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Dupilumab is a therapeutic antibody targeting IL-4 and IL-13 receptor subunit alpha used for the treatment of patients with atopic dermatitis (AD). Cases of psoriasis-like reactions induced under dupilumab treatment (dupilumab-induced psoriatic eruption [DI-Pso]) for AD were recently reported. To understand the pathogenesis of DI-Pso, we performed gene expression profiling studies on skin biopsies of DI-Pso (n = 7) compared with those of plaque psoriasis, AD, and healthy controls (n = 4 each). Differential gene expression was performed using enrichment and Gene Ontology analysis. Gene expression was validated by qPCR, and protein levels were assessed by immunohistochemistry. Transcriptomic and protein analysis of DI-Pso compared with that of healthy controls, plaque psoriasis, and AD skins revealed activation of T helper 17/IL-23 pathways associated with a significant expression of IL-36, surrogate marker of pustular psoriasis. By contrast, T helper 2 representative genes' expression was strongly decreased in DI-Pso across comparison. Matching analysis with public data of pustular psoriasis skin corroborated that DI-Pso and pustular psoriasis upstream regulators overlap, greater than the overlap with plaque psoriasis. Furthermore, DI-Pso showed strongly decreased expression of many barrier skin genes compared with healthy controls, plaque psoriasis, and AD. Our data indicate that the pathogenesis of DI-Pso relied on a shift of skin immune responses from a T helper 2 to an IL-36 and T helper 17 polarization and on intensified skin barrier alterations., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Competing Interests: Conflicts of interest Dezoteux has been an investigator and a consultant and speaker for AbbVie, Almirall, Eli Lilly, Janssen, Leo Pharma, Novartis and Sanofi-Regeneron. Jachiet has been an investigator and/or a consultant and/or speaker for AbbVie, Eli Lilly, Leo Pharma, Pfizer, Galderma and Sanofi-Regeneron. Soria has been an investigator and/or a consultant and/or speaker for AbbVie, Eli Lilly, Leo Pharma, Novartis, Pfizer and Sanofi-Regeneron. Tétart has been an investigator and/or a speaker and/or consultant for Sanofi-Regeneron. Modeste-Duval has been an investigator and/or a speaker and/or consultant fort Sanofi-Regeneron. Bursztejn has been a consultant and/or speaker for AbbVie, Almirall, Amgen, Eli Lilly, Galderma, Janssen, Leo Pharma, Novartis, Pfizer and Sanofi-Regeneron. Misery has been an investigator and/or a consultant and/or speaker for AbbVie, Almirall, Amgen, Astra-Zeneca, Eli Lilly, Galderma, Leo Pharma, Novartis, Pfizer and Sanofi-Regeneron. Aubin has been an investigator and/or a consultant and/or speaker for AbbVie, Almirall, Amgen, Astra-Zeneca, BMS, Eli Lilly, Galderma, Leo Pharma, MSD, Novartis, Pfizer, Pierre Fabre and Sanofi-Regeneron. Lasek has been an investigator and/or a speaker and/or consultant for Sanofi-Regeneron. Leleu has been an investigator for Leo Pharma, a consultant and/or speaker for AbbVie, Amgen, Eli Lilly, Novartis, and Sanofi-Regeneron. Du-Thanh has been an investigator for Leo Pharma, a consultant and/or speaker for AbbVie, Amgen, Eli Lilly, Novartis, and Sanofi-Regeneron. Pasteur has been an investigator and/or a consultant and/or speaker for AbbVie, Eli Lilly, Leo Pharma, Novartis, Pfizer, and Sanofi-Regeneron. Pralong has been an investigator for Eli Lilly, a speaker for AbbVie, Sanofi-Regeneron. Nosbaum has been an investigator and/or a consultant and/or speaker for AbbVie, Almirall, Amgen, Eli Lilly, Galderma, Leo Pharma, Medac, Novartis, Pfizer and Sanofi-Regeneron. Droitcourt has been an investigator and/or a consultant and/or speaker for AbbVie, Eli Lilly, Leo Pharma, Novartis, Pfizer and Sanofi-Regeneron. Viguier has been an investigator, a consultant and/or speaker for AbbVie, Almirall, Biogen, Galderma, Eli Lilly, Boehringer Ingelheim, Medac, Janssen Cilag and Bristol Myers Squibb. Seneschal has received personal fees from AbbVie, Almirall, Leo Pharma, Eli Lilly, Novartis, Pfizer, Pierre Fabre, Sanofi-Genzyme. Barbarot has been an investigator or a speaker for AstraZeneca, Almirall, Sanofi-Genzyme, AbbVie, Novartis, Janssen, Leo Pharma, Pfizer, Eli Lilly, UCB Pharma, Chiesi. Staumont-Sallé has been an investigator and/or a consultant and/or speaker for AbbVie, Almirall, Amgen, AstraZeneca, Eli Lilly, Galderma, Leo Pharma, Novartis, Pfizer, Janssen and Sanofi-Regeneron. Tauber is a consultant for Abbvie, Eli Lilly, Janssen, Medac and a speaker for Abbvie, Eli Lilly, Janssen and Sanofi. Vanlerberghe and Martin have no conflicts of interest to declare.

