Medical news on eczema by Dr Daniel Wallach – January 2019

Medical news on eczema by Dr Daniel Wallach – January 2019

Discover the first scientific publication in 2019 by Dr Wallach:

Discover the first scientific publication in 2019 by Dr Wallach:

  • “The role of the gastrointestinal microbiota is unknown”
  • “The itch-scratch cycle”
  • “Four groups of young children with atopy”
  • “With or without staphylococci?”
  • “Can an aggressive treatment prevent the Atopic March?”
  • “Prevalence of atopic dermatitis in tropical countries”
  • etc.

The role of the gastrointestinal microbiota is unknown

Petersen EBM, Skov L, Thyssen JP, Jensen P.

Role of the Gut Microbiota in Atopic Dermatitis: A Systematic Review.

Acta Derm Venereol 2019, published online 7 August 2018.

Let’s get one thing clear right off the bat: we don’t know. It is still unclear whether atopic dermatitis is linked to certain anomalies in the gut microbiota. We also do not know whether changes to this microbiota, induced by oral probiotics (bifidobacteria, lactobacilli), are likely to improve atopic dermatitis symptoms. This is hardly for lack of trying: the authors of this literature review identified 2,199 publications on the subject. Fortunately, if we may say so, their methodology identified just 44 of the publications as being likely to provide interesting data. 26 observational studies analyzed the gastrointestinal microbiota of children with atopy in comparison to healthy children. The results are conflicting: some found no difference, others observed a reduction in microbial diversity, and one study even indicated that an increase in this diversity was linked to the development of atopic dermatitis. It is thus impossible to draw a conclusion, and studies focusing on a specific bacterial species have shed no new light on the subject. 18 interventional studies involving a total 2,802 patients analyzed the effect of oral probiotics on fecal microbiota composition, the clinical progression of AD, and on a potential correlation between the two. Once again, the results are conflicting, but the main conclusion is that, while probiotics do affect the microbiota, they have no effect on clinical progression. Research continues, of course, and we will continue to report any and all results, whether promising or disappointing. Given the uncertainties surrounding the general physiopathology of atopic dermatitis and the heterogeneity of this disease, this is hardly surprising.

The itch-scratch cycle

Mack MR, Kim BS.

The Itch-Scratch Cycle: A Neuroimmune Perspective.

Trends Immunol 2019, published online 27 October 2018.

This cycle can certainly be classified as vicious and involves three distinct biological systems: the epidermis, the immune system and the peripheral nervous system. Each one interacts with the other two, meaning that any intervention in one of the three systems could be enough to break the cycle and thus treat pruritus successfully. For example, emollients which act on the epidermis, corticosteroids which act on inflammation, and neuropeptide inhibitors which act on peripheral neurons are all likely to reduce itching, or certain types of itching to be specific.

Although atopic dermatitis tops the list in terms of itchy dermatoses, pruritus comes in many other forms, either of cutaneous or systemic origin, and can be somatic or psychological. A number of murine animal models have been conducted on scratching, many of which have demonstrated the effect of a particular protease, cytokine or neuropeptide on pruritus. Such evidence that a molecule can induce itching behavior in animal models has prompted research on whether inhibiting it in a clinical setting would be effective against any of the various forms of pruritus. But both clinical and experimental studies clearly show that we are a long way away from having a single effective treatment against all types of itching. Many therapies currently under development have the potential to block one of the molecules involved in a clinical form of pruritus and thus break the itching cycle.

With regard to atopic dermatitis, biologics targeting TH2 cytokines—such as dupilumab (anti-IL-4 and IL-13), nemolizumab (anti-IL-31) and many others in earlier stages of development—are among the first new targeted anti-pruritus treatments. For more complex cases of pruritus, such as with atopic dermatitis, several treatment approaches may be indicated for a given patient at a particular stage of the disease. Such approaches would target the epidermis, immunological inflammation and neurogenic inflammation, which represent the three levels of action involved in breaking the vicious cycle of atopic pruritus.

Four groups of young children with atopy

Seo E, Yoon J, Jung S, Lee J, Lee BH, Yu J.

Phenotypes of atopic dermatitis identified by cluster analysis in early childhood.

J Dermatol 2019, published online 6 December 2018.

In light of the vast differences observed between atopic dermatitis cases, several attempts have been made to classify the disease: intrinsic or extrinsic AD, AD in adults or children, localized or systemic AD, AD with or without filaggrin mutation, AD with or without staphylococcus colonization, and many more. No such attempts have been successful in consistently identifying the distinct groups or sub-groups. This would make it possible to provide a specific therapy in accordance with the principles of personalized medicine.

This team of Korean pediatricians has taken a new approach to solve this problem, using the cluster analysis method. This statistical approach is used to form groups sharing the same characteristics from among a heterogeneous population. Researchers collected and analyzed detailed data covering 11 clinical and biological variables in 572 children with atopy aged 3 years and under. The analysis identified 4 groups: Group A includes children with early-onset AD, high levels of eosinophils and IgE in the blood, and allergic sensitivities; these children also presented with a higher SCORAD on average. Group B is the largest and includes children with early AD but without the biological signs of allergies. The children in Group C have early AD, high levels of circulating WBCs and C-reactive protein. The children in Group D have late-onset AD, high IgE levels and allergic sensitivities.

