Baricitinib Improvement Across Regions in Atopic Dermatitis Patients with Baseline Body Surface Area up to 40% and Severe Itch.

INTRODUCTION: Patients with moderate-to-severe atopic dermatitis (AD) who are most likely to respond to the Janus kinase (JAK) 1/2 inhibitor baricitinib (BARI) are known to have an impacted body surface area (BSA) ≤ 40% and severe itch (numerical rating scale [NRS] ≥ 7], collectively termed 'BARI itch-dominant' patients. Our objective is to build on our previous work by providing a body region-specific, clinical characterization of the BARI itch-dominant patient at baseline and their response to BARI 4 mg. METHODS: BREEZE-AD7 was a phase 3 trial in adults with moderate-to-severe AD receiving placebo or 2 mg or 4 mg BARI in combination with topical corticosteroids. Assessing only data from BARI itch-dominant patients, we summarized the baseline characteristics and conducted body region-specific analyses on Eczema Area and Severity Index (EASI) data in order to report the response to placebo versus BARI 4 mg within this patient subtype. RESULTS: BARI 4 mg was highly effective across all body regions; at week 16, 75% improvement was seen in EASI scores (EASI75), and response rates with BARI 4 mg (head/neck, 58.3%; trunk, 69.2%; upper extremities, 61.5%; lower extremities, 87.5%) all exceeded those with placebo (head/neck: 37.5%; trunk, 40.6%; upper extremities, 18.8%; lower extremities, 40.6%) as well as the overall EASI75 rates of the intent-to-treat (ITT) population (BARI, 48.0%; placebo, 23.0%). At baseline, most BARI itch-dominant patients presented with involvement of all regions (mean regional BSA 22.7%-40.3%), highest in the head and neck, mean EASI region scores of 15.7-24.0, and considerably severe sign ratings (mean EASI sub-scores: 1.4-2.3, out of 3), especially for erythema. CONCLUSION: BARI itch-dominant patients exhibit AD involvement across all body regions and considerable sign severity, especially erythema. In response to BARI 4 mg, EASI quickly improved across regions, substantially more so in this subtype than in the ITT population.

Baricitinib treatment rapidly improves the four signs of atopic dermatitis assessed by Eczema Area and Severity Index (EASI) clinical subscores.

BACKGROUND: Baricitinib treatment in adults with moderate-to-severe atopic dermatitis (AD) has demonstrated rapid improvements in itch as well as AD sign severity and affected body surface area as assessed by the Eczema Area and Severity Index (EASI) total score, whether administered as monotherapy or in combination with topical corticosteroids (TCS). As EASI clinical signs differ in time course and associated antecedents, the effects of baricitinib on each individual clinical sign are of interest. OBJECTIVES: In this post hoc analysis, we aimed to investigate the effects of baricitinib on individual EASI subscores, namely excoriation, oedema/papulation, erythema and lichenification, in both monotherapy and TCS combination therapy trials. METHODS: We analysed the percent change from baseline in individual EASI subscores from three phase-III, double-blind, 16-week trials of baricitinib in monotherapy (BREEZE-AD1/BREEZE-AD2) and TCS combination therapy (BREEZE-AD7) cohorts via mixed model repeated measures (MMRM). RESULTS: Baricitinib 4 mg showed rapid and sustained improvements in all four clinical signs in both cohorts. Significant effects emerged at week 1 for excoriation, oedema/papulation and erythema scores in monotherapy (p < 0.001) and TCS combination therapy (p < 0.001, p < 0.01, p < 0.001), plateaued at week 4, and remained significant versus placebo through week 16. The effect on lichenification scores also emerged early, at week 1 in monotherapy (p < 0.05) and week 2 in combination therapy (p < 0.001), with scores continuously improving without a clear plateau. Effect magnitude was highest in excoriation scores, exhibiting near-maximal reduction in week 1 of monotherapy and remaining highest across all timepoints in combination therapy. CONCLUSIONS: Rapid and sustained improvements were observed across clinical signs of inflammation and particularly on excoriation following baricitinib treatment. Our findings suggest that selective inhibition of janus kinases 1 and 2 leads to rapid and sustained control of skin inflammation, and that rapid reductions in itch translate into early disruption of the itch-scratch cycle.

