항체, 특히 IgE, IgM 및 IgA 자가항체의 동시 발현에 대한 증거가 증가하고 있습니다80,81. IgE 자가항체가 먼저 혈액에 나타난 후 질병이 진행되는 동안 다른 유형의 자가항체가 나타날 수 있습니다.

Neurogenic inflammation

In CSU, the bidirectional interaction of mast cells, other immune cells and sensory nerves is thought to exist through release of histamine, IL-31, neuropeptides and other mediators67,93,94. This vicious cycle causes vasodilatation, plasma extravasation, neurogenic inflammation, pruritus and other urticaria symptoms, and might be supported via MRGPRX2-mediated activation of mast cells95. MRGPRX2 is a receptor for a broad range of exogenous and endogenous substances and is responsible for IgE-independent activation of mast cells96. MBP and EPO induced histamine release from human skin mast cells via MRGPRX2 (ref.67). Levels of substance P, a neuropeptide and MRGPRX2 agonist, were elevated in CSU, correlated with disease activity in some studies97, and provocation with MRGPRX2 agonists revealed an increased skin reactivity in patients with CSU98. Lastly, the number of MRGPRX2-expressing mast cells has been found to be increased in patients with CSU67.

CSU에서 비만 세포, 다른 면역 세포 및 감각 신경의 양방향 상호 작용은 히스타민, IL-31, 신경 펩타이드 및 기타 매개체의 방출을 통해 존재하는 것으로 생각됩니다67,93,94. 이러한 악순환은 혈관 확장, 혈장 혈관 외 유출, 신경성 염증, 소양증 및 기타 두드러기 증상을 유발하며, 이는 MRGPRX2를 매개로 한 비만 세포의 활성화에 의해 뒷받침될 수 있습니다95. MRGPRX2는 광범위한 외인성 및 내인성 물질에 대한 수용체이며 비만 세포의 IgE 독립적 활성화를 담당합니다96. MBP와 EPO는 MRGPRX2를 통해 인간 피부 비만세포에서 히스타민 방출을 유도합니다(참조67). 신경 펩타이드이자 MRGPRX2 작용제인 물질 P의 수치는 일부 연구에서 질병 활성도와 상관관계가 있는 CSU에서 상승했으며97, MRGPRX2 작용제를 사용한 자극은 CSU 환자에서 피부 반응성을 증가시키는 것으로 나타났습니다98. 마지막으로, CSU 환자에서 MRGPRX2를 발현하는 비만 세포의 수가 증가하는 것으로 밝혀졌습니다67.

Chronic inducible urticaria

The pathogenesis of CIndU is largely unknown. Autoallergic IgE-mediated mast cell activation was suggested in symptomatic dermographism, ColdU, solar urticaria and CholU by passive transfer experiments and/or the efficacy of omalizumab99. IgE autoantibodies might be produced to a skin-derived protein released upon stimulation, for example by cold100. In solar urticaria, molecular alteration of chromophores by solar electromagnetic radiation and their binding to surface-bound IgE on mast cells, leading to their activation, have been suggested101. In CholU, blockade of the sweat gland duct might lead to sweat reflux and leakage into the dermis inducing the symptoms of CholU due to production of a sweat antigen. Specific IgE to sweat antigen MGL_1304 have been identified in sera of some patients with CholU102. Another proposed mechanism in CholU is reduced expression‎ of cholinergic receptor M3 (CHRM3) in eccrine sweat gland epithelial cells, which leads to escape of acetylcholine with acetylcholine-mediated degranulation of adjacent mast cells102. IgG and/or IgM directed to IgE were shown in ColdU100. In patients with heat urticaria, few cases of a positive reaction on intradermal testing with heated autologous serum, presumably containing denatured IgE and inactivated complement, were described103. Hereditary vibratory angioedema can present as an autosomal dominant variant due to a gain-of-function mutation in adhesion G-protein-coupled receptor E2 (ADGRE2), located on mast cells, which might decrease inhibitory interaction between the α-subunit and the β-subunit of this receptor leading to sensitization of mast cells to vibration-induced degranulation104. Delayed pressure urticaria is thought to occur via a non-immunologic mechanism with involvement of many pro-inflammatory mediators other than histamine, for example IL-1, IL-6, IL-3 and TNF105. In contrast to other CIndU, delayed pressure urticaria showed a substantial leukocyte infiltration in the dermis perhaps due to a sustained initiating stimulus105. Contact urticaria can be classified as an immunological reaction, that is IgE-mediated or T cell-mediated, or a non-immunological reaction106. Hypotheses explaining pathogenesis of aquagenic urticaria include the synthesis of a mast cell-degranulating substance due to interaction between water and a component in or on the skin or sebum; changes in osmotic pressure surrounding hair follicles and increased passive diffusion of water; the existence of water-soluble antigens in the epidermis; and a histamine-independent mechanism107.