Background: The TREatment of ATopic eczema (TREAT) Registry Taskforce is a collaborative international network of registries collecting data of atopic eczema (AE) patients receiving systemic and phototherapy with the common goal to provide long-term real-world data on the effectiveness, safety and cost-effectiveness of therapies. A core dataset, consisting of domains and domain items with corresponding measurement instruments, has been developed to harmonize data collection., Objectives: We aimed to give an overview of the status and characteristics of the eight established TREAT registries, and to perform a mapping exercise to examine the degree of overlap and pooling ability between the national registry datasets. This will allow us to determine which research questions can be answered in the future by pooling data., Methods: All eight registries were asked to share their dataset and information on the current status and characteristics. The overlap between the core dataset and each registry dataset was identified (according to the domains, domain items and measurement instruments of the TREAT core dataset)., Results and Conclusions: A total of 4702 participants have been recruited in the eight registries as of 1st of May 2022. Of the 69 core dataset domain items, data pooling was possible for 69 domain item outcomes in TREAT NL (the Netherlands), 61 items in A-STAR (UK and Ireland), 38 items in TREATgermany (Germany), 36 items in FIRST (France), 33 items in AtopyReg (Italy), 29 items in Biobadatop (Spain), 28 items in SCRATCH (Denmark) and 20 items in SwedAD (Sweden). Pooled analyses across all registries can be performed on multiple important domain items, covering the main aims of analysing data on the (cost-)effectiveness and safety of AE therapies. These results will facilitate future comparative or joint analyses., (© 2022 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology.)

Background: Tralokinumab is a fully human monoclonal antibody that neutralizes the activity of interleukin-13, a key pathogenic driver of atopic dermatitis (AD). Clinical trials including adults with moderate-to-severe AD, of up to 52 weeks' duration, showed tralokinumab was efficacious and well tolerated., Objectives: To characterize the safety profile of tralokinumab for the treatment of moderate-to-severe AD., Methods: Safety and laboratory measures were assessed in pooled analyses of phase II and III placebo-controlled clinical trials of tralokinumab in moderate-to-severe AD (NCT02347176, NCT03562377, NCT03131648, NCT03160885, NCT03363854)., Results: In total, 2285 patients were randomized in the initial treatment periods up to 16 weeks (1605 tralokinumab, 680 placebo). The frequencies of any adverse event (AE) were 65·7% for tralokinumab and 67·2% for placebo. The respective rates were 640 and 678 events per 100 patient-years of exposure (ep100PYE); rate ratio 1·0, 95% confidence interval (CI) 0·9-1·1. Serious AEs occurred in 2·1% of patients with tralokinumab and 2·8% with placebo (7·4 and 11·9 ep100PYE; rate ratio 0·7, 95% CI 0·4-1·2). The most common AEs occurring at a higher frequency and rate with tralokinumab vs. placebo were: viral upper respiratory tract infection (15·7% vs. 12·2%; 65·1 vs. 53·5 ep100PYE); upper respiratory tract infection (5·6% vs. 4·8%; 20·8 vs. 18·5 ep100PYE); conjunctivitis (5·4% vs. 1·9%; 21·0 vs. 6·9 ep100PYE); and injection-site reaction (3·5% vs. 0·3%; 22·9 vs. 4·0 ep100PYE). Some events in safety areas of interest occurred at a lower frequency and rate with tralokinumab vs. placebo: skin infections requiring systemic treatment (2·6% vs. 5·5%; 9·7 vs. 22·8 ep100PYE), eczema herpeticum (0·3% vs. 1·5%; 1·2 vs. 5·2 ep100PYE), opportunistic infections (3·4% vs. 4·9%; 13·0 vs. 21·3 ep100PYE) and serious infections (0·4% vs. 1·1%; 1·3 vs. 3·7 ep100PYE). AEs did not increase with continued maintenance and open-label treatment, including rates of common or serious AEs and AEs leading to study drug discontinuation. No clinically meaningful changes in mean laboratory measures were observed with treatment up to 1 year., Conclusions: Across the AD population pool from five clinical trials, tralokinumab was well tolerated, with consistent safety findings during treatment of patients with moderate-to-severe AD. The safety profile during prolonged tralokinumab treatment was consistent with that during the initial treatment period; the frequency of events did not increase over time. What is already known about this topic? Tralokinumab is a fully human monoclonal antibody that specifically neutralizes interleukin-13, a key cytokine driving skin inflammation and epidermal barrier dysfunction in atopic dermatitis (AD). In clinical trials in moderate-to-severe AD, tralokinumab provided significant and early improvements in the extent and severity of AD and was well tolerated, with an overall safety profile comparable with placebo over 52 weeks. What does this study add? We report the frequency and rate of adverse events (AEs) from pooled observations of over 2000 patients from five phase II and phase III placebo-controlled clinical trials of tralokinumab in moderate-to-severe AD. During initial treatment up to 16 weeks, the frequencies of any AE and of serious AEs were similar for tralokinumab and placebo. AE rates did not increase with continued treatment up to 52 weeks. Common AEs occurring more frequently with tralokinumab vs. placebo were viral and upper respiratory tract infection, conjunctivitis and injection-site reaction. Some events occurred at a lower frequency and rate with tralokinumab vs. placebo, such as skin infections requiring systemic treatment, eczema herpeticum and opportunistic and serious infections. No clinically meaningful changes in mean laboratory measures were observed., (© 2022 The Authors. British Journal of Dermatology published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.)