Treatment satisfaction of adult patients with moderate-to-severe atopic dermatitis treated with baricitinib in France, Germany, and the United Kingdom: results from a cross-sectional international patient survey.

INTRODUCTION: We explored patient satisfaction with baricitinib, an oral Janus kinase inhibitor, in patients with atopic dermatitis (AD) treated in routine clinical practice. METHODS: Adults with moderate-to-severe AD treated with baricitinib in clinical practice for ≥4 weeks in France, Germany, and the UK completed a one-time online survey under market research methodologies. Treatment satisfaction was assessed using a Likert scale and abbreviated Treatment Satisfaction Questionnaire for Medication (TSQM-9). Patients reported demographic, disease, and treatment information. Data were analyzed descriptively. RESULTS: The survey was completed by 170 patients with a mean age of 39.3 years (SD = 13.5), 59% (n = 101) were female. At baricitinib initiation, 79% rated their AD as "Severe", yet 28% reported body surface area (BSA) involvement ≥10%. Most were "Satisfied" or "Very satisfied" (76%/18%) with baricitinib, with high rates reported for controlling itch (36%/56%). Itch improvements were noted by 97% of patients. Some tapered/stopped (50%/32%) topical corticosteroid use, aligned with reported improvements on the patient global assessment and BSA. Mean TSQM-9 convenience score was 78.0 (SD = 14.0). CONCLUSIONS: Satisfaction with itch control was particularly high, reflected in rates of improvement in itch since starting baricitinib. On the TSQM-9, the convenience score was the highest. Many patients tapered/stopped concomitant topicals, indicating baricitinib's effect in controlling AD symptoms.

Baseline Body Surface Area and Itch Severity Define Response to Baricitinib in Patients with Moderate-to-Severe Atopic Dermatitis at Week 16.

INTRODUCTION: Atopic dermatitis (AD) is a chronic, inflammatory skin disease characterized by heterogeneous clinical phenotypes and high symptom burden, especially through itch. Baricitinib (BARI), an oral Janus Kinase 1/2 inhibitor, is approved in Europe, Japan, and other countries, for treatment of adults with moderate-to-severe AD who are candidates for systemic therapy. This post hoc analysis of a Phase 3 topical corticosteroid (TCS) combination therapy trial (BREEZE-AD7) aims to characterize patients who might benefit most from BARI. METHOD: Classification and regression tree (CART) analysis was used to identify baseline predictors for patients treated with BARI 4-mg, who achieved ≥ 75% improvement in Eczema Area and Severity Index (EASI75), or EASI75 or Itch Numerical Rating Scale (NRS) ≥ 4-point improvement at week 16 (responders), versus non-responders. Subgroup efficacy analyses were performed based on identified predictor variables, combined with Itch NRS < 7/ ≥ 7. Missing data were imputed as non-responder. RESULTS: Baseline body surface area (BSA) was identified by CART as strongest variable predicting response to BARI at week 16, with a cut-off around 40% (BSA ≤ 40%). When combining BSA with itch severity, highest response rates were achieved by BARI patients with BSA ≤ 40%/Itch NRS ≥ 7 at baseline. In this subgroup, 69% and 58% of patients treated with BARI 4-mg achieved EASI75 and Itch NRS ≥ 4-point response at week 16, respectively. While these response rates were 65% and 50% for BARI 4-mg patients with baseline BSA ≤ 40%/Itch NRS < 7, they were 33% and 11% in BSA > 40%/Itch NRS < 7, and 32% and 49% in BSA > 40%/Itch NRS ≥ 7 subgroups, respectively. CONCLUSION: Using a machine learning approach, patients with moderate-to-severe AD and a BSA affecting 10-40% and Itch NRS ≥ 7 were characterized as likely to benefit most from BARI 4-mg TCS combination therapy. This was confirmed by subgroup analyses, which showed that these patients are most likely to show favorable response rates in improving AD signs and symptoms, specifically itch, after 16 weeks of treatment.

Baricitinib provides rapid and sustained improvements in absolute EASI and SCORAD outcomes in adults with moderate-to-severe atopic dermatitis.

