Medical news on eczema by Dr Daniel Wallach - April 2021

Medical news on eczema by Dr Daniel Wallach - April 2021

Découvrez la  2eme revue scientifique 2021 du Dr Wallach

Discover the 2nd scientific publication in 2021 by Dr Wallach:

  • Dupilumab prevents flare-ups of atopic dermatitis;
  • Tralokinumab, an anti-IL-13 monoclonal antibody for atopic dermatitis;
  • Abrocitinib, an anti-JAK for AD;
  • Tapinarof, an innovative topical therapeutic;
  • Contact eczema: European statistics;
  • Updating the "facial battery";
  • Patch tests on pigmented skin;
  • Reading of patch tests by OCT technique.

Dupilumab prevents flare-ups of atopic dermatitis 

Merola JF, Sidbury R, Wollenberg A, Chen Z, Zhang A, Shumel B, Rossi AB. 
Dupilumab prevents flares in adults with moderate to severe atopic dermatitis in a 52-week randomized controlled phase 3 trial. 
J Am Acad Dermatol 2021;84:495-497

In the extensive pre-marketing clinical trials of dupilumab, the primary endpoint was improvement in atopic dermatitis severity scores between the start and end of treatment. However, we know that atopic dermatitis progresses in flare-ups, with worsening and improvement not always predictable. The occurrence of these flare-ups is obviously very distressing, and fear of them has an impact on morale and quality of life. These flare-ups lead to hospital emergency room visits and are often treated with systemic corticosteroids, despite European and North American recommendations.

The main trial of dupilumab, published in 2017 and called LIBERTY AD CHRONOS (Lancet 2017;389:2287-2303) showed the efficacy of dupilumab, combined with topical corticosteroids. In this 1-year trial, patients all received topical corticosteroids, and were randomized to dupilumab or placebo. Flare-ups were defined as worsening of the disease requiring increased treatment and were noted but not studied in detail. The data from this trial allows for a retrospective analysis of the effect of treatment on the occurrence of flare-ups. The primary endpoint used here is the annualized flare-up rate. The annualized flare-up rate was 0.17 in the dupilumab group versus 0.77 in the placebo group. In other words, in adults with atopy, dupilumab reduces the risk of inflammatory flare-ups by 78%. Thus, before treatment, about 80% of patients had flare-ups, with 4.5 to 6.2 per year. During the treatment period, 84% of patients in the dupilumab group were flare-up-free, compared with 57% of patients in the placebo group (all of whom were using topical corticosteroids). The authors conclude that patients should be informed of this positive effect of prolonged treatment on flare-up prevention. This information will improve their confidence and compliance.   


Tralokinumab, an anti-IL-13 monoclonal antibody for atopic dermatitis

Wollenberg A, Blauvelt A, Guttman-Yassky E, et al; ECZTRA 1 and ECZTRA 2 study investigators. 
Tralokinumab for moderate-to-severe atopic dermatitis: results from two 52-week, randomized, double-blind, multicentre, placebo-controlled phase III trials (ECZTRA 1 and ECZTRA 2). 
Br J Dermatol 2021;184:437-449.

Silverberg JI, Toth D, Bieber Tet al; ECZTRA 3 study investigators. 
Tralokinumab plus topical corticosteroids for the treatment of moderate-to-severe atopic dermatitis: results from the double-blind, randomized, multicentre, placebo-controlled phase III ECZTRA 3 trial. 
Br J Dermatol 2021;184:450-463.

Dupilumab inhibits the signaling of both IL-4 and IL-13, which have a common receptor. Tralokinumab, another monoclonal antibody, inhibits only IL-13; in the early stages of its development, good efficacy against atopic dermatitis was observed. Both these articles report on large, double-blind, international phase III clinical trials comparing tralokinumab to placebo. In the ECZTRA 1 and 2 trials, which included a total of 1,596 adults, patients were not using topical corticosteroids. In ECZTRA 3 (369 adults), patients in both groups applied mometasone furoate (classified as potent in Europe) to the inflamed areas, which is probably consistent with "real-life" conditions. Tralokinumab dosage was 300 mg every two weeks, subcutaneously, and the trials initially lasted 16 weeks, followed by a second phase after further randomization.

