English version of clinical practice guidelines for the management of atopic dermatitis 2024

1.1.1 Disclaimer

If the contents of medical activities based on an individual's circumstances differ from those stated in the present guidelines, they may not be checked, or the experience of healthcare professionals may not be denied. By contrast, even if the recommendations in the present guidelines are not performed, the responsibilities of physicians may not be pursued. The application of these guidelines as a basis for use in medical disputes or in medical litigation deviates from their original purpose.

Some evidence-based therapies (from Japan and other countries) with drugs that are not covered by health insurance (unapproved drugs) are described in the guidelines, with the grade of recommendation. The idea that drugs or therapies described in the guidelines are available in clinical practice is not correct. This also applies to the use of drugs of which contraindications or careful administration is described in the package inserts. Even if unapproved drugs are described in the guidelines, restrictions are not eliminated. Individual drugs should be managed based on the contents of the package insert or the latest information regarding safety.

1.1.2 Conflict of interest

According to the criteria for conflicts of interest (COI) at the institutions of each committee member or the “COI management guidelines” and the “Guidance on eligibility for participation in the formulation of clinical practice guidelines” of the Japanese Association of Medical Sciences, the committee members of the present guidelines disclosed their COIs for the past 3 years until the inauguration, and for each year until the publication of the guidelines. The costs to develop the guidelines have been supported by research grants from the JDA and JSA. The members of this committee did not receive any rewards for the development of the guidelines or participation in related meetings. There has been no intervention by the JDA or JSA that could influence the contents of the guidelines. To avoid any influence by potential COIs on the guidelines, all recommendations were determined based on consensus voting, rather than on individual opinion. With respect to voting on clinical questions (CQs), committee members with financial, academic, or other COIs beyond the regulations were required to abstain from voting, although they could participate in the discussion. Concerning CQs regarded as non-specialty by each committee member, it was possible to choose to abstain from voting. Furthermore, the contents were polished with reference to the opinions of the representatives of the JDA and JSA (public comments).

Members of the committee for the guidelines and their relatives, defined as within the first degree of consanguinity, self-reported whether they received remuneration that corresponds to one of the following categories from companies or other bodies involved in the diagnosis or treatment of AD (the target period was between January 1, 2019, and December 31, 2023): (i) directors' or advisors' fees, (ii) shares of profit, (iii) royalties, (iv) lecture fees, (v) manuscript fees, (vi) research costs, (vii) scholarship donations, (viii) chairs donated by companies or other bodies, and (ix) traveling costs or gifts relevant to a company/organization. For disclosure of COI and abstained CQs for each committee member, please refer to the JDA's website (https://www.dermatol.or.jp/modules/guideline/index.php?content_id=25).

1.2.1 Definition of AD: Concept of disease

Atopic dermatitis is pruritic, eczematous dermatitis. Its symptoms chronically fluctuate with remissions and relapses. Most individuals with AD have atopic diathesis: (i) personal or family history (asthma, allergic rhinitis and/or conjunctivitis, and AD) and/or (ii) predisposition to overproduction of immunoglobulin (Ig) E antibodies.

Atopic dermatitis is an eczematous skin disease characterized by symmetrical distribution, and the skin areas typically affected vary depending on age.^{16, 17} AD may develop during infancy or early childhood and may lead to remission during childhood; however, AD may become chronic in some cases with repeated relapses without remission, and present with characteristic eczematous lesions that persist until adulthood. Adolescent-/adult-onset AD also occurs, but with low incidence.

The presence of allergy is not always necessary for the definition of AD. This differs from allergic rhinitis, for which the presence of allergy is mandatory for diagnosis.¹⁸ Urticaria is not considered when investigating family and medical history. Total serum IgE levels and allergen-specific IgE antibody levels are considered disease markers, for the tendency to produce IgE antibodies. As the total IgE level increases in response to disease activity, it is often low in patients with mild AD. In mild AD, the allergen-specific IgE antibody level can be a disease marker.

1.2.2 Pathophysiology

Atopic dermatitis is a multifocal disease with multiple etiologies. Different etiologies are involved in the pathogenesis of AD within the context of atopic diathesis and hypersensitivity reactions of organs, including the skin, which may be caused by causative factors (physical constitution) and the vulnerability of barrier functions. The lack of hierarchy among those etiologies contributes to the diverse symptoms or phenotypes of AD.

Skin hypersensitivity: Abnormalities of the horny cell layer. The horny cell layer is a thin membrane structure of 10–20 μm located on the surface and outermost layer of the skin and is comprised of a dozen horny cells and intercellular lipids of the stratum corneum. The stratum corneum also forms a barrier contributing to the prevention of leakage of body fluids, retention of internal water within the cell layers, and contributes to biological defense (Figures 1 and 2). Dysfunction in the barrier of the horny cell layer results in enhanced cytokine production in the epidermis, activation of the Langerhans cells,¹⁹ allergen sensitization, and inflammation. Furthermore, skin irritability to non-specific stimuli is also enhanced. Intercellular lipids of the stratum corneum are mainly composed of ceramide, cholesterol, and free fatty acids, and in the case of AD, the function of the intercellular lipids of the stratum corneum deteriorates due to an abnormal decrease in ceramide content, and the moisture retention capacity is impaired.^{20, 21} The horny cell layer consisting of keratin and filaggrin is structurally robust. Its external membrane is supported by a cornified cell envelope, which contributes to the formation of a strong barrier on the skin surface. Filaggrin loss-of-function mutation and filaggrin deficiency associated with inflammation have been observed in AD.^{22, 23}

Abnormalities of the epidermis. The epidermis also plays an important skin barrier function. The epidermis has an intercellular adhesion structure known as tight junctions (Figure 1). Specifically, the tight junctions located in the granular layer regulate the movement of substances from inside to outside the body. A decreased claudin-1 expression, which serves an important role in the formation of tight junctions, and the presence of single nucleotide polymorphisms in the claudin-1 gene have been observed in patients with AD.^{24, 25}

Mechanisms involved in inflammation. The application of various external stimuli to sensitive skin leads to the production and release of interleukin (IL)-33, IL-25, and thymic stromal lymphopoietin (TSLP) from the epidermal keratinocytes. The activation of type 2 innate lymphoid cells (ILC2) and T helper 2 (Th2) cells by these agents induces type 2 inflammation, leading to the production of IL-4, IL-5, IL-13, and IL-31 (Figure 2). A decline in skin barrier function may allow allergens to easily penetrate the skin. Allergens, which are foreign (non-self) molecules, are eliminated through immune responses and excessive immune responses induce allergic reactions. Allergens, such as the dust mite allergen, induce type 2 immune reactions through protease activity.^{16, 17} Type 2 immune responses lead to allergen-specific induction of IgE antibodies. Langerhans cells and mast cells express the high-affinity IgE receptor (FcɛRI) and release cytokines and chemical transmitters (e.g., histamine) via binding of allergen-specific IgE to induce inflammation. In addition, thymus and activation-regulated chemokine (TARC) is produced from the inflamed skin, promoting the infiltration of Th2 cells into the lesion site. Th22 cells produce IL-22 after migrating to the skin, likely via regulation by activated cutaneous dendritic cells, which induces epidermal acanthosis.²⁶ The involvement of basophils in the inflammation and the infiltration of other T-cell subsets (Th1 and Th17 cells) into the skin lesion have also been reported, but their roles in the pathogenesis remain to be elucidated.

Pruritus. Chronic pruritus, a key symptom of AD that is involved in its pathogenesis, significantly impairs the quality of life (QOL) of patients. Scratching in response to pruritus impairs the function of the skin barrier and exacerbates inflammation.

Chemical mediators such as histamine, cytokines, and chemokines involved in peripheral inflammation in AD induce pruritus. AD lesions are characterized by the presence of high levels of histamine,²⁷ an activated amine primarily released from resident mast cells in the tissues, and high concentrations of histamine are present in the tissues. Histamine activates histamine type 1 receptors (H1R) on the sensory neurons, inducing acute pruritus. The involvement of histamine in the pathogenesis of pruritus in AD is considered partial, and H1R antagonists are used to provide some relief from pruritus (CQ19).²⁸ Exposure to dryness, scratching, or chemical stimuli leads to the release of the cytokines TSLP and IL-33 from the epidermis. TSLP and IL-33 act as triggers for type 2 inflammation and induce pruritus by directly acting on the sensory neurons.^{29, 30} IL-31 has been identified as a substance that directly stimulates sensory neurons, leading to acute pruritus. Thus, it is a representative cytokine involved in the immune–neuronal correlation of pruritus.^{31, 32} IL-31 enhances the irritability of nerves in the skin.³³ High levels of IL-31 have been detected in the skin lesions of AD, with the serum levels of IL-31 showing a correlation with the disease activity.^{34, 35} Monoclonal antibodies against IL-31 receptor A have demonstrated efficacy in improving pruritus in patients with moderate-to-severe AD (CQ17).³⁶ IL-4 and IL-13 act on IL-4 receptor α (IL-4Rα). Accumulated evidence from anti-IL-4Rα monoclonal antibody therapy has confirmed the significance of IL-4 and IL-13 as effector molecules in patients with AD.^37-39 IL-4Rα is expressed on sensory neurons, and IL-4 and IL-13 directly activate these neurons in vitro.⁴⁰ In contrast to pruritogens, such as IL-31, which induce acute pruritus in vivo, IL-4 and IL-13 induce chronic pruritus by enhancing the sensitivity of sensory neurons to other pruritogens, such as histamine, IL-31, and TSLP.⁴⁰

The central nervous system is thought to be involved in the induction of pruritus in patients with AD. The urge to scratch prompted by the visual/auditory stimuli to recall pruritus is induced by the central nervous system without the involvement of the skin. This urge is stronger and more pronounced in patients with AD than in healthy individuals.⁴¹

1.2.3 Genetic factors

Some genes have been described as candidate genes associated with AD: CTLA4, IL18, TLR9, CD14, CARD4, PHF11, TLR2, SCCE, MCC, IL4R, GMCSF, TIM1, CARD15, GSTT1, SPINK5, SCYA11, TGFβ1, IL13, RANTES, IL4, and FCER1B.¹³ In addition, 2q12 (IL1RL1/IL18R1/IL18RAP), 3q21.33 (GLB1), 3q13.2 (CCDC80), 6p21.3 (MHC region), 7p22 (CARD11), 10q21.2 (ZNF365), 11q15.4 (OR10A3/NLRP10), and 20q13 (CYP24A1/PFDN4) have been reported to be an AD-related region based on genome-wide linkage analysis from Japanese samples.⁴¹

1.2.4 Factors involved in onset and exacerbation

Regarding clinical pathology, factors associated with disease onset and worsening should be considered. In addition to adherence to treatment, exposure to environmental factors including allergens and stimuli in the workplace and daily environment, lifestyle factors, and temperature, in addition to dysregulation of physiological changes in skin function are associated with the maintenance and exacerbation of dermatitis. A feeling of warmth, sweating, wool fibers, psychological stress, food, alcohol consumption, and common colds are considered particularly important as inducing and exacerbating factors of itch in AD.⁴³ Details regarding the onset and exacerbating factors and their specific measures will be discussed below.