BACKGROUND: Baricitinib is an oral selective Janus kinase 1/2 inhibitor approved for moderate-to-severe atopic dermatitis (AD) in adults. OBJECTIVES: To evaluate absolute Eczema Area and Severity Index (EASI) and SCORing of Atopic Dermatitis (SCORAD) outcomes over 16 weeks and to link disease severity categories to quality of life (QoL) improvements. METHODS: This post-hoc analysis included patients enrolled in Phase3 monotherapy (BREEZE-AD1/AD2) and topical corticosteroid (TCS) combination therapy (BREEZE-AD7) trials and analyzed baricitinib 2 and 4 mg vs. placebo. Categorical outcomes were analyzed using Fisher's exact test. RESULTS: Significantly more baricitinib-treated patients reached EASI ≤ 7 and SCORAD < 25 as early as week 1 in monotherapy and week 2 in TCS combination therapy, compared to placebo. Significant response vs. placebo was sustained until week 16 for EASI ≤ 7 (AD1/2 [p-value vs. placebo]: 2 mg = 19.9%, 4 mg = 25.4% [p = 0.001] and AD7: 2 mg = 40.4% [p = 0.087], 4 mg = 48.6% [p = 0.003]) and SCORAD < 25 (AD1/2: 2 mg = 12.2%, 4 mg = 19.4% [p = 0.001] and AD7: 2 mg = 30.3% [p = 0.025], 4 mg = 34.2% [p = 0.004]) severity categories. These effects were accompanied by rapid improvements in QoL. CONCLUSION: Baricitinib-treated patients rapidly achieved recommended absolute EASI and SCORAD treatment outcomes which were sustained until week 16. Improvements in QoL were greater than EASI severity categories reflected, indicating that physician-assessed scores do not necessarily correlate with patients' impression of AD severity.

Integrated Safety Analysis on Skin Cancers among Patients with Psoriasis Receiving Ixekizumab in Clinical Trials.

INTRODUCTION: Limited data exist on skin cancer risk in patients with psoriasis using biologics. Here, we report treatment-emergent adverse events (TEAEs) of skin cancer in patients treated with ixekizumab from psoriasis clinical trials. METHODS: Integrated safety databases from 17 clinical trials of adults with moderate-to-severe psoriasis treated with ≥ 1 dose of ixekizumab for ≤ 5 years were used to analyze exposure-adjusted incidence rates (IRs) per 100 patient-years of exposure (PYE) and clinically characterize dermatologist-adjudicated skin cancer TEAEs. RESULTS: Of 6892 patients, 58 presented with ≥ 1 skin cancer TEAE (IR 0.3) with IRs remaining stable with longer ixekizumab exposure. Non-melanoma skin cancer (NMSC) was the most common event (IR 0.3) affecting 55 patients; of those, 44 had basal cell carcinoma (IR 0.2) and 16 had squamous cell carcinoma (IR 0.1). Two treatment-emergent melanoma events were identified; neither were classified as serious AEs. CONCLUSIONS: Incidence of skin neoplasms in patients with psoriasis treated with ixekizumab for ≤ 5 years was low, and among those events, NMSC was most common. Limitations included that longer exposure may be required to confirm risk of skin cancer and that the study exclusion criteria of several studies, which excluded patients with skin cancer events within 5 years prior to baseline, might limit interpretation of skin cancer risk in this cohort. These findings support the safety profile of ixekizumab for patients requiring long-term psoriasis control.

Factors Predicting Quality of Life Impairment in Adult Patients with Atopic Dermatitis: Results from a Patient Survey and Machine Learning Analysis.

