Targeting IL-13 with tralokinumab normalizes type 2 inflammation in atopic dermatitis both early and at 2 years.

BACKGROUND: Tralokinumab is a monoclonal antibody that specifically neutralizes interleukin (IL)-13, a key driver of skin inflammation and barrier abnormalities in atopic dermatitis (AD). This study evaluated early and 2-year impacts of IL-13 neutralization on skin and serum biomarkers following tralokinumab treatment in adults with moderate-to-severe AD. METHODS: Skin biopsies and blood samples were evaluated from a subset of patients enrolled in the Phase 3 ECZTRA 1 (NCT03131648) and the long-term extension ECZTEND (NCT03587805) trials. Gene expression was assessed by RNA sequencing; protein expression was assessed by immunohistochemistry and immunoassay. RESULTS: Tralokinumab improved the transcriptomic profile of lesional skin by Week 4. Mean improvements in the expression of genes dysregulated in AD were 39% at Week 16 and 85% at 2 years with tralokinumab, with 15% worsening at Week 16 with placebo. At Week 16, tralokinumab significantly decreased type 2 serum biomarkers (CCL17/TARC, periostin, and IgE), reduced epidermal thickness versus placebo, and increased loricrin coverage versus baseline. Two years of tralokinumab treatment significantly reduced expression of genes in the Th2 (IL4R, IL31, CCL17, and CCL26), Th1 (IFNG), and Th17/Th22 (IL22, S100A7, S100A8, and S100A9) pathways as well as increased expression of epidermal differentiation and barrier genes (CLDN1 and LOR). Tralokinumab also shifted atherosclerosis signaling pathway genes (SELE, IL-37, and S100A8) toward non-lesional expression. CONCLUSION: Tralokinumab treatment improved epidermal pathology, reduced systemic markers of type 2 inflammation, and shifted expression of key AD biomarkers in skin towards non-lesional levels, further highlighting the key role of IL-13 in the pathogenesis of AD. CLINICAL TRIAL REGISTRATION: NCT03131648, NCT03587805.

Management of Adult Patients With Drug Reaction With Eosinophilia and Systemic Symptoms: A Delphi-Based International Consensus.

Importance: Drug reaction with eosinophilia and systemic symptoms (DRESS) is a rare but potentially fatal drug hypersensitivity reaction. To our knowledge, there is no international consensus on its severity assessment and treatment. Objective: To reach an international, Delphi-based multinational expert consensus on the diagnostic workup, severity assessment, and treatment of patients with DRESS. Design, Setting, and Participants: The Delphi method was used to assess 100 statements related to baseline workup, evaluation of severity, acute phase, and postacute management of DRESS. Fifty-seven international experts in DRESS were invited, and 54 participated in the survey, which took place from July to September 2022. Main Outcomes/Measures: The degree of agreement was calculated with the RAND-UCLA Appropriateness Method. Consensus was defined as a statement with a median appropriateness value of 7 or higher (appropriate) and a disagreement index of lower than 1. Results: In the first Delphi round, consensus was reached on 82 statements. Thirteen statements were revised and assessed in a second round. A consensus was reached for 93 statements overall. The experts agreed on a set of basic diagnostic workup procedures as well as severity- and organ-specific further investigations. They reached a consensus on severity assessment (mild, moderate, and severe) based on the extent of liver, kidney, and blood involvement and the damage of other organs. The panel agreed on the main lines of DRESS management according to these severity grades. General recommendations were generated on the postacute phase follow-up of patients with DRESS and the allergological workup. Conclusions and Relevance: This Delphi exercise represents, to our knowledge, the first international expert consensus on diagnostic workup, severity assessment, and management of DRESS. This should support clinicians in the diagnosis and management of DRESS and constitute the basis for development of future guidelines.

Intravenous immunoglobulins improve skin fibrosis in experimental models of systemic sclerosis.