CIndU의 발병 기전은 거의 알려지지 않았습니다. 수동 전달 실험 및/또는 오말리주맙99의 효능에 의해 증상성 피부 촬영증, 콜드U, 태양 두드러기 및 콜U에서 자가 알레르기 IgE 매개 비만 세포 활성화가 제안되었습니다. IgE 자가 항체는 감기와 같은 자극에 의해 방출되는 피부 유래 단백질에 대해 생성될 수 있습니다100. 태양 두드러기의 경우, 태양 전자기 복사에 의한 발색단의 분자적 변화와 비만세포의 표면 결합 IgE에 결합하여 활성화되는 것으로 추정되고 있습니다101. 콜루에서는 땀샘관이 막히면 땀이 역류하여 진피로 누출되어 땀 항원의 생성으로 인해 콜루 증상이 유발될 수 있습니다. 일부 CholU102 환자의 혈청에서 땀 항원 MGL_1304에 대한 특정 IgE가 확인되었습니다. CholU의 또 다른 제안된 메커니즘은 에크린 땀샘 상피 세포에서 콜린성 수용체 M3(CHRM3)의 발현이 감소하여 아세틸콜린을 매개로 인접 비만 세포의 탈과립화를 통해 아세틸콜린이 빠져나가게 하는 것입니다102. ColdU100에서는 IgE로 향하는 IgG 및/또는 IgM이 나타났습니다. 열 두드러기 환자에서 가열된 자가 혈청을 이용한 피내 검사에서 변성 IgE와 비활성화된 보체를 포함하는 것으로 추정되는 양성 반응이 나타난 사례는 거의 없었습니다103. 유전성 진동 혈관 부종은 비만 세포에 위치한 접착 G 단백질 결합 수용체 E2(ADGRE2)의 기능 이득 돌연변이로 인해 상염색체 우성 변이로 나타날 수 있으며, 이는 이 수용체의 α 서브 유닛과 β 서브 유닛 사이의 억제 상호 작용을 감소시켜 진동 유발 탈과립화에 대한 비만 세포의 감작을 초래할 수 있습니다104. 지연성 두드러기는 히스타민 이외의 많은 전 염증 매개체(예: IL-1, IL-6, IL-3 및 TNF105)가 관여하는 비면역학적 메커니즘을 통해 발생하는 것으로 생각됩니다. 다른 CIndU와 달리 지연성 두드러기는 지속적인 시작 자극으로 인해 진피에 상당한 백혈구 침윤을 보였습니다105. 접촉 두드러기는 면역학적 반응, 즉 IgE 매개 또는 T 세포 매개 또는 비면역학적 반응으로 분류할 수 있습니다106. 수양성 두드러기의 병인을 설명하는 가설로는 물과 피부 또는 피지의 성분 간의 상호작용으로 인한 비만 세포 분해 물질의 합성, 모낭 주변의 삼투압 변화 및 수동적 물의 확산 증가, 표피에 수용성 항원의 존재, 히스타민 독립적 메커니즘107 등이 있습니다.

Diagnosis, screening and prevention

Diagnosis

The clinical presentation of urticaria is very similar in all age groups, ethnicities and genders. Wheals and angioedema occur with the same anatomical distributions across all skin tones. However, erythema related to whealing is more difficult to detect in pigmented skin108. A detailed history and physical examination are the essential first steps in the diagnostic workup of all patients with urticaria. However, as wheals and angioedema are transient and may not be present at physical examination, physicians should also review patients’ pictures or their documentation of signs and symptoms (Fig. 4). Diagnosis of urticaria is usually straightforward irrespective of its type or subtype4 (see Supplementary Fig. 1).

두드러기의 임상 양상은 

모든 연령대, 인종, 성별에서 매우 유사합니다. 

두드러기와 혈관 부종은 모든 피부 톤에 걸쳐 동일한 해부학적 분포로 발생합니다. 그러나 색소성 피부에서는 홍반과 관련된 홍반을 발견하기가 더 어렵습니다108. 자세한 병력과 신체 검사는 모든 두드러기 환자의 진단 검사에서 필수적인 첫 단계입니다. 그러나 수포와 혈관 부종은 일시적이며 신체 검사에서 나타나지 않을 수 있으므로 의사는 환자의 사진이나 징후 및 증상에 대한 환자의 기록도 검토해야 합니다(그림 4). 두드러기의 진단은 유형이나 아형4에 관계없이 일반적으로 간단합니다(보충 그림 1 참조).

Fig. 4: Clinical manifestations of urticaria.

a | Acute urticaria (AU). b | Chronic spontaneous urticaria (CSU) (wheals). c | CSU (angioedema). d | Cold urticaria (ColdU). e | Delayed pressure urticaria. f | Solar urticaria. g | Heat urticaria. h | Symptomatic dermographism. i | Cholinergic urticaria (CholU). j | Contact urticaria. k | Aquagenic urticaria. l | Vibratory angioedema. Part e, image courtesy of A. Kasperska-Zajac. Part g, image courtesy of L. F. C. Ensina. Part l, image courtesy of K. Brockow.

Full size image

Acute urticaria

By definition, AU is self-limiting and does not require routine or extensive diagnostic tests unless strongly suggested by patient history4. For example, in patients with a history of type I food allergy or drug hypersensitivity, urticaria symptoms can appear immediately after a contact with respective allergens and allergy tests may help avoid re-exposure to relevant causative factors.

Chronic spontaneous urticaria

Most patients with CSU present with only wheals (~57%), whereas the occurrence of wheals and angioedema (~37%) or only angioedema (~6%) is less common (see Supplementary Table 8). The signs and symptoms of CSU can occur spontaneously at any time of the day but commonly during the evening and night109, which may reflect circadian variations in mast cell activation110 and differences in the underlying pathogenesis. For example, the presence of nocturnal symptoms has been associated with an autoimmune endotype of CSU111. Wheals can occur anywhere, but favour the arms and legs109. Angioedema appears most commonly on the face, for example lips and eyelids, but also on hands and feet and other body parts1. In most patients with moderate or severe CSU, wheals and/or angioedema occur on a daily or nearly daily basis or show an intermittent–recurrent course4.

In some patients with CSU, stress, foods, drugs (mostly NSAIDs) or infections can lead to exacerbation. NSAID hypersensitivity is observed in up to 30% of patients with CSU and is classified as NSAID‐exacerbated cutaneous disease53. CSU exacerbation occurs within minutes or hours after the intake of COX1 inhibitors (selective COX2 inhibitors are usually tolerated)112 and can be confirmed by oral drug provocation testing53.

The current international urticaria guideline has introduced the 7C concept, that is, seven aims of the diagnostic workup in patients with CSU4. The 7C concept includes ruling out differential diagnoses (confirm‎); looking for markers of autoimmune urticaria (cause); identifying potential triggers (cofactors); checking for autoimmunity, mental health disorders and other comorbidities; identifying problems with sleep, distress, sexual health and social performance (consequences); assessing potential biomarkers or predictors of treatment response (components); and monitoring CSU activity, impact and control (course).

