Medical news on eczema by Dr Daniel Wallach – April 2019
Discover the second scientific publication in 2019 by Dr Wallach
“Out-of-pocket expenses for adults with atopy in France”
“What grade should we give prescribing physicians?”
“Non-invasive study on the biology of the stratum corneum”
“Stress, pruritus, scratching”
“Latest developments in the microbiome and bacteriotherapy”
“Efficacy of systemic treatments”
Out-of-pocket expenses for adults with atopy in France
Launois R, Ezzedine K, Cabout E, et al.
Importance of out-of-pocket costs for adult patients with atopic dermatitis in France.
J Eur Acad Dermatol Venereol 2019, published online on 19 March.
France has one of the best social security programs in the world. And yet, patients with atopic dermatitis are still left footing the bill for uncovered expenses which, strictly speaking, are considered to fall outside the medical sphere. The purpose of the study was to measure how much adult atopy patients pay in out-of-pocket expenses. A questionnaire was distributed to patients treated in a specialized hospital setting and asked participants to provide an estimate of personal expenses related to atopic dermatitis. A total of 1,024 patients responded. According to the PO-SCORAD (assessed concurrently), 31.9% of the patients presented with severe AD, 40.4% with moderate AD, and 27.6% with mild AD.
According to patients’ estimates, the average amount of expenses not reimbursed, neither by public nor by private health insurance, was €350 per patient annually, with a clear correlation between the amount spent and the severity of the disease. The more severe cases of AD were the costliest: average of €462 per year.
Emollients represented the largest portion of these expenses: average of €254.70 a year for severe AD, with huge variation likely due to individual choices unaccounted for in the questionnaire. The second highest expense was cleansing products (€103.40 for severe AD), followed by photoprotectors (€54.70) and dressings (€86.20). Average spending on AD-related clothing rang in at €162, and €134.90 for dietary supplements. Although many swear by it, no specific diet is recommended for AD. Nevertheless, a number of patients watch what they eat in an effort to improve their condition as much as possible. For patients with limited resources, the overall costs associated with severe AD are a major financial burden. Although AD is quite clearly a persistent disease, only 20% of patients benefit from long-term care. The study concludes that reimbursement schemes should be expanded to include products with some non-medical uses, especially, emollients. The latter have been proven to prevent inflammatory flare-ups and, as a result, should be fully covered.
“What grade should we give prescribing physicians?”
Fleischer AB Jr.
Guideline-based medicine grading on the basis of the guidelines of care for ambulatory atopic dermatitis treatment in the United States.
J Am Acad Dermatol 2019;80:417-424.
In the ideal world of “evidence-based medicine”, recommendations and guidelines are irrefutable and accepted by all; they are followed by all doctors, and patients receive the best treatments available. But what is the reality? The question is complex, and Alan Fleischer in no way claims to have all the answers, but he does offer some interesting insight. He examined the medicinal prescriptions from 228 consultations representing the more than 5 million consultations carried out in the U.S. from 2006 to 2015 with a single diagnosis of “atopic dermatitis”. Non-medicinal prescriptions, such as the ever so helpful emollients, are not taken into consideration. Half of the consultations involved young children, and the other half adults. Dermatologists conducted 30% of the consultations, pediatricians 32%, general practitioners 15%, and other specialists 29%. The prescriptions issued were graded based on their compliance with the guidelines published by the AAD. This grade, based on the American education and university system, ranges from F to A. Ideally, all the doctors should receive an A.
Unfortunately, this is not the case. While some doctors earned an A, the average grade for all prescribers was B or C, according to the recommendation model in effect. Several types of prescriptions seemed to disregard the guidelines completely. For example, 46% of patients consulting a general practitioner received systemic corticosteroids (versus no pediatricians and 18% of dermatologists). In addition, 20% of patients consulting a dermatologist were prescribed non-sedating antihistamines, which all guidelines indicate are ineffective. The author concludes that doctors would benefit from reviewing the guidelines and that research is needed to examine the discrepancy between writing guidelines and putting them into practice.
Non-invasive study on the biology of the stratum corneum
Hulshof L, Hack DP, Hasnoe QCJ, et al.
A minimally invasive tool to study immune response and skin barrier in children with atopic dermatitis.
Br J Dermatol 2019;180:621-630.
This non-invasive study uses the tape-stripping technique, which removes cells from the surface of the cornified layer using an adhesive strip or discs. Tape-stripping is used to analyze the morphology of corneocytes and to measure the components of the epidermis, such as those of the NMF which indicate hydration, as well as several inflammatory mediators. The study measured 28 mediators using superficial samples collected from the forearm of atopic children, with and without lesions, and a control group. Before sharing the results reported below, it should be stated that supporters of this technique expect mainly personalized information which would, for example, make it possible to identify the best targeted treatment for a given patient. But still have a long way to go, despite the great strides made in the field of personalized medicine. In any case, its non-invasive nature makes tape-stripping easy to accept for children and easy to repeat, unlike blood samples and skin biopsies, which are poorly suited to patients with atopic dermatitis.