Numerous details are provided in the articles, and here we will limit ourselves to the main results observed at week 16. Treatment success was defined as an IGA score of 0 or 1 (cured or nearly cured) and by EASI 75 (at least 75% improvement in EASI score). In ECZTRA 1 and 2, at 16 weeks this success was achieved by 16% to 33% of treated patients (depending on the trial and the endpoint) and only 7% to 12% of patients on placebo. In ECZTRA 3, 38.9% of treated patients achieved IGA success, and 56.0% achieved EASI success. In the placebo group, these figures were 26.2% and 35.7% respectively. Other parameters were also improved, including those recommended by the international experts of the HOME consensus (in addition to EASI and IGA, these are SCORAD, POEM, DLQI, pruritus) and topical corticosteroid consumption. All this enables the conclusion that tralokinumab, used alone or in combination with corticosteroids, is superior to placebo, with significant differences. In terms of safety, there was a 10% incidence of conjunctivitis with tralokinumab. In presenting these two articles, DE Dorra and AM Drucker (Br J Dermatol 2021;184:386-387) recall their recently published network meta-analysis (JAMA Dermatol 2020;156:659-667). According to this indirect comparison, dupilumab results in an EASI score improvement of 11.3 over placebo, compared with 5.4 to 9.9 in the ECZTRA trials. Nevertheless, tralokinumab is a promising addition to our anti-atopic dermatitis arsenal.  


Abrocitinib, an anti-JAK for AD

Bieber T, Simpson EL, Silverberg J et al; JADE COMPARE Investigators. Abrocitinib versus Placebo or Dupilumab for Atopic Dermatitis. 
N Engl J Med 2021;384:1101-1112

Several oral JAK kinase inhibitors, or anti-JAK drugs, are currently being developed for the treatment of rheumatoid arthritis and other inflammatory rheumatic diseases, as well as atopic dermatitis. Baricitinib already has marketing authorization in France for the indication of atopic dermatitis, and this article suggests that this will soon be the case for abrocitinib. This is an international multicenter phase 3 trial comparing oral abrocitinib with subcutaneous dupilumab and placebo in a double-blind fashion. In addition, all patients were using emollients, and most were applying a low- or medium-potency topical corticosteroid.
838 adult patients participated; they had severe atopic dermatitis, with a mean SCORAD of more than 65, an EASI score around 30, and involvement of about half the body. Topical treatment had been unsuccessful, so these patients were candidates for systemic treatment.

Treatment lasted 16 weeks. The authors primarily measured the percentage of patients achieving IGA 0 or 1 (eczema cured or nearly cured) and the EASI-75 criterion (at least 75% improvement in EASI score). Numerous secondary endpoints were also measured, including the intensity of pruritus.
The key finding was that at 200 mg daily, abrocitinib achieved 48.4% IGA 0/1 and 70.3% EASI 75 responses at 12 weeks. The 100 mg dose was slightly less active (36.6% and 58.7%, respectively) and close to the results for dupilumab (35.5% and 58.1%). The results in these three groups were better than those in the placebo group (14.0% and 27.1%). The article contains numerous secondary endpoints that we do not have the space to go into detail on here, all of which support the conclusion that abrocitinib is effective.
In terms of tolerance, a low percentage of patients with conjunctivitis on dupilumab (6.2% of patients) was noted. The tolerance of abrocitinib was carefully studied. Clinically, nausea, headache, and acne were observed, always mild to moderate. Biologically, abrocitinib causes dose-dependent increases in CPK levels (without rhabdomyolysis) and cholesterol, which will probably require monitoring.