Basic tests include a differential blood count and the erythrocyte sedimentation rate (ESR) and/or CRP in all patients with CSU, and measurements of IgG anti-TPO and total serum IgE levels in patients with CSU in specialist care. The latter two can help in the diagnosis of autoimmune CSU and elevated IgG anti-TPO levels point to concomitant autoimmune thyroiditis7,40,113. Further tests should only be performed if indicated by patient history and are rarely needed4.

Chronic inducible urticaria

In patients with CIndU, wheals are often of shorter duration (≤1 h) than in those with CSU (up to 24 h)4,106. High-frequency trigger exposure and a low trigger threshold are linked to high disease activity4,106. Even though the lesions are usually confined to areas of skin exposed to the trigger stimuli, systemic reactions including anaphylaxis may occur and adrenaline autoinjectors should be prescribed to high-risk patients114. During pregnancy, one-half of patients experience improvement of their CU, whereas exacerbation occurs in approximately one-third of patients115. In particular, patients with CIndU or both CSU and CIndU showed a twofold increase of disease exacerbation during pregnancy. Disease activity changes during pregnancy might be linked to changes in trigger exposure and/or hormonal and immunological changes that promote mast cell activation.

The diagnosis of CIndU is based on a thorough history and the results of provocation testing. The aims of provocation testing are to determine the relevant triggers and to assess trigger thresholds, which are useful for measuring disease activity and monitoring treatment responses. For most CIndU subtypes, validated tools for provocation testing are available (Table 2; see Supplementary Table 9 and Supplementary Fig. 2).

Comorbidities

Acute urticaria

Infection, mainly upper respiratory tract infection, is considered the most common comorbidity and aetiological factor of acute spontaneous urticaria (~30–40% of AU cases), although the preval‎ence of infectious aetiologies decreases as the age of patients increases (see Supplementary Table 4). Less frequently, reactions can be triggered by drugs, mostly NSAIDs and antibiotics, inhalant allergens (for example, pollen, dust mites), foods, stress, Hymenoptera stings and physical factors (see Supplementary Table 4). Drugs such as NSAIDs are often used when infection is present, and this makes it challenging to differentiate between medications or infection as the cause of urticaria. Inducible factors are considered to be a rare cause of AU in children but can lead to AU in <15% of all adult AU cases116 (see Supplementary Table 4). The cause of AU was more frequently detected in patients 0–6 years of age than in those 7–18 years of age51. Foods and infection caused AU more often in children <13 years of age than in children 13–18 years of age51. AU usually disappears after resolution or eradication of infection, or avoidance of drugs and other causative triggers.

Chronic spontaneous urticaria

CIndU is a frequent comorbidity of CSU, with most studies reporting rates >10% (see Supplementary Table 6). Among patients with CU, 29–93% had CSU only, 6–35% had CIndU only and 1–43% had both CSU and CIndU (see Supplementary Table 6). Of 245 patients with CSU, 36% had CIndU confirmed by a positive challenge test, mostly symptomatic dermographism (25%) and ColdU (13%)48. Multiple types of CIndU may coexist in the same patient with CSU117.

Autoimmune diseases are present in 28% of patients with CSU, most frequently autoimmune thyroid diseases (~25%, mostly Hashimoto’s thyroiditis with or without hypothyroidism), vitiligo, rheumatoid arthritis, autoimmune gastritis and diabetes mellitus (1–2%)40,118.

Bacterial infection including Helicobacter pylori and focal bacterial infections, for example dental infection, have been reported in up to 77% of patients with CSU5. However, the evidence for the causal link between bacterial infection and CSU development is still weak and conflicting5. The clinical relevance of viral infection, for example viral hepatitis and HIV infection, and fungal infection is still unknown and these infections are unlikely to contribute to the development of CSU5. In one study, CU did not affect the course of COVID-19, whereas COVID-19 induced CU exacerbation in one-third of patients, especially in patients with severe COVID-19 (ref.119). CSU improved in one-third of patients after the treatment of confirmed infection with helminths or protozoa with antiparasitic drugs, although the link between CSU and parasites is still ill-characterized5.

The evidence for the increased preval‎ence of allergic diseases in patients with CSU is inconsistent5. Three large studies suggest that individuals with CSU are considerably more likely to have allergic diseases compared with the general population or control subjects without urticaria34,120,121. Type I hypersensitivity to allergens as a cause of CSU should be ruled out in patients with intermittent symptoms, a temporal relationship to a particular allergen and possible symptoms due to other allergic diseases, for example asthma.

Cancer, mostly non-haematologic, was reported in 0–9% of patients with CSU5,26 and CSU resolved in some cases once patients were in remission122. CSU development in patients with cancer might be related to cancer-induced immune dysregulation including activation of complement and coagulation cascade123, and return to normal homeostatic conditions might parallel CSU improvement after cancer treatment. Mental health disorders, mainly depression and anxiety, are present in up to 60% of patients with CSU and are associated with considerably impaired quality of life5. Preval‎ence of one or several components of metabolic syndrome, that is, central obesity, dyslipidaemia, hyperglycaemia and hypertension, was considerably increased in patients with CU including CSU compared with control subjects without CU/CSU5.

Chronic inducible urticaria

CIndU can coexist with CSU and other CIndU forms. CSU was reported in 71%, 25% and 10% of patients with symptomatic dermographism124, CholU125 and ColdU114, respectively. Among patients with CU, symptomatic dermographism alone or in combination with CSU is more preval‎ent than other CIndU, followed by ColdU and CholU (see Supplementary Table 6). Allergic diseases were reported to be a frequent comorbidity (up to 26–48%) of CholU126, solar urticaria127, ColdU128 and symptomatic dermographism129.

Differential diagnosis

Patients with certain diseases other than urticaria can present with wheals and/or angioedema as associated or prodromic signs130 (Fig. 5; see Supplementary Table 10). The differential diagnoses of CSU are guided by the history and physical examination and supported by exploratory tests.

Fig. 5: Differential diagnosis of urticaria.

a | Urticarial vasculitis. b | Mastocytosis in the skin. c | Erythema annularis centrifugum. d | Cryopyrin-associated autoinflammatory syndrome e | Schnitzler syndrome. f | Hereditary angioedema. g | Erythema marginatum in a patient with hereditary angioedema. h | Melkersson–Rosenthal syndrome (oedema of the upper lip and fissured tongue are seen). i | Erythema multiforme. j | Hypereosinophilic syndrome.

