Effect of abrocitinib on skin biomarkers in patients with moderate-to-severe atopic dermatitis.

BACKGROUND: This is the first report on the effects of abrocitinib, a Janus kinase 1-selective inhibitor, on the expression of skin biomarkers in patients with moderate-to-severe atopic dermatitis (AD). METHODS: JADE MOA (NCT03915496) was a double-blind Phase 2a trial. Adults were randomly assigned 1:1:1 to receive monotherapy with once-daily abrocitinib 200 mg, abrocitinib 100 mg, or placebo for 12 weeks. The primary endpoint was change from baseline in markers of inflammation (matrix metalloproteinase [MMP]-12), epidermal hyperplasia (keratin-16 [KRT16]), T-helper 2 (Th2) immune response (C-C motif chemokine ligand [CCL]17, CCL18, and CCL26), and Th22 immune response (S100 calcium binding protein A8, A9, and A12 [S100A8, S100A9, and S100A12]) in skin through 12 weeks. RESULTS: A total of 46 patients received abrocitinib 200 mg (n = 14), abrocitinib 100 mg (n = 16), or placebo (n = 16). Abrocitinib improved AD clinical signs and reduced itch. Gene expression of MMP-12, KRT16, S100A8, S100A9, and S100A12 was significantly decreased from baseline with abrocitinib 200 mg (at Weeks 2, 4, and 12) and abrocitinib 100 mg (at Weeks 4 and 12) in a dose-dependent manner. Abrocitinib 200 mg resulted in significant decreases from baseline in CCL17 expression at Week 12 and CCL18 expression at Weeks 2, 4, and 12; no significant decreases were observed for CCL26. CONCLUSIONS: Alongside improvements in clinical signs and symptoms of AD, 12 weeks of abrocitinib treatment resulted in downregulation of genes associated with inflammation, epidermal hyperplasia, and Th2 and Th22 immune responses in the skin of patients with moderate-to-severe AD.

A detailed look at the European Medicines Agency's recommendations for use of Janus kinase inhibitors in patients with atopic dermatitis.

BACKGROUND: Oral Janus kinase inhibitors (JAKi) have been approved for the treatment of several chronic inflammatory conditions, including rheumatoid arthritis (RA) and atopic dermatitis (AD). Prompted by new evidence, the Pharmacovigilance Risk Assessment Committee (PRAC) of the European Medicines Agency (EMA) recently reassessed the benefit-risk balance of oral JAKi. The PRAC recommended that oral JAKi should be used only if no suitable alternatives are available in patients ≥65 years of age, or who have a history of atherosclerotic cardiovascular (CV) disease, other CV risk factors (e.g. history of long-term smoking) or have malignancy risk factors, and used with caution in patients at risk of pulmonary embolism or deep vein thrombosis. The European Commission's final decision was issued in March 2023. OBJECTIVES: Our goal was to highlight the PRAC recommendations, especially in the context of oral JAKi use in AD. METHODS: Authors summarized the PRAC recommendations, the new clinical evidence on oral JAKi safety and key differences between patients with RA and AD. RESULTS: Risk of developing adverse events of special interest (e.g. cardiovascular events, malignancy) is higher in patients with RA than in patients with AD, because of the higher prevalence of the underlying risk factors. CONCLUSIONS: The benefit-risk profile of JAKi approved for AD remains favourable, including use as first-line systemic therapy for patients with AD <65 years of age and without CV or malignancy risk factors.

Abrocitinib efficacy and safety in patients with moderate-to-severe atopic dermatitis: Results from phase 3 studies, including the long-term extension JADE EXTEND study.

