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Granuloma annulare (GA) is an idiopathic inflammatory skin condition with a chronic and unpredictable course. Although localized GA is usually cleared with topical or systemic corticosteroids, generalized GA is often difficult to treat owing to the lack of treatment options and recurrence with treatment. Recent evidence has helped to elucidate the etiology behind GA, with growing confirmation for the use of JAK inhibitors as a possible treatment for GA. We present a 61-year-old woman with recalcitrant GA who responded successfully to pulse therapy upadacitinib, a JAK1 inhibitor. Our findings demonstrate the utility of this alternative and practical treatment strategy that may reduce the cumulative toxicity of upadacitinib and optimize its risk/benefit ratio.

Lichen planus is a chronic auto-inflammatory disease that primarily affects mucocutaneous regions. There are many variants of lichen planus including cutaneous, oral, nail, follicular, and erosive forms. Without any disease-specific treatment options, multi-variant lichen planus can be a challenging disease to manage. We present a 61-year-old woman with multivariant lichen planus that was refractory to numerous systemic and topical therapies. Subsequently, her cutaneous and vulvovaginal lesions improved with the use of oral baricitinib and the erosive oral lesions improved with topical ruxolitinib.

\nIntroduction: Ruxolitinib is approved for treatment of myelofibrosis. We evaluated ruxolitinib in patients with anemia (hemoglobin <10 g/dL) or thrombocytopenia (platelet count ≤100 × 109/L) at diagnosis. Methods: This was a retrospective, secondary analysis of a Cardinal Health Oncology Provider Extended Network medical chart review of adults with myelofibrosis diagnosed between 2012 and 2016 who received first-line ruxolitinib. Results: 176 patients received first-line ruxolitinib and were included in this analysis. At diagnosis, 120 patients had hemoglobin concentrations <10 g/dL and 59 had a platelet count ≤100 × 109/L. Most patients (95%) with thrombocytopenia also had anemia. Median time of observation after diagnosis was 21.4 months. Among patients with anemia or thrombocytopenia, ruxolitinib dose at end of study was ≥10 mg twice daily (bid) in 88.3% and 83.1%, respectively. Ruxolitinib treatment was ongoing in 76.1% of patients overall and was rarely discontinued for anemia or thrombocytopenia (n = 2 total, 1.1%). Per the treating physician, 79.7% of patients had improved symptoms and 62.7% improved spleen size. Conclusion: Most patients with myelofibrosis and anemia or thrombocytopenia at diagnosis tolerated and maintained a ruxolitinib dose ≥10 mg bid for nearly 2 years, resulting in clinical benefit. This real-world evidence supports observations from prospective clinical trials of ruxolitinib in myelofibrosis. Myelofibrosis is a bone marrow cancer. Patients with myelofibrosis experience troublesome symptoms like exhaustion and weakness and may have a painfully enlarged spleen. Because myelofibrosis disrupts the production of blood cells, some patients also have anemia, or too few platelets. For these patients, myelofibrosis tends to be more severe, and they generally die sooner than patients with normal blood cell levels. Ruxolitinib is a treatment for myelofibrosis that improves symptoms and reduces spleen size. One side effect of ruxolitinib is that it can temporarily lower blood cell levels, which may be concerning for patients with low blood cell counts from their disease. More data are needed to understand how best to use ruxolitinib to treat this population. In this study, researchers collected data from doctors who used ruxolitinib to treat patients who had myelofibrosis and low blood cell counts. They collected data on how much ruxolitinib patients were prescribed, if and why patients stopped taking ruxolitinib, and how well ruxolitinib worked to treat myelofibrosis. Patients were studied for nearly 2 years. The researchers found that around a third of patients stopped taking ruxolitinib by the end of the study, but very few did so because of concerns about their blood cell counts. Most patients were able to take ruxolitinib at a high enough dose to be effective, improving spleen size and helping patients feel better. These findings suggest that ruxolitinib can be used to treat myelofibrosis, even in patients with low blood cell counts. [ABSTRACT FROM AUTHOR]

