Important Changes in the 2018 Clinical Practice Guidelines for Atopic Dermatitis

The Japanese Dermatological Association (JDA) and the Japanese Society of Allergology (JSA) worked in cooperation to compile a single 2018 Clinical Practice Guidelines for Atopic Dermatitis. This paper provides an explanation of the 2018 for Clinical Practice Guidelines AD, published at the end of 2018, along with some of the changes made to the traditional Clinical Practice Guidelines from among the 26 clinical questions regarding said guidelines.


Introduction
Around the year 2000, a trend was seen in Japan in which the use of external steroids was avoided in the treatment of atopic dermatitis (AD), resulting in a negative effect on many patients 1) . In order to improve this situation, the JDA and a research team created by the Ministry of Health and Welfare scientific research fund each published an AD clinical practice guideline to provide guidelines for general clinical practice 2) . A series of revisions have been made since then, with two AD clinical practice guidelines having been published by both the JDA and the JSA by 2016. The guideline by the JDA was made for"physicians specializing in dermatology, who examine individuals from primary care patients to patients in stages requiring a high level of expertise."The guideline by the JSA was made for"physicians with practices involving allergic diseases other than dermatology."Both guidelines play a role in providing explanations to medical personnel in related fields. However, the clinical research papers supporting the two clinical practice guidelines overlap and the AD treatment policies are basically the same. This being the case, a single clinical practice guideline was created through cooperation between the JDA and the JSA.

Atopic disposition
Atopic disposition is described in greater detail 3) . For example, the conventional definition of atopic disposition is as follows: Having a family history or anamnestic history (one or more conditions including bronchial asthma, allergic rhinitis, conjunctivitis, and AD) or dispositions that are likely to produce IgE antibodies. The existence of allergies is not required in the definition of AD. Urticaria is not considered to be a part of oneʼs family history or anamnestic history. The serum total IgE value and allergen-specific IgE antibody value are considered in dispositions that are likely to produce IgE antibodies. The total IgE value rises in accordance with the activity of dermatitis, so it is likely to be a low value in mild cases. The allergen specific IgE antibody value serves as a useful reference in mild 487 Health Topics for Tokyoites cases 3) .

Clinical condition
There was an update on the latest information regarding skin abnormalities including the horny layer (decrease in cutaneous barrier functions), the mechanism of inflammation, and itchiness. The causal agents and causal candidate genes reported in the latest study are listed. Moreover, the guidelines state that the integral involvement of these abnormalities with one another is significant to the development of AD. Further, the fact that there is no hierarchy between these causal agents contributes to the diversity in the conditions and expression of this disorder.

Photos of differential diagnosis
Since physicians other than those specializing in dermatology use these clinical practice guidelines, the guidelines explain in detail the specific conditions that should be differentiated from AD and include photos of typical clinical features.

Biomarkers
As a biomarker that serves as a useful reference in diagnosing and assessing the condition of AD, the serum squamous cell carcinoma antigen (SCCA) 2 was mentioned along with the traditionally known serum total IgE value, the number of peripheral blood eosinophils, the serum LDH value, and the serum TARC (thymus and activation-regulated chemokine). SCCA2 is a serine protease inhibitor produced from the epithelium and is induced by type 2 cytokine, IL-4, and IL-13. Since the serum SCCA2 acutely reflects the condition of AD 4) 5) and shows no difference in the nominal value in terms of age, unlike the serum TARC value, it is expected to be a more useful biomarker in clinical situations.