Systemic sclerosis (SSc) is the most severe systemic autoimmune disease with currently no cure. Intravenous immunoglobulins (IVIg) are an attractive candidate in this disease to counteract inflammation and fibrosis but data are scarce and conflicting. This study, assessed the effects of IVIg in a murine HOCl-induced model of SSc. We showed that IVIg prevented skin inflammation and fibrosis, by mitigating the immune cell infiltration (p = 0.04), proinflammatory cytokines gene overexpression (IL1ß, p = 0.04; TNFα, p = 0.04; IL6, p = 0.05), skin and dermal thickening (p = 0.003 at d21 and p = 0.0003 at d42), the expression markers of fibrosis, such as αSMA (p = 0.031 for mRNA and p = 0.05 for protein), collagen (p = 0.05 for mRNA and p = 0.04 for protein, p = 0.05 for the hydroxyproline content) and fibronectin (p = 0.033 for mRNA). Moreover, IVIg prevented HOCl-induced alterations in splenic cell homeostasis. When administered in curative mode, despite their ability to reduce skin and dermal thickness (p < 0.0001 and p = 0.0002), IVIg showed partial or more mixed effects on skin inflammation and established fibrosis. These data favor further clinical trials in SSc patients on the potential efficiency of early and/or repeated IVIg administration.

Prevalence of excessive daytime sleepiness among patients with atopic dermatitis.

Sleep disorders have received considerable attention from the dermatologic community, especially in patients with atopic dermatitis. We confirmed that excessive daytime sleepiness is a common problem among patients with atopic dermatitis, with it affecting 46.1% of the evaluated subjects. We demonstrated that excessive daytime sleepiness was also significantly associated with disease severity in patients with atopic dermatitis and had a detrimental impact on quality of life, well-being and burden. These findings suggest the importance of careful assessment and the management of sleep disorders in atopic dermatitis patients. Intervention programs for sleep disorders in this population might help to improve their quality of life and their well-being.

Omalizumab Drug Survival in Chronic Urticaria: A Retrospective Multicentric French Study.

BACKGROUND: Omalizumab (OMA) dramatically improves disease control and quality of life in patients with chronic urticaria (CU). OBJECTIVE: We aimed to evaluate the discontinuation patterns of OMA and their determinants in a cohort of French patients with CU. METHODS: We conducted a retrospective multicenter study in 9 French tertiary referral hospitals. All patients diagnosed with either spontaneous (CSU) and/or inducible (CIndU) CU who received at least 1 injection of OMA between 2009 and 2021 were included. We analyzed OMA drug survival and investigated possible determinants using Kaplan-Meier curves and log-rank tests. RESULTS: A total of 878 patients were included in this study; 48.8% had CSU, 10.1% CIndU, and 41.1% a combination of both. OMA was discontinued in 408 patients, but the drug was later reintroduced in 50% of them. The main reason for discontinuing treatment was the achievement of a well-controlled disease in 50% of patients. Half of the patients were still being treated with OMA 2.4 years after the initiation of treatment. Drug survival was shorter in patients with CIndU and in those with an autoimmune background. In atopic patients, OMA was discontinued earlier in patients achieving a well-controlled disease. A longer OMA drug survival was observed in patients with a longer disease duration at initiation. CONCLUSION: In French patients with CU, the drug survival of OMA appears to be longer than that observed in previous studies conducted elsewhere, highlighting discrepancies in prescription and reimbursement possibilities. Further studies are warranted to develop customized OMA treatment schemes based on individual patterns.

Impact of Atopic Dermatitis on Patients and their Partners.

Atopic dermatitis is a chronic, relapsing and inflammatory skin disease. The impact of atopic dermatitis on the partners living with patients has been poorly investigated. The objective of this study was to evaluate the impact of atopic dermatitis in the daily lives of adult patients and to assess the burden of the disease on their partners. A population-based study was conducted on a representative sample of the general population of French adults aged 18 years of age using stratified, proportional sampling with a replacement design. Data were collected on 1,266 atopic dermatitis patient-partner dyads (mean age of patients 41.6 years, 723 (57.1%) women). The mean age of partners was 41.8 years. Patient burden, measured by the Atopic Dermatitis Burden Scale for Adults (ABS-A) score, was closely related to the objective atopic dermatitis severity: the mean score in the mild group (29.5) was significantly lower than in the moderate (43.9) and severe groups (48.6) (p < 0.0001). Partner burden, measured by the EczemaPartner score, was highly related to atopic dermatitis severity (p < 0.0001). Daytime sleepiness, measured by the Epworth Sleepiness Scale, showed a mean score of 9.24 in patients and 9.01 in their partners, indicating impaired sleep. Atopic dermatitis was found to decrease sexual desire in 39% and 26% of partners and patients respectively.

