Re: 아토피 피부염과 접촉성 피부염 최신논문...

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Am J Clin Dermatol. Author manuscript; available in PMC 2019 Jun 1.

Published in final edited form as:

Am J Clin Dermatol. 2018 Jun; 19(3): 293–302.

doi: 10.1007/s40257-017-0340-7

PMCID: PMC5948135

NIHMSID: NIHMS932718

PMID: 29305764

The Role and Diagnosis of Allergic Contact Dermatitis in Patients with Atopic Dermatitis

Joshua L. Owen, MD, PhD,a,* Paras P. Vakharia, PharmD,a,* and Jonathan I. Silverberg, MD, PhD, MPHb,c

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Abstract

Patients with atopic dermatitis (AD) have increased penetration of allergens, immune dysregulation including shared cytokine pathways, frequent use of emollients and topical medications, all of which may predispose toward developing allergic contact dermatitis (ACD). Recent systematic reviews have suggested that ACD is a significant clinical problem in both children and adults with AD. While this remains controversial, ACD remains an important comorbidity and potential exacerbant of AD in clinical practice. Common relevant allergens, include lanolin, neomycin, formaldehyde, sesquiterpine lactone mix, compositae mix, and fragrances that are commonly found in AD patients’ personal care products. We herein review the clinical scenarios where patch testing is indicated in AD. In addition, we review the contraindications, preferred patch testing series, pitfalls, and challenges determining the relevance of positive patch test reactions in AD patients.

아토피 피부염(AD) 환자는 

알레르겐의 침투 증가, 

사이토카인 경로 공유를 포함한 

면역 조절 장애, 

완화제 및 국소 약물의 잦은 사용으로 인해 

알레르기성 접촉 피부염(ACD allergic contact dermatitis)이 발생할 가능성이 높습니다. 

최근의 체계적 문헌고찰에 따르면 

아토피피부염은 

어린이와 성인 모두에게 심각한 임상적 문제라고 합니다. 

아직 논란의 여지가 있지만, 

ACD는 

임상에서 중요한 동반 질환이자 

AD의 잠재적 악화 요인으로 남아 있습니다. 

일반적인 

관련 알레르겐으로는 

라놀린, 네오마이신, 포름알데히드, 세스키테르핀 락톤 혼합물, 컴포지테 혼합물, 그리고 

AD 환자의 퍼스널 케어 제품에서 흔히 볼 수 있는 향료 등이 있습니다. 

여기에서는 

AD에서 패치 테스트가 필요한 임상 시나리오를 검토합니다. 

또한 금기 사항, 선호되는 패치 테스트 시리즈, 함정 및 AD 환자에서 패치 테스트 양성 반응의 관련성을 결정하는 데 따르는 어려움에 대해 검토합니다.

1 Introduction

1.1 Atopic dermatitis (AD)

AD and allergic contact dermatitis (ACD) are both common and burdensome inflammatory skin disorders. AD is a chronic disease that is caused by a combination of genetic predisposition, skin-barrier disruption, immune factors, and environmental exposures. AD affects up to 15–20% of children and 1–10% of adults worldwide, including 13% of US children and 7.2% of US adults.[1–4] AD is a heterogeneous disorder associated with a constellation of signs and symptoms, including pruritus, skin pain [5], mental health symptoms, xerosis, oozing/weeping in acute lesions, lichenification and prurigo nodules in chronic lesions. AD also has a chronic relapsing or persistent course, with an age-related distribution of cutaneous lesions, with facial dermatitis affecting infants, extensor dermatitis in toddlers, flexural lesions in older children and adults, and more facial and hand dermatitis in adults.[6]

Given the varied presentation of AD, it is often challenging to diagnose with certainty, particularly in adults. AD is diagnosed clinically based on the signs and symptoms. There are no currently accepted tissue or blood biomarkers to diagnose AD. The original diagnostic criteria for AD are those of Hanifin and Rajka (HR),[7] published in 1980 and developed via clinical experience and expert consensus. However, various modifications of these criteria, as well as other diagnostic criteria were subsequently developed.[8–12]

아토피피부염과 

알레르기성 접촉 피부염(ACD)은 

흔하고 부담스러운 염증성 피부 질환입니다. 

AD는 

유전적 소인, 

피부 장벽 붕괴, 

면역 요인 및 환경 노출이 

복합적으로 작용하여 발생하는 만성 질환입니다. 

AD는 

미국 어린이의 13%, 

미국 성인의 7.2%를 포함하여 

전 세계 어린이의 15~20%, 

성인의 1~10%가 앓고 있습니다.[1-4] 

AD는 

소양증, 

피부 통증[5], 

정신 건강 증상, 

건조증, 

급성 병변의 진물/진물, 

만성 병변의 이끼화 및 소양 결절을 포함한 

일련의 징후 및 증상과 관련된 이질적인 장애입니다. 

또한

 AD는 

만성 재발성 또는 

지속성 경과를 보이며, 

연령과 관련된 피부 병변의 분포를 보이며, 

유아에게는 안면 피부염, 소아에게는 굴곡성 병변, 성인에게는 안면 및 손 피부염이 더 많이 발생합니다[6].