BACKGROUND: Abrocitinib improved signs and symptoms of moderate-to-severe atopic dermatitis (AD) at 12 or 16 weeks in phase 3 studies with a manageable safety profile. Further understanding of the abrocitinib long-term efficacy and safety profile is important for its appropriate use in treating chronic AD. OBJECTIVE: To evaluate the abrocitinib efficacy up to 48 weeks and long-term safety in patients with moderate-to-severe AD. METHODS: JADE EXTEND (NCT03422822) is an ongoing, phase 3, long-term extension study that enrolled patients from previous abrocitinib AD trials. This analysis focusses on patients from the phase 3 JADE MONO-1 (NCT03349060), JADE MONO-2 (NCT03575871) and JADE COMPARE (NCT03720470) studies who completed the full treatment period of placebo or abrocitinib (200 mg or 100 mg once daily) and subsequently entered JADE EXTEND. Efficacy endpoints included the proportion of patients achieving skin clearance (Investigator's Global Assessment [IGA] 0/1 [clear/almost clear]; ≥75% improvement in Eczema Area and Severity Index [EASI-75]) and itch response (Peak Pruritus Numerical Rating Scale [PP-NRS] severity ≥4-point improvement). Safety endpoints included treatment-emergent adverse events (TEAEs), serious TEAEs and TEAEs leading to discontinuation. Data cut-off: April 22, 2020. RESULTS: As of the data cut-off, ~70% and ~45% of patients received abrocitinib for ≥36 and ≥48 weeks, respectively. Nasopharyngitis, atopic dermatitis, nausea and upper respiratory tract infections were the most frequent TEAEs. Serious TEAEs occurred in 7% and 5% and TEAEs leading to study discontinuation occurred in 9% and 7% of patients receiving abrocitinib 200 mg and 100 mg, respectively. Week 48 efficacy responses with abrocitinib 200 mg and 100 mg were as follows: IGA 0/1 52% and 39%; EASI-75 82% and 67%, and PP-NRS severity ≥4-point improvement 68% and 51%. CONCLUSIONS: In patients with moderate-to-severe AD, long-term abrocitinib treatment resulted in clinically meaningful skin and pruritus improvement. The long-term safety profile was manageable and consistent with previous reports.

Comparing how well abrocitinib and dupilumab treat atopic dermatitis signs and symptoms: a plain language summary.

WHAT IS THIS SUMMARY ABOUT?: Atopic dermatitis (AD, also called atopic eczema) is a skin disease that that can affect a person for a long time and causes red or flaky skin that can be itchy and uncomfortable. Healthcare providers can prescribe medicated creams and ointments to reduce the visible signs and symptoms of AD, but these treatments are not always enough to keep it under control. A new medicine called abrocitinib is taken every day as a tablet. Abrocitinib works by slowing a part of the body's defense mechanism, called immune response, that is not functioning properly in AD. The clinical study described in this plain language summary, called JADE DARE, investigated how well and how safely 26 weeks of treatment with abrocitinib worked in adults with AD compared to an injected medicine, called dupilumab, that is also approved for AD. WHAT WERE THE RESULTS?: The study showed that abrocitinib was more effective than dupilumab in providing itch relief after 2 weeks. In addition, people who were taking abrocitinib for 4 and 16 weeks experienced greater improvement in the visible skin signs of AD than people who were taking dupilumab. The number of people who had health complaints while taking abrocitinib was similar to the number of people who had health complaints while taking dupilumab. Most of these complaints were minor. WHAT DO THE RESULTS MEAN?: Abrocitinib was more effective than dupilumab in quickly improving the signs and symptoms of moderate or severe AD in people who did not show improvement with prescribed medications like creams or ointments. Clinical Trial Registration: NCT04345367 (ClinicalTrials.gov).

Narrative Review of the Pathogenesis of Stasis Dermatitis: An Inflammatory Skin Manifestation of Venous Hypertension.

