AAD (American Academy of Dermatology) guideline of atopic dermatitis has been revised.

 There is unfortunate news. In the new guideline published in May 2014, Topical Steroid Addiction(TSA) or Red Burning Skin Syndrome(RBSS) was not referred to as a side effect of topical corticosteroids(TCS).
 My former article about the significance of AAD guideline is in the following URL.
 As the sunset of the new guideline is 2019 and the interval period since the sunset of the last guideline was 5 years, we must struggle and prepare for another 10 years to add TSA or RBSS to the next guideline. It must be really a hard work but we just have to do it.
In the new guideline, the section about topical corticosteroids is described as the followings (brown,italic). You can read or download the full article in the AAD site.

 I will add my comment after each paragraph.

 TCS are used in the management of AD in both adults and children and are the mainstay of anti-inflammatory therapy. They act on a variety of immune cells, including T lymphocytes, monocytes, macrophages, and dendritic cells, interfering with antigen processing and suppressing the release of proinflammatory cytokines. They are typically introduced into the treatment regimen after failure of lesions to respond to good skin care and regular use of moisturizers alone.

 The last phase is important from the viewpoint of prevention of TSA. I agree in that TCS should not be regarded as the first choice.

 TCS have been used to treat AD for more than 60 years. Their efficacy has been demonstrated with a wide variety of preparations and strengths, with more than 110 different RCTs performed to date. They are generally the standard to which other topical anti-inflammatory therapies are compared. In addition to decreasing acute and chronic signs of AD, multiple trials have shown decreased pruritus with their application. TCS are used for both active inflammatory disease and for prevention of relapses. Comparative trials are limited in duration and scope (ie, they mainly involve, and occasionally, agents), and as a result, there are no data to support or a few specific agents as being more efficacious than others. Patient vehicle preference, along with cost and availability, often determine their selection. A summary of recommendations on TCS use is in Table IV, with the level of evidence in Table III.

 TCS are grouped into 7 classes, from very low/lowest potency (VII) to very high potency (I), based on vasoconstriction assays. Table V provides some representative examples of available agents in each class. There is a paucity of studies that examine a range of TCS doses in large numbers of patients and with the lack of an established optimum, great variability in dosing exists. Some use a short burst of a high-potency TCS to rapidly control active disease, followed by a quick taper in potency, whereas others use the lowest-potency agent thought to be needed and adjust upward only if this fails.
 No universal standard exists for quantity of application, although suggested methods include use of the adult fingertip unit (the amount from the distal interphalangeal joint to the fingertip, or approximately 0.5 g, being applied over an area equal to 2 adult palms), following the rule of 9’s that measures the percent affected area, and use of charts that propose amounts based on patient age and body site.
Children have a proportionately greater body surface area to weight ratio, and as a result, have a higher degree of absorption for the same amount applied. But during significant acute flares, the use of mid- or higher-potency TCS for short courses may be appropriate to gain rapid control of symptoms, even in children.  However, for long-term management, the least-potent corticosteroid that is effective should be used to minimize the risk of adverse effects. Greater caution regarding TCS potency is also needed when treating thin skin sites (ie, face, neck, and other skin folds), where there is greater penetration and higher likelihood for systemic absorption. It is important to monitor quantities of TCS used over time, which may impact efficacy and safety.

 There is a little conflicting expression in the above paragraph. It says significant acute flares should be suppressed by potent TCS while they should be limited to be used for long-term management. The phase sounds beautifully harmonized, but is it really feasible in fact?

Frequency of application
 Most studies on the efficacy of TCS in AD management involve twice-daily application. This is the most common clinical practice and also the generally recommended frequency. However, there is evidence to suggest that once-daily application of some potent corticosteroids may be as effective as twice-daily application. Some newer formulations also use once-daily application. For acute flares, use of TCS is recommended every day until the inflammatory lesions are significantly improved and less thick, for up to several weeks at a time. After obtaining control of an outbreak, the goal is to prolong the period until the next flare.
Previously, TCS use was stopped on improvement of symptoms and signs of disease, switching to the use of moisturizers alone and reinstituting the TCS only with subsequent relapses. However, in recent years, a more proactive approach to maintenance has been advocated for those patients who experience frequent, repeated outbreaks at the same body sites. This entails the scheduled application of a TCS once to twice weekly at these particular locations, a method that has reduced rates of relapse and increased time to first flare relative to the use of moisturizers alone (to be discussed further in part 4 of these guidelines).

 The so-called proactive approach is described here. It is a method that was studied from the viewpoint of health economics. In the study patients were to be controlled by potent TCS before entry of the study. Successfully controlled patients were divided into two groups, that is, patients who use TCS regularly 1-2 days per week (proactive approach) and the others using TCS only when the flare was developed (reactive approach). In the former the interval between relapses was longer and economic burden was less.
 However, there are two points to be noted in translating the study into clinical practice. 1) The enrolled patients in the study were all successfully controlled ones by the initial treatment by potent TCS. It means patients who were judged as poorly controlled at the initial stage were not enrolled. 2) According to the proactive approach, patients can’t stop TCS theoretically forever. Eczema sufferers often become healed naturally especially in children. But in the approach such natural healing is not assumed. 