External steroids
Drug therapies that mainly use anti-inflammatory ointments are symptomatic therapies that make rashes less severe and mitigate itchiness. They are also extremely important in overcoming situations in which eczema is worsened even further by a vicious circle including the deterioration of skin barrier functions due to the occurrence of cutaneous inflammation at the lesion part of AD, progress in irritability, and stimulation of scratches 2) 3) . Today, medicines for appropriately soothing the inflammation of AD, in which efficacy and safety is considered in many clinical studies, include external steroids and tacrolimus ointment 3) . External steroids are drugs which form the basic AD treatment. In order to minimize the risk of local side effects such as dermatrophia while maximizing the anti-inflammatory effect thereof, it is important to use steroids of an appropriate rank for an appropriate period of time. To date, in the Clinical Practice Guidelines for AD by the JSA, the size of rashes with severe inflammation have been classified as moderate for less than 10%, severe for 10% and above to less than 30%, and the most severe for 30% and above as a scale determining the rank of external steroids to be used. With this classification, it was advocated that the rank of external steroids to be used be determined in accordance with both severity and age. However, in this guideline, it is suggested that ranks of external steroids be determined based on the severity of individual rashes rather than the size of rashes, as in the traditional Clinical Practice Guidelines for AD by the JDA 3) . This is because it was considered logical to determine the rank of external steroids based on the severity of individual rashes. For example, a determination could be made by selecting stronger external medicine for rashes of small size but high severity and selecting weaker external steroids for rashes of large size but low severity. In order to apply this criterion, since it is necessary to accurately determine the nature of each rash in patients, photos of typical clinical presentations were included by severity 3) . In the traditional Clinical Practice Guidelines for AD by the JDA, it was recommended, in principle, to use an external steroid that is one rank lower for rashes in which the severity is moderate to severe among babies and infants. Moreover, in the Clinical Practice Guidelines by the JSA, it was also recommended that the ranks of external steroids for moderate rashes, for example, be different for those aged under 2, 2 to 10, and 13 and over. However, many within the development committee are of the opinion that it is often the case that rashes are not Ogawa T: Important ghanges in the 2018 clinical practice guidelines for atopic dermatitis appropriately made less severe and in fact become even more severe and more intractable due to the use of external steroids that are 1 rank lower than the rank considered necessary based on the severity of rashes in infants. Therefore, the state that it is not necessary to lower the rank based on age, particularly among babies and infants 3) . On the other hand, the guidelines note that attention should be paid to the period of use as the effect is likely to be seen over a short period of time among babies and infants. Among babies and infants, since the expression of side effects of external steroids are of concern compared to adults, clinical examinations should be more frequent in order to stop or reduce the use of external steroids immediately when rashes become less severe. Alternatively, a switch should be made to external steroids of lower rank or to tacrolimus ointment (if the child is two years of age or older).
For patients with a severity of moderate to severe conditions with repeated exacerbation, it is often the case that there is no other choice but to continue applying external steroids. In such cases, as a method of maintaining remission while avoiding side effects through the use of external steroids, options include either reducing the frequency of application or lowering the rank of the external steroid. As such, a clinical question was included in this Clinical Practice Guideline that asks, "In the case of continuing the use of external steroids even after the rash has appropriately improved, is it better to reduce the frequency of use or lower the rank of the external steroid?"As of today, there have been no reports on clinical studies comparing these two therapies. There have been several clinical studies that used external steroids of strong class (Group III) on patients with moderate severity approximately three consecutive times during remission. They all exhibited exacerbation prevention effects and indicated no increase in the risk of side effects during several weeks of use. Consequently, the guidelines have noted that it is recommended to continuously apply external steroids with reduced frequency of use as a treatment method to safely prevent exacerbation. On the other hand, there have been no reports to date on clinical studies that verify the effect of exacerbation prevention and remission maintenance when using external steroids of a lower rank on a daily basis. Moreover, there have been a small number of reports on local side effects caused by external steroids of a lower rank. That is to say, the effect of applying external steroids of a lower rank on a daily basis is unknown. Therefore, much caution is required in terms of the side effects thereof when using this method. Although the choice depends on various factors such as patient preference and the severity of their rash, the evidence shows that when using strong class external steroids, it is considered preferable to reduce the number of applications and switch to a moisture retention ointment 3) .