Introduction: High baseline neutrophil-to-lymphocyte ratio (NLR) in rheumatoid arthritis (RA) has been associated with positive responses to biologic tumor necrosis factor inhibition and negative responses to conventional synthetic disease-modifying antirheumatic drug (csDMARD) triple therapy. Datasets from three randomized clinical trials in patients with RA were used to test the hypothesis that baseline NLR is associated with improved clinical response to filgotinib in methotrexate (MTX)-naïve or MTX-experienced RA populations. Methods: Patients from FINCH 1 (inadequate response to MTX, MTX-IR; NCT02889796), FINCH 2 (inadequate response to biologic DMARDs; NCT02873936), and FINCH 3 (MTX-naïve; NCT02886728) were classified as baseline NLR-High or baseline NLR-Low based on a previously published cut point of 2.7. In total, 3365 patients were included across the three studies. Differences in clinical outcomes and patient-reported outcomes (PROs) were determined using linear-regression models. Results: Control-arm patients (placebo + MTX/placebo + csDMARD) classified as NLR-High exhibited worse continuous clinical and PRO responses at week 12 across clinical trials compared to NLR-Low patients. In contrast, NLR-High patients who received FIL 200 mg + MTX/csDMARD exhibited consistently better responses after 12 weeks compared to NLR-Low patients across clinical trials, clinical endpoints, and PROs. These trends were most prominent among the MTX-IR population. Conclusion: The 2.7 baseline NLR cut point could be used to enrich for patients most likely to benefit from the addition of filgotinib to background MTX/csDMARD. Use of baseline NLR as part of therapeutic decision-making would not require additional diagnostics and could contribute to improved outcomes for patients with RA. Trial Registration: Clinicaltrials.gov: NCT02889796; NCT02873936; NCT02886728. Plain Language Summary: Rheumatoid arthritis is a disease that results in swollen and painful joints. There is currently no method to determine which treatment will work best for an individual patient. However, there may be identifying markers found in the blood that could indicate how a patient will respond to treatment. One of these possible markers is a ratio of two types of white blood cells, neutrophils and lymphocytes, which are part of the body's immune system and help the body detect and fight infection and other diseases. This ratio is referred to as the neutrophil-to-lymphocyte ratio. The current study evaluated whether the neutrophil-to-lymphocyte ratio at the beginning of treatment was associated with rheumatoid arthritis treatment outcomes. Blood test results were used from 3365 patients receiving filgotinib (a medicine used to treat rheumatoid arthritis) or other therapies as part of the FINCH clinical trials. Patients were classified as having a high or low neutrophil-to-lymphocyte ratio at the start of treatment. Patients receiving filgotinib over 24 weeks who had a high neutrophil-to-lymphocyte ratio showed less disease activity than patients whose ratio was low. This study provides support for the use of the neutrophil-to-lymphocyte ratio as a way to help determine whether a patient would benefit from filgotinib as part of their rheumatoid arthritis treatment and may help improve rheumatoid arthritis treatment outcomes. [ABSTRACT FROM AUTHOR]

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Objectives: Standardized criteria for disease activity and end of treatment of systemic treatment of atopic dermatitis have not been established. The objective of this study is to explore the experience using upadacitinib retrospectively, to find clues to weaning from systemic treatment, and to determine the algorithm for setting treatment goals and terminating systemic treatment. Methods: Fourteen patients treated with upadacitinib between 1 November 2021 and 31 December 2023 were enrolled in the study. Topical antiinflammatory treatments were combined. Treatment outcomes were established according to the European Task Force of Atopic Dermatitis guidelines. To evaluate disease status and control, we adopted the Treat to target strategy. Changes in serum biomarkers (TARC and IgE) were also observed. Results: All patients achieved EASI 50 after 52 weeks. At 76 weeks, 80% and 30% of patients achieved EASI 75 and EASI 90, respectively. Four patients completed upadacitinib, five patients discontinued treatment, and five patients remained on treatment. Two patients achieved complete remission without topical antiinflammatory treatment. Two patients discontinued due to adverse events. Patients with better treatment adherence, mainly topical treatment, tended to be able to withdraw from UPA. IgE increased from baseline in 11 patients (78.6%) and TARC increased in 14 patients (100%). These biomarkers decreased from the peak 24-48 weeks after initiating treatment, after the improvement of eczema. Conclusion: Combining systemic and topical treatments effectively induces remission in AD patients. Transitioning off systemic treatment begins by achieving remission maintained solely with topical therapy, emphasizing the importance of adherence. [ABSTRACT FROM AUTHOR]