1.2.5 Epidemiology

Epidemiology of AD in Japan

Prevalence during childhood to early adolescence. AD generally has onset during infancy and childhood, and the number of newly diagnosed cases decreases with age. Expectedly, some patients will shift to adult type AD. In an analysis of 14 studies, reporting the results of AD prevalence surveys conducted using dermatological medical examination data from 1992 to 2002 in Japan, the prevalence rates for different age groups varied and depended on the report. AD prevalence rates ranged from 6%–32% in infants, 5%–27% in preschool children, 5%–15% in school-age children, and 5%–9% in university students; the overall prevalence tended to decrease with increasing age.⁴⁶ A nationwide AD prevalence survey was conducted from 2000 to 2002 using medical examination records from public health centers and elementary schools as a part of the Health Labor Sciences Research initiative.^{47, 48} Base facilities were set-up in Hokkaido, Tohoku, Kanto, Chubu, Kinki, Chugoku, Shikoku, and Kyushu, and medical examinations were performed by specialists. Figure 3a exhibits the prevalence rates stratified according to age. National averages for prevalence rates based on medical examination were 12.8% (351/2744), 9.8% (631/6424), 13.2% (906/6868), 11.8% (1479/12489), 10.6% (1185/11230), and 8.2% (684/8317) in 4-month-old infants, 1.5-year-old children, 3-year-old children, first graders, sixth graders, and university students, respectively. Although the prevalence rate by district is believed to be higher in cities and lower in suburban areas, no significant difference in the prevalence rates among school children was observed between cities and suburban areas in this survey. Moreover, no differences in rates between boys and girls were observed.

Prevalence rates in the adult population. Between 2006 and 2008, the Health Labor Sciences Research study, a prevalence survey of AD in adults, was conducted through medical examinations performed on 4826 university staff members of Tokyo University, Kinki (Kindai) University, and Asahikawa Medical University.⁴⁷ The prevalence rates of AD by age group were 10.2%, 8.3%, 4.1%, and 2.5% in adults in their 20s, 30s, 40s, and 50s to 60s, respectively (Figure 3b). The prevalence rates stratified by sex were 5.4% and 8.4% in male and female participants, respectively, indicating a higher prevalence in women, which was particularly higher in women in between the ages of 20 and 30 years. This medical examination survey among university staff can be considered reference data given the small sample size, and the geographic areas and occupations surveyed were also limited. Nonetheless, the results of this survey indicate that AD may be the most common cutaneous disease observed among young adults in their 20s and 30s as well as in children and adolescents.

Severity. Figure 4a presents the distribution of patients with AD by severity from individuals aged 1.5 years to university students in a nationwide epidemiological survey. The proportions of patients with moderate, severe, or very severe AD according to age were 16%, 15%, 24%, 28%, and 27% for 1.5-year-old infants, 3-year-old children, first graders, sixth graders, and university students, respectively.⁴⁷ Based on these results, worse symptoms were generally more often exhibited in school-aged children than in preschool children. The proportions of patients with severe or very severe AD according to age were 1.7%, 2.2%, and 5.5% in first graders, sixth graders, and university students, respectively, showing a tendency for AD to increase in prevalence with age.

The distributions of AD according to severity based on the medical examination survey conducted among university staff of Tokyo University, Kindai University, and Asahikawa Medical University were 80.1%, 17.7%, 1.5%, and 0.6% for mild, moderate, severe, and very severe cases, respectively. The proportion of patients with moderate, severe. or very severe AD was smaller in individuals in their 40s or older than in individuals in their 20s and 30s (Figure 4b).⁴⁹

Annual changes in prevalence. The number of patients with AD has been increasing. A survey of changes in prevalence over time of physician-diagnosed AD in the same geographical area was conducted in the Aichi prefecture. Accordingly, the AD prevalence was 2.8% among 3- to 15-year-old children in 1981 and increased in a stepwise fashion to 6.6% in 1992. After 1992, it reached a plateau, and the prevalence rate remained 6.6% in 1999.⁵⁰

According to the AD prevalence survey in infants conducted by the Research Project of Child and Maternal Health of the MHLW, the prevalence of nationwide, physician-diagnosed AD was 5.3% and 8.0% in 1.5- and 3-year-old children respectively, in 1992.⁵¹ A slight difference was found in the survey method used between the nationwide survey conducted during the 2000–2002 period and the survey conducted in 1992; nonetheless, the number of infants reported to have AD may have increased. In an allergic disease prevalence survey conducted in elementary-school children living in western Japan, the prevalence rate of AD in 2002 was lower than that in 1992, although this was a questionnaire-based survey.⁵² Conversely, in an epidemiological study using ISAAC questionnaires on the prevalence of allergic diseases in schoolchildren (aged 7–15 years) in Kyoto City, the prevalence of AD increased slightly from 4.2% (1996) to 5.6% (2006).⁵³

Studies on the prognosis of AD

Studies abroad. In Italy, Ricci et al.⁵⁴ followed up 252 children diagnosed with AD, ranging in age from 6 months to 3 years, who were referred to specialized hospitals for an average of 16.9 years to evaluate their clinical course. During the follow-up period, complete remission of AD was observed in 60.5% of children. Sensitization to eggs was associated with a delay in remission. Illi et al. extracted data from 1314 of 7609 neonates born in six facilities across five cities in Germany in 1990 and followed up the children until age 7 years. Of these, 1123 children (85.5%), 13.4% were diagnosed with AD before age 1 year, and the cumulative prevalence rate at 2 years of age was 21.5%.⁵⁵ Of the children diagnosed with AD before age 2 years, 43.2% were cured by age 3 without any evidence of eczema until age 7, although, eczema appeared until age 7 in 38.3% of children, and symptoms persisted in 18.7% of children. Poor prognostic factors included AD severity at age 2 years, allergen sensitization (particularly to wheat and soybean), a strong family history, and early wheezing complications. In China, Zhang et al. followed 260 children who developed AD before age 2 years. The remission rates at 6 and 12 years were 50.8% and 70.3%, respectively. Factors such as severity, family history of asthma, and sensitization to food contributed to the persistence of AD.⁵⁶

While there are few studies on the prognosis of AD in children (from pre-adolescence to adulthood), in a report from Sweden that followed up patients aged ≥20 years at the initial consultation for 25–38 years, symptoms persisted in the latter 12 months of follow-up in more than half of the patients.⁵⁷

Studies in Japan. Regarding the onset and clinical course of AD during infancy, the Health Labor Sciences Research 2006–2008 study reported the results of a survey in which infants were followed up from age 4 months to 3 years using medical examination data obtained in Yokohama City, Chiba City, and Fukuoka City. According to this report, the onset of AD was observed in 16.2% of infants who participated in the 4-month medical examination (Figure 5).⁵⁸ Interestingly, 70% of the children diagnosed with AD within 4 months demonstrated complete remission at age 1.5 years. In this survey, the cumulative onset rate up to age 3 years was ≥30%, which is very similar to the rates reported in studies from abroad. Fukiwake et al.⁵⁹ (Kyushu University) examined kindergarten children in the Ishigaki Island for 4 years and reported that 53 of 74 (71.6%) children diagnosed with AD experienced complete remission within 3 years, whereas 5.5% of the children not previously diagnosed with AD, were eventually diagnosed with new-onset AD within 3 years.

Ohshima et al.⁶⁰ followed up 169 infants aged <1 year diagnosed with AD by pediatric allergy specialists for 4 years and reported that Symptoms imprroved in 51% and disappeared in 34 %, respectively. Shibuya and Saito⁶¹ conducted a birth-cohort survey involving infants or children aged ≤4 years and reported that the remission of AD was achieved at age 4 years in 30 (75%) of 40 children diagnosed with AD at age 1 year. Yamamoto-Hanada et al.⁶² performed a birth-cohort study involving the general population (T-CHILD study) and confirmed that AD can be classified into four types (never/infrequent, 62.7%; early onset, 17.8%; late onset, 9.5%; persistent, 10.1%) based on the follow-up course for 9 years. Furthermore, they conducted a multicenter birth-cohort survey involving the general population (JECS cohort) and reported that the prevalence rates of AD symptoms at age 1, 2, and 3 years were 4.0%, 7.3%, and 6.0%, respectively.⁶³ Anan et al. conducted a questionnaire survey among family members of patients considered to have achieved a spontaneous remission and reported that spontaneous remission was observed starting at age 2–3 years, and 50% of the children achieved spontaneous remission at age 8–9 years. Approximately 90% of children achieved spontaneous remission after age 16 years.⁶⁴ Wakamori et al. reported that three-quarters of children who had AD at the first grade of elementary school experienced remission before entering junior high school. The study surveyed AD outcomes in elementary school children and junior high school children using dermatological medical examination data spanning over 10 years in the mountainous areas of Kyoto prefecture.⁶⁵ Katoh et al.⁶⁶ investigated the prognosis of AD in adulthood; the number of affected patients gradually decreased from a peak in patients aged 20–30 years, and by age 40, two-thirds of the patients experienced improvement to the level where they no longer needed to visit the dermatological department.

1.2.6 Diagnostic criteria

Based on the Definition and Diagnostic Criteria for AD prepared by the JDA, patients meeting three basic items are regarded as having AD regardless of the severity of symptoms, namely, (i) pruritus, (ii) typical morphology and distribution of eczema, and (iii) a chronic or chronically relapsing course (Table 1).^{16, 17} Patients suspected of AD are regarded as having acute or chronic eczema, and diagnoses are made based on their age and disease course. Thus, it is essential to differentiate the disorders that should be ruled out in the diagnosis of AD and be familiar with the complications of AD. Internationally, the diagnostic criteria prepared by Hanifin and Rajka in 1980⁶⁷ and by the UK Working Party⁶⁸ are widely used.

1.2.7 Characteristics of eruption

Infancy (aged <2 years). Eruptions usually initially develop on the cheek, forehead, or head (exposed area), appearing as skin dryness followed by flushing or papules during early infancy. With disease progression, flushing becomes more severe and is associated with itching; thus, eruptions will worsen by scratching and may lead to the formation of eczema and crusts. Concurrently, the eruption extends to the entire face including the ears, mouth, cheek, jaw, and surrounding areas. With a slight delay following the occurrence of facial symptoms, exudative erythema develops in intertriginous zones such as the neck, cubital fossa, and popliteal fossa; moreover, erythema and papules develop on the thoraco-abdominal region, back, and extremities (Figure S1).

Childhood or school age (2–12 years old). From early childhood to school age, eruptions on the face decrease, but eruptions are typically observed on the neck, cubital fossa, popliteal fossa, inguinal area, wrist, and ankle.⁶⁹ In severe cases, eruptions extend to the face and limbs, and repeated scratching leads to repeated erosions and blood crusts. Lichen papule and prurigo nodularis may develop on the elbows, knees, hands, and legs. Dry skin- or goose bump-like follicular papules may be observed on the trunk and extremities (Figure S2).

Adolescence or adulthood (aged ≥13 years). After puberty, eruptions are more likely to develop on the upper body including the face, neck, chest, and back. In some cases, facial-type eruptions markedly affecting the face to neck or a prurigo-type eruption consisting of multiple papules of the trunk and extremities with strong itching is observed. In severe cases, eruptions extend throughout the body resulting in erythroderma (Figures S3–S6).

Site of eruption. While eruptions can develop in any body area, eruptions develop more rapidly and intensely in regions influenced by external factors. Generally, eruptions develop symmetrically.

Characteristics of eruption. Eruptions present morphological characteristics of both eczema and dermatitis. The manifestation can be divided into acute and chronic lesions. Across all age groups, patients with AD are likely to have dry skin (dried skin, xeroderma, dry skin, and atopic skin). This characteristic is not visible in the absence of inflammation of the skin; however, it is remarkable in the presence of dermatitis.

Acute lesions occur at the initial onset or acute progression of eruption in the chronic phase. Eruptions immediately after acute onset present with erythema and papules. Some may have vesicles in the epidermis, which are considered eczema erythema, and may include serous papules. When the epidermis is damaged by disease progression or scratching, exudative fluid leaks from the lesion, which leads to crust formation.