Real-life use of apremilast for the treatment of psoriasis in patients with oncological comorbidities: a retrospective descriptive multicentre study in France.

BACKGROUND: Systemic treatment options for psoriasis are limited for patients with recent neoplasia. OBJECTIVES: We report the real-life use of apremilast (APR) in patients with psoriasis and recent cancer. MATERIALS & METHODS: We conducted a retrospective, multicentre study in five hospitals and among 120 private dermatologists in the north of France from January 2015 to May 2021. We included patients treated with APR for psoriasis and suffering from an active cancer or who had been diagnosed with a cancer or treated for a cancer within the last five years. RESULTS: We included 23 patients diagnosed with a cancer, on average 2.6 years before the introduction of APR for psoriasis. In most patients, APR was specifically chosen due to oncological history. At 16±8 weeks, 55% (n=11/20) of patients had achieved PASI 50 score, 30% (n=6/20) PASI 75, 5% (n=3/20) PASI 90 and 37.5% (n=3/8) of them had a significant improvement in quality of life. Non-serious adverse events were observed in 65.2% (n=15/23) of patients (diarrhoea in 39%), resulting in discontinuation of treatment for 27.8%. The average duration of treatment was 303.8±252.4 days. For four patients, a recurrence or a progression of cancer was recorded during APR treatment. CONCLUSION: In our patients with both psoriasis and cancer, APR improved quality of life, with a good safety profile. A larger study, matched for type, stage and treatment of underlying cancer, would be necessary to draw further conclusions about the oncological safety of APR.

French guidelines for the etiological workup of eosinophilia and the management of hypereosinophilic syndromes.

Eosinophilic-related clinical manifestations are protean and the underlying conditions underpinning eosinophilia are highly diverse. The etiological workup of unexplained eosinophilia/hypereosinophilia can be challenging, and can lead sometimes to extensive, inappropriate, costly and/or invasive investigations. To date, guidelines for the etiological workup and management of eosinophilia are mainly issued by hematologists, and thus mostly cover the scope of clonal hypereosinophilic syndromes (HES). Here, thanks to an extensive literature review, and thanks to the joint work of a large panel of experts involving physicians from both adult and pediatric medicine and from various subspecialties (as well as a representative of a patients' association representative), we provide recommendations for both the step-by step diagnostic workup of eosinophilia (whether unexplained or within specific contexts) as well as the management and follow-up of the full spectrum of eosinophilic disorders (including clonal, reactive, lymphocytic and idiopathic HES, as well as single-organ diseases). Didactic prescription summaries intended to facilitate the prescription of eosinophil-targeted drugs are also provided, as are practical diagnostic and therapeutic algorithms. Lastly, this set of recommendations also includes a summary intended for general practitioners, as well as an overview of the therapeutic patient education program set up by the French reference center for HES. Further updates will be mandatory as new validated information emerges.

Multicenter prospective observational study of dupilumab-induced ocular events in atopic dermatitis patients.

BACKGROUND: Although ocular adverse events are frequent in AD patients treated with dupilumab, their characterization remains limited due to a lack of prospective studies with a systematic ophthalmological examination. OBJECTIVE: To examine the incidence, characteristics and risk factors of dupilumab-induced ocular adverse events. METHODS: A prospective, multicenter, and real-life study in adult AD patients treated with dupilumab. RESULTS: At baseline, 27 out of 181 patients (14.9%) had conjunctivitis. At week 16 (W16), 25 out of 27 had improved their conjunctivitis and 2 remained stable and 34 out of 181 patients (18.7%) had dupilumab-induced blepharoconjunctivitis: either de novo (n = 32) or worsening of underlying blepharoconjunctivitis (n = 2). Most events (27/34; 79.4%) were moderate. A multivariate analysis showed that head and neck AD (OR = 7.254; 95%CI [1.938-30.07]; p = 0.004), erythroderma (OR = 5.635; 95%CI [1.635-21.50]; p = 0.007) and the presence of dry eye syndrome at baseline (OR = 3.51; 95%CI [3.158-13.90]; p = 0.031) were independent factors associated with dupilumab-induced blepharoconjunctivitis. LIMITATIONS: Our follow-up period was 16 weeks and some late-onset time effects may still occur. CONCLUSION: This study showed that most dupilumab-induced blepharoconjunctivitis cases are de novo. AD severity and conjunctivitis at baseline were not found to be associated risk factors in this study.