Background: Alopecia areata (AA) is an autoimmune hair loss disorder characterised by collapse of hair follicle immune privilege and mediated by autoreactive CD8+ T lymphocytes and natural killer cells. Treatment is often unsatisfactory. The Janus kinase‐signal transducer and activator of transcription (JAK–STAT) pathway is implicated in the pathogenesis of AA and Janus Kinase inhibitor (JAKi) medications are promising emerging treatments for AA. Objectives: We evaluated the safety and effectiveness of tofacitinib in a real‐world setting over 18 months of treatment. Methods: A retrospective cohort study of all patients with scalp AA commenced on tofacitinib between 1 November 2016 and 31 May 2019. The primary endpoint was the percent change in Severity of Alopecia Tool (SALT) score at 18 months. Results: Two hundred and two patients were included. After 18 months of treatment, 55.9%, 42.6% and 29.2% achieved 50%, 75% and 90% reductions in their SALT scores respectively. Increased duration of AA was a negative predictor of hair regrowth. Males and patients with baseline SALT ≥90 were slower to respond to treatment in the first 12 months. One hundred and twenty‐four patients and 168 patients received concomitant systemic corticosteroids or low‐dose oral minoxidil during tofacitinib therapy respectively. There were no serious adverse events. Conclusion: Tofacitinib was a safe and effective treatment for patients with moderate‐to‐severe AA. Further randomised controlled studies are needed to establish the optimal treatment regimen. [ABSTRACT FROM AUTHOR]

Baricitinib is an oral Janus kinase (JAK) inhibitor and a member of the targeted synthetic disease-modifying anti-rheumatic drugs. Baricitinib competitively binds to adenosine triphosphate and inhibits the synthesis of cytokines that play prominent roles in arthritis rheumatoid arthritis pathogenesis by selectively inhibiting JAK1 and JAK2 at an effective dose. Its bioavailability is approximately 80%, and 64% is excreted via the kidney. To evaluate the efficacy and safety of baricitinib, 19 clinical pharmacological studies and 3 phase II, 4 phase III, and one extension study were conducted in patients with rheumatoid RA. The effectiveness of baricitinib has been shown in these studies. Clinical research and real-world data suggest that barictinib is a safe drug; however, it has been reported to have some well-known side effects such as neutropenia, anemia, elevation of transaminase levels, hyperlipidemia, and increased risk of infections. In these studies, major cardiovascular events were found to be similar in frequency to placebo, and the incidence of malignancy was found to be similar to that of age-related cancer in the general population. However, as is the case with other JAK inhibitors, it is recommended to be used with caution in patients with risk factors for deep vein thrombosis, such as advanced age, obesity, and inactivity. [ABSTRACT FROM AUTHOR]

Abrocitinib is a novel oral small molecule which acts as a selective JAK-1 inhibitor. Currently approved for use in moderate-to-severe cases of atopic dermatitis, this drug is gaining a rapid impetus for its use across various inflammatory dermatoses for its selective downstream action on cytokines of the JAK-1 pathway. Its efficacy and safety in atopic dermatitis has been established in phase 3 clinical trials. The future implication of this drug will depend largely on feasibility and practical use in Indian scenario.

Abstract Introduction High baseline neutrophil-to-lymphocyte ratio (NLR) in rheumatoid arthritis (RA) has been associated with positive responses to biologic tumor necrosis factor inhibition and negative responses to conventional synthetic disease-modifying antirheumatic drug (csDMARD) triple therapy. Datasets from three randomized clinical trials in patients with RA were used to test the hypothesis that baseline NLR is associated with improved clinical response to filgotinib in methotrexate (MTX)-naïve or MTX-experienced RA populations. Methods Patients from FINCH 1 (inadequate response to MTX, MTX-IR; NCT02889796), FINCH 2 (inadequate response to biologic DMARDs; NCT02873936), and FINCH 3 (MTX-naïve; NCT02886728) were classified as baseline NLR-High or baseline NLR-Low based on a previously published cut point of 2.7. In total, 3365 patients were included across the three studies. Differences in clinical outcomes and patient-reported outcomes (PROs) were determined using linear-regression models. Results Control-arm patients (placebo + MTX/placebo + csDMARD) classified as NLR-High exhibited worse continuous clinical and PRO responses at week 12 across clinical trials compared to NLR-Low patients. In contrast, NLR-High patients who received FIL 200 mg + MTX/csDMARD exhibited consistently better responses after 12 weeks compared to NLR-Low patients across clinical trials, clinical endpoints, and PROs. These trends were most prominent among the MTX-IR population. Conclusion The 2.7 baseline NLR cut point could be used to enrich for patients most likely to benefit from the addition of filgotinib to background MTX/csDMARD. Use of baseline NLR as part of therapeutic decision-making would not require additional diagnostics and could contribute to improved outcomes for patients with RA. Trial Registration Clinicaltrials.gov: NCT02889796; NCT02873936; NCT02886728.