Chronic lesions are eruptions that have transitioned mainly due to scratching. Repeated scratching results in a thickened skin because of mechanical irritation forming lichenified lesions and prurigo nodularis.

1.2.8 Differential diagnosis

The main differential diagnostic criteria to consider when distinguishing diseases from AD are presented below. These diseases may occur in association with AD.

Contact dermatitis. In this disease, eczema develops on a site where an allergen has come into contact with an individual sensitized to that antigen. Eruptions are often well-circumscribed. Various substances such as cosmetics, metals, and topical drugs can act as potential allergens. It is important to be suspicious of contact dermatitis if eruptions are localized only on the face or other regions and are refractory to treatment, or if a localized eczema lesion is asymmetrical (Figure S7).

Seborrheic dermatitis. Erythema and scales develop on seborrheic sites (i.e., scalp, eyebrows, mesophryon, forehead, sulcus nasolabialis, pinna and back pinna, axilla, anterior chest, umbilical region, and genitals, etc.). Itching is generally mild. Lipophilic fungi such as Malassezia furfur that normally present on the skin appear to be associated with the pathophysiology. During infancy, scaly erythema with yellow crusts is observed at 1 month after birth (Figure S8); thereafter, it often naturally resolves within 1–2 months. When it develops in adults (especially after middle age), chronic pale erythema and scales are observed during the clinical course (Figure S9). Whether an eczematous lesion or dry skin can be observed on the trunk or limbs as well as the presence of eruption on the seborrheic site such as the sulcus nasolabialis, is a differential diagnosis point (if present, it is highly likely to be AD).

Prurigo simplex. Papules or small nodules develop with a strong itch. Generally, uniformly sized papules or small nodules often develop and spread. Insect bites may be one of the causes. A prurigo eruption frequently develops as a type of AD eruption. The presence and clinical course of eczematous lesions or dry skin other than prurigo and a history of atopy can help in the diagnosis (Figure S10).

Scabies. Scabies is caused by Sarcoptes scabiei infestation on the skin, and infection usually occurs following long-term contact with the skin, bedding, or clothes of the infected patients. Papules accompanied by severe itching are observed on the body trunk and limbs (Figure S11), and linear scaling is observed on the palmar or interdigital area (so-called scabious tunnel). As infections are often observed in elderly care facilities or hospitals, opportunistic infections should be considered. Scales should be dissolved with potassium hydroxide (KOH) solution for microscopic observation. If mites or eggs are detected, the diagnosis can be confirmed.

Miliaria. Red papules often develop following the occlusion of eccrine sweat glands. Miliaria is often observed in neonates and individuals affected by excessive perspiration. It is commonly called a “heat eruption.” Red papules of 1–2 mm in size accompanied by itching occur frequently and are often observed on the trunk, flexion side of the limbs, neck, and axilla. The presence of the eruption on other sites, observation of its characteristics, and medical interviews on the clinical course are useful to differentiate this lesion from AD.

Ichthyosis. The skin of the entire body becomes dry and rough and develops fish-like scales. Ichthyosis vulgaris is an autosomal dominant cutaneous disorder with onset during infancy. It resolves during summer. It may be complicated by AD. The presence of an eczematous lesion is the differential diagnostic point.

Xerotic eczema. Xerotic eczema is caused by dry skin and is often observed in the winter among older people. It often occurs on the extension side of the lower leg. In many cases skin dryness can be observed even on sites without eczema. Patients with AD can also develop eczema due to dry skin, which often progresses during winter; however, xerotic eczema can be differentiated from AD by its clinical course and distribution and properties of the eruption.

Hand dermatitis (to distinguish hand dermatitis from AD). Eczema occurs on the hands following physical and chemical stimulation or allergy and is commonly referred to as “damaged hands.” It is often observed in individuals with occupations requiring substantial exposure to water, such as hairstylists, cooks, healthcare professionals, and stay-at-home parents. Eczema on the hands is a symptom of AD; thus, the presence of eruption on sites other than the hands or the clinical course can be used in the differential diagnosis.

Cutaneous lymphoma. Malignant lymphoma primarily develops on the skin, and its representative diseases are mycosis fungoides and Sézary syndrome (Figure S12A,B). Mycosis fungoides is a T-cell lymphoma with a chronically progressive clinical course. It typically worsens from an erythematous stage, in which various sizes of erythema are observed on the trunk and limbs, evolving to the plaque stage (infiltrative stage) and a tumor phase after a prolonged clinical course. In the erythema stage, a light red to brownish-red erythema is often observed with mild scales. When making a diagnosis, differentiating from eruption due to AD is sometimes clinically challenging. When the diagnosis is uncertain, it is important to perform a skin biopsy to examine the pathological findings (e.g., presence of lymphocyte infiltration on the epidermis). Sézary syndrome is characterized by three features, namely, erythroderma, superficial lymph node swelling, and presence of atypical lymphocytes in the peripheral blood, and is often accompanied by intense itching. To differentiate from AD presenting with erythroderma, peripheral blood smears and dermato-histopathological findings are important.

Psoriasis. Psoriasis is an inflammatory keratosis presenting with well-circumscribed red plaques with thickened scales. It commonly appears on sites susceptible to external stimuli, such as the elbow, knee, and scalp, while the eruption can appear throughout the body including the palmar and plantar regions. Scales can be described as silvery white. Various eruptions, such as serous papules, and eczema erythema observed in patients with AD are generally not present in psoriasis. Pathological differential diagnosis based on a skin biopsy is useful.

1.2.9 Severity assessment

A precise severity assessment is essential for appropriate treatment selection. While overall severity is assessed, assessment of the severity of the local lesion (i.e., individual eruption) is also important to select the topical drug to be applied locally.

1.2.10 Useful biomarkers for diagnosis and severity assessment (Table 3)

Serum IgE levels. A high serum total IgE level is observed in patients with allergic diseases; however, a clear cut-off cannot be established because its distribution greatly overlaps with that of healthy individuals. In patients with AD, a total serum IgE level of ≥500 IU/mL is commonly observed.⁹⁸ The serum total IgE level may represent allergic diathesis rather than short-term disease activity in AD. However, it can be an indicator of long-term response in severe cases, as the high serum total IgE level decreases after several months of follow-up.

In addition, patients with AD are often sensitized to multiple allergens including mites, house dust, pollen, fungi, and food. These allergens can be detected by specific serum IgE antibody tests and the skin prick test; however, non-specific sensitization is often observed, that is, the presence of positive specific IgE antibodies is not always causally related to the exacerbation of symptoms. In examining the causal relationship between allergens and symptoms, an adequate medical interview is a fundamental approach.

Peripheral eosinophil count. Peripheral eosinophilia is more significant in patients with AD compared with other allergic diseases such as bronchial asthma or allergic rhinitis. As the peripheral eosinophil count increases with disease severity, it can be a marker of disease progression.

Serum lactate dehydrogenase (LDH) level. Serum LDH level increases in more severe cases; thus, it acts as a marker of disease progression. An increase in LDH levels may reflect tissue damage caused by skin inflammation, and it returns to a normal level when the eruption is resolved. Nonetheless, in cases in which LDH levels remain elevated, complications due to other diseases leading to tissue damage should be suspected and a differential diagnosis considered.

Serum TARC level. TARC (CCL17) is a ligand of the chemokine receptor CCR4 and induces Th2 cell migration.⁹⁹ The serum TARC level in patients with AD increases consistently with severity, and testing for TARC levels is covered by the national insurance, as it reflects disease progression more strongly than serum total IgE levels, LDH levels, or peripheral eosinophil counts.^{100, 101} Moreover, patient education and treatment can be reviewed using serum TARC levels as an index.¹⁰² However, test values should be carefully interpreted because TARC levels are generally higher in younger children, especially in children aged <2 years.¹⁰³ The reference levels according to age are shown in Table 3. When treated with nemolizumab, serum TARC levels may transiently increase, exhibiting no correlation with the clinical symptoms; therefore, caution is required.¹⁰⁴

Serum squamous cell carcinoma antigen (SCCA2) is a serine protease inhibitor that belongs to the serpin superfamily (serpin is derived from the SERine Protease INhibitor). It is classified into two proteins, SCCA1 and SCCA2, coded by the high-homology genes, SERPINB3 and SERPINB4, respectively, which are located on chromosome 18q21.3.¹⁰⁵ They were first identified in patients with cervical carcinoma,¹⁰⁶ and they have been utilized for monitoring several squamous cell carcinomas.⁹⁶ Moreover, SCCA1 and SCCA2 are Th2-related molecules induced by IL-4 and IL-13,¹⁰⁷ and they play an important role in barrier dysfunction or skin inflammation in an AD animal model.¹⁰⁸ Thus, these proteins have also been clinically examined as important biomarkers in patients with AD. Particularly high serum SCCA2 levels have been observed in AD among individuals with pediatric allergic disorders,¹⁰⁹ showing a strong correlation with SCORAD and EASI and accurately reflecting treatment responsiveness.^110-112 Serum SCCA2 testing is covered by health insurance for children (aged ≤15 years). The reference range is unified regardless of age.¹¹⁰

1.3.1 Goal of treatment

The goal of treatment is to reach and maintain a state in which symptoms are absent or mild without disturbance of daily activities and drug therapy is not required. Even when this level is not reached, the objective is to maintain a state in which symptoms are mild without rapid exacerbations that affect daily activities.

1.3.2 Treatment measures

Figure 6 illustrates the algorithm used for the management of AD. Making a definite diagnosis of AD and performing a severity assessment is the first essential step. The diagnosis of AD should be made in accordance with the definition and diagnostic criteria proposed by the JDA (Table 1). Furthermore, it is essential to accurately differentiate diagnoses to be excluded (although they may coexist). The overall severity of AD must be assessed based on criteria such as the “severity index” of AD (Table 2) after making the definitive diagnosis. Factors such as current medical history, past medical history, family history, and evaluation of the extent and severity of AD (including the social background of the patient and family) should be considered while making the definitive diagnosis and performing the severity assessment. In the treatment of AD, it is important to explain to the patient the disease and the goal of treatment and to share the goal with the patient. In addition, the patient must be provided with concrete explanations regarding drug therapy and skin care, and patient education for optimal treatment should be conducted. The prompt inducing of remission via the suppression of existing skin inflammation and pruritus is a crucial aspect of AD treatment. Topical anti-inflammatory drugs, such as topical corticosteroids (TCS), tacrolimus ointment, delgocitinib ointment, and difamilast ointment, are used to achieve remission. When the remission is achieved, it is important to maintain the remission. In cases where the inflammation is prone to flares, proactive therapy with regular intermittent administration of topical anti-inflammatory drugs can effectively suppress the flare of inflammation. Patients must continue skin care using moisturizers on days when topical anti-inflammatory drugs are not used. When there is minimal flare of inflammation, topical anti-inflammatory drugs must be used at the earliest signs of local flare to prevent the progression of symptoms and their exacerbation.

Topical therapy must be optimized via patient education if the remission cannot be achieved. A sufficient amount (referred to as finger-tip units) of an appropriate rank of topical anti-inflammatory drugs must be applied to the affected areas based on the severity of the eruption. In addition, the diagnosis of the severity of AD must be reconfirmed. A skin biopsy must be performed, if necessary, to exclude diagnoses such as cutaneous lymphoma. For patients with refractory moderate-to-severe AD, despite the confirmation of the diagnosis and optimization of topical therapy, the following treatments should be considered in addition to topical therapy: oral cyclosporine, subcutaneous injections of biologics (dupilumab, nemolizumab, and tralokinumab), oral Janus kinase (JAK) inhibitors (baricitinib, upadacitinib, and abrocitinib), phototherapy, and psychosomatic therapy. If the remission is achieved via the above-mentioned treatment strategies, the treatment goal should be aimed at maintaining the remission.

