Medical news on eczema by Dr Daniel Wallach - July 2021

Medical news on eczema by Dr Daniel Wallach - July 2021

Discover the 3rd scientific publication in 2021 by Dr Wallach

Discover the 3rd scientific publication in 2021 by Dr Wallach

  • The performance of upadacitinib
  • Personalized bacteriotherapy
  • The role of pollution
  • The benefits of qualitative studies
  • The proper use of severity scores
  • Incidence of hand eczema
  • Nummular eczema and contact allergies
  • The latest on dupilumab

The performance of upadacitinib  

Guttman-Yassky E, Teixeira HD, Simpson EL et al. 
Once-daily upadacitinib versus placebo in adolescents and adults with moderate-to-severe atopic dermatitis (Measure Up 1 and Measure Up 2): results from two replicate double-blind, randomised controlled phase 3 trials. 
Lancet 2021;397:2151-2168.

Reich K, Teixeira HD, de Bruin-Weller M et al. 
Safety and efficacy of upadacitinib in combination with topical corticosteroids in adolescents and adults with moderate-to-severe atopic dermatitis (AD Up): results from a randomised, double-blind, placebo-controlled, phase 3 trial. 
Lancet 2021; 397:2169-2181.

These two long papers published in The Lancet could well be a significant milestone in the treatment of serious forms of atopic dermatitis. They present the results from three large-scale international phase 3 clinical trials on upadacitinib, a JAK-1 inhibitor already marketed for the treatment of rheumatoid polyarthritis. 

Measure Up 1 and Measure Up 2 included nearly 1700 patients in 24 countries. The patients, adolescents and adults with moderate-to-severe AD (Atopic Dermatitis), received oral upadacitinib 15 mg or 30 mg, or a placebo once daily for 16 weeks. The patients had no other treatment. The assessment was very comprehensive, taking into account the usual severity scores for AD, pruritus, other symptoms, and quality of life. In this summary, I will only cite the results of the treatment based on the EASI score, which is very representative of overall efficacy and well correlated with the other results. In Measure Up 1, 80% of patients treated with upadacitinib 30 mg (70% in the 15 mg group, 16% in the placebo group) achieved an EASI-75 score at 16 weeks. The scores and pruritus improved rapidly, from the first days of treatment for some patients. This result is quite remarkable and the authors even boldly indicated EASI-90 (66%) and EASI-100 scores (27%) for the patients in the upadacitinib 30 mg group. We know how difficult it is to treat severe AD and I do not think any other studies have mentioned an EASI-100. This study is expected to be extended five years and will, therefore, provide long-term data, essential for this chronic disease.  

The AD Up trial was designed in the same way but here the patients in the three groups also used topical corticosteroids according to a very specific protocol. The main conclusion was that this additional topical treatment did not significantly improve the good results obtained with upadacitinib alone, which is also very interesting. 
With regard to tolerance, acne was observed in 15% to 17% of patients treated with the 30 mg dose. This acne was generally mild to moderate; only one patient had severe widespread acne. This adverse event had not been observed in rheumatology patients, who are of course older than atopic patients, and we do not yet have any data on the pathophysiology of this acne caused by JAK inhibitors. 

Our avid readers may recall the papers on the treatment of AD with two other JAK inhibitors, abrocitinib and baricitinib, discussed in previous news articles. Upadacitinib will soon provide clinicians with new oral treatments, which will probably need to be compared with the Biologics. 


Personalized bacteriotherapy 

Nakatsuji T, Gallo RL, Shafiq F et al.  Use of Autologous Bacteriotherapy to Treat Staphylococcus aureus in Patients With Atopic Dermatitis: A Randomized Double-blind Clinical Trial. 
JAMA Dermatol 2021, published online on 16 June.

Could recent findings regarding the importance of staphylococcal dysbiosis in atopic dermatitis have direct therapeutic consequences? Well, this is what the work Pr Richard Gallo's team has been undertaking for several years suggests. These researchers have shown that one of the causes of the excessive presence of Staphylococcus aureus on atopic skin is a lack of non-pathogenic commensal coagulase-negative staphylococci. These commensals are normally capable of destroying S. aureus, hence the idea of increasing their presence on the skin of atopic patients.