INTRODUCTION: Stasis dermatitis (SD), also known as venous dermatitis, is a form of inflammatory dermatitis of the lower extremities that typically occurs in older individuals and represents a cutaneous manifestation of venous hypertension. Venous hypertension (also known as sustained ambulatory venous pressure) is most often due to retrograde blood flow, which occurs due to calf muscle pump failure. This failure is most commonly secondary to incompetent venous valves, valve destruction, or obstruction of the venous system. Many of the common symptoms associated with SD are caused by inflammatory processes. METHODS: This review summarizes the pathogenesis and key role of inflammation in SD by reviewing inflammatory biomarkers associated with SD. The literature was selected though a high-level PubMed search focusing on keywords relating to inflammation associated with SD. RESULTS: Venous reflux at the lower extremities causes venous hypertension, which leads to chronic venous insufficiency. High venous pressure due to venous hypertension promotes the local accumulation and extravasation of inflammatory cells across the vascular endothelium. Leukocyte trapping in the microcirculation and perivascular space is associated with trophic skin changes. Cell adhesion molecules are linked with the perpetuated influx of activated leukocytes into inflammatory sites. Here, inflammatory cells may influence the remodeling of the extracellular matrix by inducing the secretion of proteinases such as matrix metalloproteinases (MMPs). The increased expression of MMPs is associated with the formation of venous leg ulcers and lesions. Phosphodiesterase 4 activity has also been shown to be elevated in individuals with inflammatory dermatoses compared to healthy individuals. DISCUSSION: Because inflammation is a key driver of the signs and symptoms of SD, several of the highlighted biomarkers of inflammation represent potential opportunities to target and interrupt molecular pathways of cutaneous inflammation and, therefore, remediate the signs and symptoms of SD. CONCLUSION: Understanding the pathogenesis of SD may help clinicians identify drivers of inflammation to use as potential targets for the development of new treatment options.

Stasis dermatitis is a skin disease that affects the legs, most often of older people, with chronic venous insufficiency. Chronic venous insufficiency is when veins cannot return blood from the legs back to the heart. This leads to high blood pressure in veins and causes blood in those veins to flow backwards. If stasis dermatitis is left untreated, complications, including skin ulcers, can result. Other skin symptoms of stasis dermatitis include itchiness, scaling, and discoloration. Such skin symptoms can have a negative effect on a person's quality of life. Inflammation that lasts a long time is likely the main link between the skin changes seen in people with stasis dermatitis and the increased pressure in leg veins. Several molecules are associated with the inflammation observed in stasis dermatitis, including white blood cells, matrix metalloproteinases, phosphodiesterase 4, and interleukin-31. Treatment for stasis dermatitis should focus both on the underlying chronic venous insufficiency and the associated skin issues. Identifying inflammatory markers and pathways could help treat the signs and symptoms associated with stasis dermatitis, including the skin symptoms.

Efficacy and safety of abrocitinib versus dupilumab in adults with moderate-to-severe atopic dermatitis: a randomised, double-blind, multicentre phase 3 trial.

BACKGROUND: Phase 3 trials have assessed efficacy of abrocitinib versus placebo in moderate-to-severe atopic dermatitis, a common immunoinflammatory skin disease. This study assessed the efficacy and safety of abrocitinib versus dupilumab. METHODS: This randomised, double-blind, double-dummy, active-controlled, parallel-treatment, phase 3 trial enrolled adults with moderate-to-severe atopic dermatitis who requir=ed systemic therapy or had inadequate response to topical medications. Participants were enrolled from 151 sites, located in Australia, Bulgaria, Canada, Chile, Finland, Germany, Hungary, Italy, Latvia, Poland, Slovakia, South Korea, Spain, Taiwan, and the USA. These participants were then randomly assigned (1:1) with block randomisation to receive oral abrocitinib (200 mg per day) or subcutaneous dupilumab (300 mg every 2 weeks) for 26 weeks. Participants were required to apply topical corticosteroids (medium or low potency), topical calcineurin inhibitors, or a topical phosphodiesterase 4 inhibitor to active lesion areas. Primary endpoints were response based on achieving a 4 point or higher improvement in Peak Pruritus Numerical Rating Scale (PP-NRS4) at week 2 and a 90% or better improvement in Eczema Area and Severity Index (EASI-90) at week 4. Family-wise type 1 error was controlled via a sequential multiple-testing procedure (two sided, α=0·05). Randomly assigned participants who received at least one dose of study intervention were included in the efficacy and safety analysis sets. This trial was completed on July 13, 2021 (NCT04345367). FINDINGS: Between June 11, 2020, and Dec 16, 2020, 940 patients were screened and 727 were enrolled (362 in the abrocitinib group and 365 in the dupilumab group). Compared with dupilumab, a larger proportion of patients treated with abrocitinib reached the primary outcomes, PP-NRS4 at week 2 (172 [48%] of 357, 95% CI 43·0-53·4 vs 93 [26%] of 364, 21·1-30·0; difference 22·6%, 15·8-29·5; p<0·0001), and EASI-90 at week 4 (101 [29%] of 354, 23·8-33·2 vs 53 [15%] of 364, 10·9-18·2; difference 14·1%, 8·2-20·0; p<0·0001). Treatment-emergent adverse events were reported by 268 (74%) of 362 patients treated with abrocitinib and by 239 (65%) of 365 patients treated with dupilumab. Two non-treatment-related deaths occurred in the abrocitinib group. INTERPRETATION: Abrocitinib 200 mg per day was more efficacious than dupilumab in adults with moderate-to-severe atopic dermatitis on background topical therapy in inducing early reductions of itch and atopic dermatitis disease signs. Both treatments were well tolerated over 26 weeks. FUNDING: Pfizer.