Atopic dermatitis is a multifactorial disease involving genetic predispositions. Currently, no treatment can completely cure this disease. However, in the lesion site, a further inflammation-related reduction in skin barrier function, enhanced irritability, and scratching-related stimuli deteriorate eczema, leading to a vicious cycle of inflammation. Therefore, controlling inflammation by drug therapy will also reduce AD-exacerbating factors.

1.3.3 Drug treatment

Topical anti-inflammatory drugs. These drugs are used to provide adequate attenuation of inflammation in AD. The efficacy and safety of topical TCS, tacrolimus ointments (topical calcineurin inhibitor), delgocitinib ointments (JAK inhibitor), and difamilast ointments (phosphodiesterase 4 [PDE4] inhibitor) have been examined in numerous clinical studies.

Hydrocortisone was the first TCS developed in 1952 and has been used as topical drug therapy for AD for over 60 years.¹¹³ The efficacy and safety of TCS have been examined in many clinical studies.¹¹⁴ TCS are often used as first-line anti-inflammatory topical agents for both children and adults.

Tacrolimus ointment is an inhibitor of calcineurin. Protopic ointment 0.1% was approved and introduced in 1999, and protopic ointment 0.03% was approved and introduced for use in children in 2003.

Delgocitinib ointment inhibits intracellular signal transduction (JAK). In 2020, CORECTIM® Ointment 0.5% was first approved and marketed in Japan.

Difamilast ointment inhibits the expression of PDE4. After receiving approval in 2021, Moizerto® Ointments 1% and 0.3% have been available in the market since 2022.

Other topical drugs include non-steroidal anti-inflammatory drugs (NSAIDs), which have an extremely weak anti-inflammatory effect and are not an uncommon cause of contact dermatitis; indications for their application are narrow. It is important to promptly and effectively attenuate inflammation in AD; thus, combination strategies of TCS, tacrolimus ointments, and delgocitinib ointments should be considered a basis of treatment. The extent of inflammation should be appropriately understood by inspection and palpation to adequately apply these drugs to a sufficient degree.

Topical corticosteroids are used as a basic drug in the treatment of AD (CQ1: Recommendation grade 1, evidence level A). Their intensity (rank) should be fully comprehended to select the most appropriate TCS, based on the severity of the individual lesions. It is necessary to use different dosage forms of topical steroids according to the features and site of lesions to maximize their anti-inflammatory effects. Patients should receive adequate instructions and education to improve adherence.

If eruptions are stable with suitable treatment, AD can achieve remission. It is important to use appropriate TCS to promptly proceed with remission induction therapy to reduce inflammation and itching and to maintain remission by concurrent use of moisturizing agents. Cases showing no improvement in eruption, even after 4-week's treatment with topical drugs or severe cases, should be referred to a dermatologist.

Use of TCS

Selection of rank. A rank table of TCS, as a modification of Takeda's classification, is presented in Table 4.^{16, 17, 75, 115} In Japan, TCS are generally classified into five ranks: strongest (group 1), very strong (group 2), strong (group 3), medium (group 4), and weak (group 5). It is important to carefully select drugs at a rank that matches the severity of each eruption and use them at the required volume for the required period (Table 5).

Severe cases include primarily acute and progressive severe inflammatory lesions, retractable lesions such as lichenification, erythema, multiple papules, multiple scratch scars, or prurigo nodularis. The use of a very strong TCS is the first-line treatment (Figures S15–S20). When sufficient effects are not obtained from a very strong TCS, the strongest TCS is also available.

Moderate cases include primarily inflammatory findings of moderate or less severe erythema, scales, few papules, and scratch scar. The use of a strong or medium TCS is the first-line treatment (Figure S21).

Mild cases include primarily mild dry skin, mild erythema, and scales, and the use of a medium or weak TCS is the first-line treatment (Figures S22 and S23).^{16, 17}

Although there is no need to decrease the rank of the TCS because of age, for infants and children the duration of use should be carefully monitored, as efficacy is likely to appear in a short time in these age groups.

Selection of vehicles. Vehicles, such as ointment, cream, lotion, and tape preparations, should be selected based on lesion characteristics or sites. Ointments should be the basic method selected to treat this disease, which involves dryness. On the other hand, when the oily sensation of ointment use reduces adherence to topical preparations (e.g., summer), a cream base is sometimes selected while avoiding the erosive surface or scratching marks. Lotion preparations are basically used for scalp lesions. Tape preparations could be considered for pruriginous lesions and lichenified lesions.

Way of application

Volume. A volume (~0.5 g) measuring 5 mm in diameter that is pushed out from a tube to an area between the tip and first joint of the second finger is appropriate for two palms of British adults, that is, approximately 2% of the body surface area of adults (fingertip unit)^{16, 17, 116, 117} (Table 6). This may be adopted as a reference, considering the physical status of Japanese individuals and the tube size of TCS available in Japan. On the other hand, the appropriate volume would change according to some factors including skin condition and vehicle of a topical drug.

Frequency of application. Generally, TCS should be applied twice a day (morning and evening after bathing) in cases of acute exacerbation. When inflammation is reduced, the frequency of applications should be decreased to once a day to induce remission. Further evidence is needed to determine whether efficacy differs between twice-a-day and once-a-day applications. However, several randomized controlled studies (RCTs) and systematic reviews have reported no significant difference in the efficacy between twice-a-day and once-a-day applications.^{118, 119} It is generally recognized that even a once-a-day application exhibits potent effects. If the number of applications is low, the incidence of adverse reactions may be low, thereby improving adherence. Therefore, TCS should be applied twice a day to control acutely exacerbated eruptions for an early recovery. When the condition subsides, TCS should be applied once a day to achieve remission.

Consideration for the use of TCS

Regions of application. The absorption rate of topical steroids by skin region is 13.0 on the cheek, 6.0 on the neck and 42.0 on the scrotum, with the extensor surface of forearm defined as having a rate of 1.0.¹²⁰ Such skin regions with a high drug absorption rate require attentive monitoring for the development of local side effects of TCS treatment; prolonged use should be avoided. For the face, medium or weak TCS are generally used, whereas drugs consistent with the severity rank are used for severe dermatitis to introduce prompt remission, and the drugs are then tapered gradually or administered intermittently. Moreover, an effort to transition from TCS to tacrolimus, delgocitinib, or difamilast ointment is made.

Discontinuation of topical drug treatment. When attenuation of inflammation symptoms is achieved, TCS should not be discontinued abruptly; they should be tapered gradually or administered intermittently while maintaining remission. Topical drugs can be discontinued, if possible; however, proactive therapy, as discussed later, should be considered for patients with repeated relapses.

If TCS are suddenly discontinued in adult patients after prolonged use on the face or genitals, erythema, flushing, edema, papules, and pustules may appear and worsen.¹²¹ In such cases, the patient should be referred to a dermatologist.

Side effects of TCS

Systemic side effects. The systemic side effects of TCS depend on the rank of steroids, application volume, and application period. The long-term massive-volume application of high-ranked TCS may induce such side effects.¹²² Furthermore, they may often develop because of high level percutaneous absorption in a skin-barrier-reduced state such as erythroderma. In children, the percutaneous absorption rate is high, and the ratio of the body surface area to the bodyweight is also high; therefore, systemic side effects might occur.¹²² They include suppression of the hypothalamus-pituitary–adrenal system, hypertension, hyperlipidemia, diabetes mellitus, moon face, and Cushing's syndrome.^{122, 123} Studies have suggested that TCS are not a risk factor for osteoporosis.^124-126

However, such systemic effects may not occur in clinical practice for the following reasons. In skin lesions where the barrier function is reduced, the percutaneous absorption rate of steroids increases, and steroid application for extensive eruptions transiently suppresses the adrenal function. However, when barrier function recovery is achieved through anti-inflammatory effects, the percutaneous absorption rate of steroids rapidly decreases.^{127, 128} According to a study regarding the long-term use of very strong TCS, when starting at an initial dose of approximately 5 or 10 g/day in adults and gradually decreasing the dose in accordance with symptoms, there may be no irreversible systemic side effects even after 3 months of treatment, although transient, reversible adrenal function suppression may occur. A study reported that the occlusive dressing technique with a strong TCS, 0.12% betamethasone valerate ointment, at 10 g/day, or simple application at 20 g/day induced adrenal function suppression.¹²⁹ The percutaneous absorption rate after the simple application of the strongest TCS, (0.05% clobetasol propionate ointment, at 10 g/day) corresponds to that of betamethasone administered orally at 0.5 mg/day. The absorption rate after simple application at 40 g/day corresponds to that of betamethasone administered orally at ≤1 mg/day.¹³⁰

However, it is highly exceptional to continue topical steroid therapy at such a large volume in clinical practice¹²⁷ because sufficient volume application promptly controls eczema lesions, leading to decreases in the TCS volume or extent of application and a reduction in the steroid rank. Thus, if TCS are appropriately used, systemic side effects may not develop through standard application methods. Indeed, in a meta-analysis of studies regarding AD in children treated with steroids for ≥2 weeks, the rate of patients with suppression of the hypothalamus-pituitary–adrenal system was 3.8%, and there was no association with symptoms of adrenal failure. When stratifying the patients with respect to low-, medium-, and high-potency steroids, the rates of those with suppression were 2.0, 3.1, and 6.6%, respectively.¹³¹

We cannot conclude that TCS have no systemic side effects;¹²³ therefore, when administering massive TCS volume for a long period or when applying TCS to the lesions where the barrier function is reduced, sufficient examinations of systemic side effects, such as adrenal function suppression, must be periodically conducted. In such cases, adequate management, such as a combination of TCS therapy and systemic treatment other than oral steroid administration, should be considered to achieve a dose reduction of TCS.

Local side effects. Local side effects may develop through the immunosuppressive, cell-proliferation- or stroma-production-suppressing, and hormonal actions of steroids.¹²⁸ Local side effects of TCS include telangiectasia, skin atrophy, striae cutis (striae distensae and striae atrophicae), purpura, rosacea-like dermatitis or perioral dermatitis, hypertrichosis, depigmentation, delayed wound healing, contact dermatitis, acne or folliculitis, and cutaneous infection with bacteria, fungus, or viruses such as herpes simplex, molluscum contagiosum, tinea corporis, and scabies.^{122, 123, 127, 128, 132-134}

Local side effects depend on the steroid rank, application period, application site, and patient age. They may occur when high-ranked steroids are used, steroids are used over a long period, they are applied to areas with high absorption rates, such as the face and genital area, and they are used in older people.^{122, 128} Such side effects are also influenced by the type of base. The percutaneous absorption rate of cream is higher than that of ointment.¹²⁸ Some are based on the specificity of the site, and rosacea-like dermatitis and perioral dermatitis are side effects on the face where the pilosebaceous system is developed.

Most local side effects resolve with the discontinuation of TCS or adequate treatment.^{127, 133} However, striae cutis is irreversible. The percutaneous absorption rate of steroids is high in the axilla, inguinal region, and genital area, often causing striae cutis.¹²⁷

The incidence of the local side effects of TCS can be reduced by selecting an adequate rank and limiting the application period to a necessary one based on the grade or site of eruptions and age. When the skin condition improves, the steroid rank should be adequately reduced, or TCS may be intermittently used. Switching to tacrolimus, delgocitinib, or difamilast ointment after reducing inflammation with TCS is also a good method. A study suggested that the use of tacrolimus ointment reduced the dose of steroid ointment, markedly reducing the local side effects of TCS.¹³⁴

The incidence of local side effects increases with age because the cumulative frequency of TCS usage increases. However, these side effects do not occur in all patients. Furthermore, the incidence of side effects in patients aged <2 years is low.¹³³ Therefore, the necessary TCS should be adequately used without getting excessively anxious, paying attention to the appearance of local side effects.