Tapinarof, an innovative topical therapeutic

Paller AS, Stein Gold L, Soung J, Tallman AM, Rubenstein DS, Gooderham M. 
Efficacy and patient-reported outcomes from a phase 2b, randomized clinical trial of tapinarof cream for the treatment of adolescents and adults with atopic dermatitis. 
J Am Acad Dermatol 2021;84:632-638

Tapinarof is a selective activator of the transcription factor AhR, the aryl hydrocarbon receptor. The AhR receptor is widely expressed in the skin and in many other tissues. It responds to environmental toxins (including dioxin) and plays a role in many immune system functions. Activation of AhR modulates the expression and activity of several cytokines, including those involved in skin inflammation, such as IL-4 and IL-13. This activation also strengthens the barrier functions of the epidermis. This is an original mode of action, different from that of corticoids which are currently the only effective topical anti-inflammatory drugs. Tapinarof therefore appears as a potential effective topical anti-inflammatory. A tapinarof cream is currently being developed in atopic dermatitis and also in psoriasis, with favorable initial results. This article presents a phase 2b clinical study conducted in 191 adults and adolescents with moderate to severe atopic dermatitis. They were treated for 12 weeks with a tapinarof cream (0.5% and 1% concentrations) or an excipient, once or twice daily. The many clinical parameters used to evaluate AD were measured, and showed positive results. For example, the EASI 75 criterion was met by 60% of patients using the 1% cream twice a day, compared with 26% of patients in the excipient group. The other objective and subjective parameters provided comparable results, with efficacy always dependent on the concentration and frequency of application. Local tolerance was good and no mention is made of systemic tolerance. It should be remembered here that the tolerance of a new active ingredient must be carefully monitored, well beyond preliminary clinical studies.


Contact eczema: European statistics 

Uter W, Bauer A, Belloni Fortina A, et al; ESSCA Working Group. 
Patch test results with the European baseline series and additions thereof in the ESSCA network, 2015-2018. 
Contact Dermatitis 2021;84:109-120

In the field of contact eczema, patch tests are of paramount importance, both on an individual level, to confirm a diagnosis, and on a collective level, to monitor the evolution of skin allergies to environmental components, both personal (hygiene, cosmetics) and professional. This requires a rigorous and well-defined technique, and international cooperation between specialists in contact allergology. The European Surveillance System on Contact Allergies (ESSCA) brings together specialists from 13 countries, and this article presents the results observed in 51,914 patients tested between 2014 and 2018 with the European standard battery. The comparison with previous years enables observation of the impact of preventive measures, such as the decrease of chromium in cements and leathers, and also the emergence of new allergens, such as methylisothiazolinone. The centralized processing of European data is valuable, as is that of North American data, which is also published regularly. Overall, it appears that the prevalence of contact allergies is decreasing, while that of atopic history (a vague concept) is increasing in the patients tested. The most frequently found contact allergens are nickel (by far the most prevalent), followed by fragrances, methylisothiazolinone and Peruvian balsam (resin). Many others were also found. 


Updating the "facial battery" 

Rolls S, Owen E, Bertram CG, et al.
What is in? What is out? Updating the British Society for Cutaneous Allergy facial series. 
Br J Dermatol 2021;184:151-155. 