INTRODUCTION: Atopic dermatitis (AD) is a chronic, inflammatory skin disorder that impairs patients' quality of life (QoL). Physician assessment of AD disease severity is determined by clinical scales and assessment of affected body surface area (BSA), which might not mirror patients' perceived disease burden. METHODS: Using data from an international cross-sectional web-based survey of patients with AD and a machine learning approach, we sought to identify disease attributes with the highest impact on QoL for patients with AD. Adults with dermatologist-confirmed AD participated in the survey between July-September 2019. Eight machine learning models were applied to the data with dichotomised Dermatology Life Quality Index (DLQI) as the response variable to identify factors most predictive of AD-related QoL burden. Variables tested were demographics, affected BSA and affected body areas, flare characteristics, activity impairment, hospitalisation and AD therapies. Three machine learning models, logistic regression model, random forest and neural network, were selected on the basis of predictive performance. Each variable's contribution was computed via importance values from 0 to 100. For relevant predictive factors, further descriptive analyses were conducted to characterise those findings. RESULTS: In total, 2314 patients completed the survey with mean age 39.2 years (standard deviation 12.6) and average disease duration of 19 years. Measured by affected BSA, 13.3% of patients had moderate-to-severe disease. However, 44% of patients reported a DLQI > 10, indicative of a very large to extremely large impact on QoL. Activity impairment was the most important factor predicting high QoL burden (DLQI > 10) across models. Hospitalisation during the past year and flare type were also highly ranked. Current BSA involvement was not a strong predictor of AD-related QoL impairment. CONCLUSIONS: Activity impairment was the single most important factor for AD-related QoL impairment while current extent of AD did not predict higher disease burden. These results support the importance of considering patients' perspectives when determining the severity of AD.

Baricitinib Safety for Events of Special Interest in Populations at Risk: Analysis from Randomised Trial Data Across Rheumatologic and Dermatologic Indications.

INTRODUCTION: Baricitinib, a Janus kinase (JAK) 1/2 inhibitor, is an approved treatment for rheumatoid arthritis (RA), atopic dermatitis (AD), and alopecia areata (AA). Further characterisation of adverse events of special interest (AESI) for JAK inhibitors in at-risk populations will improve benefit-risk assessment for individual patients and diseases. METHODS: Data were pooled from clinical trials and long-term extensions in moderate-to-severe active RA, moderate-to-severe AD, and severe AA. Incidence rates (IR) per 100 patient-years of major adverse cardiovascular event (MACE), malignancy, venous thromboembolism (VTE), serious infection, and mortality were calculated for patients with low risk (younger than 65 years with no specified risk factors), and patients at risk (≥ 1 of: aged 65 years or older, atherosclerotic cardiovascular disease, diabetes mellitus, hypertension, current smoking, HDL cholesterol < 40 mg/dL, BMI ≥ 30 kg/m2, poor mobility on EQ-5D, or history of malignancy). RESULTS: Datasets included baricitinib exposure up to 9.3 years with 14,744 person-years of exposure (PYE) (RA), 3.9 years with 4628 PYE (AD), and 3.1 years with 1868 PYE (AA). In patients with low risk (RA: 31%, AD: 48%, AA: 49%), IRs for MACE (0.05, 0.04, 0), malignancies (0.20, 0.13, 0), VTE (0.09, 0.04, 0), serious infection (1.73, 1.18, 0.6), and mortality (0.04, 0, 0) in the RA, AD, and AA datasets, respectively, were low. In patients at risk (RA: 69%, AD: 52%, AA: 51%), IRs were for MACE (0.70, 0.25, 0.10), malignancies (1.23, 0.45, 0.31), VTE (0.66, 0.12, 0.10), serious infection (2.95, 2.30, 1.05), and mortality (0.78, 0.16, 0) for RA, AD, and AA datasets, respectively. CONCLUSION: Populations with low risk have low incidence of the examined JAK inhibitor-related AESI. In the dermatologic indications, incidence is also low for patients at risk. Considering individual disease burden, risk factors, and response to treatment is relevant to make informed decisions for individual patients treated with baricitinib.

Safety of baricitinib for the treatment of atopic dermatitis over a median of 1.6 years and up to 3.9 years of treatment: an updated integrated analysis of eight clinical trials.