Pigmentation is sometimes observed after the use of TCS. However, this is post-inflammatory pigmentation related to persistent dermatitis, and it becomes apparent when TCS application leads to the disappearance of inflammation; such a pigmentation is not related to TCS.¹²⁷ Instead, to prevent pigmentation, topical anti-inflammatory medications, including TCS, should be used in the early stage for the dermatitis to sufficiently subside.

Adverse reactions to TCS in the eyes. The frequent application of high-ranked TCS may induce cataracts,^{135, 136} but it is not always associated.^{137, 138} On the contrary, AD itself is a risk factor for cataracts. It is also associated with facial eruptions, and the onset of cataracts may be related to eye-rubbing or scratching activities (CQ6).^138-143 Severe cataract occurrence was frequently observed in patients inadequately treated with drugs other than TCS, supporting its association with the severity of eruptions, but not with TCS.¹⁴⁴ Many case reports on TCS-related glaucoma have been published. The use of high-ranked TCS, frequent applications, or a prolonged application period increases the risk of such a glaucoma (CQ6).¹³⁵ Specifically, TCS use around the eyes may increase the intraocular pressure or risk of glaucoma.¹³⁵ When low-ranked TCS are used, the risk is low.¹⁴⁵

Strong TCS should not be used around the eyes, unnecessarily and chronically for a long period. After improvement is achieved by TCS therapy, the condition should be maintained with tacrolimus ointment.^{136, 146}

How should anxiety about steroids be addressed?

Owing to the misconceptions about treatment with TCS, fears about TCS or avoidance often reduces adherence. Concretely, the side effects of orally administered steroids are wrongly regarded as those of TCS, or the deterioration of AD as the side effects of TCS. Furthermore, misusage makes it impossible for each patient to consider TCS effective, leading to a feeling of distrust for TCS in some cases. To resolve these misconceptions, patients should be educated and instructed by sufficient consultation. Furthermore, the presence of the side effects of TCS should be examined on consultation, and it is important to establish a strong relationship between the healthcare professional and patient by selecting TCS in accordance with symptoms and explaining the frequency of application.

Tacrolimus. Tacrolimus inhibits the activity of intracellular calcineurin. It reduces inflammation via an action mechanism that differs from that of corticosteroids. Tacrolimus ointment can be expected to demonstrate a high level of effectiveness for AD-related eruption, which was difficult to treat with TCS because of adverse reactions (CQ7: Recommendation grade 1, Evidence level: A).

The efficacy of this drug depends on its absorption, application site and barrier function. It is recognized as a drug to be frequently indicated for the eruption on the face and neck. However, there are restrictions for its application that differ from TCS: tacrolimus ointment cannot be applied to erosive or ulcerative surfaces, and its drug efficacy is limited. This drug must be administered according to the “Guidance for the Application of Tacrolimus Ointment in Patients with Atopic Dermatitis.”¹⁴⁷ Tacrolimus ointment is available as 0.1% for adults and 0.03% for children. It cannot be selected for children aged ≤1 year as its safety has not yet been established for this age group. Its application should also be avoided in lactating women.

Volume of application. A volume of 0.1 g (corresponding to a volume squeezed by 1 cm from a 5-g tube commercially available in Japan) is appropriate for an area 10-cm square. Based on the findings of a long-term observational study involving adults, the upper limit of the volume of a 0.1% ointment per session for adults was established as 5 g, to avoid an increase in its blood concentration and maintain its safety. In accordance with the physical status, the maximum volume of a 0.03% ointment per use was established as 1 g for children aged 2–5 years (bodyweight <20 kg), 2–4 g for those aged 6–12 years (bodyweight 20–50 kg), and a maximum of 5 g for those aged ≥13 years (bodyweight ≥50 kg).

Way of application. Irritative symptoms, such as a transient burning sensation and hot flushes, often appear at application sites. However, these symptoms appear at the start of treatment, and most symptoms disappear with improvements in eruptions. This should be explained to patients before the start of treatment. This ointment is very effective for the face and neck, and its percutaneous absorption is favorable. This ointment should be indicated when conventional therapy with TCS is ineffective (e.g., sites in which local adverse reactions to TCS are observed) or when physicians hesitate to administer TCS because of adverse reactions.

The efficacy of this ointment (0.1% for adults) for the trunk and limbs may be similar to that of strong TCS.¹⁴⁷ Generally, when treating the site of severe eruption, which requires potent drug efficacy, very strong or the strongest TCS should initially be used to reduce eruption. The regimen should then be switched to tacrolimus ointment. The TCS volume can be decreased in many cases by combining it with this ointment. If an improvement in eruption is achieved by this ointment, the interval of application should be prolonged at an appropriate time.

Tacrolimus should not be used in sites or eruption areas in which blood transfer of this drug may increase and enhance irritability, i.e., mucosa or genital areas and erosive or ulcerative surfaces. Occlusive dressing techniques and superposition methods should not be adopted because they may increase the blood transfer of this ointment. When erosive or ulcerative surfaces are markedly affected, the application of this ointment should be started after the amelioration of the eruption using other topical drugs.

Adverse reactions. Burning sensation, pruritus, and erythema have been identified as local adverse events. These symptoms decrease or disappear with improvements in eruptions in many cases. Furthermore, the appearance of infectious diseases of the skin, such as secondary skin infections with bacteria and viruses (e.g., herpes simplex, molluscum contagiosum, and verruca), must be considered. Skin atrophy, which is observed with the long-term use of TCS, has not been confirmed. Tacrolimus is detected in the blood following its topical application. Individual differences in blood levels of tacrolimus have been reported due to differences in percutaneous absorption (application of 0.1% tacrolimus: ≤1 ng/mL). Neither systemic adverse events nor toxicity related to blood transfer has been confirmed. We should explain to patients the precautions for use written in the package insert and should obtain their consent.

Risk of carcinogenesis. Evidence showing that the use of tacrolimus ointment does not increase the risk of skin cancer or lymphoma is increasing (CQ8: Evidence level: B). Although previous studies have reported the development of lymphoma during treatments with tacrolimus ointment, these were retrospective in nature. Limitations have been associated with the accuracy of lymphoma diagnoses, and lesions evaluated as AD-related eruptions before the use of this ointment may have been lymphoma.^{148, 149} In addition, a previous study indicated that severe AD increased the risk of lymphoma. Therefore, AD may increase the incidence of lymphoma. Regarding the safety of the long-term use of tacrolimus ointment for children for the treatment of childhood AD, no malignant tumor was found as an adverse event based on the results of follow-up for 10 years maximum in Japan.¹⁵⁰ However, large sample size and long-term follow-up are needed for a carcinogenetic analysis. In the future, the relationship between the volume of tacrolimus ointment or application period and the development of malignant neoplasms must be analyzed through a long-term follow-up.

Delgocitinib. Delgocitinib is a JAK inhibitor that is important for the signal transduction of various cytokines. It inhibits all types of JAK family kinases (JAK1, JAK2, JAK3, and tyrosine kinase 2), suppressing the activation of immune cells.¹⁵² Some clinical studies involving patients with moderate to severe adult AD have reported significant improvement in the eruption score in the 0.5% delgocitinib ointment group in comparison with the vehicle group,^{153, 154} and a phase 3 trial targeting pediatric patients with AD aged 2–15 years demonstrated that delgocitinib at concentrations of 0.5% and 0.25% was more effective in improving eruptions than the vehicle.¹⁵⁵ As topical side effects, folliculitis, acne, Kaposi's varicelliform eruption, herpes simplex, and contact dermatitis have been reported.^153-155 Moreover, based on the results of a phase 3 trial (QBB4-2 study) evaluating the efficacy and safety of 0.25% and 0.5% delgocitinib ointment during a 52-week period of application in mild to severe patients with AD aged 6 months to less than 2 years, in an open-label, non-controlled design, delgocitinib became available for use for pediatric (infant and toddler) patients aged 6 months and older, starting from January 30, 2023.¹⁵⁶

The administration of delgocitinib in excessive doses may induce systemic effects via the increased percutaneous absorption rate.^153-157 Thus, delgocitinib ointment should be used according to its administration method or usage: “for adults, twice a day, with a single application not exceeding 5 g;” “for children aged ≥6 months, twice a day, with a single application not exceeding 5 g based on the body size;” and “the application area should not exceed about 30% of body surface area.” Application to erosive or mucosal surfaces, the occlusive dressing technique, and pasting a cloth on which zinc oxide ointment is spread increase percutaneous absorption; therefore, these should be avoided.¹⁵⁸ As delgocitinib ointment exhibits immunosuppressive actions, much attention must be paid to prevent its application to the site of cutaneous infection. During administration, folliculitis, acne, and cutaneous infection, such as herpes virus infection, including Kaposi's varicelliform eruption, must be considered. If these occur, the application of this agent to the corresponding site should be discontinued and adequate infectious disease treatment must be performed. With respect to information on the safety of delgocitinib ointment and combination therapy with other treatment methods, please refer to the “Manual for the safe use of delgocitinib ointment (CORECTIM® Ointment 0.5%).”¹⁵⁸

Difamilast. Difamilast exhibits selective inhibitory effects on PDE4, a member of the PDE family that is present in several immune cells. It can selectively resolve cyclic adenosine monophosphate (cAMP). Difamilast increases the intracellular cAMP levels in inflammatory cells and epithelial cells by inhibiting PDE4 and suppresses the inflammation of the skin by controlling the production of inflammatory cytokines and chemokines.¹⁵⁹

Some clinical studies have reported significant improvement in the eruption and pruritus scores in patients in the difamilast ointment group in comparison with that in the vehicle group.^{160, 161} Hyperpigmentation, folliculitis, pruritus, impetigo, acne, and contact dermatitis have been reported as topical side effects of difamilast.¹⁵⁹

Adults are instructed to apply 1% difamilast ointment twice daily, whereas children are instructed to apply an appropriate amount of 0.3% difamilast ointment to the affected area. The recommended application amount is approximately 1 g/0.1 m² of the eruption. Application on eroded surfaces, occlusive dressing, and pasting a cloth with zinc oxide ointment should be avoided as they increase percutaneous absorption.¹⁶² There is minimal concern for an increase in clinically significant adverse events when using difamilast ointment with TCS, tacrolimus ointment, or delgocitinib ointment. Concurrent use of difamilast with these drugs is considered feasible; however, caution must be exercised as data regarding the application of these drugs to the same site are lacking.¹⁶² For women of childbearing age, it is advisable to provide guidance on practicing appropriate contraception methods, during and for a certain period after, the administration of difamilast. The administration of this drug to pregnant women and those who may be pregnant is not recommended.¹⁵⁹ Please refer to the “Manual for the safe use of difamilast ointment (Moizerto® ointment 0.3% and 1%) for the safe use of this drug.¹⁶² The use of difamilast in children aged ≥3 months (including infants) was approved from December 11, 2023.

NSAIDs. These drugs inhibit the cyclooxygenase enzyme of the arachidonate cascade and exert anti-inflammatory activity by inhibiting prostaglandin production. The anti-inflammatory effects of NSAIDs are extremely weak compared with those of TCS; thus, no evidence can support their efficacy in AD. NSAIDs are not included in the Guidelines for Management of Atopic Dermatitis in Western countries.^{146, 164} Side effects of NSAIDs include contact dermatitis and potential exacerbation of eczema. Specifically, the use of bufexamac is associated with a potentially high-risk of contact dermatitis; therefore, the European Medicines Agency has recommended discontinuing the marketing of bufexamac across Europe. In response to this recommendation, Japan also banned the sale of all bufexamac-based preparations. Benefits from NSAIDs for the treatment of AD are poor; thus, NSAIDs are not recommended in light of the potential side effects.

