Metabolic and Innate Immune Cues Merge into a Specific Inflammatory Response via the UPR.

Innate immune responses are intricately linked with intracellular metabolism of myeloid cells. Toll-like receptor (TLR) stimulation shifts intracellular metabolism toward glycolysis, while anti-inflammatory signals depend on enhanced mitochondrial respiration. How exogenous metabolic signals affect the immune response is unknown. We demonstrate that TLR-dependent responses of dendritic cells (DCs) are exacerbated by a high-fatty-acid (FA) metabolic environment. FAs suppress the TLR-induced hexokinase activity and perturb tricarboxylic acid cycle metabolism. These metabolic changes enhance mitochondrial reactive oxygen species (mtROS) production and, in turn, the unfolded protein response (UPR), leading to a distinct transcriptomic signature with IL-23 as hallmark. Interestingly, chemical or genetic suppression of glycolysis was sufficient to induce this specific immune response. Conversely, reducing mtROS production or DC-specific deficiency in XBP1 attenuated IL-23 expression and skin inflammation in an IL-23-dependent model of psoriasis. Thus, fine-tuning of innate immunity depends on optimization of metabolic demands and minimization of mtROS-induced UPR.

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.

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.

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.

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.

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.

New-onset inflammatory bowel diseases among IL-17 inhibitor-treated patients: results from the case-control MISSIL study.

OBJECTIVES: To describe new-onset IBD (new IBD) in patients treated with IL-17 inhibitors (IL-17i), to assess their incidence and to identify their risk factors in real life. METHODS: A French national registry (MISSIL) aimed to report all cases of new IBD in patients treated with IL-17i from January 2016 to December 2019. Using the estimated number of patients treated by IL-17 in France during the study period, the annual incidence rates of new IBD was reported in IL-17i-treated patients. A case-control study was performed with two controls per new IBD case matched by gender, age and underlying inflammatory disease. RESULTS: Thirty-one cases of new IBD under IL-17i were collected: 27 patients treated for spondyloarthritis and four patients for psoriasis. All were observed with secukinumab (SEK). The median time to onset of new IBD symptoms was 4.0 (1.5-7.5) months. SEK was discontinued in all patients. The evolution was favourable with complete resolution (17/31), improvement (7/31) or stabilization (5/31). Two patients died: one due to a massive myocardial infarction and one due to post-colectomy complications. The incidence of new IBD decreased from 0.69/100 patient-years [PY] (7/1010) in 2016 to 0.08/100 PY (6/7951) in 2019. No previous treatment with etanercept (odds ratio [OR] = 0.33, 95% CI: 0.14-0.80, P = 0.014) and low number of previous biologic therapies (OR = 0.67, 95% CI: 0.47, 0.94, P = 0.021) were significantly associated with new IBD. CONCLUSION: The incidence of new IBD was low and decreased from 2016 to 2019. The outcome was favourable in 24 out of 31 patients, but two patients died.

Safety of tralokinumab in adult patients with moderate-to-severe atopic dermatitis: pooled analysis of five randomized, double-blind, placebo-controlled phase II and phase III trials.

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.

Initial characteristics and follow-up of patients with a diagnosis of angiotensin-converting enzyme inhibitor induced angioedema.

Background: A differential diagnosis between angiotensin-converting enzyme inhibitor (ACEi) angioedema (AE) and histaminergic AE (hAE) might be challenging. Follow-up data may help discriminate these conditions but are scarcely reported. Objective: To report on the follow-up of patients with suspected ACEi-AE and to describe the baseline characteristics of AE attacks in patients with a diagnosis of ACEi-AE after follow-up. Methods: Sixty-four patients with suspected ACEi-AE (i.e., with exposure to ACEi before the first attack, no urticaria associated, and normal C1-inhibitor levels) and at least one follow-up visit were included. Data were retrospectively collected at baseline and during the follow-up. Results: After the follow-up, the diagnosis of ACEi-AE was probable in only 30 patients. The remaining patients were reclassified as having probable hAE (21 patients) or undetermined-mechanism AE (13 patients). Patients with ACEi-AE were mostly men (61%), with a median age of 64 years (interquartile range [IQR] ±17 years), with a highly variable delay from ACEi introduction (median: 23 months; interquartile range: 103 months). Attacks preferentially involved lips (50%), tongue (47%), and throat (30%). Interestingly, patients with probable ACEi-AE after a follow-up also frequently presented with a history of allergy and atopic conditions (20%), attacks with preferential evening onset (25%), and spontaneous resolution in < 24 hours (26%), which are usually considered as suggestive of hAE. ACEi-AE attacks responded to icatibant in 79% of the patients. Conclusion: Patients with probable ACEi-AE were mostly men with facial involvement. A third of the patients with an initial suspected diagnosis of ACEi-AE had a final diagnosis of probable hAE. Although a follow-up of all patients should be a standard of care, it is critical to the correct diagnosis in the case of suspected bradykinin-associated AE, which may actually be due to histamine.

General Burden of Adult Atopic Dermatitis: An Observational Study of Disease Perceptions among Patients and Dermatologists in France.

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.

The Atopic Dermatitis Control Tool: A High-Performance Tool for Optimal Support.

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.

Effectiveness and safety of dupilumab for the treatment of atopic dermatitis in a real-life French multicenter adult cohort.

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/mm3) 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.