BACKGROUND: Baricitinib, a selective Janus kinase (JAK)1/JAK2 inhibitor, is approved for treatment of moderate-to-severe atopic dermatitis (AD) in adults. OBJECTIVES: We report integrated baricitinib safety data in patients with up to 3.9-years exposure. METHODS: Three datasets from the integrated AD clinical trial program were analyzed: placebo-controlled, 2-mg-4-mg extended, and All-bari. Data cutoffs were up to 21-December-2021 for long-term extension studies. Proportions of patients with events and incidence rates (IR)/100 patient years (PY) at risk were calculated. RESULTS: 2636 patients received baricitinib for 4628.4 PY. Discontinuation due to adverse events was low (IR = 3.4). IRs in All-bari were: serious adverse events, 5.2; infection, 67.2 (any infection), 6.7 (herpes simplex), 2.8 (herpes zoster), and 0.3 (opportunistic infections). Adverse events of special interest in All-bari included seven patients with positively adjudicated major adverse cardiovascular events (MACE) (IR = 0.15), three pulmonary emboli (PE) (IR = 0.06), 14 malignancies excluding nonmelanoma skin cancer (IR = 0.3), one gastrointestinal perforation (IR = 0.02), and four deaths (IR = 0.1). No deep vein thromboses (DVT) or tuberculosis were reported. CONCLUSION: In this analysis, baricitinib maintained a similar safety profile to earlier analyses with no new safety signals. Rates of MACE, DVT/PE, malignancies, and serious infections were within ranges of background rates in patients with AD. CLINICALTRIALS.GOV: NCT02576938 (JAHG), NCT03334396 (JAHL; BREEZE-AD1), NCT03334422 (JAHM; BREEZE-AD2), NCT03334435 (JAHN; BREEZE-AD3), NCT03428100 (JAIN; BREEZE-AD4), NCT03435081 (JAIW; BREEZE-AD5), NCT03559270 (JAIX; BREEZE-AD6), NCT03733301 (JAIY; BREEZE-AD7).

Real-World Treatment Patterns and Treatment Benefits among Adult Patients with Atopic Dermatitis: Results from the Atopic Dermatitis Patient Satisfaction and Unmet Need Survey.

Atopic dermatitis is a chronic inflammatory skin disorder associated with a heterogeneous presentation and considerable disease burden. Exploring atopic dermatitis treatment patterns and patient benefits could improve disease management and patients' quality of life. This study aimed to describe current and previous atopic dermatitis treatment patterns and patient benefits from those treatments to inform disease management. Data were collected in 10 countries. Adults (n = 1,988) with confirmed moderate-to-severe atopic dermatitis completed a web-based cross-sectional survey. Most patients (86.6%) had body surface area involvement <10%, and therapies used were topical (69.7%), systemic (28.1%), and biologics (2.3%). Most flares were managed by topical monotherapies (73.4%), even in patients with body surface area involvement ≥10%. Treatment expectations were met only partially, or not at all, in 75% of patients. Those with body surface area involvement ≥10% reported lower treatment satisfaction. Overall, this study highlights the unmet medical needs in atopic dermatitis management.

A Review of Safety Outcomes from Clinical Trials of Baricitinib in Rheumatology, Dermatology and COVID-19.

Baricitinib is an oral, selective inhibitor of Janus kinase (JAK)1/JAK2 that transiently and reversibly inhibits many proinflammatory cytokines. This mechanism is a key mediator in a number of chronic inflammatory diseases; accordingly, baricitinib has been studied and approved for the treatment of several rheumatological and dermatological disorders, as well as COVID-19. This narrative review summarises and discusses the safety profile of baricitinib across these diseases, with special focus on adverse events of special interest (AESI) for JAK inhibitors, using integrated safety data sets of clinical trial data, and puts findings into context with the underlying risk in the respective disease populations, using supporting literature. We show that rates of infection with baricitinib generally reflected the inherent risk of the disease populations being treated, with serious infections and herpes zoster being more frequent in rheumatic diseases than in dermatological disorders, and herpes simplex being reported particularly in atopic dermatitis. Similarly, rates of major adverse cardiovascular events (MACE), venous thromboembolism (VTE) and malignancies were generally within or below the ranges reported for the respective disease populations, thereby reflecting the underlying risk; these events were therefore more frequent in patients with rheumatic diseases than in those with dermatological disorders, the latter of whom generally had low absolute risk. AESI were usually more common in patients with risk factors specific for each event. When a population similar to that of ORAL Surveillance was considered, the incidence rate of MACE with baricitinib was numerically lower than that reported with tofacitinib and similar to that of tumour necrosis factor inhibitors. No safety concerns were observed in hospitalised patients with COVID-19 who received baricitinib for up to 14 days. Identifying the patterns and likelihoods of AEs that occur during treatment in large groups of patients with different diseases can help the physician and patient better contextualise the benefit-to-risk ratio for the individual patient.