아토피피부염의 다양한 증상을 고려할 때, 

특히 성인의 경우 확실하게 진단하기 어려운 경우가 많습니다. 

AD는 

징후와 증상을 바탕으로 

임상적으로 진단합니다. 

현재 

AD를 진단할 수 있는 

조직 또는 혈액 바이오마커는 아직 없습니다. 

1980년에 발표된 하니핀과 라즈카(HR)의 진단 기준[7]은 임상 경험과 전문가 합의를 통해 개발된 최초의 알츠하이머 진단 기준입니다. 그러나 이후 이 기준을 다양하게 수정하고 다른 진단 기준이 개발되었습니다[8-12].

1.2 ACD

ACD is caused by a delayed-type hypersensitivity response to contact allergens. The incidence of ACD is not clearly defined, but is thought to be rising.[13] A recent study found that all forms of contact dermatitis (CD), including irritant contact dermatitis (ICD) and ACD, had a claims-based preval‎ence of 4.17% within the US.[14] The most recent estimated annual medical costs in the US in 2013 for AD and CD is $314,000,000 and $1,529,000,000, respectively.[14] ACD is the second most common type of CD after irritant contact dermatitis (ICD), and may present with similar signs and symptoms to AD. The most common symptoms are pruritus, along with burning and stinging. ACD commonly presents acutely with erythematous, indurated papules and plaques, vesiculation, edema and bullae formation in severe cases. Chronic ACD can present with scaling, lichenification, and fissuring. ACD typically presents with a well-defined, exposure-dependent distribution, commonly involving the hands, face, or eyelids. However, irregular or diffuse distributions can occur due to secondary allergen transfer or systemic allergen sensitization. ACD is diagnosed via a combination of clinical signs and symptoms and patch testing, the gold standard for ACD diagnosis, where non-irritating concentrations of allergens are used to determine the presence of an allergic reaction in vivo.[15]

Importantly, due to the large symptom-burden, including the sequela of itch, pain, sleep, and mental health disturbance, AD and ACD both have a significant negative impact on quality of life (QOL).[16–20] While these two cutaneous eruptions may appear similar and often coexist,[21] the etiologies, distributions, and therapeutic options often differ. This makes differentiating the two diseases critical to the successful treatment of the dermatitis. The goal of this article is to review ACD in AD patients: when to suspect ACD and how best to test for ACD in patients with AD.

ACD는 

접촉 알레르겐에 대한 

지연형 과민 반응으로 인해 발생합니다. 

ACD의 발병률은 명확하게 정의되어 있지 않지만 

증가 추세에 있는 것으로 추정됩니다.[13] 

최근 연구에 따르면 

자극성 접촉 피부염(ICD)과 

ACD를 포함한 

모든 형태의 접촉 피부염(CD)은 

미국 내에서 청구 기준 유병률이 4.17%에 달했습니다. [14] 

2013년 미국에서 가장 최근에 추정된 

AD와 CD의 연간 의료 비용은 

각각 314,000,000달러와 1,529,000달러입니다.[14] 

ACD는 

자극성 접촉 피부염(ICD) 다음으로 가장 흔한 유형의 CD로, 

AD와 유사한 징후와 증상을 나타낼 수 있습니다. 

가장 흔한 증상은 

가려움증과 작열감 및 따가움입니다. 

ACD는 

일반적으로 

홍반성, 경화성 구진 및 플라크, 수포, 부종, 수포 형성을 동반하며 

심한 경우 급성으로 나타납니다. 

만성 ACD는 

각질화, 이끼화, 균열이 나타날 수 있습니다. 

ACD는 

일반적으로 손, 얼굴 또는 눈꺼풀에 잘 정의되고 

노출에 의존적인 분포로 나타납니다. 

그러나 

이차적인 알레르겐 전이 또는 

전신 알레르겐 감작으로 인해 

불규칙하거나 확산된 분포가 발생할 수 있습니다. 

ACD는 

임상 징후 및 증상과 패치 테스트의 조합을 통해 진단되며, 

패치 테스트는 생체 내 알레르기 반응의 존재 여부를 확인하기 위해 

자극적이지 않은 농도의 알레르겐을 사용하는 

ACD 진단의 표준입니다[15].

중요한 것은 

가려움증, 통증, 수면 및 정신 건강 장애의 후유증을 포함한 

증상 부담이 크기 때문에 

아토피피부염과 ACD 모두 

삶의 질(QOL)에 상당한 부정적인 영향을 미친다는 것입니다.[16-20] 

이 두 피부 발진은 

비슷해 보일 수 있고 

종종 공존하기도 하지만[21] 

원인, 분포 및 치료 옵션이 서로 다른 경우가 많다는 점입니다. 

따라서 

두 질환을 구별하는 것은 

피부염을 성공적으로 치료하는 데 매우 중요합니다. 

이 글의 목표는 

아토피피부염 환자에서 

아토피피부염을 의심해야 할 때와 

아토피피부염 환자에서 아토피피부염을 가장 잘 검사하는 방법을 검토하는 것입니다.