The study presented here must be considered as preliminary as it only involved 11 atopic patients whose skin was colonized with S. aureus and only 5 received the active treatment. For each patient, the authors obtained commensal staphylococci from swabs and isolated in vitro those that could kill S. aureus. The various strains of coagulase-negative staphylococci isolated (S. epidermis, S. hominis, S. capitis, S. warneri) were grown and formulated in a topical cream. For each patient, the cream contained autologous staphylococci and was applied twice daily for a week on the forearm and elbow crease. Compared with the control group of 6 patients who received the vehicle, the treatment led to a decrease (99.2%) in pathogenic Staphylococcus aureus and an improvement in inflammation, measured according to a local variant of the EASI score. This demonstration however elegant needs to be confirmed and we will make no attempt to speculate on the future of this personalized autologous bacteriotherapy. 


The role of pollution 

Wang HL, Sun J, Qian ZM et al. 
Association between air pollution and atopic dermatitis in Guangzhou, China: modification by age and season. 
Br J Dermatol 2021;184:1068-1076. 

Fadadu RP, Grimes B, Jewell NP et al. 
Association of Wildfire Air Pollution and Health Care Use for Atopic Dermatitis and Itch. JAMA Dermatol 2021;157:658-666.

The harmful effects of pollution are well known. High levels of atmospheric pollution lead to an increase in cardiovascular events and cancer, worsening of respiratory diseases (asthma, COPD), and are a significant factor of mortality. The effects of pollution on the skin are less serious and have therefore been studied less. These two publications confirm however that pollution, especially fine particles, has harmful effects on atopic dermatitis.

In the Chinese province of Guangzhou with its subtropical climate, an extremely precise environmental and clinical study highlighted a correlation between the levels of atmospheric pollution (fine particles, SO2, NO2, ozone) and hospital consultations for atopic dermatitis. This correlation was more pronounced in children than in adults, and greater during the cold season when the skin is drier than during the hot season.   
Other than chronic urban pollution, acute peaks in pollution also affect skin disorders. The huge forest fires that hit California between October 2018 and February 2019 led to a peak in pollution for several weeks in San Francisco, which is located 280 km from the fires. RP Fadadu and his collaborators studied the effect of this acute pollution on the skin. They examined consultations for atopic dermatitis, as well as pruritus in general, in an establishment in San Francisco, and compared the data from 2018 and 2019 with an equivalent prior period when there was no specific pollution. The environmental factors taken into account were the concentration of fine particles (less than 2.5 nm) and the density of the columns of smoke visible on the satellite images. We can see that during and following this period of acute pollution, consultations for AD and pruritus (without AD) were significantly higher for adults and more particularly children. Furthermore, drug prescriptions for AD also increased, indicating a direct effect of the pollution on the severity of AD. Beyond the theoretical interest regarding the importance of environmental factors on AD, the authors provide a practical recommendation: during peaks of pollution, it is necessary to wear clothing that covers the body to prevent the direct effect of the particulate pollutants on the epidermis.  


The benefits of qualitative studies 

Teasdale E, Muller I, Sivyer K et al. 
Views and experiences of managing eczema: systematic review and thematic synthesis of qualitative studies. 
Br J Dermatol 2021;184:627-637.

For a disease as complex as atopic dermatitis, simply referred to as eczema in this British paper, quantitative data are extremely useful. A SCORAD or EASI score provides information about the intensity of the disease, a figure between 0 and 10 indicates the severity of the pruritus, another measures the effects on quality of life. We can even use the TOPICOP score to assess corticophobia. These quantitative data, essential in clinical research, are probably used much less in daily practice. Indeed, they do not tell the whole story, and these are concepts for doctors, not patients. Patients or parents of young patients are not interested in these figures; they have experience, feelings, perceptions, fears, questions that cannot be quantified. All doctors know that it is from talking to patients that we learn the most about their disease. All this to justify the qualitative studies that gather and analyze the perceptions and experiences of patients or parents regarding eczema and its treatment. The medical literature summarized in this article thus contains hundreds of quotes from patients about their eczema and its treatment, of which several have been cited in the article. The main views expressed by the patients can be divided into four themes: (1) Many patients, and more particularly parents, do not consider eczema as a chronic disease that can be at best controlled but not cured. Consequently, they seek a specific cause (allergy, diet...) and do not appreciate treatments that do not definitively cure the disease; (2) Patients complain that the psychological and social impact of eczema is underestimated, including by doctors. In society, eczema is perceived as a mundane, insignificant condition and not a serious chronic disease. (3) Concerns regarding treatments are a major topic. What is known as corticophobia, which is more a hesitancy or reluctance regarding the use of topical corticosteroids, is a complex problem for which there are numerous explanations. In particular, the discrepancy between opinions expressed by doctors, pharmacists, and the lay public is an understandable source of anxiety. Of course, doctors do not devote enough time to detailing all the aspects of topical corticosteroid therapy, which has probably been insufficiently studied, and patients still have many unresolved theoretical and practical questions. All this is also true for other treatments, including new systemic treatments. (4) Finally, regarding eczema in general, patients consider they are not provided with enough information. We can see that qualitative studies have the advantage of exploring the doctor-patient relationship, which is so difficult when it comes to atopic dermatitis.      