The oral selective inhibitor of Janus kinase (JAK)1/JAK2 baricitinib transiently and reversibly inhibits elements of the inflammatory pathway, which are key mechanisms for several chronic, inflammatory rheumatological and dermatological diseases but, as with all drugs, it can be associated with unwanted effects. This narrative review summarises adverse events of special interest (AESI) for baricitinib, considered as such either because of characteristics of patients with the disease being treated (rheumatological and dermatological disorders and COVID-19) or the mechanism of action of the drug. The risk of these events is considered in light of the inherent risk of each event in populations with the respective diseases. We show that serious infections and herpes zoster during baricitinib therapy were most common in patients with rheumatological disorders, and herpes simplex was reported particularly in patients with atopic dermatitis, likely because of disease-related risk factors. MACE, VTE and malignancies generally occurred in baricitinib-treated patients with a frequency within or below the ranges reported for the respective disease populations. Rates generally reflected the underlying risk of the disease populations, being higher in patients with rheumatological diseases than in those with dermatological disorders, and mostly occurring in patients with underlying risk factors for the AESI. No safety concerns were observed in hospitalised patients with COVID-19 who received baricitinib for up to 14 days. Characterising patterns and likelihoods of unwanted events that occur during treatment in large groups of patients with different diseases can help put the actual risk to an individual patient into perspective.

Burden of Moderate to Severe Atopic Dermatitis in Adults from France, Italy, and the UK: Patient-Reported Outcomes and Treatment Patterns.

INTRODUCTION: Moderate to severe atopic dermatitis (AD) is associated with a significant disease burden, impacting sleep, quality of life, and treatment needs. The aim of this study was to characterize disease burden and treatment patterns for adults with moderate to severe AD in three European countries: France, Italy, and the UK. METHODS: This retrospective analysis of adult patients with moderate to severe AD in Europe used medical records and physician/patient survey data collected in August 2019 to April 2020. Demographic and baseline disease characteristics, information on current comorbidities, disease flares, and current and previous treatments were collected by the physician. Patient-perceived burden was assessed using patient-reported outcome (PRO) questionnaires, which were completed on a voluntary basis and included the following instruments: Patient-Oriented Eczema Measure (POEM), Dermatology Life Quality Index (DLQI), EuroQol five-dimensional (EQ-5D), and Work Productivity and Activity Impairment (WPAI). Disease severity was subjectively assessed by physicians and was based on their own definition of the terms mild, moderate, and severe. Data were analyzed descriptively. RESULTS: The physician-reported sample included 912 patients with moderate to severe disease from France (n = 314), Italy (n = 309), and the UK (n = 289); approximately 30% of patients provided PRO data. Across these countries, 22-41% of patients reported current flares; mean POEM and DLQI scores were 10.6-13.1 and 9.5-11.1, respectively, indicating a high disease burden. However, systemic therapy use was low (e.g., conventional systemics were used by 18-24% of patients). Physician-assessed disease severity did not fully align with EASI scores, indicating that factors in addition to skin signs are impacting AD severity. CONCLUSION: Patients with moderate to severe AD report significant disease burden, highlighting unmet treatment needs, particularly with respect to the underuse of systemic treatments despite AD being a systemic disease and the associated disease burden.

Indirect Treatment Comparison of Baricitinib versus Dupilumab in Adults with Moderate-to-Severe Atopic Dermatitis.

INTRODUCTION: Indirect treatment comparison was used to compare approved doses of baricitinib and dupilumab for treating adult patients with moderate-to-severe atopic dermatitis (AD) who are candidates for systemic therapy. METHODS: Baricitinib and dupilumab were compared (Bucher method) at weeks 4 and 16. Performance in combination with topical corticosteroids (TCS) was analyzed in patients with inadequate response or inadvisable to topical therapies (population A) and cyclosporine (population B). Population A was additionally examined as monotherapy. RESULTS: For the Eczema Area and Severity Index (EASI) 75, baricitinib and dupilumab were similar. A ≥ 4-point improvement in itch numerical rating scale (NRS) was significantly more likely with baricitinib 4 mg than dupilumab in population A as monotherapy (RR = 2.62, 95% CI 1.22, 5.61, p = 0.013) and in TCS combination at week 4. These differences were not significant by week 16. For the Dermatology Life Quality Index (DLQI), baricitinib 4 mg and dupilumab were similar on mean difference in change from baseline (MDcfb), though some differences were seen between baricitinib 2 mg and dupilumab at week 16 for the population A monotherapy (MDcfb = 2.05, 95% CI 0.53, 3.56, p = 0.016) and TCS combination therapy (MDcfb = 2.48, 95% CI 0.46, 4.50, p = 0.016) groups, and in population B (MDcfb = 3.38 95% CI 1.18, 5.58, p = 0.003). CONCLUSIONS: Baricitinib potentially offers more rapid improvement in itch while providing similar efficacy on EASI75 and DLQI outcomes compared with dupilumab.