Autoimmune dermatosis (AID) occurs when the body's immune system attacks skin or tissue, leading to various types of skin disorders or injuries. Recent studies show that Janus kinases (JAKs) play critical roles in autoimmune diseases including AID by regulating multiple cytokine signaling pathways. CS12192, a novel JAK3/JAK1/TBK1 inhibitor, has been reported to exert ameliorative effects in rheumatoid arthritis. However, the efficacy of CS12192 on AID is undetermined. This study aims to investigate the therapeutic efficacy of CS12192 on psoriasis (PSO), systemic lupus erythematosus (SLE) and atopic dermatitis (AD) in mouse models. Interleukin-23 (IL-23)-induced PSO model, spontaneous SLE model of MRL/MpJ-Faslpr/J (MRL/lpr) mice, and oxazolone (OXA) and dinitrochlorobenzene (DNCB)-induced murine AD models were used for the evaluation of curative effects of CS12192, respectively. The skin lesion, biochemical parameters, ear thickness, ear weight and histopathology were assessed accordingly. In PSO model, mice treated with CS12192 show reduced ear thickness and ear weight as compared with vehicle. In SLE model, CS12192 ameliorates cutaneous parameters such as lymphadenectasis and skin lesion but not systematic parameters such as proteinuria concentration and score, serum dsDNA and BUN concentration. In AD models, CS12192 dose-dependently improves ear swelling and reduces histological scores, exerting equivalent efficacy with baricitinib, a marketed JAK1/JAK2 inhibitor. Our findings suggest that the novel JAK3/JAK1/TBK1 inhibitor CS12192 is potentially to alleviate autoimmune dermatosis. [ABSTRACT FROM AUTHOR]

The mechanisms underlying the development of steroid resistance in asthma remain unclear. To establish whether as well as the mechanisms by which the activation of Janus kinases (JAKs) is involved in the development of steroid resistance in asthma, murine steroid‐resistant models of the proliferation of group 2 innate lymphoid cells (ILC2s) in vitro and asthmatic airway inflammation in vivo were analysed. ILC2s in the lungs of BALB/c mice were sorted and then incubated with IL‐33, thymic stromal lymphopoietin (TSLP), and/or IL‐7 with or without dexamethasone (10 nM), the pan‐JAK inhibitor, delgocitinib (1–10 000 nM), and/or the Bcl‐xL inhibitor, navitoclax (1–100 nM), followed by the detection of viable and apoptotic cells. The anti‐apoptotic factor, Bcl‐xL was detected in ILC2s by flow cytometry. As a steroid‐resistant asthma model, ovalbumin (OVA)‐sensitized BALB/c mice were intratracheally challenged with OVA at a high dose of 500 μg four times. Dexamethasone (1 mg/kg, i.p.), delgocitinib (3–30 mg/kg, p.o.), or navitoclax (30 mg/kg, p.o.) was administered during the challenges. Cellular infiltration into the lungs was analysed by flow cytometry. Airway remodelling was histologically evaluated. The following results were obtained. (1) Cell proliferation concomitant with a decrease in apoptotic cells was induced when ILC2s were cultured with TSLP and/or IL‐7, and was potently inhibited by dexamethasone. In contrast, when the culture with TSLP and IL‐7 was performed in the presence of IL‐33, the proliferative response exhibited steroid resistance. Steroid‐resistant ILC2 proliferation was suppressed by delgocitinib in a concentration‐dependent manner. (2) The culture with IL‐33, TSLP, and IL‐7 induced the overexpression of Bcl‐xL, which was clearly inhibited by delgocitinib, but not by dexamethasone. When ILC2s were treated with navitoclax, insensitivity to dexamethasone was significantly cancelled. (3) The development of airway remodelling and the infiltration of ILC2s into the lungs in the asthma model were not suppressed by dexamethasone, but were dose‐dependently inhibited by delgocitinib. Combination treatment with dexamethasone and either delgocitinib or navitoclax synergistically suppressed these responses. Therefore, JAKs appear to play significant roles in the induction of steroid resistance by up‐regulating Bcl‐xL in ILC2s. The inhibition of JAKs and Bcl‐xL has potential as pharmacotherapy for steroid‐resistant asthma, particularly that mediated by ILC2s. [ABSTRACT FROM AUTHOR]