The proper use of severity scores 

Silverberg JI, Lei D, Yousaf M et al. What are the best endpoints for Eczema Area and Severity Index and Scoring Atopic Dermatitis in clinical practice? A prospective observational study. 
Br J Dermatol 2021;184:888-895. 

The benefits of qualitative studies seem even greater when we consider the huge amount of literature dedicated to quantitative scores, their benefits, and their interpretation. Among these quantitative scores, there are so-called objective scores, assessed by a doctor during a clinical examination, and so-called subjective scores, assessed by the patient and known as patient-reported outcomes (PRO). These two types of assessment of AD are not equivalent and it is important to understand the correlations. So, when treatment results in a 50% or 75% decrease in the EASI score, this figure can be enough for assessors and registration agencies, but what does it mean for the patient?

The authors of this study wanted to answer this simple question: what is the minimal clinically meaningful change in EASI and SCORAD?
To achieve this, they assessed 826 patients with atopic dermatitis (of which 88% adults). The patients filled in questionnaires to assess the main PRO: assessment of overall severity (PtGA on a 5-grade scale: clear, almost clear, mild, moderate, severe), pruritus and sleep disorders (visual scale of 0 to 10), POEM score, and quality of life index. 

The dermatologist assessed overall severity (PGA, same scale as PtGA), EASI score, and objective SCORAD (symptoms and area affected). 
The comparison of the "patient" and "doctor" scores enabled the authors to answer the question. A 50% improvement in the EASI score could be considered as the minimal clinically important change (1-grade PGA and 2-grade PtGA). A two-grade improvement of PGA corresponded to EASI 75. For SCORAD, an improvement of 35% was clinically significant. 
We can retain that EASI 50 and SCORAD 35 are the thresholds of patient-observed improvement. 


Prevalence of hand eczema  

Quaade AS, Simonsen AB, Halling AS, Thyssen JP, Johansen JD. 
Prevalence, incidence, and severity of hand eczema in the general population - A systematic review and meta-analysis. 
Contact Dermatitis 2021;84:361-374. 

This systematic review of the literature examined the prevalence and incidence of hand eczema in the general population rather than selected populations. Allergological studies are too often restricted to hospital consultations or even patients referred for patch tests, which are very specific populations. By applying an adapted methodology, the authors analyzed 69 studies encompassing 600 000 individuals, most of which were conducted in Northern Europe. They concluded that 14.5% of the population suffered from hand eczema at some point in their lifetime and that this prevalence is probably increasing. The prevalence over 1 year was 9.1% and the point prevalence, at a given point in time, was 4.0%. However, the data was obtained through interviews; if we only consider eczema confirmed by a physician, the overall prevalence was only 5.2%. Hand eczema is more common in women than men, including in children and adolescents. This female preponderance can generally be explained by a greater use of toiletries in daily life and by health care professionals.

Approximately one-third of adult patients and 80% of children and adolescents have a history of atopic dermatitis. Some studies recorded the severity of this eczema: in half of the cases, it was considered as not very severe. Eczema appears to be a chronic disease with a low tendency to heal over the years.

This study confirms that hand eczema is a serious problem. However, it does not provide any information regarding contact factors involved, or on the situation outside Scandinavian countries.    