2 Mechanisms

2.1 AD

The pathogenesis of AD is multifactorial, with both epidermal barrier and immunologic defects. A subset of AD patients have filaggrin (FLG) gene null mutations that are inherited in an autosomal semi-dominant fashion. Barrier disruption may occur secondary to exogenous insults, even in those without germline FLG mutations, possibly through direct insult to the skin-barrier and/or epigenetic alterations.[22, 23] Such factors include fragrances, pruritogens, stress, climate, pollution, among others. Thymic stromal lymphopoietin (TSLP) and other cytokines are released by damaged keratinocytes from the disrupted skin-barrier and contribute to skin inflammation, and may also be involved in gene-environment interactions in AD.[23] Due to impaired barrier function, there is an increased risk of transcutaneous allergen penetrance[24] and potentially antigen sensitization and presentation.

The AD inflammatory signature is primarily of the T-helper (Th) cell 2 type in both the acute and chronic phases, with a contribution from Th1 in the chronic phase.[25–27] Th2 cells produce interleukins (IL-) 4, 5, 13, and 31, all of which have downstream effects in AD. Notably, IL-4 and IL-13 promote skin barrier disruption. Thus, epidermal inflammation may precede and be sufficient to cause skin-barrier disruption, even in those without preceding barrier defects. Some studies have shown upregulation of IL-17 and IL-22 (secreted by Th17 and Th22 cells, respectively) in the acute phase of AD. These cytokines may induce epidermal hyperplasia and/or alter terminal differentiation proteins. Th2 cytokines also impair antimicrobial peptide (AMP) responses to pathogens, which, in conjunction with barrier disruption, allows for increased pathogen penetration.[28–35]

Recent studies have also shown a potential role for Th9 and Th17 pathways in AD. The mechanism by which IL-9, secreted by Th9 cells, contributes to AD pathogenesis is not fully known. However, IL-9 promotes mast cell activity, eosinophils, and innate immune cells.[36] IL-9 levels have been shown to be increased in both pediatric and adult AD patients and correlate with AD severity.[31, 37, 38] IL-9 also enhances the secretion of IL-13, a key cytokine in AD pathogenesis. Importantly, a significant association between IL-9 and IL-9 receptor gene polymorphisms with atopic dermatitis was found in a Korean population.[39] Th17 levels have also been found to correlate with AD severity,[32] and may be related to host-defense and skin remodeling.[40, 41] Th17 cytokines may play a greater role in intrinsic AD, i.e. AD without comorbid atopy or atopic disease.[35]

AD의 발병 기전은 

표피 장벽과 면역학적 결함을 

모두 포함하는 다인성입니다. 

AD 환자의 일부는 

상염색체 반우성 방식으로 유전되는 

필라그린(FLG) 유전자 결핍 돌연변이를 가지고 있습니다. 

장벽 장애는 

생식세포 FLG 돌연변이가 없는 경우에도 

외인성 모욕에 의해 이차적으로 발생할 수 있으며, 

피부 장벽에 대한 직접적인 모욕 및/또는 

후성유전학적 변화를 통해 발생할 수 있습니다.[22, 23] 

이러한 요인에는 향기, 소양인자, 스트레스, 기후, 공해 등이 포함됩니다. 흉선 기질 림포포이에틴(TSLP) 및 기타 사이토카인은 피부 장벽이 손상된 각질 세포에서 방출되어 피부 염증을 일으키고, AD의 유전자-환경 상호작용에도 관여할 수 있습니다.[23] 장벽 기능이 손상되면 경피 알레르겐 침투[24] 및 항원 민감화 및 발현 위험이 증가합니다.

AD 염증 징후는 

급성기와 만성기 모두에서 

주로 T 헬퍼(Th) 세포 2 유형이며, 

만성기에는 Th1이 기여합니다.[25-27] 

Th2 세포는 

인터루킨(IL-) 4, 5, 13, 31을 생성하며, 

모두 AD에서 다운스트림 영향을 미칩니다. 

특히 IL-4와 IL-13은 

피부 장벽 파괴를 촉진합니다. 

따라서 

표피 염증은 

장벽 결함이 없는 경우에도 

피부 장벽 장애를 일으키기에 충분할 정도로 선행될 수 있습니다. 

일부 연구에 따르면 

아토피피부염의 급성기에 

IL-17과 IL-22(각각 Th17과 Th22 세포에서 분비됨)가 

상향 조절되는 것으로 나타났습니다. 

이러한 사이토카인은 

표피 과형성을 유도하거나 

말단 분화 단백질을 변화시킬 수 있습니다. 

또한 

Th2 사이토카인은 

병원체에 대한 항균 펩타이드(AMP) 반응을 손상시켜 

장벽 파괴와 함께 병원체 침투를 증가시킵니다[28-35].

최근 연구에 따르면 

알츠하이머병에서 

Th9 및 Th17 경로의 잠재적 역할도 밝혀졌습니다. 

Th9 세포에서 분비되는 

IL-9이 AD 발병에 기여하는 메커니즘은 완전히 밝혀지지 않았습니다. 