Dupilumab is a recombinant monoclonal IgG4 type antibody which inhibits IL4 and IL13 signaling. It is indicated in moderate to severe atopic dermatitis (AD) in adults and adolescents over 12 years of age. Its side effects include conjunctivitis and blepharoconjunctivitis, affecting between 4.7% and 28% of patients depending on the study. The incidence of conjunctivitis in patients treated with dupilumab for AD appears to be higher than placebo in clinical studies. This increase was not observed in patients treated with dupilumab for asthma or sinonasal polyposis. The risk factors for conjunctivitis in patients with AD are disease severity, pre-existence of conjunctivitis and low concentrations of dupilumab, but the pathophysiology of this disease is poorly understood. A literature search carried out in April and May 2020 showed an increase in the number of publications on the subject, but there are currently no official joint dermatologist-ophthalmologist recommendations for prevention and management. The objective of this article is to provide an overview of the status of this subject, to address the main questions raised by this type of conjunctivitis and to suggest a course of action for starting and continuing treatment with dupilumab in patients with AD, according to the recommendations of the French Ophthalmologist/Dermatologist group CEDRE., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

The evaluation of global atopic dermatitis control is key to minimizing disease burden. The Atopic Dermatitis Control Tool (ADCT) has been developed for this purpose. Participants (diagnosed by a physician) were recruited to this observational cross-sectional study using real-life methodology and completed a questionnaire on sociodemographic and personal information. The ADCT algorithm, described by Pariser, was used to categorize patients as having controlled or uncontrolled atopic dermatitis. Data were collected for 1,606 patients. Median age of the patients was 40 years , and 1,023 (63.7%) patients were women. A total of 1,146 (71.4%) patients had uncontrolled atopic dermatitis according to the ADCT score. Patients with uncontrolled disease were at significantly higher risk of a high stress level and were more likely to be absent from work than those with controlled disease. In conclusion, a key factor for predicting disease burden in atopic dermatitis is patient self-assessed disease control in terms of multiple dimensions: stress, sleep, quality of life, work absenteeism and loss of productivity.

It is important to understand patients' and dermatologists' perceptions of various aspects of atopic dermatitis, but there is a lack of studies on quality of life and stakeholder viewpoints in this therapy area. The aim of this study was to compare patients' and dermatologists' viewpoints regarding the impact of atopic dermatitis that is uncontrolled by topical corticosteroids. Data were collected from 348 adult patients who responded to self-administered questionnaires, and 150 telephone interviews with the dermatologists who selected them. Patients and dermatologists reported both convergent and divergent assessments of the impact of atopic dermatitis and its treatment. Notable areas of agreement were regarding the safety of emollients, the time required and difficulty of applying topical corticosteroids, especially to certain parts of the body. Divergent views involved the perceived efficacy of available treatments and the impact of atopic dermatitis on professional life. A greater understanding of these differences would help dermatologists to optimize patient care.