Rapid Improvement of Itch Associated With Atopic Dermatitis With Abrocitinib Is Partially Independent of Overall Disease Improvement: Results From Pooled Phase 2b and 3 Monotherapy Studies.

BACKGROUND: Itch, the most bothersome symptom in atopic dermatitis, is largely mediated by pruritogenic cytokines via Janus kinase 1 signaling in cutaneous sensory neurons. OBJECTIVES: The aims of the study were to assess the magnitude and rapidity of itch relief with the Janus kinase 1 selective inhibitor abrocitinib and to evaluate the extent to which the effect of abrocitinib on itch relief is independent of overall disease improvement. METHODS: Pooled data from 1 phase 2b (NCT02780167) and 2 phase 3 (NCT03349060, NCT03575871) double-blind, randomized, placebo-controlled monotherapy trials in moderate to severe atopic dermatitis (N = 942) were analyzed. RESULTS: Abrocitinib produced significant and clinically meaningful itch relief versus placebo from week 2 through week 12 (end of treatment) that was associated with marked sleep and quality-of-life improvements. Mean percentage reductions in itch scores 24 hours after the first dose were greater for both abrocitinib doses (200 and 100 mg) versus placebo. Itch improvement occurred regardless of baseline itch severity, sex, race, body mass index, or Investigator Global Assessment response, suggesting that abrocitinib-associated itch relief is at least partially independent of overall disease improvement. CONCLUSIONS: Abrocitinib showed a rapid and profound antipruritic effect, partially independent of improvement in overall disease.

Comparison of Etanercept Monotherapy and Combination Therapy with Methotrexate in Psoriatic Arthritis: Results from 2 Clinical Trials.

OBJECTIVE: To evaluate the clinical/functional outcomes associated with etanercept (ETN) monotherapy versus combination therapy in psoriatic arthritis (PsA). METHODS: Data from patients with PsA who received ETN alone (n = 322) or combined with methotrexate (MTX; n = 152) for 24 weeks in 2 placebo-controlled clinical trials were summarized across studies. RESULTS: Similar proportions of patients in the monotherapy and combination therapy groups achieved the PsA Response Criteria (80% and 83%) and the American College of Rheumatology improvements of 20% (ACR20; both 70%); numerically higher proportions receiving monotherapy achieved ACR50 (55% vs 48%) and ACR70 (35% vs 27%). Little between-group difference was observed in the 28-joint Disease Activity Score with C-reactive protein, the Psoriasis Area and Severity Index, and the Health Assessment Questionnaire-Disability Index improvement. CONCLUSION: ETN with and without MTX provided similar benefits in active PsA.