The gastrointestinal (GI) tract, home to the largest microbial population in the human body, plays a crucial role in overall health through various mechanisms. Recent advancements in research have revealed the potential implications of gut-brain and vice-versa communication mediated by gut-microbiota and their microbial products in various diseases including type-2 diabetes and Alzheimer's disease (AD). AD is the most common type of dementia where most of cases are sporadic with no clearly identified cause. However, multiple factors are implicated in the progression of sporadic AD which can be classified as non-modifiable (e.g., genetic) and modifiable (e.g. Type-2 diabetes, diet etc.). Present review focusses on key players particularly the modifiable factors such as Type-2 diabetes (T2D) and diet and their implications in microbiota-gut-brain (MGB) and brain-gut (BG) communication and cognitive functions of healthy brain and their dysfunction in Alzheimer's Disease. Special emphasis has been given on elucidation of the mechanistic aspects of the impact of diet on gut-microbiota and the implications of some of the gut-microbial products in T2D and AD pathology. For example, mechanistically, HFD induces gut dysbiosis with driven metabolites that in turn cause loss of integrity of intestinal barrier with concomitant colonic and systemic chronic low-grade inflammation, associated with obesity and T2D. HFD-induced obesity and T2D parallel neuroinflammation, deposition of Amyloid β (Aβ), and ultimately cognitive impairment. The review also provides a new perspective of the impact of diet on brain-gut and microbiota-gut-brain communication in terms of transcription factors as a commonly spoken language that may facilitates the interaction between gut and brain of obese diabetic patients who are at a higher risk of developing cognitive impairment and AD. Other commonality such as tyrosine kinase expression and functions maintaining intestinal integrity on one hand and the phagocytic clarence by migratory microglial functions in brain are also discussed. Lastly, the characterization of the key players future research that might shed lights on novel potential pharmacological target to impede AD progression are also discussed. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Purpose of Review: Summarize best practices for management of patients with early myelofibrosis (MF). Recent Findings: Myelofibrosis is a progressive myeloproliferative neoplasm (MPN) that generally produces burdensome symptoms and ultimately leads to worse overall survival than that observed in healthy controls or patients with other MPNs. Several Janus kinase inhibitors and various interferon formulations are now available for treatment of MF, with ruxolitinib notable for extending overall survival in addition to improving MF signs and symptoms. Summary: The chronic nature of the disease can lead some patients to avoid immediate treatment in favor of a watch-and-wait approach. This review summarizes the patient management approach taken in my practice, providing guidance and a discussion of best practices with an emphasis on the importance and clinical benefits of active treatment in early MF. In particular, a case is made to consider treatment with ruxolitinib for patients with intermediate-1 risk disease and to minimize delay between diagnosis and treatment initiation for patients with intermediate or high-risk disease. [ABSTRACT FROM AUTHOR]

Objective: To investigate the effect of honokiol (HON) and the role of high-mobility group protein B1 (HMGB1) on the pathogenesis of severe acute pancreatitis (SAP). Methods: Thirty mice were numbered according to weight, and randomly divided into 5 groups using a random number table, including control, SAP, SAP and normal saline (SAP+NS), SAP and ethyl pyruvate (SAP+EP), or SAP+HON groups, 6 mice in each group. Samples of pancreas, intestine, and blood were collected 12 h after SAP model induction for examination of pathologic changes, immune function alterations by enzyme linked immunosorbent assay (ELISA), and Western blot. In vitro experiments, macrophages were divided into 5 groups, the control, lipopolysaccharide (LPS), LPS+DMSO (DMSO), LPS+anti-HMGB1 monoclonal antibody (mAb), and LPS+ HON groups. The tight connection level was determined by transmission electron microscopy and fluorescein isothiocyanate-labeled. The location and acetylation of HMGB1 were measured by Western blot. Finally, pyridone 6 and silencing signal transducer and activator of the transcription 1 (siSTAT1) combined with honokiol were added to determine whether the Janus kinase (JAK)/ STAT1 participated in the regulation of honokiol on HMGB1. The protein expression levels of HMGB1, JAK, and STAT1 were detected using Western blot. Results: Mice with SAP had inflammatory injury in the pancreas, bleeding of intestinal tissues, and cells with disrupted histology. Mice in the SAP+HON group had significantly fewer pathological changes. Mice with SAP also had significant increases in the serum levels of amylase, lipase, HMGB1, tumor necrosis factor- α, interleukin-6, diamine oxidase, endotoxin-1, and procalcitonin. Mice in the SAP+HON group did not show these abnormalities (P<0.01). Studies of Caco-2 cells indicated that LPS increased the levels of occludin and claudin-1 as well as tight junction permeability, decreased the levels of junctional adhesion molecule C, and elevated intercellular permeability (P<0.01). HON treatment blocked these effects. Studies of macrophages indicated that LPS led to low nuclear levels of HMGB1, however, HON treatment increased the nuclear level of HMGB1 (P<0.01). HON treatment also inhibited the expressions of JAK1, JAK2, and STAT1 (P<0.01) and increased the acetylation of HMGB1 (P<0.05). Conclusion: HON prevented intestinal barrier dysfunction in SAP by inhibiting HMGB1 acetylation and JAK/STAT1 pathway. [ABSTRACT FROM AUTHOR]

Abstract 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.