그러나 

IL-9은 

비만세포, 호산구 및 선천성 면역 세포의 활동을 촉진합니다.[36] 

IL-9 수치는 

소아 및 성인 AD 환자 모두에서 증가하며 

AD 중증도와 상관관계가 있는 것으로 나타났습니다.[31, 37, 38] 

또한 

IL-9은 

AD 발병의 핵심 사이토카인인 IL-13의 분비를 촉진합니다. 

중요한 것은 한국인 집단에서 

IL-9 및 IL-9 수용체 유전자 다형성과 아토피 피부염 사이에 

유의미한 연관성이 발견되었다는 것입니다.[39] 

Th17 수준은 

또한 AD 중증도와 상관관계가 있는 것으로 밝혀졌으며[32] 

숙주 방어 및 피부 리모델링과 관련이 있을 수 있습니다.[40, 41] 

Th17 사이토카인은 

내재성 AD, 즉 

동반 아토피 또는 아토피 질환 없는 AD에서 

더 큰 역할을 할 수 있습니다[35].

2.2 ACD

ACD is a classic type IV hypersensitivity reaction requiring two phases: sensitization and elicitation. In the sensitization phase, an allergen is captured by antigen-presenting cells (APCs), which migrate to the draining lymphoid tissue. Subsequent activation of naïve T cells occurs, leading to differentiation of memory T cells specific for that allergen. In the elicitation phase, re-exposure to the allergen or a cross-reacting allergen results in activation of memory T cells. T cytotoxic (Tc) 1 cells are activated and lead to the hallmark inflammation and adaptive immune response resulting in dermatitis.[42] The primary ACD inflammatory signature is a T cytotoxic (Tc) 1 or Th1 response. However, Th2, Th17, and Th22 responses appear to play a role in ACD, sometimes depending on the allergen.[43–45] For example, nickel was found to be a potent inducer of the innate immune Th1, Th17, and Th22 pathways, while fragrance and rubber promoted Th2 activity with less Th1 and Th17 involvement.[46]

IL-9 expression‎ has also been found to be elevated in skin from positive patch-test reactions in ACD patients, including reactions to metals, drugs, and polymers; IL-9 also increased in nickel-allergic patients after nickel stimulation.[47–49] Th17 cell expansion occurs upon allergen contact in individuals with ACD.[50] IL-17 secretion increases local inflammation via induction of proinflammatory cytokines, chemokines, and adhesion molecules.[51–54] The potential role of Th17 in ACD was also demonstrated by a recent experimental study showing that ACD reactions were decreased in the absence of IL-17.[55]

ACD는 

감작과 유발의 두 단계가 필요한 

전형적인 4형 과민 반응입니다. 

감작 단계에서 알레르겐은 

항원 제시 세포(APC)에 의해 

포획되어 림프 조직으로 이동합니다. 

이후 순진한 T 세포가 활성화되어 

해당 알레르겐에 특이적인 기억 T 세포가 분화됩니다. 

유도 단계에서는 

알레르겐 또는 교차 반응하는 알레르겐에 다시 노출되면 

기억 T 세포가 활성화됩니다. 

T 세포독성(Tc) 1 세포가 활성화되어 

특징적인 염증과 적응 면역 반응을 일으켜 

피부염을 유발합니다.[42] 

주요 ACD 염증 징후는 

T 세포독성(Tc) 1 또는 

Th1 반응입니다. 

그러나 

알레르겐에 따라 Th2, Th17, Th22 반응이 

ACD에서 중요한 역할을 하는 것으로 보입니다.[43-45] 

예를 들어, 

니켈은 

선천 면역 Th1, Th17, Th22 경로를 강력하게 유도하는 것으로 밝혀졌고 

향과 고무는 Th1과 Th17의 관여가 적은 

Th2 활동을 촉진하는 것으로 나타났습니다.[46]

IL-9 발현은 또한 

금속, 약물 및 폴리머에 대한 반응을 포함하여 

ACD 환자의 양성 패치 테스트 반응에서 

피부에서 상승하는 것으로 밝혀졌으며, 

니켈 자극 후 니켈 알레르기 환자에서도 IL-9이 증가했습니다.[47-49] 

Th17 세포 확장은 

ACD 환자에서 알레르겐 접촉시 발생합니다. 

[IL-17 분비는 

염증성 사이토카인, 케모카인 및 접착 분자의 유도를 통해 

국소 염증을 증가시킵니다.[51-54] 

ACD에서 

Th17의 잠재적 역할은 

최근 실험 연구를 통해 IL-17이 없을 때 ACD 반응이 감소한다는 사실도 입증되었습니다.[55]

3 Allergic Contact Dermatitis in Patients with Atopic Dermatitis

3.1 Plausibility

Many factors are thought to affect preval‎ence of ACD in patients with AD. The historical perspective is that the Th2-skewed inflammatory response of AD results in less contact sensitivity.[60] For example, some studies have shown an increased elicitation threshold in patients with AD compared to controls.[60–63] Other studies have demonstrated several reasons for AD patients to have similar or even increased risk of ACD compared to those without AD. Patients with AD have skin-barrier disruption, with an approximately two-fold increase in skin absorption of irritants and contact allergens.[64–66] Irritants lead to further breakdown of the skin barrier, increased penetration of contact allergens, and eventually increased risk of contact sensitization.[67, 68] It has also been demonstrated that cutaneous responses and elicitation thresholds in ACD patients were considerably influenced by combined allergen and irritant exposure.[69–71] Additionally, the treatment of AD requires chronic topical application of emollients and anti-inflammatories, and many of these topical products have been found to be contact sensitizers.[72, 73] More recently, potential shared immune pathways have been demonstrated for subsets of AD and ACD, including Th1, Th2, Th9 and/or Th17, as reviewed above. An emerging idea is the role of bacterial colonization in AD and how, by stimulating an inflammatory environment, may lead to enhanced contact sensitization.[67, 74–76]