Proactive therapy. This therapy is used to maintain remission via the intermittent application of TCS or tacrolimus ointment (e.g., twice a week) to recurrently relapsing eruptions, in addition to skin care with moisturizing topical drugs, after obtaining remission with treatments in the acute phase (Figure 7, CQ11: Recommendation grade 1, Evidence level A). By contrast, reactive therapy is used to control inflammation with anti-inflammatory topical drugs on relapse. Reactive therapy should be used in areas less prone to relapse, as it is difficult to maintain remission in areas susceptible to relapse or where dermatitis has become chronic. Topical anti-inflammatory drugs should be applied to such areas intermittently to maintain remission.

In AD, histological evidence of inflammatory cells is still present despite the normally appearing skin following the resolution of inflammation; inflammation can easily relapse because of external or internal factors.^{165, 166} In such cases, markers indicating disease progression, such as TARC, do not decrease to normal levels in many cases. During this latent inflammation stage, proactive treatment with anti-inflammatory topical drugs including TCS or tacrolimus ointment may prevent relapse of inflammation.¹⁶⁷ However, it is important to transit from the successive application of anti-inflammatory topical drugs to proactive treatment based on laboratory data indicative of disease progression, such as TARC levels, after the dermatitis has fully improved and there is no evidence of itching or erythema and any slight elevation of the skin on palpation. Moreover, the dose, application range, and time to complete the treatment of topical drugs should be determined individually for each patient. The development of side effects should also be carefully monitored. Proactive treatment is necessary for collaboration with a physician experienced in the evaluation of cutaneous symptoms of AD or cutaneous symptoms in general.

A previous study indicated that the improvement in AD induced by acute-phase treatment for 1–3 months had a positive impact on the condition the skin 1 year later.¹⁶⁸ When adopting proactive therapy, it is important to initially and promptly induce remission. During proactive therapy, daily skin care with moisturizing topical drugs should be continued.

1.3.4 Ultraviolet irradiation therapy

Ultraviolet (UV) irradiation therapy is considered for non-responders to treatments with topical anti-inflammatory drugs, antihistamines, or moisturizers, and patients with adverse reactions to conventional treatments.^{16, 17, 255} In UV therapy for AD, many studies have reported the efficacy of UVA1 therapy at a wavelength of 340–400 nm and narrow-band UVB with a peak of 311 nm;^256-258 however, no protocol or guidelines of UV therapy involving patients with AD have been established. When administering UV therapy, it is important to initially consider whether it should be indicated, and it should be carefully performed by UV therapy-skilled physicians who sufficiently understand the action mechanism, radiation dose, acute skin disorders, deterioration of concomitant infectious diseases, various long-term adverse reactions, including skin cancer, and management methods. Because information on the safety of long-term treatment with UV in children is insufficient, UV irradiation therapy can be used for children with psoriasis aged ≥10 years, but it is not recommended for children aged <10 years.²⁵⁹

1.3.5 Skin care

1.3.6 Search for exacerbating factors and measures

1.3.7 Psychosomatic aspects

The psychosomatic aspects of AD were previously emphasized as a classic psychosomatic disease called “holy seven.” Psychosomatic approaches are still important even after its immunological pathogenesis became clear.³⁰⁰ For example, the risk of concomitant developmental disabilities such as attention-deficit/hyperactivity disorder (ADHD), is high in patients with AD;³⁰¹ this must be considered for patient education. In patients with a severe or poorly controlled disease, secondary psychological disorders often occur, and their background should be accurately understood. Thus, comprehensive treatment and management involving psychosomatic assessment and management are necessary for patients with AD.

1.3.8 Treatment of complications (including allergic diseases)

Atopic dermatitis often complicates allergic diseases such as food allergies, bronchial asthma, allergic rhinitis, and allergic conjunctivitis. Allergic diseases are closely related; thus, consultation with a clinical team that includes a pediatrician, dermatologist, otolaryngologist, and ophthalmologist is necessary to implement comprehensive management.

Food allergy. Numerous studies have examined the relationship between AD and food allergy. In 2003, Lack et al.³⁰⁴ reported that peanut allergy was associated with the presence of inflamed skin and the use of skin care products containing peanut oil, suggesting that sensitization to allergens could occur through the skin (or via epicutaneous sensitization). The “dual allergen exposure hypothesis” proposed by Lack,³⁰⁵ indicated the importance of “cutaneous sensitization” and “oral tolerance” in the development of food allergies.

Atopic dermatitis development during infancy is associated with a higher risk of developing food allergies,^{304, 306, 307} and this fact supports the concept of “epicutaneous sensitization” in which exposure to food allergens via the skin may induce sensitization. Observational studies demonstrated that early skincare intervention reduced the incidence of AD among high-risk children with a family history of allergies.^{308, 309} Furthermore, commencing an aggressive treatment strategy in the early stages of AD had a preventive effect on the development of food allergies in an RCT.³¹⁰

Children with AD who ingest eggs at a later age are at higher risk of developing egg allergy. Natsume et al. reported that the start of egg ingestion at age 6 months, early after weaning, in infants with AD in whom the remission of AD was achieved with topical steroids reduced the incidence of egg allergy at age 1 year. Thus, this study supports the importance of inducing oral tolerance to allergens to prevent the onset of food allergy during infancy.³¹¹

In relation to the above studies, the Japanese Society of Pediatric Allergy and Clinical Immunology released their “Recommendations for the prevention of the development of egg allergy” in 2017.³¹² Accordingly, the society specified that allergen elimination on the sole grounds of avoiding sensitization to eggs should not be recommended without careful consideration. Furthermore, these recommendations underlined the importance of AD treatment before commencing baby food and provided suggestions regarding timing and amount of egg intake.

Food causes AD exacerbation in some cases during infancy. According to the Japanese Pediatric Guidelines for Food Allergy 2016, this condition is clinically classified as AD during infancy associated with food allergy.^{131, 313} Please refer to the guidelines for a detailed description of medical procedures.

Bronchial asthma. Approximately, 25% of patients with AD have bronchial asthma.³¹⁴ When bronchial asthma in combination with AD is suspected to occur, intervention by a clinical team of dermatologists, pediatricians, and internal medicine specialists should collectively provide treatment.

Allergic rhinitis. Allergic rhinitis often occurs in association with AD, and extra caution is warranted during the cedar pollen-scattering period in Japan. For patients with allergic rhinitis sensitive to cedar pollens, contact with cedar pollens may worsen AD.³¹⁵ Abroad, the exacerbation of cutaneous symptoms due to the presence of other pollens was reported.³¹⁶ Symptoms may extend to the entire body, not only to the exposed skin areas such as the face. In addition, external stimuli, including blowing and scratching the nose to address nasal discharge and itching sensations, may worsen perirhinal cutaneous symptoms. When allergic rhinitis is intractable, patients should be managed in collaboration with an otolaryngologist.

Allergic conjunctivitis. Concurrent allergic conjunctivitis is an exacerbation factor of cutaneous symptoms on the eyelids. The spread of inflammation to the eyelids because of conjunctivitis and scratching the eyelids make cutaneous symptoms on the eyelids obstinate. Frequent opening and closing of the eyes due to itchiness also serves as chronic stimulation and may make the symptoms refractory. Long-term eyelid scratching behavior may result in eye complications such as cataracts. Collaborating with ophthalmologists is recommended in cases presenting with complications of allergic conjunctivitis or skin eruptions of the eyelids which are difficult to treat.

Diagnosis of infectious disease and its treatment. AD is likely to occur with microbes, fungi, and viral infections because of decreased skin barrier functions and skin immune activity. Bacterial infections include impetigo contagiosa, erysipelas, and cellulitis, whereas viral infections include Kaposi's varicelliform eruption and molluscum contagiosum.

Impetigo contagiosa is caused by S. aureus or Streptococci. In cases of impetigo contagiosa attributable to S. aureus, bullae frequently appear and are easily ruptured, expanding redness peripherally. In cases of Streptococci infection, especially group A β-hemolytic Streptococcus, pustules rapidly appear with systemic symptoms, such as fever, followed by significant crust formation. Cephem-based oral antibiotics and penicillin are administered for bullous impetigo and crusted impetigo, respectively. Showering to keep lesions clean, use of topical antibiotic ointments, and protection of the lesions with gauzes are recommended.

Erysipelas is a dermal infectious disease mainly caused by β-hemolytic Streptococcus.³¹⁷ Chills, fever, well-circumscribed glossy red plaques with heat sensation, and marked pressure pain develop, frequently on the face. Initially, it appears on the unilateral side, extending to the contralateral side. The systemic administration of penicillin or cephem antibiotics is necessary.

Cellulitis is a bacterial infectious disease in the deep layer of the dermis and extends to the subcutaneous tissue. β-hemolytic Streptococcus is the most frequently detected causative bacteria, followed by Gram-negative bacteria and S. aureus.³¹⁸ The possibility of S. aureus, particularly community-acquired methicillin-resistant S. aureus, being the causative pathogen is higher in cases accompanied by purulent exudate.³¹⁹ Cellulitis is accompanied by local heat sensations and pain on the lower limbs, in addition to well-circumscribed erythema and swelling. The systemic administration of penicillin or cephem antibiotics and rest are necessary.

Kaposi's varicelliform eruption is caused by a primary infection or reactivation of the herpes simplex virus. In contrast to typical herpes simplex, many vesicles and pustules appear on the eczema lesions mainly on the face and neck. This eruption is accompanied by fever and lymph node enlargement. The administration of antiviral drugs (oral administration of aciclovir or valaciclovir and intravenous infusion of aciclovir) is necessary. It may also be associated with a secondary infection to bacteria, making a differential diagnosis from impetigo difficult in some cases.

Although molluscum contagiosum is a poxvirus infection originally observed in children, it can be also observed in adult patients with AD. Lesions are glossy skin color to yellow papules of about 2–5 mm in diameter with a central umbilication and can be treated by the complete expulsion of the white vesicle using trachoma tweezers.

Since these infectious diseases occur often and become severe in patients with uncontrolled AD, it is important to maintain the skin condition well with basic treatments.

Ocular diseases. Ocular complications related to AD other than allergic conjunctivitis include blepharitis, keratoconjunctivitis, keratoconus, cataract, glaucoma, retinal detachment, and bacterial or viral infection.^{136, 137, 320, 321} In AD patients with severe and refractory facial eruptions, ocular complications are likely to occur.^{136, 321} Furthermore, AD treatment causes ocular diseases in some cases (CQ6). Patients with AD may have ocular complications despite the absence of ophthalmological complaints. Such complications lead to irreversible visual impairment in some cases. Therefore, considering ocular complications, dermatologists should instruct patients to consult an ophthalmologist to maintain visual function.^{135-137, 320} Furthermore, sufficient control of facial eruptions is important, especially around the eyes, to prevent ocular complications.^{135, 136}

1.3.9 Hospital care

The goal of basic drug therapy for AD is to achieve early remission using topical anti-inflammatory drugs such as TCS and tacrolimus ointment and then maintain it using a minimum number of drugs. However, it is difficult to induce remission in some patients with severe AD and extensive areas of eruption. Hospital care is indicated for such patients. Some patients with severe AD exhibit acute exacerbation, whereas severe dermatitis is chronically protracted in others. Both groups of patients should be admitted, with hospital care being more significant for the latter.