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In patients who exclusively develop wheals but not angioedema, autoinflammatory disorders, such as Schnitzler syndrome or cryopyrin-associated periodic syndromes, should be considered differential diagnoses4. Wheals in patients with autoinflammatory disorders are refractory to antihistamines and can present a distinct entity called neutrophilic urticarial dermatosis with a dense perivascular and interstitial infiltrate of neutrophils with leukocytoclasia but without vessel wall necrosis131.

In urticarial vasculitis, both long-lasting wheals (>24 h) and angioedema can occur and the diagnosis is confirmed by a combination of three histological criteria: leukocytoclasia, fibrin deposits and extravasated erythrocytes132,133. By contrast, CSU histopathology usually shows dermal oedema with an inflammatory infiltrate consisting of lymphocytes, eosinophils, neutrophils and nuclear dust, without evidence of vasculitis60,132.

When patients show recurrent angioedema without wheals, bradykinin-mediated angioedema including angiotensin-converting enzyme inhibitor-induced angioedema and hereditary angioedema should be excluded4.

Disease activity and control

Several patient-reported outcome measures, global and validated tools, were developed to assess CU activity and control and are used both in clinical care and in trials134 (Box 1). The Urticaria Activity Score (UAS) is a gold standard to assess disease activity (wheals number and itch intensity) in CSU and is usually used prospectively during seven consecutive days (UAS7)4,135. Similarly, the Angioedema Activity Score (AAS) is a prospective, diary-type tool that enables clinicians to measure angioedema activity in patients with all forms of recurrent angioedema136. In CIndU, the Cholinergic Urticaria Activity Score (CholUAS; not yet validated) and the Cold Urticaria Activity Score (ColdUAS), modified versions of the UAS, collect data on a daily basis assessing the intensity of wheals and pruritus as well as the intensity of exposure to specific triggers with a recall period of 24 h134,137,138. The Urticaria Control Test (UCT)139 and the Angioedema Control Test (AECT)140 are retrospective tools with a recall period of 4 weeks used to assess disease control in all forms of CU.

Box 1 Established disease-specific instruments to assess activity and control of chronic urticaria and patient quality of life

Disease activity

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Disease control

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Patient quality of life

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Screening

No screening methods are available for urticaria in the general population. Patients with autoimmune diseases, especially autoimmune thyroiditis, should be asked for signs and symptoms of CSU40,42,118. Similarly, patients with CSU should be regularly checked for autoimmune thyroid disease by palpation of the thyroid, thyroid function tests and anti-TPO and anti-thyroglobulin antibodies4,40,118.

In CSU, basic screening tests (differential blood count, ESR and/or CRP) and screening tests performed in specialist care (total IgE and IgG anti-TPO) can help in identifying comorbid and underlying diseases, for example chronic infection, autoimmune disease and allergy, as well as differential diagnoses, for example urticarial vasculitis or autoinflammatory disorder4. Mental health disorders, namely depression and anxiety, common comorbidities and consequences of CSU should be checked for in every patient with CSU4.

Prevention

No primary prevention exists for urticaria with the possible exception of allergic urticaria, in which general preventive measures for allergic diseases may apply (especially in children with high risk of allergy). A population-based cross-sectional study in China found that breastfeeding >6 months after birth can lower the risk of urticaria33. Secondary prevention measures include avoidance of exposure to a relevant trigger, for example wearing of tight-fitting clothes by a patient with delayed pressure urticaria or intake of particular food or drug by a patient with allergic urticaria4. Migration to different geographic regions with different ambient temperatures might decrease the risk of development of CIndU such as ColdU. Finally, tertiary prevention is possible with treatment of symptoms using guideline-recommended options, for example antihistamines and omalizumab4, and might be possible with induction of long-lasting remission with disease-modifying treatments, for example allergen-specific immune therapy in patients with allergic urticaria84, cyclosporine in patients with autoimmune CSU141,142 and novel mast cell-reducing therapies143.

Management

The management of urticaria has progressed substantially over the past two decades, with disease control possible for at least two-thirds of patients144,145,146. Increased understanding of disease pathogenesis underpins an expanding pipeline of targeted therapies with improved adverse effect profiles compared with traditional immunosuppressants (Table 3). Structured assembly of the evidence for pharmacological and non-pharmacological agents using GRADE methodologies (Grading of Recommendations Assessment, Development and Eval‎uation methodologies), together with publication of up-to-date international consensus guidelines, has led to the establishment and regular review of an international standard of care for urticaria4. The overall goal of treatment is safe and effective attainment of complete disease control (UAS7 = 0 and UCT = 16) with a normal quality of life. Figure 6 provides the current consensus algorithm for urticaria treatment4.

Table 3 Potential molecular targets, candidate drugs and clinical trials in chronic urticaria

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Fig. 6: Algorithm of chronic urticaria treatment.

The 3A management approach of assess, act and adjust recognizes the importance of several comorbidities associated with urticaria; and the wide range and dynamic nature of disease severity across time, with the need to step up and step down therapies to achieve complete disease control while limiting cost and adverse effects. Only some biomarkers of response to treatment are shown246,259 and other biomarkers are listed in Supplementary Box 1. AAS7, Angioedema Activity Score used prospectively during 7 consecutive days; AECT, Angioedema Control Test; AE-QoL, Angioedema-Quality of Life Questionnaire; ASST, autologous serum skin test; BHRA, basophil histamine release assay; CholUAS, Cholinergic Urticaria Activity Score; CholU-QoL, Cholinergic Urticaria-Quality of Life Questionnaire; CIndU, chronic inducible urticaria; ColdUAS, Cold Urticaria Activity Score; CSU, chronic spontaneous urticaria; CU-Q2oL, Chronic Urticaria-Quality of Life Questionnaire; H1-AH, H1 antihistamines; UAS7, Urticaria Activity Score used prospectively during 7 consecutive days; UCT, Urticaria Control Test. Adapted with permission from ref.4, Wiley.