많은 요인이 AD 환자의 ACD 유병률에 영향을 미치는 것으로 생각됩니다. 역사적인 관점은 AD의 Th2 왜곡된 염증 반응이 접촉 민감도를 낮춘다는 것입니다.[60] 예를 들어, 일부 연구에서는 대조군에 비해 AD 환자에서 유발 역치가 증가하는 것으로 나타났습니다.[60-63] 다른 연구에서는 AD 환자가 AD가 없는 환자에 비해 ACD 위험이 비슷하거나 심지어 증가하는 몇 가지 이유가 밝혀졌습니다. AD 환자는 피부 장벽이 파괴되어 자극제와 접촉 알레르겐의 피부 흡수가 약 2배 증가합니다.[64-66] 자극제는 피부 장벽을 더욱 파괴하고 접촉 알레르겐의 침투를 증가시켜 결국 접촉 감작의 위험을 증가시킵니다.[67, 68] 또한 ACD 환자의 피부 반응과 유발 역치는 알레르겐과 자극제의 복합 노출에 상당한 영향을 받는다는 것이 입증되었습니다. [69-71] 또한 AD 치료에는 완화제와 항염증제를 만성적으로 국소 도포해야 하며, 이러한 국소 제품 중 상당수가 접촉 감작제인 것으로 밝혀졌습니다.[72, 73] 최근에는 위에서 검토한 것처럼 Th1, Th2, Th9, Th17을 포함한 AD 및 ACD의 하위 집합에 대해 잠재적인 공유 면역 경로가 입증되었습니다. 새롭게 떠오르는 아이디어는 AD에서 박테리아 군집화의 역할과 염증 환경을 자극하여 접촉 감작을 강화할 수 있는 방법입니다.[67, 74-76][67, 74-76]

3.2 Evidence

A recent systematic review was performed assessing contact allergy in children with AD. The review assessed 31 studies and found that ACD was significantly greater in children without AD vs those with AD (46.6% and 41.7% sensitized to at least one allergen, respectively; I-squared=61.7%, P<0.001). However, the authors noted significant variability of sensitization rates, study designs and criteria that limit conclusions being drawn. The results of the available studies were conflicting with respect to whether AD patients have higher rates of ACD than the rest of the population. Nevertheless, ACD was found to be a common clinical problem in AD, with approximately one-third of children with AD that were patch-tested having at least one contact allergy.[77]

Another systematic review and meta-analysis, including 74 studies eval‎uating the preval‎ence of contact sensitization (defined as a positive patch test reaction to any allergen) in various patient populations found that AD patients had increased preval‎ence of contact sensitization compared to the general population.[78] However, there was an inverse association when patients with AD were compared to a patch-test referral population. The authors postulated that this latter relationship could be because AD patients in a referral population have more severe and recalcitrant disease, which has been shown to have a higher elicitation threshold for contact sensitization.[60–62] Further, severe AD patients are often referred for patch testing to rule out contact sensitization even without clear clinical suspicion prior to initiating systemic AD therapy.[78]

최근 아토피피부염 어린이의 접촉 알레르기를 평가하는 체계적 문헌고찰이 수행되었습니다. 이 검토에서는 31개의 연구를 평가한 결과, AD가 없는 어린이와 AD가 있는 어린이에서 ACD가 유의하게 더 큰 것으로 나타났습니다(각각 46.6%와 41.7%가 적어도 하나의 알레르겐에 민감하게 반응; I-제곱=61.7%, P<0.001). 그러나 저자는 감작률, 연구 설계 및 기준의 상당한 변동성이 있어 결론 도출을 제한한다고 지적했습니다. 이용 가능한 연구 결과는 AD 환자가 나머지 인구보다 ACD 비율이 더 높은지에 대해 상충되는 결과를 보였습니다. 그럼에도 불구하고, 패치 테스트를 받은 AD 아동의 약 1/3이 적어도 한 가지 이상의 접촉 알레르기가 있는 것으로 나타나 ACD는 AD에서 흔한 임상 문제인 것으로 밝혀졌습니다[77].

다양한 환자 집단에서 접촉 감작(알레르기 항원에 대한 패치 테스트 양성 반응으로 정의)의 유병률을 평가한 74건의 연구를 포함한 또 다른 체계적 검토 및 메타 분석에 따르면 AD 환자는 일반 인구에 비해 접촉 감작 유병률이 높았습니다.[78] 그러나 AD 환자를 패치 테스트 의뢰 집단과 비교하면 반대의 연관성이 있었습니다. 저자들은 이러한 후자의 관계가 의뢰 집단에서 AD 환자가 더 심각하고 난치성 질환을 앓고 있어 접촉 감작 유발 역치가 더 높기 때문일 수 있다고 가정했습니다.[60-62] 또한 중증 AD 환자는 전신 AD 치료를 시작하기 전에 명확한 임상적 의심 없이도 접촉 감작을 배제하기 위해 패치 테스트를 의뢰받는 경우가 많습니다[78].