Adverse effects and monitoring
 The incidence of reported side effects from TCS use is low; however, most studies fail to follow up patients long term for potential complications. Cutaneous side effects include purpura, telangiectasia, striae, focal hypertrichosis, and acneform or rosacea-like eruptions. Of greatest concern is skin atrophy, which can be induced by any TCS, though higher-potency agents, occlusion, use on thinner skin, and older patient age increase this risk. Many of these side effects will resolve after discontinuing TCS use, but may take months. Sites of treatment should be assessed regularly for these adverse effects, particularly with use of more potent agents. Continuous application of TCS for long periods of time should be avoided, to limit the occurrence of negative changes. Proactive, once to twice weekly application of mid-potency TCS for up to 40 weeks has not demonstrated these adverse events in clinical trials.

TCS application on AD lesions does reduce Staphylococcus aureus bacterial load, likely via decreasing the inflammatory cytokines that inhibit antimicrobial peptide production. There is some worry that TCS may impair the process of wound healing and re-epithelialization, although excoriated and fissured lesions should be included in treatment given that the underlying inflammation and pruritus lead to these secondary changes. Allergic contact dermatitis/type IV hypersensitivity can develop to TCS or other ingredients in their formulations, such as propylene glycol and preservatives. This should be considered if lesions fail to respond as expected or worsen with application. Patch testing is needed to determine if the allergen is the steroid compound itself or a component of the vehicle. Development of tachyphylaxis is of concern for some practitioners, where the efficacy is thought to decrease with repeated use of the same agent, although data are lacking to suggest that this is a significant clinical problem. Although there is documented risk with systemic corticosteroid use, an association between topical steroid use and the development of cataracts or glaucoma is not as clear. Nonetheless, minimizing use at periocular sites may be prudent.

 Although the term “tachyphylaxis” is not appropriate to represent TSA or RBSS, the above phrase might refer to it. (Please refer to my article in the following URL about the difference of both.
 If the “ tachyphylaxis” here is used in the original meaning as epinephrine becomes weakened to the blood vessels in efficacy, the above phrase is true. Tachyphylaxis of TCS must be of little importance in clinical practice. But if the authors use the term as the representative of TSA or RBSS, the phrase “data are lacking to suggest that this is a significant clinical problem” is wrong. There are several medical case reports for examples by me or Dr Rapaport.
If the authors confuse tachyphylaxis and TSA or RBSS, it expresses ironically the fact that most dermatologists have not experienced to see patients at withdrawal from TCS. It is because tachyphylaxis resembles the situation before stopping TCS while TSA or RBSS is the term expressing the rebound after withdrawal.
 In the world of medical journals or in the practicing rooms of dermatologists, there might be very few TSA sufferers. That is probably because they don’t visit dermatologists. But is it really “data are lacking to suggest that this is a significant clinical problem”?  Is the number or comments of ITSAN’s member not a data for example?

 Topically applied corticosteroids, particularly high- and very high potency agents, can be absorbed at a degree sufficient to cause systemic side effects. The risk of hypothalamic-pituitary-adrenal axis suppression is low but increases with prolonged continuous use, especially in individuals receiving corticosteroids concurrently in other forms (inhaled, intranasal, or oral). As discussed above, children are more susceptible as a result of a greater body surface to weight ratio. There is also some concern for negative effects on linear growth, although reports have given mixed conclusions. Hyperglycemia and hypertension have rarely been reported.
 A systematic review concluded that TCS overall have a good safety profile. No specific monitoring for systemic side effects is recommended for patients with AD at this time. However, if hypothalamic-pituitary-adrenal axis suppression is a concern, this can be assessed by performing a cortisol stimulation test to check for appropriate adrenal response. As discussed in part 1 of these guidelines, some children with AD are underweight as a result of severe disease, although further decline in growth should prompt consideration for investigation.

Addressing concerns with TCS use
 Although judicious use of TCS is certainly warranted, recognition of undertreatment as a result of steroid phobia is also important. One survey of 200 dermatology outpatients with AD found that 72.5% were worried about use of TCS on their own or their child’s skin, with 24% admitting
noncompliance with therapy as a result of these concerns. Other studies have shown that patient knowledge of steroid class potencies is poor and leads to inappropriate use. Thus, to achieve good response, it is important to address such fears and incorrect beliefs. The risks associated with TCS use do appear to be low with appropriate application and choice of potency, combined with periods of nonuse. A higher strength of recommendation (than actual level of evidence) is therefore placed on counseling, because the benefits outweigh the risks.