Unbound Corneocyte Lipid Envelopes in 12R-Lipoxygenase Deficiency Support a Specific Role in Lipid-Protein Cross-Linking.

Loss-of-function mutations in arachidonate lipoxygenase 12B (ALOX12B) are an important cause of autosomal recessive congenital ichthyosis (ARCI). 12R-lipoxygenase (12R-LOX), the protein product of ALOX12B, has been proposed to covalently bind the corneocyte lipid envelope (CLE) to the proteinaceous corneocyte envelope, thereby providing a scaffold for the assembly of barrier-providing, mature lipid lamellae. To test this hypothesis, an in-depth ultrastructural examination of CLEs was performed in ALOX12B-/- human and Alox12b-/- mouse epidermis, extracting samples with pyridine to distinguish covalently attached CLEs from unbound (ie, noncovalently bound) CLEs. ALOX12B--/- stratum corneum contained abundant pyridine-extractable (ie, unbound) CLEs, compared with normal stratum corneum. These unbound CLEs were associated with defective post-secretory lipid processing, and were specific to 12R-LOX deficiency, because they were not observed with deficiency of the related ARCI-associated proteins, patatin-like phospholipase 1 (Pnpla1) or abhydrolase domain containing 5 (Abhd5). These results suggest that 12R-LOX contributes specifically to CLE-corneocyte envelope cross-linking, which appears to be a prerequisite for post-secretory lipid processing, and provide insights into the pathogenesis of 12R-LOX deficiency in this subtype of ARCI, as well as other conditions that display a defective CLE.

ABHD5 stimulates PNPLA1-mediated ω-O-acylceramide biosynthesis essential for a functional skin permeability barrier.

Mutations in the genes coding for patatin-like phospholipase domain-containing 1 (PNPLA1) and α/ß-hydrolase domain-containing 5 (ABHD5), also known as comparative gene identification 58, are causative for ichthyosis, a severe skin barrier disorder. Individuals with mutations in either of these genes show a defect in epidermal ω-O-acylceramide (AcylCer) biosynthesis, suggesting that PNPLA1 and ABHD5 act in the same metabolic pathway. In this report, we identified ABHD5 as a coactivator of PNPLA1 that stimulates the esterification of ω-hydroxy ceramides with linoleic acid for AcylCer biosynthesis. ABHD5 interacts with PNPLA1 and recruits the enzyme to its putative triacylglycerol substrate onto cytosolic lipid droplets. Conversely, alleles of ABHD5 carrying point mutations associated with ichthyosis in humans failed to accelerate PNPLA1-mediated AcylCer biosynthesis. Our findings establish an important biochemical function of ABHD5 in interacting with PNPLA1 to synthesize crucial epidermal lipids, emphasizing the significance of these proteins in the formation of a functional skin permeability barrier.

Skin Barrier Development Depends on CGI-58 Protein Expression during Late-Stage Keratinocyte Differentiation.

Adipose triglyceride lipase (ATGL) and its coactivator comparative gene identification-58 (CGI-58) are limiting in cellular triglyceride catabolism. Although ATGL deficiency is compatible with normal skin development, mice globally lacking CGI-58 die postnatally and exhibit a severe epidermal permeability barrier defect, which may originate from epidermal and/or peripheral changes in lipid and energy metabolism. Here, we show that epidermis-specific disruption of CGI-58 is sufficient to provoke a defect in the formation of a functional corneocyte lipid envelope linked to impaired ω-O-acylceramide synthesis. As a result, epidermis-specific CGI-58-deficient mice show severe skin dysfunction, arguing for a tissue autonomous cause of disease development. Defective skin permeability barrier formation in global CGI-58-deficient mice could be reversed via transgenic restoration of CGI-58 expression in differentiated but not basal keratinocytes suggesting that CGI-58 is essential for lipid metabolism in suprabasal epidermal layers. The compatibility of ATGL deficiency with normal epidermal function indicated that CGI-58 may stimulate an epidermal triglyceride lipase beyond ATGL required for the adequate provision of fatty acids as a substrate for ω-O-acylceramide synthesis. Pharmacological inhibition of ATGL enzyme activity similarly reduced triglyceride-hydrolytic activities in wild-type and CGI-58 overexpressing epidermis implicating that CGI-58 participates in ω-O-acylceramide biogenesis independent of its role as a coactivator of epidermal triglyceride catabolism.