Abstract Background Vitiligo is a disease that affects people of all skin shades and can impact their quality of life. Reliable evidence on the effectiveness and adverse events associated with the recent use of Janus kinase (JAK) inhibitors to treat vitiligo is needed. This protocol for a systematic review and meta-analysis seeks to collect evidence from both randomized controlled trials (RCTs) and observational studies to determine the effectiveness and patient-centered outcomes concerning treatment with JAK inhibitors. Methods We will conduct a systematic review of the literature for RCTs and observational studies that used upadacitinib, ritlecitinib, brepocitinib, ifidancitinib, cerdulatinib, deglocitinib, baricitinib, tofacitinib, and ruxolitinib JAK inhibitors as treatments for vitiligo compared to placebo, no treatment, or combination therapies. We will systematically search from inception in Epistemonikos, MEDLINE, Scopus, Cochrane Central Register of Controlled Trials, EMBASE, ClinicalTrials.gov, PsycINFO, Allied and Complementary Medicine Database, Latin American and Caribbean Health Sciences Literature, Web of Science Core Collection, relevant preprint servers, and the gray literature. Ethics approval was not sought as the protocol and systematic review will not involve human participants, but rather summarized and anonymous data from studies. Primary outcomes include quality of life, percentage repigmentation, decreased vitiligo within 1 year or more, lasting repigmentation after a 2-year follow-up, cosmetic acceptability of repigmentation and tolerability or burden of treatment, and adverse events. Secondary outcomes are patient and study characteristics. We will include full-text articles, preprints, and clinical trial data in any language and all geographic regions. For data sources unavailable in English, we will obtain translations from global collaborators via the Cochrane Engage network. We will exclude articles for which sufficient information cannot be obtained from the authors of articles and systematic reviews. At least two investigators will independently assess articles for inclusion and extract data; reliability will be assessed before subsequent selection and data extraction of remaining studies. The risk of bias and certainty of evidence with Grading of Recommendations Assessment, Development, and Evaluation guidelines will be assessed independently by at least two investigators. We will estimate treatment effects by random-effects meta-analyses and assess heterogeneity using I 2. Data that cannot be included in the meta-analysis will be reported narratively using themes. Discussion The proposed systematic review and meta-analysis describe the methods for summarizing and synthesizing the evidence on the effectiveness and patient-centered outcomes concerning the treatment of vitiligo with JAK inhibitors that were recently approved for this indication. To disseminate further the results of our systematic review, we plan to present them at international conferences and meetings. Our findings will provide robust evidence to facilitate decision-making at the policy or practitioner level. Systematic review registration PROSPERO CRD42023383920.

Triple-negative breast cancer (TNBC) poses a significant clinical challenge due to its propensity for metastasis and poor prognosis. TNBC evades the body's immune system recognition and attack through various mechanisms, including the Janus Kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling pathway. This pathway, characterized by heightened activity in numerous solid tumors, exhibits pronounced activation in specific TNBC subtypes. Consequently, targeting the JAK2/STAT3 signaling pathway emerges as a promising and precise therapeutic strategy for TNBC. The signal transduction cascade of the JAK2/STAT3 pathway predominantly involves receptor tyrosine kinases, the tyrosine kinase JAK2, and the transcription factor STAT3. Ongoing preclinical studies and clinical research are actively investigating this pathway as a potential therapeutic target for TNBC treatment. This article comprehensively reviews preclinical and clinical investigations into TNBC treatment by targeting the JAK2/STAT3 signaling pathway using small molecule compounds. The review explores the role of the JAK2/STAT3 pathway in TNBC therapeutics, evaluating the benefits and limitations of active inhibitors and proteolysis-targeting chimeras in TNBC treatment. The aim is to facilitate the development of novel small-molecule compounds that target TNBC effectively. Ultimately, this work seeks to contribute to enhancing therapeutic efficacy for patients with TNBC. [ABSTRACT FROM AUTHOR]