Background: Atopic dermatitis (AD) in adults over 45 years of age (AD≥45) has been poorly studied., Objectives: To determine whether the AD phenotype varies according to the pattern of AD onset in AD≥45 patients and whether response to cyclosporine A (CsA) is influenced by age., Materials and Methods: This monocentric retrospective study was performed in a French university department of dermatology. We included 409 AD<45 patients (111 treated with CsA) and 124 AD≥45 patients (26 treated with CsA). Among AD≥45 patients, 20% were categorised into Subgroup 1 (persistence of AD since childhood), 52% into Subgroup 2 (recurrence of AD with a history of classic childhood AD), and 28% into Subgroup 3 (adult-onset AD)., Results: Gender, associated atopic comorbidities, a family history of atopy, and AD severity were similar regarding the different patterns of AD onset in AD≥45 patients. Skin lesions predominated on the face and neck in AD≥45 patients with AD since childhood (30% in Subgroups 1 and 2) compared to those with adult-onset AD (14% in Subgroup 3). The efficacy of CsA was similar between groups AD≥45 and AD<45, but 28% of AD≥45 patients versus 20% of AD<45 patients had increased serum creatinine levels under CsA., Conclusion: No significant association seems to exist between the onset of AD and demographic or clinical characteristics in AD≥45 patients (except that head and neck involvement is rarer in adult-onset AD). Patient age does not influence response to CsA, but this drug appears to be less well tolerated in older patients.

Background: Dupilumab is the first biologic available to treat atopic dermatitis (AD). Its effectiveness and safety were demonstrated in clinical trials., Objective: We sought to assess the effectiveness and safety of dupilumab in adults with AD in a real-life French multicenter retrospective cohort., Methods: We included patients treated during March 2017-April 2018. Efficacy outcomes, including Scoring Atopic Dermatitis (SCORAD) and Eczema Area and Severity Index (EASI) scores, were collected at baseline and 3 months when available. Adverse events (AEs) were recorded at follow-up., Results: We included 241 patients. The median ± interquartile range (IQR) follow-up time was 3.8 ± 3.7 months. A ≥75% improvement in SCORAD was achieved in 27 of 163 (16.6%) patients, and a ≥75% improvement in EASI was achieved in 40 of 82 (48.8%) patients. The median SCORAD and EASI scores at 3 months were significantly lower than those at baseline (SCORAD ± IQR, 25 ± 21 vs 56 ± 27.4, P < 10 -9 and EASI ± IQR, 4.1 ± 6.8 vs 17.9 ± 15.4, P < 10 -9 , respectively). Conjunctivitis was reported in 84 of 241 (38.2%) patients. The proportion with eosinophilia (>500 cells/mm 3 ) during follow-up (57%) was higher than that at baseline (33.7%) (n = 172, P < 10 -6 ). Dupilumab was stopped in 42 cases; 27 patients stopped because of AEs., Limitations: No control group, missing data., Conclusion: This real-life study demonstrated a similar dupilumab effectiveness as that seen in clinical trials, but it also revealed a higher frequency of conjunctivitis and eosinophilia., (Copyright © 2019 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Methotrexate is currently used to treat atopic dermatitis but has never been assessed versus cyclosporine in adults., Objective: This study evaluated the efficacy and safety of methotrexate versus cyclosporine in patients with moderate-to-severe atopic dermatitis., Methods: Patients were randomized to receive either oral methotrexate (15 mg/wk) or cyclosporine (2.5 mg/kg/d) for 8 weeks. The primary end point was a patient achieving 50% improvement in the SCORing Atopic Dermatitis index (SCORAD 50) at week 8. When the primary end point was not achieved, methotrexate was increased to 25 mg and cyclosporine to 5 mg during the next 16 weeks. The secondary end points were a patient achieving a 50% reduction in the Eczema Area Severity Intensity index (EASI 50) and SCORAD 50 at each visit (ClinicalTrials.gov no. NCT00809172)., Results: A total of 97 patients received methotrexate 15 mg (n = 50) or cyclosporine 2.5 mg (n = 47). Regarding the primary end point at week 8, methotrexate was inferior to cyclosporine because the proportion of patients with SCORAD 50 was 8% (4 of 50) in the methotrexate arm versus 42% (18 of 43) in the cyclosporine arm. The difference in percentages for the 2 treatment groups (2-sided 90% CI) was -34% (-48% to -20%). At week 8, methotrexate and cyclosporine dosages were increased in 56% and 49% of the patients, respectively. Regarding EASI 50, the noninferiority end point was reached at week 20 in 92% (22 of 24) of patients in the methotrexate arm and 87% (26 of 30) of patients in the cyclosporine arm. The treatment-related adverse events were more frequent with cyclosporine (P < .0001)., Conclusions: Methotrexate 15 mg/wk was inferior to cyclosporine 2.5 mg/kg/d at week 8. Increasing the doses of methotrexate to 25 mg/wk induced a significant improvement versus cyclosporine at week 20., (Copyright © 2017 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Atopic dermatitis (AD) is a chronic allergic dermatosis characterized by epidermal thickening and dermal inflammatory infiltrates with a dominant Th2 profile during the acute phase, whereas a Th1 profile is characteristic of the chronic stage. Among chemokines and chemokine receptors associated with inflammation, increased levels of CX3CL1 (fractalkine) and its unique receptor, CX3CR1, have been observed in human AD. We have thus investigated their role and mechanism of action in experimental models of AD and psoriasis. AD pathology and immune responses, but not psoriasis, were profoundly decreased in CX3CR1-deficient mice and upon blocking CX3CL1-CX3CR1 interactions in wild-type mice. CX3CR1 deficiency affected neither antigen presentation nor T cell proliferation in vivo upon skin sensitization, but CX3CR1 expression by both Th2 and Th1 cells was required to induce AD. Surprisingly, unlike in allergic asthma, where CX3CL1 and CX3CR1 regulate the pathology by controlling effector CD4(+) T cell survival within inflamed tissues, adoptive transfer experiments established CX3CR1 as a key regulator of CD4(+) T cell retention in inflamed skin, indicating a new function for this chemokine receptor. Therefore, although CX3CR1 and CX3CL1 act through distinct mechanisms in different pathologies, our results further indicate their interest as promising therapeutic targets in allergic diseases., (© 2014 Staumont-Sallé et al.)