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Elimination of causes and avoidance of triggers

AU or CSU with an intermittent–recurrent course with an identifiable exogenous trigger, for example an NSAID, is effectively managed with avoidance of the trigger and cross-reacting molecules4,147. Inducible urticaria, by definition, has an eliciting factor, or group of factors, and exposure reduction methods are a mainstay of therapy; however, avoidance might be hard to achieve, for example avoiding cold ambient temperatures, or might negatively affect quality of life4. Autoimmunity underlying CSU cannot be eliminated, although direct autoantibody removal through plasmapheresis has been successful, with high financial cost, in a limited number of patients with severe treatment resistance148,149. Removal of inciting antigens, either spontaneously (for example, resolution of an acute viral or bacterial infection) or through treatment of an underlying condition (for example, solid cancer surgery), can lead to resolution of urticaria122. Disappointingly, especially in CU, the treatment of underlying or associated factors often fails to alter the trajectory of CU. Eradication therapies for chronic infections, such as H. pylori, are a good example, and an analysis of studies based on the GRADE approach demonstrated weak and conflicting evidence between H. pylori eradication and improvement of CU150. Thyroid supplementation or anti-thyroid drugs in patients with CSU with Hashimoto’s thyroiditis or Graves’ disease, respectively, is another example when associated disease treatments have limited efficacy in reducing urticaria118,151. In most of these instances, no randomized controlled trial data are available and the evidence quality is low4,151. Thus, the intensive and costly general screening programmes for causes of CSU should not be performed, unless indicated by the patient’s clinical history, physical examination and/or initial CSU workup. In addition, the treatment of associated thyroid autoimmunity and other comorbidities should be individualized and based on disease-specific complications, for example hypothyroidism4.

Second-generation H1 antihistamines

Multiple effective and affordable second-generation antihistamines (sgAHs) that block the H1 receptor are available and are the standard and first step in urticaria treatment152,153. They do not antagonize the binding of histamine but act as inverse agonists and have the opposite effect on the receptor to histamine, therefore shifting the equilibrium towards the inactive state154. Most guidelines recommend against the use of first-generation H1-AH due to sedative and anticholinergic effects, and drug–drug interactions4,155. Most, but not all, sgAHs have been eval‎uated and shown effective in urticaria at standard doses4. Studies have also confirmed the safety and efficacy of using off-label high-dose sgAH therapy (up to fourfold the recommended daily dose), including for bilastine, cetirizine, desloratadine, ebastine, fexofenadine, levocetirizine and rupatadine145,156,157,158,159,160 However, the use of updosed sgAHs is associated with a higher risk of somnolence than the use of standard dose of sgAHs (relative risk 3.28; 95% confidence interval 1.55–6.95; p = 0.002)161. Of note, British urticaria guidelines from 2021 recommend against updosing on mizolastine162. High-dose sgAHs are now considered part of the first step in urticaria treatment, if the standard dose is not sufficient to control symptoms4. The optimal timing and approach to step up or step down antihistamine therapy are still based on expert opinion, and include both tapering or immediate discontinuation. Based on half-life considerations, a 2-week period is generally considered sufficient to observe the effect of antihistamine changes in CU163.

Around 61% of patients with CSU do not respond to the licensed doses of sgAHs and only ~63% of these non-responders benefit from updosed sgAHs145. The second-line therapy with omalizumab as an add-on to sgAHs is indicated in patients with CSU who do not respond to increased doses of sgAHs4.

Omalizumab

Omalizumab is the first in-class anti-IgE monoclonal antibody (mAb) and binds and lowers free IgE, with subsequent downregulation of FcεRI on basophils and mast cells164,165,166,167. Lowered FcεRI expression‎ may render the cells less susceptible to activation by IgE and IgG anti-FcεRI and prevent histamine release and inflammation167. As the step-up treatment from antihistamines, omalizumab, as an add-on therapy, has the strongest evidence base and recommendations of all possible treatments for CSU in patients ≥12 years of age146. A meta-analysis of 67 real-life CSU studies reported complete and partial response rates of 72% and 18%, respectively, comparable with efficacy in clinical trials, with a mean adverse effect rate of 4%168. Omalizumab improves various aspects of quality of life in patients with CSU in both clinical trials and real-life studies169,170,171. It has also been shown to be effective (although has not yet been approved) in the management of CIndU, particularly symptomatic dermographism, ColdU, CholU and solar urticaria166,172,173,174,175. Poor and/or slow response to omalizumab was linked to several markers and features of autoimmune CSU, including BHRA positivity and low total IgE levels (see Supplementary Box 1).

Real-world practice continues to raise several questions around omalizumab use as monotherapy (without antihistamines): the initial treatment duration, updosing or a shortened dosing interval and discontinuation strategies176. Alternative approaches include combination therapy with other systemic immunosuppressives (cyclosporine, dapsone and colchine), although evidence is very limited, or a complete switch to cyclosporine, a third-line treatment of CU4,164,177,178.

Cyclosporine

Cyclosporine is a T cell immunosuppressive agent that also inhibits mediator release from basophils and mast cells179. It has been used for more than three decades for the treatment of CU180. Current guidelines recommend off-label use of cyclosporine as an add-on to sgAHs for patients with CSU with severe disease that is refractory to the combination of high-dose antihistamine and omalizumab4. Efficacy has been demonstrated in placebo-controlled randomized control trials180,181,182 and open-label studies183, with meta-analysis data suggesting response rates up to 73%182. Adverse effects can be severe, particularly renal impairment, and occur in up to 50% of patients; hence, most guidelines do not recommend cyclosporine as standard treatment4. However, in many countries without access to omalizumab, cyclosprine is used as a step-up therapy from antihistamines, owing to a more favourable risk–benefit profile than long-term corticosteroid use4.