3.3 Relevant allergens

Results from various studies assessing the relationship of ACD in AD patients have led to the identification of common allergens (Table 1), including nickel, cobalt, potassium dichromate, chromium, lanolin, neomycin, formaldehyde, sesquiterpine lactone mix, compositae mix, and fragrance markers (e.g. fragrance mix I, fragrance mix II, Myroxylon pereirae, and hydroxyisohexyl-3-cyclohexenecarboxaldehyde).[73, 77–90]

AD 환자에서 ACD의 관계를 평가한 다양한 연구 결과에 따르면 니켈, 코발트, 중크롬산칼륨, 크롬, 라놀린, 네오마이신, 포름알데히드, 세스키테르핀 락톤 혼합물, 컴포지테 혼합물, 향료 마커(예: 향료 혼합물 I, 향료 혼합물 II, 미록실론 페레이라, 하이드록시소헥실-3-사이클로헥센카복알데히드)를 포함한 일반적인 알레르기 유발 물질이 확인되었습니다[73, 77-90].

Table 1

Common contact allergens identified in patients with atopic dermatitis.

Bacitracin

Carba mix

Chromium

Cinnamic aldehyde

Cobalt

Cocamidopropyl betaine

Colophonium

Compositae mix

Disperse blue dye 106

Epoxy resin

Formaldehyde

Fragrance markers (e.g. fragrance mix I, fragrance mix II, Myroxylon pereirae, and

hydroxyisohexyl-3-cyclohexenecarboxaldehyde)

Isothiazolinones (e.g. methylisothiazolinone and methylchloroisothiazolinone)

Lanolin

Mercaptobenzothiazole and mercaptans

Myroxylon pereirae

Neomycin

Nickel

Para-tertiarybutyl-phenol (PTBP) formaldehyde resin

Paraphenylenediamine

Potassium dichromate

Quaternium-15

Rubber or rubber mixes

Sesquiterpene lactone mix

Topical antiseptics (e.g. chlorhexidine, hexamidine)

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It has been recently demonstrated that commonly used personal care products, including those self-identified as hypoallergenic, contain potent contact allergens.[72, 91] Furthermore, AD patients with frequent emollient use were found to have increased urinary levels of such allergens, particularly parabens and phthalate metabolites, indicating that such allergens do have cutaneous penetrance.[92] Topical treatment with emollients in AD has been shown to be associated with cutaneous sensitization.[73] A retrospective Dutch study of pediatric patients found that children with AD had significantly increased reactivity to lanolin and fragrances.[87] Further, a retrospective analysis of 26,479 patients patch tested with the NACDG screening series found that patients with positive reactions to lanolin were more likely to have a history of AD.[93]

최근 저자극성이라고 스스로 밝힌 제품을 포함하여 일반적으로 사용되는 퍼스널 케어 제품에는 강력한 접촉 알레르겐이 포함되어 있다는 사실이 입증되었습니다.[72, 91] 또한 완화제를 자주 사용하는 AD 환자는 이러한 알레르겐, 특히 파라벤 및 프탈레이트 대사 산물의 소변 수치가 증가하여 이러한 알레르기 항원이 피부 침투력이 있음을 나타내는 것으로 밝혀졌습니다. [92] 아토피 피부염에서 완화제를 사용한 국소 치료는 피부 감작과 관련이 있는 것으로 나타났습니다.[73] 소아 환자를 대상으로 한 네덜란드의 후향적 연구에 따르면 아토피 피부염 환자는 라놀린과 향료에 대한 반응성이 크게 증가했습니다.[87] 또한 NACDG 선별 검사 시리즈를 통해 패치 테스트를 받은 26,479명의 환자를 후향적으로 분석한 결과 라놀린에 양성 반응을 보인 환자들은 AD 병력이 있을 가능성이 더 높았습니다.[93]는 다음과 같습니다.

4 Clinical Assessment for Contact Dermatitis in Patients with Atopic Dermatitis

4.1 When to Consider Patch Testing in a Patient with AD

Guidelines for when to perform patch testing in AD patients are based largely upon consensus expert opinion.[94] Recommendations for when to consider patch testing include: adolescent- or adult-onset AD, as ACD can occasionally present with a flexural distribution and mimic AD. Pediatric and adult AD patients with worsening or more generalized dermatitis should also be patch tested, as there may be an allergenic trigger of their underlying AD.

Patch testing is also indicated in both children and adults when there is a lesional distribution that is atypical for AD, or one that is localized and suggestive of contact dermatitis (e.g., eyelids, head and neck, hand and foot, perioral, or periorbital). This is a particularly important consideration in adults with AD, for whom previous studies have demonstrated higher rates of lesions affecting the head and neck, or hands and feet (even in the absence of contact dermatitis).[95]

Patch testing should be considered in both children and adults if the dermatitis is recalcitrant to topical therapy and prior to initiation of systemic immunosuppressive therapy. Identification and avoidance of a relevant positive allergen on patch testing may decrease the severity of the underlying AD and abrogate the need for systemic therapy.