 The undertreatment due to steroid phobia is taken up here. There exist such patients really. Some patients even believe their eczema must be healed only if they never use TCS. However, they might be true because atopic dermatitis has a tendency of self-healing originally and nobody can deny that TCS disturb it. Moreover, when the patient becomes addicted to TCS, the recovery can’t be obtained without the “undertreatment”.
 From the short term observation in the clinical practice, it certainly looks successful to treat the “undertreated” patients by TCS. That is why so many medical studies exist suggesting TCS are useful. However, is it successful even from the long-term viewpoint also? Hasn’t the number of patients with adulthood atopic dermatitis increased after the dermatologists began to prescribe TCS several decades ago?  Why do patients with atopic dermatitis only complain or worry about TCS use?  I have once researched about the problem. The patients’ phobia to TCS originated  mostly from their own experience
(http://topicalsteroidaddiction.weebly.com/chapter-1612288steroid-refusal-irrelevant-to-media-coverage.html). I suggest dermatologists should investigate the reason of the patients’ fear, not worrying about incompliance of the patients.

 Please click here as for the clofibrate ointment. It is a non-steroidal agent with mild anti-inflammatory effect.
Sorry, the comment column is not available now. But the author believes readers can find some hints to overcome their own situations by the previous comments.

10 件のコメント:

  1. Hello Dr. Fukaya,

    Joey here from ITSAN. :)

    We have learned of a clinical study that University of California is going to conduct and thought you might want to look into it and perhaps contact them with what you know? We are going to reach out to them to see if they would consider making this a longer time frame of studying patients on and off TCS since we all know 6 weeks is not sufficient. Here is the brief write-up and link:

    "Detailed Description:

    This exploratory study consists of four visits to the investigator site post screening: at Weeks 0 (baseline), 2, 6 and 8 (Figure 1). At the first visit (baseline), patients who have met the screening eligibility criteria will be started on a stable TCS regimen for a total of two weeks. At the second visit (Week 6) following two weeks of therapy on stable TCS, patients will stop TCS and blood, serum, plasma and two 6mm punch biopsies (one lesional (L) and one non-lesional (NL) skin) will be obtained. At the third visit (Week 6), after four weeks receiving no TCS, the same sample collections will be repeated and the patients will then enter a two week safety follow up. At the end of the safety follow up (last visit, Week 8) and after obtaining written informed consent by the patient, blood, serum and plasma samples may be collected."


    1. Thank you for the useful information.
      As the TCS application is only for two weeks, the 6 weeks may be enough for assessment of before and after TSW. Of course TSA can’t be observed by this study because 2 weeks are too short to make patients addicted.
      The sponsor of the study is the company that developed Xolair (Omalizumab).
      I can’t judge weather this study favors to enlightenment of TSA or only rationalizes TCS use to steroid-phobic patients.
      By the way, we Japanese doctors started a study assessing long term (6 months) prognosis of non-steroidal treatment of atopic patients.
      Please wait until the outcome is got.

  2. Thank you Dr. Fukaya, we wonder how this will help as well and want to contact them to ask for a study of patients who stop all TCS for a good length of time. ITSAN has action groups now that are working on many areas and appreciate the derms in Japan who believe in this. We will watch your studies!

  3. Hello Dr. Fukaya,

    I stopped using topical steroids 14 months ago. I was flaring for the first 4 months and I have had clear skin for about 10 months. Recently I had a wisdom tooth removed and about 4 weeks later the left side of my face was flaring. I found out that there was also epinephrine in the local anesthetic. There was about 0,006 mg of epinephrine in one shot of local anesthetics and the doctor used about 5 shots. Only the left side of my face is oozing where the local anesthetics were used. I googled epinephrine and found out that it closes the blood vessels.

    Is it possible that I am flaring because of the adrenaline in the local anesthetic?

    1. No. Don’t worry. The reason why the left side only worsened is unknown but it will soon subside.

  4. Thank you very much Dr. Fukaya. I am relieved to hear it is not because of the adrenaline.

  5. Hi Dr Fukaya,
    I'm hoping this isn't a duplicate post, but I need your expertise... After 23 months of complete withdrawal (began tsw in March 2013) from clobetasol propionate, and IV and oral steroids due to idiopathic thrombocytopenia, I was forced to go back on 2 weeks of prednisone (40mg-20mg-10mg) for another round of ITP in Feb 2015. I was about 80% healed. I am now throw into a flare of face and neck reminiscent of my first 2 months of withdrawal. What's the expectation in your experience for going back on prednisone after withdrawal? Am I starting over?

    1. Don’t worry. Steroid addiction occurs by topical steroids. You are going through withdrawal even if you are taking oral steroids now.

  6. Very informative blog post for readers. You can also try for other Dermatologist and skincare expert for better results.



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