Among the wide range of clinical and biological parameters taken into account, age at disease onset, age at diagnosis, complete blood count (CBC), C-reactive protein levels, and the total IgE are the best predictors of belonging to one of the four groups. At the moment, it is unclear how this stratification of AD may be useful. But long-term monitoring of the children may reveal whether this classification correlates with the type of atopic disease (localized AD or accompanied by asthma) and may help provide the appropriate care. On a broader scale, we may be able to adapt the therapies for each sub-group, if the relevance of this classification is indeed confirmed.

With or without staphylococci?

Simpson EL, Villarreal M, Jepson B, et al.

Patients with Atopic Dermatitis Colonized with Staphylococcus aureus Have a Distinct Phenotype and Endotype.

J Invest Dermatol 2018;138:2224-2233.

The degree to which staphylococcus colonization contributes to atopic skin remains unclear. Is it simply the result of skin anomalies? Is it due to a specific immune deficiency? Does it cause eczema flare-ups? This study provides no answers to these questions, but it does suggest that atopic patients whose skin (lesional and/or non-lesional) is colonized with Staphylococcus aureus form a specific group, different from those patients without S. aureus colonization.

The study included 96 adults with atopy: 51 carriers of S. aureus (SA+) and 45 subjects negative for S. aureus (SA-). A control group of healthy subjects, without atopy or S. aureus, were studied as a comparison. Several parameters were measured: severity scores, pruritus scales, quality of life scores, epidermal functions (water loss, hydration, pH) and serum biomarkers (including eosinophils and IgE ). The only commonality in both groups is pruritus. For all other parameters, clinical and biological, the SA+ group had the most severe atopic dermatitis. For example, the average EASI score is 23.8 versus 8.6 in the SA- group.

The results also confirmed that staphylococcal status is independent of filaggrin mutations. Thus, staphylococcus colonization appears to be a marker of AD severity. The publication does not discuss the therapeutic consequences of this discovery. Most of the authors recommend a combined anti-infection and anti-inflammatory treatment for acute AD flare-ups. For the long term, other approaches are currently being studied.

Can an aggressive treatment prevent the Atopic March?

Yamamoto-Hanada K, Kobayashi T, Williams HC, et al.

Early aggressive intervention for infantile atopic dermatitis to prevent development of food allergy: a multicenter, investigator-blinded, randomized, parallel group controlled trial (PACI Study)-protocol for a randomized controlled trial.

Clin Transl Allergy 2018;8:47.

The question of how to prevent the progression of atopic dermatitis is at the center of discussions on how to treat the disease in infants and children. Current treatments provide quick relief from eczema symptoms, but their impact on the long-term progression of the condition remains unknown. Many dermatologists recommend an early, aggressive treatment of atopic dermatitis, but the validity of this opinion has yet to actually be proven. It seems likely, however, and recent data on the importance of skin barrier anomalies and the preventive role of emollient treatments appear to support this conclusion.

Food allergy sensitivities are the second manifestation of the Atopic March, followed by respiratory sensitivities which appear later. In Japan, the prevalence of food allergies is 9% among infants under the age of 12 months, and children with severe AD are at higher risk for developing a food allergy. Prevention is thus critical. The project is based on the hypothesis that an aggressive treatment of atopic dermatitis would help prevent food allergies by eliminating epidermal hyperpermeability, which is a key factor in digestive sensitivities. The authors thus present a detailed protocol for a randomized pragmatic clinical trial, called PACI (Prevention of Allergy via Cutaneous Intervention). This trial will involve 650 infants with atopy between the ages of 7 and 13 weeks. Subjects will be divided into two groups. An emollient will be applied to the children twice daily, and parents will receive information adapted to their situation. The groups will differ in their approach to topical corticosteroid therapy: the children in the control group will receive the standard treatment consisting of the so-called “reactive” use of topical corticosteroids, prescribed only for cases of inflammatory flare-ups (acute eczema). The other group will receive a so-called “aggressive” treatment that consists of the “proactive” use of topical corticosteroids, applied twice daily for two weeks, then two days a week for 6 months, the entire duration of the study. This proactive treatment should eliminate eczema flare-ups, and the purpose of the study is to uncover whether it will eliminate food allergies as well, and even respiratory allergies over the long term.

The results of this ambitious trial will be assessed based on the prevalence of egg allergy, the most common food allergy in Japan, and on a number of clinical parameters of atopic dermatitis. The treatment’s side effects will also be monitored closely. All methodological precautions have been taken to ensure the validity of the conclusions. The details of the PACI project are presented in this publication, and we optimistically look forward to the results.

Prevalence of atopic dermatitis in tropical countries

Sánchez J, Sánchez A, Cardona R.