Alternative and specific treatments

Intravenous or oral systemic corticosteroids are effective for AU, and for rapid control of severe disease flares in CSU4. Guidelines and experts recommend limiting oral steroid therapy to a maximum of 10 days using the lowest effective dose, due to severe adverse effects associated with long therapy duration4. Other immunosuppressant or immunomodulatory therapies were used in CSU with various success rates, including dapsone, colchicine, sulfasalazine, methotrexate, interferon, phototherapy, intravenous immunoglobulin and plasmapheresis4,184. Few of these approaches have been studied in well-designed randomized control trials, with most data published as case series; hence, all have a low-quality evidence base4. Some immune therapies have shown efficacy including anti-TNF in CSU and delayed pressure urticaria185,186, and UVA, UVB and psoralen plus UVA (commonly termed PUVA) treatment in CSU, ColdU, CholU and symptomatic dermographism187,188,189.

Evidence for other therapies, such as H2 antihistamines, leukotriene receptor antagonists, diets, such as a pseudo-allergen-free diet, and mast cell stabilizers also remains low4. However, subgroups of patients with CSU might benefit from specific approaches, for example the use of leukotriene receptor antagonists in patients who are aspirin-intolerant4,190. Tolerance induction can be useful in selected patients with ColdU, CholU or solar urticaria191, but tolerance is lost without continuous daily exposure, making the therapy impractical for many patients, for example the need for daily cold baths or showers in patients with ColdU4.

정맥 또는 경구용 전신 코르티코스테로이드는 AU와 CSU의 중증 질환 발작을 빠르게 조절하는 데 효과적입니다4. 가이드라인과 전문가들은 경구 스테로이드 요법은 긴 치료 기간과 관련된 심각한 부작용으로 인해 가장 낮은 유효 용량을 사용하여 최대 10일로 제한할 것을 권장합니다4. 다른 면역 억제제 또는 면역 조절 요법은 답손, 콜히친, 설파살라진, 메토트렉세이트, 인터페론, 광선 요법, 정맥 내 면역 글로불린 및 혈장 분리법을 포함하여 다양한 성공률로 CSU에서 사용되었습니다4,184. 이러한 접근법 중 잘 설계된 무작위 대조 시험에서 연구된 것은 거의 없으며, 대부분의 데이터가 사례 시리즈로 발표되었기 때문에 모두 근거의 질이 낮습니다4. 일부 면역 요법은 CSU 및 지연성 두드러기185,186에 대한 항TNF, CSU, 콜드U, 콜U 및 증상성 피부묘기증187,188,189에 대한 UVA, UVB 및 소랄렌과 UVA(일반적으로 PUVA라고 함) 치료 등의 효과를 입증한 바 있습니다.

H2 항히스타민제, 류코트리엔 수용체 길항제, 유사 알레르겐 없는 식단과 같은 식이요법, 비만 세포 안정제와 같은 다른 치료법에 대한 증거도 여전히 낮습니다4. 그러나 아스피린 불내성 환자에게 류코트리엔 수용체 길항제를 사용하는 것과 같은 특정 접근법을 통해 CSU 환자의 하위 그룹이 혜택을 볼 수 있습니다4,190. 내성 유도는 일부 한랭 두드러기, 만성 두드러기 또는 태양 두드러기 환자에게 유용할 수 있지만191 매일 지속적으로 노출되지 않으면 내성이 사라지기 때문에 많은 환자에게는 이 치료법이 비실용적입니다(예: 냉수욕이나 샤워를 매일 해야 하는 한랭 두드러기 환자4).

Treatment of special populations

Pregnant women, breastfeeding women, children and geriatric populations require special consideration in CSU. The over-the-counter use of first-generation antihistamines and sgAHs for allergic disease makes it likely that, at least, early pregnancy exposure to these drugs is common4. However, safety in pregnancy has been shown for cetirizine and loratadine only, and these drugs are therefore preferred192,193. The use of sgAHs such as loratadine and cetirizine is also advised in breastfeeding women4, as nursing infants can develop sedation from first-generation antihistamines secreted into breast milk194. Omalizumab is reported safe in pregnancy115,195,196,197,198 and in younger children, although current licensing is for individuals aged 12 years and older146.

In the paediatric population, several sgAHs have proven efficacy and safety: bilastine, cetirizine, desloratadine, fexofenadine, levocetirizine, loratadine and rupatadine4. The individual choice should consider country-specific availability of suitable preparations, such as syrups.

The older population is particularly sensitive to adverse effects from first-generation antihistamines, which should be avoided199. Data have shown efficacy and safety of standard doses of sgAHs and omalizumab in older patients199,200 (≥65 years old). However, older populations may be particularly susceptible to the sedative action of some sgAHs, such as cetirizine and loratadine, when recommended doses are exceeded199. Also, sgAHs updosing might cause risks in some older patients with renal, hepatic and/or cardiac disorders.

Risk–benefit profiles for immunosuppressive therapies, including corticosteroids and cyclosporine, need to be carefully considered given the increased toxic effects in all three of these patient populations. Detailed reviews of all aspects of CSU management in these groups are available115,199,201,202,203.

Therapies in development

Various therapies, targeting mediators, receptors and signalling pathways of mast and other immune cells, are in preclinical and clinical development13,164,204,205,206 (Fig. 3; all ongoing studies are listed in Table 3). Most therapies are focused on patients with antihistamine-refractory and/or omalizumab-refractory CSU.

Ligelizumab, a humanized anti-IgE mAb, had a greater affinity to IgE and showed higher efficacy than omalizumab in a phase IIb trial207 but not in the phase III PEARL1 and PEARL2 trials208.

Fenebrutinib, a selective, reversible, oral BTK inhibitor, improved CSU within the first week and demonstrated a substantial benefit in patients with antihistamine-resistant CSU including patients with circulating anti-FcεRI autoantibodies; however, reversible grade 3 liver enzyme abnormalities were observed209. Another BTK inhibitor, remibrutinib, provided improvements in UAS7 versus placebo, increased patient quality of life210 and had a favourable safety profile211; a phase III trial is ongoing.