The study assessed 53 children with atopic dermatitis and 50 controls. The expression of several cytokines and chimiokines in higher in lesional atopic skin than in non-lesional skin. Some of the variations showed a correlation with the SCORAD. In children with light skin, the NMF is lower in atopic skin; however, this trend was not observed in children with dark skin. It is thus possible to measure inflammation and the skin barrier’s components, which should provide a better understanding of atopic anomalies and the best way to treat them.
Stress, pruritus, scratching
Mochizuki H, Lavery MJ, Nattkemper LA, et al.
Impact of acute stress on itch sensation and scratching behaviour in patients with atopic dermatitis and healthy controls.
Br J Dermatol 2019;180:821-827.
This experimental study sheds light on the important role psychological stress plays in patients with atopic dermatitis. The authors compared adult AD patients with healthy subjects in order to evaluate the impacts of standardized psychological stress. The Trier social stress test (named after the German city where it was designed) consists of placing subjects in a job interview setting and asking them to solve an arithmetic problem in front of a “jury”. The simulation showed that the atopic and control subjects perceived stress in the same way. In the atopic subjects, however, this stress level was correlated with the severity of the eczema, measured according to the EASI score. The authors then studied the impact of this stress test on the pruritus induced by applying cowhage spicules (hairs that cause itching) to the forearm, the resulting urge to scratch locally, and on scratching gestures over the entire body.
Overall, stress in atopic subjects caused a reduction in perceived localized itching but an increase in off-site scratching. Such changes in itch perception and scratching behavior were not observed in the healthy controls. This aspect of the central nervous system’s response to stressful stimuli likely plays a significant role in atopic dermatitis. In launching this study, Sonia Ständer wondered whether any consideration for the neuro-psychological aspect of pruritus and scratching may contribute to the success of immunological treatments, to which sensitivity varies among patients. Stress reduction techniques are likely beneficial to at least some patients with atopic dermatitis.
Latest developments in the microbiome and bacteriotherapy
Paller AS, Kong HH, Seed P, et al.
The microbiome in patients with atopic dermatitis.
J Allergy Clin Immunol 2019;143:26-35.
If you are a regular follower of our Medical News, you know that, over the last several years, skin commensal bacteria, previously called the skin flora and known today as the microbiome, are a key factor in skin immunity and atopic dermatitis in particular. More specifically, non-pathogenic staphylococci protect against pathogenic Staphylococcus aureus, and results show a reduction in this protection in the case of AD, especially during flare-ups. We have yet to uncover whether these bacteria cause inflammation, or if inflammation and barrier alterations cause a bacterial imbalance. Several studies are currently looking for the answer. Non-pathogenic staphylococci such as S. epidermidis, S. hominis and S. lugdunensis produce anti-microbial substances that may correct the lack of defense mechanisms in atopic skin. The application of commensal bacteria has proven effective in AD mouse models. Recent positive preliminary clinical trials have demonstrated the efficacy of applying non-pathogenic staphylococci and Roseomonas mucosa extracts to the skin. Thus, the anti-AD arsenal, which currently includes barrier treatments (emollients) and inflammation treatments, could one day add treatments that target bacterial dysbiosis directly.
“Efficacy of systemic treatments”
Seger EW, Wechter T, Strowd L, Feldman SR.
Relative efficacy of systemic treatments for atopic dermatitis.
J Am Acad Dermatol 2019;80:411-416.
In an age where numerous systemic treatments are being developed for atopic dermatitis, it is important to understand the efficacy of the treatments currently available. This is easier said than done, partly because these medicines have rarely been compared to one another and because different evaluation criteria are used, although the EASI and SCORAD scores are gaining in popularity. This article reviews 4 1 publications on systemic AD treatments in adults and children. Rather than children, we should refer to patients under the age of 18, on whom hardly any trials have been conducted: only 6 publications. Unsurprisingly, the review concluded that both cyclosporine and dupilumab improved the progression of AD significantly, in terms of eczema scores as well as quality of life scores. A number of medical and economic factors should be taken into consideration when choosing between the two treatment. This conclusion should be considered as provisional. The new treatments under development (read on to learn more), trials on children (as of now, only cyclosporine has been proven effective on this group), long-term efficacy tests and evaluations of long-terms tolerance should expand our knowledge of the performance of these treatments.
A critical appraisal and implications of the new National Institute for Health and Care Excellence guideline on dupilumab for treating moderate-to-severe atopic eczema.
Br J Dermatol 2019;180:435-437.
Dupilumab is undoubtedly a significant advancement in the treatment of atopic dermatitis, and stakeholders are eagerly awaiting the day when it will be available to all patients. However, before the results of clinical trials conducts be experts for manufacturers can be applied “in real life” by prescribers, it is subject to decisions of registration agencies and paying bodies. In the U.S., the FDA authorizes the release of drugs on the market, and insurance providers are private. In France, the national medicine and health insurance agencies—which are public institutions—evaluate the efficacy, safety and medical benefits of medications. In the U.K., the recommendations of the National Institute for Health and Care Excellence (NICE) carry a lot of weight. Other countries also rely on NICE recommendations when making decisions on reimbursement.