Proactive therapy
Proactive therapy refers to local drug treatments that maintain a state of remission by continuously applying anti-inflammatory ointment approximately twice per week, in addition to performing skin care using moisture retention ointment once a state of remission is achieved by the treatment during the acute stage. This is performed on rashes with repeated exacerbations once the use of antiinflammatory ointment is stopped after the eczema becomes less severe through the use of steroids and tacrolimus ointments. Proactive therapy is performed within a limited period of observation compared to reactive therapy in which an antiinflammatory ointment is used only when eczema has exacerbated. Its usefulness has been demonstrated in extending the period of time prior to the exacerbation of rashes after the use of an antiinflammatory ointment is stopped along with a reduction in the number of exacerbations and the amount of anti-inflammatory ointment used 6) . On the other hand, it is important that the transition from daily application of anti-inflammatory ointment to proactive therapy be made under the condition that the dermatitis is appropriately improved (i.e. no itchiness or erythema and no spreading of infiltration upon palpation). The amount used and the area of application of an antiinflammatory ointment as well as the serum TARC value serve as a useful reference. The timing to end application must be determined on an individual basis depending on each case. Regarding the safety of proactive therapy, many reports have indicated that there is no significant difference in adverse events compared to the base ointment during the observation period of 16 weeks for steroids and one year for tacrolimus. Therefore, it is considered to be a relatively safe therapy 3) . However, since no studies have been conducted on periods longer than these, careful observation is necessary in regard to the exhibition of side effects caused by long-term use of an anti-inflammatory ointment 2) 3) . Based on the above, the guidelines state that proactive therapy is a relatively safe remedy that is useful in the maintenance of remission of eczematous lesions. Moreover, it is preferably performed by a physician specializing in the assessment of cutaneous symptoms of AD or in cooperation with a physician specializing in the assessment of cutaneous symptoms 2) .

Home remedies
Home remedies refer to remedies other than those practiced by the majority of physicians at medical facilities and, in many cases, is a generic term referring to medicinal working mechanisms for which there is no scientific verification 2) . Moreover, it has been reported that 44% of cases which were admitted to the hospital due to an increase in severity from aggravation or complications of AD were caused by inappropriate home remedies 6) . As a result of relying on such home remedies, adherence to regular remedies drops decreases, problematically creating cases in which conditions are worsened. Multiple randomized control studies have been reported which look at the efficacy of complementary therapies that complement regular medicine. The guidelines have concluded that there is insufficient scientific evidence regarding the efficacy of home remedies 2) .

Diet restrictions during pregnancy and lactation
In 2000, the American Academy of Pediatrics recommended allergy-free food to pregnant women. However, in a systematic review of the randomized control studies on allergen-free food for pregnant and lactating women (2006 and 2012), it was later reported that diet restrictions including allergy-free food for pregnant and lactating women had no effect in terms of inhibiting AD in children from birth until 18 months old 7) . Furthermore, as it was also reported that diet restrictions during pregnancy can impair the growth of the fetus, it was concluded that diet restrictions during pregnancy are not effective in preventing AD and therefore not recommended 3) .

Skin care
In recent years, awareness of the importance of transdermal immunization has been on the rise and it is thought that transdermal immunization due to allergens which have invaded through the skin with lower barrier functions is the start of the allergic march 8) . As a result, there is now higher expectation that the onset of AD may be prevented by performing skin care using moisture retention ointments that complement the skin barrier functions from an early stage since birth prior to the onset of AD. A report by two Japanese and Western groups in 2014 shows the results of a randomized control study that investigated whether or not there is an effect on the prevention of the onset of AD by applying moisture retention ointment daily from an early stage from birth (study among nursing infants at higher risk for the onset of AD, such as those with a family history of AD). It was demonstrated that performing skin care by applying moisture retention ointment daily from an early stage from birth prevents the onset of AD to a certain extent during infancy 8) .

Conclusion
The above revisions were made to the 2018 Clinical Practice Guidelines for Atopic Dermatitis. I hope this paper might be useful for clinical practice and providing explanations to patients.