Critical review of ISAAC results for atopic dermatitis in tropical cities.

Rev Alerg Mex 2018;65:389-399.

Diagnosing atopic dermatitis is a challenge. These difficulties are compounded when trying to assess the prevalence of AD through an array of epidemiological surveys in which the diagnosis is made based on questionnaire data without a clinical exam. This was the case for the infamous ISAAC study (International Studies of Asthma and Allergies in Childhood), which was published about 20 years ago and remains the authoritative study on the matter. It involved approximately one million children across 50 countries. The prevalence of AD varied greatly, with Albania having the lowest rates (about 2%) and Nigeria and the United Kingdom the highest (about 25%).

The prevalence of AD in France was assessed at between 10% and 15%. These data were obtained through a survey of parents, who, in brief, were asked whether their children had an itchy dermatosis. Despite all the precautions with regard to methodology and translation, a number of obstacles arise when applying the British AD criteria to the entire planet more generally. Before we are able to conclude that atopic dermatitis is different in temperate and tropical countries, a critical evaluation of the ISAAC methodology is needed, which is the recommendation of the Mexican authors of this publication. According to the ISAAC study, the prevalence of AD in tropical cities, such as in Latin America for example, was approximately 23%, compared to 15% in subtropical regions. In tropical regions, however, several common dermatoses in children present with clinical characteristics (an itchy rash) which may be confused with AD. These mainly include miliaria, also called “sweat rash”, common in children in hot countries, and scabies.

When AD prevalence is measured based on examining children rather than questioning their parents, the figures are very different: if the exam is conducted by trained, non-physician professionals, prevalence is just 15%; if done by physicians, this drops to 7%, a rate which is virtually identical to that in non-tropical countries when evaluated in the same manner. The authors list the many problems that undermine the results of the ISAAC study and several similar studies which fail to include a clinical examination of the children.

Factors associated with persistent atopic dermatitis

Thorsteinsdottir S, Stokholm J, Thyssen JP, et al.

Genetic, Clinical, and Environmental Factors Associated With Persistent Atopic Dermatitis in Childhood.

JAMA Dermatol 2019, published online 14 November 2018.

From 1998 to 2015, 411 children born to a mother with asthma, and thus at high risk of atopy, were carefully monitored in Copenhagen. Among them, 166 presented with atopic dermatitis in childhood. It should be noted that the diagnosis was determined based on Hanifin and Rajka’s very precise clinical criteria and that severity was measured based on the objective SCORAD, also very precise. At the age of 13 years, only 40 of the children, approximately 25%, still presented with signs of AD. The purpose of the study was to identify the factors contributing to this persistence. There are, in fact, many factors: a genetic score analyzing filaggrin variants, the presence of asthma or atopic dermatitis in the father (all the mothers were asthmatic), a higher social status, and certain minor criteria of Hanifin and Rajka. These minor criteria include the Dennie-Morgan palpebral fold, neck folds, white dermographism, an intolerance to wool, sweat-induced itching, a proneness to skin infections, and food allergies. The severity of eczema upon diagnosis was also a factor in the persistence of AD in adolescence.

It remains unclear whether or not these data are applicable to the general unselected atopic population, but the value of minor clinical criteria should be considered when making a diagnosis and proposing adapted measures.

Sleep and eczema: it’s complicated

Chang YS, Chiang BL.

Sleep disorders and atopic dermatitis: A 2-way street?

J Allergy Clin Immunol 2018;142:1033-1040.

More than 80% of patients with atopy report having sleep problems. The extent of these problems and their impact on quality of life are well known. And yet, they are usually considered as a simple consequence of pruritus; perhaps they need to be examined more closely. This is no easy task, first because it is difficult to pinpoint their definition. Ideally, we would like to measure them objectively, but polysomnographies are difficult to conduct. Even the more basic actigraphy is rarely performed. Like with pruritus, the other major symptom of AD, we must, therefore, settle for questionnaire data.

Clinically, there are several distinct sleep disorders: difficulty falling asleep, nocturnal awakenings, difficulties waking up, sleep efficiency, breathing difficulties (snoring, apnea). All of these anomalies are more common in people with atopy. The ramifications of sleep problems include mood disorders, attention deficit and learning difficulties, thus affecting your family, social, school and professional life. The mechanism of these sleep disorders in AD is unclear, and several factors seem to be involved, such as scratching, of course, but also alterations in neuropeptides and cytokines with a neurotropic effect, like IL-31.

Anomalies in the circadian rhythm have also been attributed to the secretion of certain hormones (cortisol) and cytokines, the balance of which can affect sleep. Melatonin metabolism may also play a role. Sleep disorders and atopic dermatitis therefore maintain two-way relationships. Once again, we have a vicious cycle. Practically speaking, there are currently no recommendations regarding sleep disorders specifically. The authors propose a decision-making tree that indicates specific sleep approaches if problems persist after proper eczema treatment: sedative antihistamines, melatonin, and even benzodiazepines and behavioral techniques.


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