The FDA has authorized dupilumab for the treatment of adult patients with atopic eczema whose condition is not adequately controlled with topical treatments. In Europe, agencies such as NICE are more restrictive, particularly with regards the price/efficacy ratio, and recommend the treatment only after the failure (or intolerance or contra-indication) of another systemic treatment, usually cyclosporine. All of this is problematic, which is unsurprising given the complexity involved in treating atopic eczema. How do you define “adequately controlled”? What role do topical corticosteroids play? Should cyclosporine really be prioritized over dupilumab? How long is the treatment? These questions are complex, but answers are urgently needed, mainly because other treatments are currently being developed, which we will discuss further below. One solution would be to strengthen international collaboration and cooperative research between manufacturers and universities. Such initiatives are already under way, including, for example, the HOME group on the need to harmonize clinical evaluations and the TREAT group to compile a treatment register.
The pipeline is full
In the pharmaceutical industry, the “pipeline” refers to all the medications under development. The road is long—very long—from the conception of a molecule to its pre-clinical evaluation, the various clinical trial phases, and finally its release on the market. Not all candidates will make it to the finish line. For a long time, the pipeline for atopic dermatitis was empty, or nearly empty, in stark contrast to psoriasis, for which several treatments have recently been launched on the market. The landscape is changing, however, and a number of medications are currently at various stages of development. Some fall under the Biologics category (monoclonal antibodies) following dupilumab. Others are small active molecules, administered orally or topically, which act on other levels of atopic inflammation. These medications are yet to be available for use, but a few clinical trials, published in the international press, are encouraging. Here are four clinical trials recently published, and this list is barely scratching the surface. (For example, we previously discussed nemolizumab, which will not be mentioned again here. Other innovations are under way as well...). Just a reminder that all of these trials are preliminary and that these treatments will be subject to additional studies before being presented to registration authorities.
Wollenberg A, Howell MD, Guttman-Yassky E, et al.
Treatment of atopic dermatitis with tralokinumab, an anti-IL-13 mAb.
J Allergy Clin Immunol 2019;143:135-141.
Dupilumab inhibits a common IL-4 and IL-13 receptor. Given the role IL-13 plays in atopic inflammation, it makes sense to explore the efficacy of an antibody targeting IL-13 alone. Two such antibodies are currently being developed: lebrikizumab and tralokinumab. In the clinical trial reported here, several doses of tralokinumab were compared to a placebo in adult patients with atopy. At increased doses, its efficacy far exceeds that of the placebo, which is encouraging. There have been no reports of side effects, including those affecting the eyes, but preliminary trials rarely provide the whole picture with regard to medicinal tolerance.
Simpson EL, Parnes JR, She D, Crouch S, Rees W, Mo M, van der Merwe R.
Tezepelumab, an anti-thymic stromal lymphopoietin monoclonal antibody, in the treatment of moderate to severe atopic dermatitis: A randomized phase 2a clinical trial.
J Am Acad Dermatol 2019;80:1013-1021.
Tezepelumab is an antibody targeting the TSLP cytokine, which plays a key role in the physiopathology of atopic eczema. In this clinical trial, the response to tezepelumab was superior to the placebo, but not significantly. This may be due to the fact that patients were also using topical corticosteroids and that the response to the placebo was unusually positive. Additional clinical trials are planned.
Guttman-Yassky E, Silverberg JI, Nemoto O, et al.
Baricitinib in adult patients with moderate-to-severe atopic dermatitis: A phase 2 parallel, double-blinded, randomized placebo-controlled multiple-dose study.
J Am Acad Dermatol 2019;80:913-921.
Baricitinib is a JAK inhibitor. These medications, available in oral or topical formulations, inhibit Janus kinases (JAK) which provide a signaling pathway for inflammatory cytokines inside the cells. This makes them a potential inhibitor of atopic inflammation as well other inflammatory diseases, such as rheumatism. This clinical trial included 124 adults with atopy. Following an initial treatment phase of topical corticosteroids alone, baricitinib, at doses of 2 mg or 4 mg per day, was more effective than the placebo: after four months of treatment, more than 60% of the patients obtained an EASI score of -50, meaning their eczema score was reduced by half. These preliminary results are encouraging.
A phase 2, randomized dose-finding study of tapinarof (GSK2894512 cream) for the treatment of atopic dermatitis.
J Am Acad Dermatol 2019;80:89-98.
Tapinarof is a unique topical anti-inflammatory. It activates the hydrocarbon receptor (AhR, aryl-hydrocarbon receptor), which affects both TH2 differentiation and the expression of epidermal genes. This mode of action is similar to that of the tars once used as topical treatments for chronic eczema and psoriasis. Today, these tars have fallen out of use mainly due to their appearance. This research focuses on determining the most effective concentration and dosage. Without going into detail, a 1% concentration produced significantly better results than the excipient. Of course, more research is needed. there is certainly high demand for a non-steroidal topical anti-inflammatory that is effective and well tolerated.
"Dans la peau de Xavier", the first book for children written by Xavier Léost, expert patient
Interview with Xavier Léost, expert patient, about his very first book for children "Dans la peau de Xavier" (In Xavier's skin) dealing with bullying at school. A book inspired by his own personal story.
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