Patch testing should be considered in children and adults when the AD worsens with therapy, or rebounds quickly upon cessation of therapy. This may signal that the patient has developed ACD to the active ingredients or excipients in their topical therapy, e.g. corticosteroids or propylene glycol.

In addition, previous studies have shown high rates of ACD in patients with nummular eczema. Nummular lesions have been shown to occur with greater frequency in school age children with AD [96] and adult-onset AD [97]. However, widespread nummular lesions may be a sign of ACD in an AD patient.[98, 99]

4.2 When is Patch Testing Not Routinely Recommended in AD

Situations in which patch testing is less likely to be helpful include stable and well-controlled AD, AD flare and/or active dermatitis involving the back and other potential sites of application for the patch tests, current or recent use of systemic immunosuppressive medications, recent exposure to ultraviolet therapy or excessive solar radiation, and use of a limited patch testing series that do not incorporate the full-spectrum of allergens previously shown to be relevant in AD.[94]

A commonly encountered clinical situation is the patient with active, often severe, dermatitis on the back and other potential sites of application for the patch tests. This scenario should delay and may even prevent patch testing. Patch testing on actively inflamed skin may lead to both false positive and false negative reactions. The patient may also experience immense discomfort secondary to pruritus and pain from the adhesives used, increased heat and sweat and exposure to potentially irritating reagents being tested. In addition, the term “angry back syndrome” has been used to describe when patients develop positive reactions to most or all allergens tested.

Efforts should be made to first treat and resolve the active dermatitis on the back and other potential sites of application for the patch tests. Ideally, this should be done using topical therapy, e.g. corticosteroids and calcineurin inhibitors. If successful, the patient should discontinue application of topical therapy to the back for 1–2 weeks and then undergo patch testing. Systemic therapy or phototherapy may be required if the patient has an inadequate response to topical therapy or immediately experiences a flare of their dermatitis. However, such therapies may decrease the sensitivity of the patch testing process.

There is insufficient experimental data to precisely define the extent to which each immunosuppressive medication decreases the sensitivity threshold of patch testing. An expert consensus opinion from the North American Contact Dermatitis Group[100] suggested that the following medications were at high risk for leading to false negative patch test results: prednisone >10 mg/d and intramuscular triamcinolone (avoid for 4 weeks), topical corticosteroids or calcineurin inhibitors at patch test application sites (avoid for 1 week), azathioprine, cyclosporine, mycophenolate mofetil, and systemic tacrolimus. There was not enough data for the panel to make specific avoidance period recommendations for the non-corticosteroid immunosuppressants, other than to say that their effect on the results of patch testing are dose-dependent. Ultraviolet exposure to the testing site was recommended to be avoided for 1 week prior to testing. [100] The following medications were considered generally acceptable for patients to be taking during patch testing: methotrexate, prednisone <10 mg/d, tumor necrosis factor α inhibitors, ustekinumab, and antihistamines. Another expert consensus opinion echoed these suggestions, but noted the lack of information regarding immunosuppressive agent effects on patch test reactions. [101] There is no consensus regarding avoidance of newer agents being used in the treatment of AD, including crisaborole, Janus kinase inhibitors, or dupilumab.

In the authors personal experience, many patients experience false negative reactions to patch testing up to 4 weeks (or longer) after intense ultraviolet radiation, e.g. sunny vacation, cyclosporine at a dose of >2.0 mg/kg/day, methotrexate at a dose of >0.20 mg/kg/week. If patch testing is performed in these scenarios, results should be interpreted with caution. Weak or irritant reactions should be considered as true positives. Negative patch tests should be considered as false negatives and repeat patch testing should be considered upon discontinuation and washout from such treatments.

Go to:

5 Patch Testing in Patients with AD

5.1 Choosing the Right Patch Testing Series

Once the decision has been made to perform patch testing, allergen selection is critical for a satisfactory outcome and should be made on an individual patient basis. Factors to be considered during allergen selection include the region or country, occupation, hobbies and recreations, and other exposures. One option is the Thin-Layer Rapid Use Epicutaneous (T.R.U.E.) test; however, it should be noted that this test lacks multiple allergens that are commonly relevant and present on expanded patch testing series, e.g. American Contact Dermatitis Society (ACDS) or NACDG core series. Examples include cinnamic aldehyde, propylene glycol, dimethylol dimethyl hydantoin, iodopropynyl butyl carbamate, amidoamine, acrylates, tea tree oil, propolis, benzophenone-3, and sesquiterpene lactone mix.