Background: Vitiligo is a disease that affects people of all skin shades and can impact their quality of life. Reliable evidence on the effectiveness and adverse events associated with the recent use of Janus kinase (JAK) inhibitors to treat vitiligo is needed. This protocol for a systematic review and meta-analysis seeks to collect evidence from both randomized controlled trials (RCTs) and observational studies to determine the effectiveness and patient-centered outcomes concerning treatment with JAK inhibitors. Methods: We will conduct a systematic review of the literature for RCTs and observational studies that used upadacitinib, ritlecitinib, brepocitinib, ifidancitinib, cerdulatinib, deglocitinib, baricitinib, tofacitinib, and ruxolitinib JAK inhibitors as treatments for vitiligo compared to placebo, no treatment, or combination therapies. We will systematically search from inception in Epistemonikos, MEDLINE, Scopus, Cochrane Central Register of Controlled Trials, EMBASE, ClinicalTrials.gov, PsycINFO, Allied and Complementary Medicine Database, Latin American and Caribbean Health Sciences Literature, Web of Science Core Collection, relevant preprint servers, and the gray literature. Ethics approval was not sought as the protocol and systematic review will not involve human participants, but rather summarized and anonymous data from studies. Primary outcomes include quality of life, percentage repigmentation, decreased vitiligo within 1 year or more, lasting repigmentation after a 2-year follow-up, cosmetic acceptability of repigmentation and tolerability or burden of treatment, and adverse events. Secondary outcomes are patient and study characteristics. We will include full-text articles, preprints, and clinical trial data in any language and all geographic regions. For data sources unavailable in English, we will obtain translations from global collaborators via the Cochrane Engage network. We will exclude articles for which sufficient information cannot be obtained from the authors of articles and systematic reviews. At least two investigators will independently assess articles for inclusion and extract data; reliability will be assessed before subsequent selection and data extraction of remaining studies. The risk of bias and certainty of evidence with Grading of Recommendations Assessment, Development, and Evaluation guidelines will be assessed independently by at least two investigators. We will estimate treatment effects by random-effects meta-analyses and assess heterogeneity using I2. Data that cannot be included in the meta-analysis will be reported narratively using themes. Discussion: The proposed systematic review and meta-analysis describe the methods for summarizing and synthesizing the evidence on the effectiveness and patient-centered outcomes concerning the treatment of vitiligo with JAK inhibitors that were recently approved for this indication. To disseminate further the results of our systematic review, we plan to present them at international conferences and meetings. Our findings will provide robust evidence to facilitate decision-making at the policy or practitioner level. Systematic review registration: PROSPERO CRD42023383920. [ABSTRACT FROM AUTHOR]

Clinical trials and real-world studies have shown the effectiveness of upadacitinib for treating rash and pruritus in patients with atopic dermatitis (AD). This study aimed to determine whether the early reduction in rash or pruritus at week 12 of upadacitinib treatment could be maintained at later treatment stages. This retrospective study involved 227 and 73 patients with moderate-to-severe AD treated with 15 and 30 mg upadacitinib daily, respectively. The eczema area and severity index (EASI) scores, peak pruritus numerical rating scale (PP-NRS), and investigator's global assessment (IGA) were analyzed. At week 12, patients were divided into achievers and non-achievers of EASI 75, 90, 100, absolute EASI ≤ 2, IGA0/1, PP-NRS4, or absolute PP-NRS ≤ 1. Achievement rates for each endpoint were assessed at later time points (weeks 24, 36, and 48) in both groups. Week 12 achievers largely maintained their endpoint achievements until week 48, regardless of dosage (15 mg or 30 mg). Week 12 non-achievers saw an increasing achievement rate of EASI 75 until week 48. The initial reduction in rash and pruritus at week 12 persisted until week 48 with upadacitinib treatment, suggesting potential benefits for patients requiring prolonged treatment despite not achieving EASI 75 at week 12. [ABSTRACT FROM AUTHOR]

Background Janus kinase [JAK] inhibitors [JAKinibs] are effective small molecule therapies for treating Crohn's disease [CD] and ulcerative colitis [UC], collectively known as inflammatory bowel disease [IBD]. By preventing JAKs from phosphorylating signal transducer and activator of transcription proteins, JAKinibs disrupt cytokine signalling pathways that promote inflammation. Despite considerable overlap in the JAKs they target, first- and second-generation JAKinibs display different clinical efficacies in CD and UC. Methods We conducted a comparative phosflow study of four JAKinibs [filgotinib, upadacitinib, tofacitinib, and deucravacitinib] to observe subtle mechanistic differences that may dictate their clinical behaviour. Resected mesenteric lymph node [MLN] cells from 19 patients [9 CD, 10 UC] were analysed by flow cytometry in the presence or absence of different cytokine stimuli and titrated JAKinibs. Results We found a higher potency of the JAK 1/3-preferential inhibitor, tofacitinib, for JAK 3-dependent cytokine signalling pathways in comparison to filgotinib, but a higher potency of the JAK 1-preferential inhibitors, filgotinib and upadacitinib, for JAK 3-independent cytokine signalling pathways. Deucravacitinib, a TYK2-preferential inhibitor, demonstrated a much narrower selectivity by inhibiting only IL-10 and IFN-β pathways, albeit more potently than the other JAKinibs. Additionally, we found some differences in the sensitivity of immune cells from CD versus UC, and patients with versus without a CD-associated NOD2 polymorphism, to phosphorylate signal transducer and activator of transcriptions in response to specific cytokine stimulation. Conclusions Despite their similarities, differences exist in the relative potencies of different JAKinibs against distinct cytokine families, to explain their clinical efficacy. [ABSTRACT FROM AUTHOR]