IL-4/IL-13 Inhibitors for Atopic Dermatitis Induce Psoriatic Rash Transcriptionally Close to Pustular Psoriasis.

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.

Mapping exercise and status update of eight established registries within the TREatment of ATopic eczema Registry Taskforce.

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.

Intravenous and subcutaneous immunoglobulins-associated eczematous reactions occur with a broad range of immunoglobulin types: A French national multicenter study.

BACKGROUND: Human immunoglobulins are used for treating diverse inflammatory and autoimmune disorders. Eczema is an adverse event reported but poorly described. OBJECTIVES: To describe the clinical presentation, severity, outcome, and therapeutic management of immunoglobulin-associated eczema. METHODS: This retrospective and descriptive study included a query of the French national pharmacovigilance database, together with a national call for cases among dermatologists. RESULTS: We included 322 patients. Eczema occurred preferentially in men (78.9%) and in patients treated for neurological pathologies (76%). The clinical presentation consisted mainly of dyshidrosis (32.7%) and dry palmoplantar eczema (32.6%); 5% of cases exhibited erythroderma. Sixty-two percent of the eczema flares occurred after the first immunoglobulin course. Eczema was observed with 13 intravenous or subcutaneous immunoglobulin types and recurred in 84% of patients who maintained the same treatment and in 68% who switched the immunoglobulin type. After immunoglobulin discontinuation, 30% of patients still had persistent eczema. LIMITATIONS: Retrospective study, with possible missing data or memory bias. CONCLUSION: Immunoglobulin-associated eczema occurred with all immunoglobulin types, preferentially in patients with neurologic diseases who required prolonged immunoglobulin treatment. Recurrence was frequent, even after switching the immunoglobulin type, which can lead to a challenging therapeutic situation when immunoglobulin maintenance is required.

Self-reported Impact of the Early 2020 COVID-19 Crisis on the Healthcare Pathway During and After Lockdown in Patients With Chronic Immune-Mediated Inflammatory Diseases: A Practical Survey.

Introduction: Global lockdown in the context of the coronavirus disease 2019 (COVID-19) pandemic is an unprecedented experience. We report here the results of an anonymous questionnaire-based survey on the healthcare and control of chronic IMIDs (chronic immune-mediated inflammatory diseases) within the IMMINENT network during the French lockdown (March 17, 2020-May 11, 2020) and the 2-month period following the end of the lockdown (July 11, 2020). Methods: Two anonymous questionnaires were sent by email to 4500 patients who were followed in a university hospital for an IMID in the departments of gastroenterology, rheumatology, dermatology, pneumology, neurology, and internal medicine. Results: A total of 921/4500 (20.46%) responded to the first survey (impact of the lockdown), and 553/4500 (12.28%) to the second (impact at 2-months post-lockdown). Concerning the impact of the lockdown, 420/915 (45.9%) reported affected follow-up. Similarly, after the lockdown, 248/544 (45.6%) declared a negative impact on their follow-up. The repartition by departments of patients' perception of an altered follow-up during (P = .72) and at the end of the lockdown (P = .77) was not statistically different. Our study highlighted the effects of the COVID-19 pandemic and the restriction measures implemented on the self-reported impact felt by patients on the follow-up of their chronic IMIDs without significant differences among all departments. Conclusion: Our study is original by showing that patients, whatever the type of IMID, shared this same negative perception. This transdisciplinary study demonstrated the importance of a collaborative network among all departments.