While evidence-based guidelines are lacking for which allergens to include for patch testing in AD patients, several recommendations have been made by different authors. In summary, the majority of studies recommend expanded screening for the most commonly encountered allergens in AD patients (e.g. metals such as nickel, potassium dichromate, carba mix, formaldehyde, neomycin sulfate, balsam of Peru, fragrances, and preservatives), allergens that are common components of over-the-counter and prescription topical therapies, and allergens specific to a patient’s environment (i.e. patient’s personal care products or occupational exposures). For adults in North America, an expanded screening series, such as the American Contact Dermatitis Society or North American Contact Dermatitis Group core series, appear to reasonable. Screening series may vary regionally based on the most preval‎ent allergens. More targeted patch testing can be considered in younger children,[73, 94, 102–105] but standardized screening series are not well-established. Patch test reads should be performed at 48 and 72 hours and preferably a delayed read between 96 and 144 hours.

All personal care products and topical medications should be inspected for possible allergens. An important limitation is the U.S. Food and Drug Administration’s Cosmetic Labeling Guide regulations. Although all ingredients, including those with less than 1% concentration, are supposed to be listed on product labels, there are numerous ways around this. “Incidental Ingredients” (ingredients present at an insignificant level and having no technical or functional effect) and/or a “Trade Secret Ingredient” (an ingredient that offers one’s business potential to obtain an advantage over those not using or knowing about it) are exempt from ingredient declaration, and the phrase “and other ingredients” may be used in place.[106] Thus, there may be additional unknown exposures to lower concentrations of allergens. Leave on products can be patch-tested as they are formulated, but may be subject to false-negative reactions. However, rinse-off products should be diluted given their high potential for irritancy.[101]

5.2 Pitfalls and Determining the Relevance of Positive Patch Test Reactions in Patients with AD

There are several potential pitfalls to be considered when patch testing patients with AD. As mentioned previously, patients with AD have a lower irritancy threshold. This may lead to higher rates of irritant or false positive reactions, the most common of which are metals, fragrance, formaldehyde, and lanolin.[67, 103, 107] Additionally, as mentioned, patch test reactions should be interpreted with caution in patients on specific immunosuppressants. Weak or irritant reactions should be considered as true positives, while negative patch tests should be considered as possible false negatives.

On the other hand, irritant reactions may also be more difficult to distinguish from true positive reactions. That is, some relevant positive reactions in AD patients may display as weaker reactions that would be mistaken as irritant reactions, i.e. a negative patch test. One reason for this is that patients with AD are less likely to exhibit the “crescendo” pattern of increasing reactivity between patch test reads seen in true positive reactions.[103] Another reason is that positive reactions may be weaker in patients with AD, especially with increasing severity of disease, as they may be less effective at acquiring sensitization.[60, 108] Delayed reads of >96 hours may be somewhat helpful to overcome this.[109–111] Some patients may benefit from an empiric trial of allergen avoidance despite only displaying an irritant or weak positive reaction. In addition, if patch testing was performed but only displayed no or irritant reactions in a patient with a compelling history and/or physical exam for ACD, then false negatives should be contemplated. In such patients, particularly those with uncontrolled dermatitis during patch testing, repeat patch testing should be considered at a later date and may successfully identify relevant positive reactions, despite false negative or weak reactions upon initial patch testing.

Finally, active AD may paradoxically result in false negative reactions on patch testing. The risk of false negatives was found to be higher with increasing severity of AD; this may be true even when the patches are applied to apparently non-lesional skin and patients are not on systemic immunosuppressive medications.[94, 101] One experimental report demonstrated that well-controlled AD (less than 10% body surface for at least one month) is associated with lower rates of false negative reactions.[60] Taken together, the results of patch testing in AD patients should be interpreted with caution.

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6 Conclusion

The risk of ACD appears to be increased in patients with AD, though this association remains controversial. Regardless, ACD is an important comorbidity and potential exacerbant of AD in clinical practice. Mechanisms of ACD developing in AD patients include epidermal barrier dysfunction leading to increased allergen and irritant penetrance, repetitive exposure to allergens secondary to frequent use of topical medications and personal care products, and bacterial colonization in AD promoting inflammation and potentiating contact sensitization.

Patch testing should be considered in adolescent- or adult-onset AD, worsening or more generalized dermatitis, localized or atypical lesional distribution suggestive of contact dermatitis, refractory AD, prior to systemic immunosuppressive treatment, or when AD worsens with topical therapy. Patch testing in AD should use an expanded patch-test series, though more research is needed to determine the optimal screening series in AD patients.

Table 2

Pitfalls in patch testing in atopic dermatitis (AD) patients.

Current or recent exposure to systemic immunosuppressive medications (Section 4.2), ultraviolet therapy or excessive solar radiation can decrease the sensitivity threshold of patch testing and lead to false negatives. Repeat patch testing should be considered upon treatment discontinuation and washout.

Patients with AD have a lower irritancy threshold, which may lead to higher rates of irritant or false positive reactions (most commonly with metals, fragrance, formaldehyde, and lanolin)

Positive reactions in AD patients may display as weaker reactions and be misdiagnosed as an irritant reaction (i.e. negative reaction)

Active or flaring AD may result in false negative reactions due to decreased contact sensitization

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Key points

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Acknowledgments

This publication was made possible with support from the Agency for Healthcare Research and Quality (AHRQ), grant number K12 HS023011, and the Dermatology Foundation.

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Footnotes

Compliance with Ethical Standards

J Owen, P Vakharia and JI Silverberg have no relevant conflicts of interest to declare.

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