The high-affinity IgE receptor Fc(epsilon)RI and, in some models, the low-affinity IgG receptor Fc(epsilon)RIIII/CD16 play an essential role in allergic diseases. In human skin, they are present on APCs and effector cells recruited into the inflamed dermis. FcRgamma is a subunit shared, among other FcRs, by Fc(epsilon)RI and CD16 and is essential to their assembly and signal transduction. Using an experimental model reproducing some features of human atopic dermatitis and specific FcR-deficient mice, we have herein delineated the respective contribution of Fc(epsilon)RIand Fc(epsilon)RIII/CD16 to the pathology. We demonstrate that symptoms of atopic dermatitis are completely absent in FcRgamma-deficient animals but only partially inhibited in either Fc(epsilon)RI- or FcgammaRIII/CD16-deficient animals. Absence or attenuation of the pathology is correlated to increased skin expression of regulatory IL-10 and Foxp3. While Fc(epsilon)RI controls both Th1 and Th2 skin response, mast cell recruitment into draining lymph nodes and IgE production, CD16 regulates only Th2 skin response, as well as T cell proliferation and IgG1 production. This isotype-specific regulation by the cognate FcR is associated to a differential regulation of IL-4 and IL-21 expression in the draining lymph nodes. Fc(epsilon)RIand CD16 thus contribute to atopic dermatitis but differentially regulate immune responses associated with the disease. Targeting both IgE/Fc(epsilon)RI and IgG/CD16 interactions might represent an efficient therapeutic strategy for allergic diseases.

Background: The peroxisome proliferator-activated receptors (PPARs) alpha, beta/delta, and gamma are ligand-activated transcription factors belonging to the nuclear receptor superfamily. In addition to their regulatory role on lipid and glucose metabolism, they exert anti-inflammatory properties. In skin both PPAR-alpha and PPAR-beta/delta regulate keratinocyte proliferation/differentiation and contribute to wound healing. The 3 PPAR isoforms are expressed by several cell types recruited into the dermis during inflammation., Objective: We have investigated the role of PPAR-alpha in the regulation of atopic dermatitis (AD), a common skin inflammatory disease., Methods: We chose a mouse model of inflammatory dermatosis with immunologic features of AD and used epicutaneous sensitization with ovalbumin in the absence of adjuvant, which mimics the human pathology., Results: On antigen sensitization, PPAR-alpha-deficient mice display increased epidermal thickening, dermal recruitment of inflammatory cells, lung inflammation, airway hyperresponsiveness, and IgE and IgG2a production compared with their wild-type counterparts. Increased inflammation was correlated to an enhancement of TH2 and, to a greater extent, TH1 responses and to increased skin expression of nuclear factor kappaB. Interestingly, PPAR-alpha expression was decreased in eczematous skin from patients with AD compared with skin from nonatopic donors, suggesting that defective PPAR-alpha expression might contribute to the pathology. Topical application of WY14643, a specific PPAR-alpha agonist, significantly decreased antigen-induced skin inflammation in the AD model., Conclusion: PPAR-alpha acts as a negative regulator of skin inflammation in AD.