Members of the British Society for Skin Allergy (BSCA) provide work to update the allergens in the "facial battery." The last list of allergens in this battery dated from 2012, and the BSCA conducted an audit of the practices of 12 British and Irish centers in 2016-2017, involving 4,224 patients tested with this 2012 BSCA battery. This recommended 26 allergens, but in reality the centers tested each patient with between 24 and 66 allergens, taking into account local practices, individual situations and probably the experience of allergists. In all, 103 allergens were tested. These were almost exclusively allergens present in cosmetics, and those already included in the standard battery were not included in this specialized battery for facial eczema. For this update, the authors retained the positivity threshold of 0.3%, which ensures a good probability of not omitting a frequent allergen, and also of not testing incorrectly with an allergen that is too rare. The authors therefore propose a new BSCA battery of facial cosmetics, which contains 24 allergens. Of these, 15 were already in the 2012 battery, and 9 are new. 11 allergens from the 2012 battery have been dropped. For information purposes, here is the list of the 9 new allergens: panthenol, decyl glucoside, octyl gallate, propylene glycol, dodecyl gallate, benzophenone-4, octocrylene, lauryl glucoside and tocopherol acetate. It can be expected that this battery, developed from 2016-2017 UK practices, will be further updated in the near future, as numerous potentially allergenic constituents are continuously added to cosmetics. This important article highlights the importance of dermato-allergology's ongoing adaptation to regulations, new products and local practices. Allergens that were once common have become very rare, and new allergens are emerging. The authors also stress the importance of testing patients with their own products, which is always very useful for identifying their contact allergies. 


Patch tests on pigmented skin 

Tamazian S, Oboite M, Treat JR. 
Patch testing in skin of color: A brief report. 
Pediatr Dermatol 2021, published online on 20 Mars.  

We may start by noting that it is mainly women that are concerned here as 90% of professionals and customers affected are women. Hairdressers are at very high risk of professional eczema. They are prone to irritant dermatitis, due to contact with detergents and working with wet hands. And above all, hairdressers are in contact with many allergenic chemical products: dyes, perm liquids, hair straightening products, shampoos, hygiene and toiletry products. They also handle cleaning products. Finally, protective gloves can also be allergenic. Most often, occupational dermatitis starts at the beginning of activity, or even during apprenticeship and is a major cause of change of profession. A study conducted in the north-eastern Italy shows that although the incidence of occupational eczema has decreased in recent years, it remains high. The main sites are the hands and forearms, and also the face (airborne allergens, hand contact). The main allergens involved are p-phenylenediamine (dye product), thiuram mix (rubber gloves), ammonium persulfate, toluene-2,5 diamine and para-aminobenzene. In addition, like the rest of the population, hairdressers are frequently sensitized to nickel. Protective measures are therefore essential, right from the start of apprenticeship, but we know that they are difficult to apply rigorously.                               

A Greek study shows that customers of hairdressers can also suffer from contact eczema to products used in hairdressing. Contact tests show that the same allergens are responsible. In this study, of course, it is the scalp that is affected.


Reading of patch tests by OCT technique 

Ruini C, Rahimi F, Fiocco Z, French LE, Hartmann D, Oppel E, Sattler E. 
Optical coherence tomography for patch test grading: A prospective study on its use for noninvasive diagnosis of allergic contact dermatitis. 
Contact Dermatitis 2021;84:183-191.

The clinical reading of patch tests is subject to the clinician's own judgment, and to various difficulties, particularly in distinguishing mild allergic reactions from irritation reactions. Several techniques have been proposed to improve this reading, which remains the "gold standard" of contact eczema diagnosis.
Optical coherence tomography (OCT) is a noninvasive tissue visualization technique, widely used in ophthalmology, but which also has many potential applications in dermatology, particularly for the evaluation of skin cancers. 

The authors observed 129 positive patch test areas using static and also dynamic OCT. This enables assessment of microscopic skin morphology to a depth of 1 to 1.5 mm, and also of blood flow. They were therefore able to use OCT to characterize positive allergic reactions, doubtful reactions, irritation reactions, and healthy skin. Morphologically, OCT images can be used to evaluate spongiosis, microvesicles, blurring of the dermal-epidermal junction, pustules, erosions, epidermal thickness, microvessels and their appearance. The device's software also enables measuring capillary blood flow, and an optical attenuation coefficient. All this results in an OCT score for patch test positivity. It is clear that OCT will not solve all the problems of weak reactions and irritations, but in experienced hands, it can contribute to a more accurate and objective reading of patch tests.    



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