In patients with chronically protracted severe dermatitis, problems are identified regarding disease activity (enlargement of eruption related to inflammation with rigorous activity or scratching), patient adherence (insufficient understanding of the pathogenesis of AD or treatment methods, no treatment goal in the absence of experience at the level of remission, experience-based misunderstanding of topical therapy, and insufficient understanding of the significance of topical therapy or its methods), and aggravation factors (environment- or lifestyle-related factors and overworking) as background factors. In many cases, these problems become deadlocked through interactions. Hospital care may make it possible to thoroughly perform intensive topical therapy with isolation from the daily environment, establish a healthcare professional–patient relationship of mutual trust, review triggering factors, application methods and skin care and overcome these problems in the early phase. Several hospitals reported that such therapeutic interventions improved long-term prognoses after patient discharge.^{322, 323} In addition, patients often cannot continue the drug therapy appropriately, resulting in unexpected effects. For such patients with moderate-to-severe AD, hospital care would be considered as required. Because continuous topical treatment is required after discharge of patients with severe AD for whom hospital care is indicated, it is essential to understand their conditions and treatment methods. Therefore, hospital care aims to achieve the early remission of dermatitis by intensive topical therapy and improve adherence through educational guidance.

1.3.10 Patient education

For AD mainly treated by topical therapy at outpatient clinics, patients and their families have a key role in treatment. The patient's family should properly understand the clinical conditions and treatment of the patient to improve adherence and achieve successful treatment (see “Treatment adherence”).

In Japan and abroad, various methods of patient education have been attempted, and each has been reported to be effective in decreasing the severity of eczema and improving QOL. Different approaches have been successful in many studies on children, specifically education by a multidisciplinary medical team, group work by a specialized nurse, a short education program during the hospital stay, and education using online videos.^324-328 In addition, websites and leaflets for young patients have been developed and used as educational tools for patients with AD in Japan.^{329, 330}

In clinical practice, the above tools should be selected as effective and feasible educational methods taking into account the characteristics of each patient and medical-care system provided at the treatment facility. Confirmation of the use of topical drugs is important, and appropriate instructions should be provided before changing treatment, not only during the treatment introduction phase but also when the expected efficacy of the therapy is not achievable.

1.3.11 Probiotics/prebiotics

Enterobacteria play an important role in the immune response in vivo and have been reported to be associated with various diseases. Many studies have reported their association with allergic diseases such as AD. A study compared the intestinal flora between children with allergic diseases and healthy children and noted a significant decrease in the number of Lactobacillus sp. in the former.³³¹ Many studies have examined the effects of intervention by enterobacteria on preventing the development of allergic diseases or treatment after development. Probiotics (live microorganisms yield useful effects on the host), prebiotics (food ingredients promoting the growth of microorganisms useful for the host), and synbiotics (combination of probiotics and prebiotics) are the representative preparations.

Concerning the prevention of onset, meta-analyses concluded that continuous administration of probiotics to mothers during pregnancy and, subsequently, to infants after birth was effective in preventing the onset of allergic diseases.^{332, 333} However, the preventive effects of the administration of single-strain probiotics or administration to infants alone have not been confirmed.^{333, 334} Other meta-analyses did not find preventive effects of prebiotics and synbiotics against the onset of allergic diseases.^{335, 336} The preventive effects of probiotics may be obtained to some degree with certain bacteria in certain methods of administration. However, there is no evidence on specific species of bacteria or methods of administration that can be used practically. The present guidelines do not recommend probiotics as a preventive method (CQ38).

Several studies have examined the therapeutic effects of probiotics on AD. A meta-analysis revealed that probiotics significantly reduce the SCORAD index. However, there are RCTs that show no effect in pediatric patients (CQ37); thus, the results are not consistent.^{333, 337} Some RCTs have reported the efficacy of synbiotics, whereas others did not. Their meta-analysis demonstrated that synbiotics significantly reduced the SCORAD index in children aged ≥1 year and adults.³³⁶ Some RCTs have noted the therapeutic effects of prebiotics, whereas others demonstrated their ineffectiveness (CQ37).^338-340 A meta-analysis of these RCTs has not been conducted.

The efficacy of probiotics, prebiotics, and synbiotics varies depending on various factors, such as species, combination, dose timing, living environment including dietary habits, and race. Thus, for practical use or clinical application, this must be further examined in the future.

1.3.12 Complementary and alternative medicine

Complementary and alternative medicine means the provision of care other than standard medical treatment implemented by the physician at a healthcare facility, and it is a collective term for care whose precise mechanism of action has not been scientifically validated in most cases. Alternative therapy is used as a substitute for standard guideline medical care and often complementary therapy supplements standard medical care. There is much publicity and information relating to complementary and alternative medicine for AD in so-called health magazines and available on the internet and it represents a controversial industry.

According to a survey conducted in Hiroshima in 1997, 67.4% of patients with AD have tried alternative medicine.³⁴¹ According to another questionnaire survey involving the parents of children with AD at the time of initial consultation in Tokyo in 2003–2006, those with steroid phobia had more frequently received alternative medicine than those without it (22.2% vs 13.0%, p = 0.013).³⁴² In patients hospitalized for exacerbation of AD or aggravation due to complications, in 44% of the patients, these complications were caused by inappropriate treatment using alternative medicine.³⁴³ As a result of excessive reliance on alternative medicine, adherence to standard medical care decreases and the worsening of symptoms has been the main concern.

Several RCTs have investigated the efficacy of complementary and alternative medicine. Although one study reported the efficacy of acupuncture in improving itching, the sample size was small, and the quality of the study was not good.³⁴⁴ In an RCT evaluating the efficacy of homeopathy, no significant differences in improvement were observed when compared with the placebo group.³⁴⁵ No adequate scientific evidence supports the efficacy of complementary and alternative medicine.

1.3.13 Treatment adherence

In medical care for AD, a chronic disease, patients and their parents/families must understand the condition or significance of treatments, positively participate in the selection of therapeutic strategies, accomplish treatments according to these strategies, and improve the will to continue treatments, i.e., adherence to treatments. Treatment adherence-associated factors include patient-, disease-, treatment-, healthcare professional-related, and socioeconomic factors.^{346, 347} Patient-related factors include the pressure of business and belief in medical care or drug therapy. In treatment-related factors, complex treatment methods, a high incidence of adverse reactions, and expensive procedures reduce treatment adherence. Thus, politely explaining the merits and demerits of respective treatment methods and concrete application methods for improving adherence is important. Regarding healthcare professional-related factors, their relationships with patients, explanations of the disease and treatment methods, and continuous provisions of information or support contribute to improvements in adherence. Moreover, the necessity of drug therapy or skin care must be explained to patients and thereby motivate them. The process of shared decision making, where patients and healthcare professionals share and discuss information and collaborate to make medical decisions, enhances patient treatment satisfaction and treatment adherence.^{348, 349} Socioeconomic factors include a family's cooperation and babysitter's support. To improve adherence, healthcare professionals should initially try to achieve factors that they can perform.^350-352

1.3.14 Referral to a specialist

When no improvement of eczema is observed even after implementing treatment in accordance with the present clinical practice guidelines (Figure 6) for a period of approximately 1 month, referral to a specialist or to a specialized facility should be considered.^{16, 17} When prominent erythema, scars from scratching, erosion, lichenification, prurigo, or a wide range of erythema-like erythroderma is observed, referral to a specialist should be considered. In addition, when infection by bacteria or virus is concomitantly observed, or a detailed examination of the exacerbating factors including food allergies and contact allergy is necessary, referral to a specialist should also be considered.

1.3.15 Maintenance phase treatment using telemedicine

For AD treatment, it is important to maintain favorable control over a long period by adequate maintenance therapy after inducing remission. To achieve this, good adherence is necessary; however, the continuation of treatment is sometimes stressful for the patients. Specifically, regular hospital visits affect going to work or school for patients with AD, many of whom have social activities, reducing the QOL in some of these patients. However, low compliance with regular hospital visits easily leads to exacerbation. Therefore, telemedicine is one of the useful options for minimizing the stress level and continuing the treatment. Indeed, numerous studies have supported the usefulness of telemedicine for AD treatment.

In a randomized study of telemedicine and face-to-face medical care at a ratio of 1:1 involving 156 children and adults with AD who did not require systemic therapy, such as oral immunosuppressive drugs or phototherapy, the improvement rates for the POEM and IGA scores during the 12-month follow-up were comparable between the telemedicine and face-to-face medical care groups.³⁵³ Similarly, improvement in the QOL, which was assessed based on the DLQI, CDLQI, and Short Form-12, was comparable between the two groups.³⁵⁴

From the viewpoint of cost-effectiveness, a study involving 199 patients diagnosed with AD on the initial consultation reported that outpatient follow-up with “e-health (online consultation)” between face-to-face consultations led to an improvement in the cost, while the QOL and disease severity were comparable with those receiving face-to-face medical care.³⁵⁵ The e-health program includes the provision of materials for education and patient monitoring; therefore, it is not completely consistent with telemedicine in Japan. However, there may be a certain value from the viewpoint of cost-effectiveness.

To establish evidence in Japan, further examination is necessary. However, remission may be maintained through adherence support while minimizing the stress levels of the patients and their families by providing medical care in combination with telemedicine in patients with stable AD. For this purpose, medical fees must be adequately approved.

1.4.1 Clinical presentation

Eczematous lesions are subject to change during growth and development. The definition of “chronic” also differs, and it is defined as a disease persisting for ≥2 months and ≥6 months in infants and older children, respectively. During infancy, erythema and infiltrative erythema initially appear on the face, specifically on the cheek, and head, and then extend to the neck, trunk, and limbs on disease progression. Eruptions on the face gradually stabilize with a peak at 4–6 months and transition to the lesions on the neck and joints of limbs. Eczematous lesions occurring from preschool to school ages mainly appear on the neck and limb joints. After adolescence, eruptions tend to appear on the upper body including the head, neck, chest, and back similarly to adults.

It is not always the case that children with a severe disease during infancy will experience the same severe disease as they grow older, and many children achieve near remission at age 1–1.5 years. There are two types of AD-affected preschool children: those with persistent disease from infancy and those with new disease onset at around age 3 years.

1.4.2 Exacerbating factors

During infancy, “food allergy-sensitized infant AD” is the predominant form of AD; however, this does not mean that food allergy causes AD. In infants with AD, sensitization with food allergens (in the order of egg, milk, and wheat) is established through percutaneous sensitization before ingestion, especially in severe cases. Thus, these causal foods that the mother has ingested may cause exacerbation of eruptions via breastmilk. However, this is not observed in all infants. After reducing symptoms through suspected food removal by the mother and maintaining remission by topical therapy for 1–2 months, the resumption of such food ingestion by the mother and breastfeeding results in the disappearance of symptom exacerbation in many cases. Therefore, even when sensitization is present, neither long-term food removal by the mother nor breastmilk discontinuation is necessary in many cases.

In older preschool or school age children, the contribution of inhaled allergens intensifies. Other than mites, special attention is necessary to allergens derived from animals such as dogs and cats. The patient should be questioned about potential exposure to pets during the medical interview. Eruptions may worsen mainly on the face during the cedar pollen-scattering period. As the development of cedar pollen allergy has been observed in younger children in recent years, preschool-aged children should also receive particular attention.

Atopic dermatitis is likely to worsen in the summer because of sunburn and sweating, and patients tend to have difficulties in school activities. AD can be improved with appropriate management including showering at school (CQ26). AD is likely to worsen because of skin dryness during the winter, and special attention is required in relation to school activities. Stress is also an important exacerbating factor. Special attention is necessary, as younger patients are likely to fall into a vicious cycle if they become indifferent or are bullied because of AD, further increasing the stress level.