An anti-KIT mAb, barzolvolimab, was tested in CSU and CIndU212. In 95% of patients with antihistamine-resistant ColdU and symptomatic dermographism, a complete response (negative provocation testing) was observed after a single dose of barzolvolimab. Serum tryptase and skin mast cell depletion mirrored barzolvolimab clinical activity. Similar effects of multiple-dose treatment with barzolvolimab were seen in patients with CSU213 and a phase II study is ongoing. Barzolvolimab was generally well tolerated and most adverse effects were mild or moderate in severity including urinary tract infections, headache, neutropenia and back pain in patients with CSU214 and hair colour changes, mild infusion reactions and transient changes in taste in patients with CIndU212.

Benralizumab, an anti-IL-5Rα mAb, demonstrated sustained mean changes in UAS7 from baseline to week 24 in patients with CSU in a single-centre study: both components of the UAS7, pruritus severity and wheal size, decreased to a similar extent215. In a phase III trial, dupilumab, an anti-IL-4Rα mAb, reduced itch and wheals in patients with CSU who were omalizumab-naïve sgAH-resistant, but failed to meet primary end points in patients with poor response to omalizumab216.

Lirentelimab, an anti-Siglec 8 mAb, increased UCT scores across cohorts of patients with CSU and CIndU, with complete response rates of 92%, 36%, 82% and 40% in patients who are omalizumab-naïve, patients who are omalizumab-refractory, patients with CholU and patients with symptomatic dermographism, respectively217. Secukinumab, an anti-IL-17 mAb, was effective in eight patients with CSU who were omalizumab-refractory, but onset of action was slow218. Other promising targets include tryptase, SYK, C5aR, MRGPRX2, IL-33, thymic stromal lymphopoietin (TSLP) and H4R; for some of them, drugs are already in development (Table 3 and Fig. 3).

Quality of life

The quality of life of patients with urticaria, especially CU, is often severely impaired, with marked physical, psychological, social and emotional effects11. Many different instruments are available for the assessment of quality of life impairment in patients with urticaria, ranging from generic questionnaires, such as the Short Form-36 (SF-36)219 or the Nottingham Health Profile (NHP)220, to organ-specific quality of life questionnaires, such as the Skindex-29 (ref.221) or the Dermatology Life Quality Index (DLQI)222, to disease-specific instruments such as the Chronic Urticaria-Quality of Life Questionnaire (CU-Q2oL)223, Cholinergic Urticaria-Quality of Life Questionnaire (CholU-QoL)224 and Angioedema-Quality of Life Questionnaire (AE-QoL)225 (Box 1). These questionnaires are available in validated form for many countries and languages, and the disease-specific questionnaires are recommended by the current international guideline on the diagnosis and treatment of urticaria for all patients with CU4.

Owing to its short duration, AU has only a limited effect on patient quality of life, showing mean DLQI scores <1 for questions regarding social or leisure activities and personal relationships226. Patients with AU expressed greater satisfaction with life compared with patients with CU227. Patients with CIndU have a slightly better quality of life than patients with CSU, probably due to the transient nature of stimulus, whereas a combination of CSU and CIndU showed the highest DLQI scores, indicating the largest impact on quality of life228.

The two most important drivers of quality of life impairment in CSU are the unpredictable course of the disease with the sudden onset of wheals and angioedema, and the severe pruritus. Consequences of pruritus in patients with CSU include lack of sleep, fatigue and lack of concentration12,18,109,229,230. Many patients with CSU suffer from daily or almost daily occurrence of the symptoms4,231, which can lead to patients feeling loss of control over their lives229. The signs and symptoms of urticaria also result in embarrassment, frustration, sadness and anxiety in many patients18,223,229. These feelings are further exacerbated by the fact that the importance of urticaria is underestimated by others, including treating physicians232,233. In addition to reduced quality of life, CSU also leads to limitations in social interactions, work performance and functioning in daily life, including impairments in interpersonal relationships and sexual life12,18,229,234,235.

Few direct comparisons of quality of life impairment in CU with other skin diseases exist. Independent studies with large numbers of patients in Europe and the USA have shown that quality of life impairment in CU is comparable with that in patients with moderate to severe psoriasis18,236,237 and atopic dermatitis236. Compared with non-dermatologic conditions, social quality of life impairments in patients with CU were shown to be similar to those in patients with coronary artery disease who were about to undergo arterial bypass surgery229 and worse than in patients with type I diabetes mellitus238.

Untreated CU has substantial negative effects on patient quality of life, but response to therapy is associated with a corresponding improvement in quality of life: the more effective the therapy, the better the quality of life239,240,241,242.

Outlook

Personalized treatment

AU is a disease with transient manifestations and without long-standing impairment of quality of life. However, for CU, no cure exists and the burden of disease is substantial. Future research should focus on the aetiology and pathogenesis of CU, which are currently poorly investigated and understood. Patients with CU often present with the same type of skin rash but differ in genotype, endotype and phenotype38,91,243.

Genetic contributions to urticaria pathogenesis should be elucidated in high-throughput genetic studies, including whole-genome sequencing. Presence of comorbid diseases along with the phenotypes of CU subtypes are factors that contribute to the heterogeneity of the disease and can influence the variable therapeutic response and adverse effects to available drugs. Differences in CU phenotypes have been reported, including better response to antihistamines in patients with exclusive CIndU and less psychiatric comorbidities in patients with isolated CIndU or recurrent CSU243. Defining disease endotypes and their biomarkers is a major unmet need and will enable the identification of novel therapeutic targets, refine disease management via optimization of prevention and treatment with the available drugs, and assign newly developed drugs to those patients who will have the best benefit to risk ratio. Ultimately, this will also contribute to reducing healthcare costs, with improved quality of life for patients with CU. In this regard, mast cell, basophil and eosinophil activating factors have to be identified to better characterize the aetiology and pathogenesis of CU. For example, commercially available in vitro tests for detecting serum autoantibodies need to be developed.