PNPLA1 Deficiency in Mice and Humans Leads to a Defect in the Synthesis of Omega-O-Acylceramides.

Mutations in PNPLA1 have been identified as causative for autosomal recessive congenital ichthyosis in humans and dogs. So far, the underlying molecular mechanisms are unknown. In this study, we generated and characterized PNPLA1-deficient mice and found that PNPLA1 is crucial for epidermal sphingolipid synthesis. The absence of functional PNPLA1 in mice impaired the formation of omega-O-acylceramides and led to an accumulation of nonesterified omega-hydroxy-ceramides. As a consequence, PNPLA1-deficient mice lacked a functional corneocyte-bound lipid envelope leading to a severe skin barrier defect and premature death of newborn animals. Functional analyses of differentiated keratinocytes from a patient with mutated PNPLA1 demonstrated an identical defect in omega-O-acylceramide synthesis in human cells, indicating that PNPLA1 function is conserved among mammals and indispensable for normal skin physiology. Notably, topical application of epidermal lipids from wild-type onto Pnpla1-mutant mice promoted rebuilding of the corneocyte-bound lipid envelope, indicating that supplementation of ichthyotic skin with omega-O-acylceramides might be a therapeutic approach for the treatment of skin symptoms in individuals affected by omega-O-acylceramide deficiency.

Mice lacking lipid droplet-associated hydrolase, a gene linked to human prostate cancer, have normal cholesterol ester metabolism.

Variations in the gene LDAH (C2ORF43), which encodes lipid droplet-associated hydrolase (LDAH), are among few loci associated with human prostate cancer. Homologs of LDAH have been identified as proteins of lipid droplets (LDs). LDs are cellular organelles that store neutral lipids, such as triacylglycerols and sterol esters, as precursors for membrane components and as reservoirs of metabolic energy. LDAH is reported to hydrolyze cholesterol esters and to be important in macrophage cholesterol ester metabolism. Here, we confirm that LDAH is localized to LDs in several model systems. We generated a murine model in which Ldah is disrupted but found no evidence for a major function of LDAH in cholesterol ester or triacylglycerol metabolism in vivo, nor a role in energy or glucose metabolism. Our data suggest that LDAH is not a major cholesterol ester hydrolase, and an alternative metabolic function may be responsible for its possible effect on development of prostate cancer.

Monoacylglycerol Lipases Act as Evolutionarily Conserved Regulators of Non-oxidative Ethanol Metabolism.

Fatty acid ethyl esters (FAEEs) are non-oxidative metabolites of ethanol that accumulate in human tissues upon ethanol intake. Although FAEEs are considered as toxic metabolites causing cellular dysfunction and tissue damage, the enzymology of FAEE metabolism remains poorly understood. In this study, we used a biochemical screen in Saccharomyces cerevisiae to identify and characterize putative hydrolases involved in FAEE catabolism. We found that Yju3p, the functional orthologue of mammalian monoacylglycerol lipase (MGL), contributes >90% of cellular FAEE hydrolase activity, and its loss leads to the accumulation of FAEE. Heterologous expression of mammalian MGL in yju3Δ mutants restored cellular FAEE hydrolase activity and FAEE catabolism. Moreover, overexpression or pharmacological inhibition of MGL in mouse AML-12 hepatocytes decreased or increased FAEE levels, respectively. FAEEs were transiently incorporated into lipid droplets (LDs) and both Yju3p and MGL co-localized with these organelles. We conclude that the storage of FAEE in inert LDs and their mobilization by LD-resident FAEE hydrolases facilitate a controlled metabolism of these potentially toxic lipid metabolites.