Nummular eczema and contact allergies 

Silverberg JI, Hou A, Warshaw EM et al. 
Prevalence and trend of allergen sensitization in patients with nummular (discoid) eczema referred for patch testing: North American Contact Dermatitis Group data, 2001-2016. 
Contact Dermatitis 2021;85:46-57.

Nummular eczema is a clinical form of eczema that is still relatively unknown. It causes relatively well-defined coin-shaped plaques mainly on the torso and limbs. Nummular eczema is very rare in children and more common in men and people of Asian descent. It can be atopic or of unknown cause, and sometimes associated with infection (Staphylococcus). Finally, even though it is not very suggestive clinically, it could be contact eczema. In any case, it is important to identify any possible contact allergen to advise removal. 
This article reports an epidemiological study on patients referred for patch tests at a specialist center in North America between 2001 and 2016. The population, therefore, included patients already selected for a suspected contact allergy and not all the patients who consulted for eczema. The study involved 38723 patients of which 748 (1.9%) had nummular eczema. The comparison of these patients with nummular eczema with all the other patients showed that nummular eczema is rarely atopic (little atopic dermatitis, asthma, hayfever). A contact allergy considered as clinically pertinent was diagnosed in 23% of cases of nummular eczema. There was nothing special about the most frequently positive allergens: formaldehyde and its releasers, methylisothiazolinone, quaternium-15, perfumes, propylene glycol. We can logically conclude that it is wise to look for a contact allergy in all cases of nummular eczema, as well as for all cases of eczema in general.  


The latest on dupilumab 

Cork MJ, Thaçi D, Eichenfield LF et al. 
Dupilumab provides favourable long-term safety and efficacy in children aged ≥ 6 to < 12 years with uncontrolled severe atopic dermatitis: results from an open-label phase IIa study and subsequent phase III open-label extension study. 
Br J Dermatol 2021;184 :857-870

Cheng J, Jiang L, Morrow NC, Avdic A, Fairley JA, Ling JJ, Greiner MA. 
Recognition of atopic keratoconjunctivitis during treatment with dupilumab for atopic dermatitis. 
J Am Acad Dermatol 2021;85:265-267. 

Thompson AM, Yu L, Hsiao JL, Shi VY. 
Dermatology-ophthalmology collaborations are needed in dupilumab-associated ocular events. 
J Am Acad Dermatol 2021;84:e279-e280. 

Jo CE, Finstad A, Georgakopoulos JR, Piguet V, Yeung J, Drucker AM. 
Facial and neck erythema associated with dupilumab treatment: A systematic review. 
J Am Acad Dermatol 2021;84:1339-1347. 

Dupilumab has been used for several years now for the management of atopic dermatitis not controlled with topical treatments. The first clinical trials were conducted on adults, but new studies have shown its benefits in adolescents (12-17 years) and children (6-12 years). 

Regarding tolerance, this broad use has highlighted the incidence of ocular adverse events, which can occur in one-third of patients. It is generally mild conjunctivitis that is easily improved. However, we know that dermatologists and pediatricians are unfamiliar with the ocular disease, so they can miss other conditions such as atopic keratoconjunctivitis. Cheng et al. proposed a diagnostic algorithm comprising a few simple questions to be asked before initiating dupilumab and during treatment, thus making it easier to know when referral to an ophthalmologist is necessary. As AM Thompson et al. indicate, collaboration between specialties is necessary to ensure treatment safety, as well as to improve understanding of the involvement of the eyes in atopic dermatitis. We must remember that dupilumab used to treat asthma or atopic rhinitis does not cause ocular complications. 

Our final article here concerns face and neck erythema that often occurs during treatment with dupilumab (4.2% of patients in the large French set published in 2019). This erythema, which was not observed during the clinical trials, is different from atopic dermatitis lesions and it is important to look for the cause. Among the cases described in the literature, we have highlighted rosacea, flushes linked to the consumption of alcohol, contact allergies (cosmetics, shampoo, perfumes), and we have also incriminated "head and neck dermatitis" due to a reaction to Malassezia furfur, which can be treated with antifungal therapy. This erythema can thus often be improved. In any event, it is not linked to the ineffectiveness of or intolerance to dupilumab and rarely leads to the treatment being discontinued.          



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