1.4.3 Laboratory testing

Concerning the serum total IgE level, the upper limit of the normal range is lower at a younger age. However, there is no definite cut-off value at respective ages. In severe AD, this level is markedly high, as described for adults. In the allergen-specific IgE antibody test, food allergen sensitization (such as egg, milk, and wheat) can be observed in many cases during infancy. Sensitization to mites and pollen is observed more often at preschool. Food allergen sensitization does not always require the elimination of causal allergens, and making a careful diagnosis is necessary through a medical interview or the oral challenge test. In particular, the specific IgE antibody level is high in patients with severe AD. A higher probability of symptom induction is estimated through the interpretation of a probability curve; thus, caution is needed (refer to “Japanese Pediatric Guidelines for Food Allergy 2021”).³⁵⁶

The serum eosinophil count increases in correlation with severity, and during infancy sometimes a markedly high value can be detected. However, levels improve promptly with the improvement of the lesions. As serum TARC and SCCA2 levels correlate well with AD severity, they are useful as a marker of disease progression. The reference range of SCCA2 is unified.⁹⁷ However, in children, the TARC level is higher at a younger age, therefore, it is necessary to refer to its range with respect to age.¹⁰¹ In infants with severe AD, hyponatremia or hypoproteinemia may develop,³⁵⁷ and biochemical testing is also necessary.

1.4.4 Treatment

To manage infants, schoolchildren or adolescents widely ranging in age, drugs to be used in each age group must be considered. The basic treatment approach is the same as that of adult patients; however, remission can be achieved in a relatively shorter period during childhood; appropriate treatment should be given according to disease severity. Even in younger children, therapy with medium (group 4) TCS should not be chronically continued. When eruption reduction is not apparent, ranking up is necessary. A 0.03% tacrolimus ointment should be used in children. This drug is not indicated for infants. In accordance with the physical status, the maximum volume of a 0.03% ointment per use was established as 1 g for children aged 2–5 years (bodyweight <20 kg), 2–4 g for those aged 6–12 years (bodyweight 20–50 kg), and a maximum of 5 g for those aged ≥13 years (bodyweight ≥50 kg); caution is thus needed.

Children, especially infants, cannot understand that scratching the skin further promotes pruritus, exacerbating dermatitis, and, thus, they should stop scratching; therefore, for pruritus control, TCS are combined with oral antihistamines in many cases. First-generation antihistamines exhibit potent sedative actions, and second-generation antihistamines with low-level intracerebral transfer should be used in children. Specifically, these drugs should be carefully administered to infants or children with febrile convulsions or epilepsy.

The systemic administration of oral steroids has been recommended for the treatment of bronchial asthma attacks or anaphylaxis; however, its effectiveness in the treatment of AD is short-term, and rebound effects are observed following the discontinuation of treatment. Side effects such as growth retardation, osteoporosis, and increased susceptibility to infections, are common with the use of systemic steroids. Thus, their use is not recommended in children as the risk of side effects outweighs the treatment benefits. The administration of oral JAK inhibitors and biologics has commenced in refractory cases that do not improve with conventional treatment in recent years. The age when oral JAK inhibitors or biologics can be used is limited, and caution is needed when indicating these drugs.

The occurrence of eruption around the eyes may become refractory in some cases. Rapid induction therapy with TCS, following maintenance therapy with tacrolimus ointment, is recommended in refractory or recurrent cases. Anti-allergic eye drops for pruritus caused by allergic conjunctivitis may be used concurrently. However, steroid eye drops should be prescribed by ophthalmologists owing to the potential side effect of increased intraocular pressure.

1.4.5 Change in key caregivers of treatment

Treatment for children is often given through parents or carers, and patient education is usually directed towards them. In particular, during infancy, topical therapy is conducted through the understanding of the disease by parents or carers. However, for children aged ≥2 years, it is possible to approach the patients themselves. It is important to perform topical application while praising the child so that it can be completed without causing discomfort or resistance and make it a habit. The children become somewhat capable of understanding the necessity of ongoing treatment by the time they reach school age. The key caregivers of treatment may shift from parents or carers to the patients themselves when the children reach the upper grades of elementary school. Thus, patient education is not only provided through parents or carers, but also requires the pathophysiology and necessity of treatment to be explained directly to the children in words tailored to their level of understanding. Kindergartens, nursery schools, and elementary schools use the school life guidance form for allergic diseases to ask for cooperation. It provides details on the patient's current treatment, severity, and factors to be considered while at school. As the guidance form is drawn up by family doctors, adequate cooperation may be obtained. As matters to be managed at school, concrete instructions, such as wiping the child's body with a wet towel after sweating, showering if possible, and application of a moisturizer when the air is very dry in winter, should be described.

After adolescence, the key caregiver of treatment will be the patients themself; however, the patient may not have a full understanding of their disease and treatment. It is also common for adolescents to enter a growth phase specific to puberty where they become less inclined to heed the words of parents or carers. This attitude is further compounded by feelings of shame, leading to decreased adherence to topical treatment, thereby potentially exacerbating the eruption. When treating adolescent patients, it is important to confirm who applies the topical drugs and whether they understand the treatment regimen themselves.

When continuing topical treatment beyond adolescence, it is necessary to ensure that patients have an awareness of “accepting the disease” and “managing it well,” as the treatment may extend over a long period. To achieve this, it is important for patients to actively confront the disease, and transitional medical care that encourages patient independence is required. Providing transitional support that fosters patient independence from pre-adolescence, taking into account the shift in key caregivers of treatment, plays a crucial role in completing transitional treatment.

1.4.6 Complications

During childhood, other allergic diseases (such as food allergy, allergic rhinitis, and bronchial asthma) may occur concomitantly in many cases. During infancy, prevention of the development or inducing of rapid remission of food allergy by controlling dermatitis is recommended; thus, appropriate continuous skin care is an important concern.

The prevalence of pollen allergies, represented by cedar pollen, among infants has been increasing in recent years. Some of these patients present with noticeable exacerbation of eruption, in addition to eye and nasal symptoms.

The risk of developing asthma in children with AD is higher than that in the general population. If symptoms suggestive of airway hypersensitivity, such as prolonged post-infection cough and frequent cough related to a loud laugh or inhalation of cold air, are observed, follow-up should be performed while paying attention to the severity. If there is no improvement, medical care should be provided in cooperation with a pediatrician and not by a dermatologist alone.

1.4.7 Differential diagnosis

In children, AD is frequently observed as a skin disease. However, diseases to be excluded should be considered, as described in the diagnostic criteria. Diseases to be differentiated vary (refer to “Differential diagnosis”). They include neonatal acne, neonatal toxicoderma, seborrheic dermatitis, contact dermatitis, nummular dermatitis, miliaria, candidal intertrigo, and psoriasis vulgaris. Furthermore, AD-associated immunodeficiency syndromes include Wiskott–Aldrich syndrome, HIES, Omenn syndrome, and immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome. Congenital skin diseases such as Netherton syndrome, hereditary ichthyosis syndrome (such as recessive X-linked ichthyosis syndrome), and peeling skin syndrome must be differentiated from AD. Extrinsic skin diseases such as scabies, tinea corporis, and insect bites (that secondarily deteriorate to eczema in some cases) must be differentiated from AD in some cases. Zinc or vitamin B deficiency and metabolic diseases, such as phenylketonuria, also cause eczema as a symptom; therefore, they should be differentiated. The above diseases may be complicated by AD; this must be considered for consultation.

Neonatal acne is an acne-like eruption observed mainly on the face, occurs approximately 2 weeks after birth, and transiently improves thereafter. Seborrheic dermatitis during infancy is an eczematous lesion presenting as erythema with yellow desquamation at seborrheic sites (head and face during infancy) and is often observed around 1 month after birth. There is no itching, and if any, it is minor and may improve by washing the face thoroughly with soap. If effusion is observed from the lesions, it may be resolved by applying medium TCS (group 4), and recurrence is unlikely when the TCS are stopped as in AD. Conversely, in some cases, seborrheic dermatitis during infancy can transition to AD despite improvement. This is because it is difficult to determine a definite diagnosis of AD at 1 month after birth, despite it having exhibited signs of development. According to the criteria set forth by the UK Working Party, infants with AD exhibit decreased barrier function and increased markers of type 2 inflammation at the age of 1 month. Easily distinguishable methods should be developed using objective biomarkers in the future.³⁵⁸ To distinguish AD in the early stages, the presence of itching is an important sign. If an infant rubs his or her cheek due to itching when lifted, shows scratching behavior on the body when undressed, or if a scratching scar is observed at a reachable site for the infant, these are potential signs to be observed.

In addition, a differential diagnosis of diaper dermatitis is also necessary during infancy. Diaper dermatitis is erythema appearing on sites in direct contact with the diaper, and dermatitis in this region may also be accompanied by skin erosion. If an eruption is observed elsewhere on the body, either diaper dermatitis may have occurred concomitantly with AD or AD may have worsened because of stimulus by the diaper.

Contact dermatitis may occur due to daily use of soap, baby bathing products, and detergents used for washing clothes. It is sometimes necessary to be careful about commercially available fabric softeners or detergents that appear harmless for clothes.

If an AD-specific eruption is excluded, or sufficient improvement is not obtained following treatment with TCS, differential diagnosis from other congenital skin diseases is necessary, and referral to a dermatologist should be considered.

1.4.8 Death owing to medical neglect and complications

Atopic dermatitis is a chronic disease, but severe cases carry a higher risk of complications owing to eczema, sometimes leading to death. Severe AD can be accompanied by hypoalbuminemia and electrolyte imbalances, especially in infants; this can cause life-threatening emergencies.³⁵⁹ A case of an infant who deteriorated into multi-organ dysfunction owing to the exacerbation of eczema resulting from avoidance of standard treatment with TCS, and who required requiring intensive care unit treatment, has been reported in Hong Kong.³⁶⁰ Similarly, another case of a patient with AD where dietary therapy was commenced at a private facility to avoid treatment with TCS at the insistence of their caregivers resulting in malnutrition and death was reported in Japan.³⁶¹ A further case of an infant who died due to parental TCS phobia led to the arrest of the parents in Australia.³⁶² In childhood, especially in infancy, it is important to understand that there is a non-zero possibility of deterioration leading to “eczema death.” Medical neglect in children refers to situations where, despite the child needing medical care, caregivers fail to provide appropriate medical attention. The MHLW defines medical neglect as situations where caregivers fail to provide necessary medical care to children. Medical neglect is deemed to have serious implications on the life and health of the child. Medical intervention is necessary to ensure the child's safety in such cases; however, consent from the guardian is required for medical institutions to perform these medical procedures. In other words, medical procedures cannot be performed if consent cannot be obtained from the guardian. When actions towards a child are deemed as medical neglect by caregivers, it is necessary for medical institutions or child welfare offices involved in treatment to take appropriate action.³⁶³ Reports from domestic child welfare offices have documented fatalities due to AD resulting from medical neglect.³⁶⁴

In adults, there has been a case where a patient with severe AD refused treatment for years owing to TCS phobia. This patient developed infective endocarditis caused by methicillin-sensitive S. aureus, further complicated by disseminated intravascular coagulation, resulting in the death of the patient.³⁶⁵ Large-scale epidemiological studies conducted overseas revealed that patients with severe AD had a significantly higher risk of mortality than healthy individuals. In addition, a significant increase in the risk of mortality associated with infectious diseases, respiratory diseases, and urinary tract diseases was also observed.³⁶⁶ Similar to children, adults are also at an increased risk of developing various complications and mortality owing to deterioration of poorly controlled severe AD.