The efficacy and safety of infliximab in patients with plaque psoriasis who had an inadequate response to etanercept: results of a prospective, multicenter, open-label study.

BACKGROUND: In patients with psoriasis and inadequate response (IR) to tumor necrosis factor-α antagonist treatment, the incremental benefit of switching to another tumor necrosis factor-α antagonist is unknown. OBJECTIVE: We sought to evaluate the clinical response to an etanercept-to-infliximab switch in patients with psoriasis and IR to etanercept. METHODS: Adults with moderate-to-severe plaque psoriasis and IR to etanercept (≥ 4 months) were eligible for this open-label study (called PSUNRISE). Patients had a Physician Global Assessment (PGA) score of at least 2 (mild) on a 5-point scale with etanercept, with or without concomitant oral systemic methotrexate or cyclosporine at baseline and during the study. Patients received intravenous infusions of infliximab 5 mg/kg at weeks 0, 2, 6, 14, and 22. PGA was used to evaluate efficacy at week 10 (primary end point) and week 26 (durability). Safety was evaluated through the end of the study. RESULTS: Of 215 patients, only 10 received concomitant immunomodulators. At week 10, 65.4% of patients (138 of 211; 95% confidence interval 58.6%-71.8%) achieved a PGA score of clear (0) or minimal (1) (primary end point). This response was durable through week 26, at which time 61.3% (122 of 199; 95% confidence interval 54.2%-68.1%) achieved a PGA score of clear (0) or minimal (1). There were no unexpected side effects or safety concerns. LIMITATIONS: This was an open-label, 26-week study; an incremental change of 1 PGA point, even mild to minimal, was considered clinically significant, as most psoriasis practitioners seek to achieve minimal psoriasis or clear skin. CONCLUSION: After switching to infliximab, a substantial proportion of patients with psoriasis and IR to etanercept experienced rapid and durable improvement.

Skin and nail responses after 1 year of infliximab therapy in patients with moderate-to-severe psoriasis: a retrospective analysis of the EXPRESS Trial.

BACKGROUND: The EXPRESS study demonstrated the initial efficacy of infliximab in psoriasis affecting the skin and nails. OBJECTIVE: To further assess how patients with a positive initial response to infliximab respond to 1 year of continuous infliximab treatment. METHODS: A retrospective analysis of patients with moderate-to-severe plaque and nail psoriasis who initiated and continued infliximab treatment up to week 46 was conducted. RESULTS: Among all nail psoriasis patients receiving 1 year of infliximab (n = 186), 74.6 and 54.1% achieved at least 75 or 90% improvement in the Psoriasis Area and Severity Index (PASI) at week 50. These PASI-75 (n = 138) and PASI-90 (n = 100) responders had respective mean improvements from baseline to week 50 of 93.6 and 97.3% for the PASI, 90.6 and 94.1% for the Dermatology Life Quality Index (DLQI) and 78.2 and 80.3% for the Nail Psoriasis Severity Index (NAPSI). CONCLUSIONS: Infliximab treatment for 1 year produced sustained improvement in PASI, DLQI and NAPSI scores.

Ultraviolet B-induced DNA damage in human epidermis is modified by the antioxidants ascorbic acid and D-alpha-tocopherol.

DNA damage caused by ultraviolet (UV) irradiation is considered the main etiologic factor contributing to the development of skin cancer. Systemic or topical application of antioxidants has been suggested as a protective measure against UV-induced skin damage. We investigated the effect of long-term oral administration of a combination of the antioxidants ascorbic acid (vitamin C) and D-alpha-tocopherol (vitamin E) in human volunteers on UVB-induced epidermal damage. The intake of vitamins C and E for a period of 3 mo significantly reduced the sunburn reaction to UVB irradiation. Detection of thymine dimers in the skin using a specific antibody revealed a significant increase of this type of DNA damage following UVB exposure. After 3 mo of antioxidant administration, significantly less thymine dimers were induced by the UVB challenge, suggesting that antioxidant treatment protected against DNA damage.