A multi-omics approach, using data from genomics, transcriptomics and proteomics, can help identify relevant biomarkers to objectively measure characteristics of the disease. Reliable biomarkers, either alone or in combination, can help stratify patients with CU according to phenotypes and endotypes of disease, predict progression from AU to CU and measure disease activity, relapse and response to treatment, all of which would lead to a more precise treatment approach. Markers of CSU activity are already emerging, including increased levels of CRP, IL-6 and D-dimer78,79,244. The autoimmune endotype of CSU is associated with basopenia, eosinopenia, elevated IgG anti-TPO and low total IgE levels, which were linked to poor response to treatment with antihistamines and/or omalizumab. By contrast, higher baseline levels of total IgE were associated with better clinical responses to omalizumab245, whereas low total IgE levels and a positive BHRA were linked to good response to cyclosporine246. Further promising markers exist (see Supplementary Box 1). Nevertheless, prospective multicentre studies are needed to further investigate these markers and identify new biomarkers, as well as to study pathogenesis in antihistamine-resistant urticaria and angioedema.

Drugs that failed to meet the primary end points in phase II/III trials in the classic one-size-fits-all approach may still be promising candidates in certain subpopulations of patients. Finally, drugs that have the potential to modify the disease course and induce sustained remission, especially in patients with CSU who are non-responders to sgAHs and omalizumab, are urgently needed.

Multidisciplinary approach including patients

A multidisciplinary approach should involve patients, dermatologists, allergists, rheumatologists, geneticists, pharmacologists, immunologists and researchers in these fields. Patient-reported outcome measures require more explicit recognition both in trials and in clinical practice. Specific quality of life instruments for ColdU, symptomatic dermographism and CholU already exist or are under development, but tools for the other forms of CIndU are missing and should be developed.

Patients with CU are interested in using mobile applications to monitor their disease activity and control247. For example, several mobile applications for the self-eval‎uation of CU and angioedema are available including UrCare, Urticaria, UrticariApp-Control Urticaria, SymTrac HIVES and TARGET My Hives248. However, existing mobile applications are limited in function and geographical reach248. The Chronic Urticaria Self Eval‎uation App (CRUSE) was developed in 2022 by the CRUSE core team and CRUSE advisory board, an international team of expert dermatologists and allergists, based on validated patient-reported outcome measures to help patients assess CSU activity and control and effects of CSU on quality of life. Patient’s data can be sent directly to the treating physician and included in the Chronic Urticaria Registry (CURE). Initially launched in Germany, the CRUSE team aims to cover patients with CSU worldwide in the near future. Patients with CU are increasingly seeking information from information and communications technologies with web browsers being the preferred platform to obtain general health information249, followed by email to contact physicians and WhatsApp for communicating with other patients250. The educational needs of patients can be addressed by urticaria-related websites and groups on social media, webinars and urticaria seminars.

Global approach

All urticaria stakeholders, including those in basic science, medical specialists, the pharmaceutical industry and health authorities together with patients, should contribute to creating solid evidence that enables identifying, managing and treating urticaria early with the aim of minimizing its effects on individuals and society. Awareness of up-to-date urticaria management should be increased worldwide to decrease diagnostic and therapeutic delays (Box 2). Several global initiatives have been launched to address these objectives.

First, international guidelines for diagnosis and treatment of urticaria endorsed by 50 national and international societies from 31 countries are revised every 4 years4. Second, networks of Urticaria and Angioedema Centers of Reference and Excellence (UCARE and ACARE, respectively)251,252 have been launched by the Global Allergy and Asthma European Network (GA2LEN) with the aim to provide excellence in urticaria and angioedema management and to increase the knowledge of urticaria and angioedema through research and education. Third, the CURE253 is the first international academia-driven registry to collect high-quality, real-life data on CU including patient characteristics, course of disease including cause, comorbidities, treatment response, quality of life impairment and healthcare data. Fourth, UCARE initiatives (UCARE LevelUp for physicians and UCARE 4U for patients) present up-to-date urticaria-related educational webinars. Finally, the Global Burden of Disease initiative can help assess urticaria preval‎ence, incidence and disability-adjusted life years14. However, as yet, these data do not differentiate between AU and CU, and therefore CU preval‎ence data for some countries and continents, for example Africa, are still lacking14,22.

A global approach together with mobile health and personalized medicine should help implement prevention and control of urticaria in a cost-effective manner with each patient getting the best available treatment.

Box 2 Global variations in diagnosis and management of urticaria

Approaches to the diagnosis and treatment of urticaria, as well as healthcare resource utilization, differ worldwide260,261. For example, patients residing in Europe compared with those in Central/South America have higher incidence of general practitioner visits and higher rates of controlled disease and treatment, including higher frequency of escalation to omalizumab261. This disparity can be explained by differences in awareness of the use of best available treatment options, differences in availability of diagnostic tests, treatment options and economic resources.

The mean time from chronic urticaria (CU) onset to proper diagnosis is ~2–4 years and considerably varies across countries11,12,262. Adherence to best-practice international urticaria guidelines has a direct affect on the quality of care of patients with urticaria and is associated with quicker diagnosis and treatment, and better treatment efficacy12,260,263. Approximately 60% of specialists follow international urticaria guidelines260 and discrepancies in physicians’ awareness of the guidelines among countries exist263. Although national and international urticaria guidelines usually agree on most points regarding urticaria management, some expert-based recommendations differ (mostly because of weak scientific evidence) that can also affect the final patient outcome264.

One-fifth of physicians think that some of the guidelines’ recommendations cannot be implemented in the physician’s country of residency260. Availability of drugs and diagnostic tests, economic considerations, differences in coverage and payment for healthcare among different regions influence the choice of diagnostic and treatment strategies. Omalizumab is unavailable in some countries or its cost is high and not covered by health insurance programmes265; thus, systemic corticosteroids and first-generation H1 antihistamines (H1-AH), which are cheaper than omalizumab and second-generation H1-AH, may be preferred263. Similarly, some diagnostic tests, for example the basophil histamine release test and basophil activation test for diagnosis of autoimmune chronic spontaneous urticaria (CSU) or TempTest for diagnosis of cold and heat urticaria, are not standardized, are expensive and/or are available only at some urticaria centres, which may contribute to diagnosis delay92.

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