Baricitinib demonstrated efficacy and tolerable safety in clinical trials for atopic dermatitis (AD); however, real-world data are limited. We examined effectiveness and safety of baricitinib, and laboratory data in AD patients treated with baricitinib in our department. We also evaluated baseline clinical severity in responders and non-responders. All adult AD patients treated with baricitinib in our department between January 2021 and February 2023 were included. Data on 30 Japanese AD patients were analyzed. Objective severity scores and patient-reported outcomes improved at one and 3 months, except for the affected body surface area at 1 month. The proportions of patients who achieved eczema area and severity index-50% improvement were 30.0% (9/30) at 1 month and 53.3% (16/30) at 3 months. There were no significant changes in AD biomarkers. No significant difference was observed in baseline clinical severity between responders and non-responders. No significant changes were observed in laboratory results except for increased serum creatine phosphokinase levels at 3 months. One case of herpes zoster and one case of ocular herpes were observed. Baricitinib showed mild effectiveness and favorable safety including laboratory findings. Biomarkers did not reflect clinical improvement. Further study is needed to identify characteristics of responders. [ABSTRACT FROM AUTHOR]

Vitiligo is an autoimmune disease involving melanocyte-targeting T cells initiated by environmental and genetic factors. Steroids and tacrolimus have been used as topical treatments. Recently, novel topical agents targeting Janus kinase (JAK), a family of tyrosine kinases that regulates cytokine signaling, have emerged. Ruxolitinib is the first approved in vitiligo therapy. Furthermore, ritlecitinib is currently under clinical trials for oral treatment of active vitiligo. In this review, we discuss the possibility of topical JAK inhibitors as promising options for the treatment of vitiligo with regard to their mechanism of action, efficacy and safety. • Novel vitiligo treatments have been developed that targets JAKs. • Topical ruxolitinib, a pan-JAK inhibitor, has been approved in the U.S. • JAK3-selective litrecitinib is under clinical trials as an oral formulation. • JAKs are promising targets for the treatment of vitiligo with various stages. • Topical application has the advantage of avoiding systemic side effects. [ABSTRACT FROM AUTHOR]

Simple Summary: Cutaneous T-cell lymphomas (CTCLs) are a rare kind of skin cancer that currently has no curative treatment except allogeneic stem cell transplantation. The aim of this systematic review is to investigate the effectiveness of Janus kinase inhibitor drugs as a treatment for CTCLs. This study showed that Janus kinase inhibitors can be effective in the treatment of CTCLswith acceptable adverse effects. Adverse events have been reported especially in patients with immunosuppression or an underlying autoimmune disease. We recommend conducting more studies, especially clinical trials, to investigate the benefits of these drugs for the treatment of cutaneous T-cell lymphomas. Cutaneous T-cell lymphomas (CTCLs) are a group of lymphoid neoplasms with high relapse rates and no curative treatment other than allogeneic stem cell transplantation (allo-SCT). CTCL is significantly influenced by disruption of JAK/STAT signaling. Therefore, Janus kinase (JAK) inhibitors may be promising for CTCL treatment. This study is a systematic review aiming to investigate the role of JAK inhibitors in the treatment of CTCL, including their efficacy and safety. Out of 438 initially searched articles, we present 13 eligible ones. The overall response rate (ORR) in the treatment with JAK inhibitors in clinical trials was 11–35%, although different subtypes of CTCL showed different ORRs. Mycosis fungoides showed an ORR of 14–45%, while subcutaneous-panniculitis-like T-cell lymphoma (SPTCL) displayed an ORR ranging from 75% to 100%. Five cases were reported having a relapse/incident of CTCL after using JAK inhibitors; of these, three cases were de novo CTCLs in patients under treatment with a JAK inhibitor due to refractory arthritis, and two cases were relapsed disease after graft-versus-host disease treatment following allo-SCT. In conclusion, using JAK inhibitors for CTCL treatment seems promising with acceptable side effects, especially in patients with SPTCL. Some biomarkers, like pS6, showed an association with better responses. Caution should be taken when treating patients with an underlying autoimmune disease and prior immunosuppression. [ABSTRACT FROM AUTHOR]

At present, the effect of angiotensin II on the biological behavior of smooth muscle cells of thoracic aortic aneurysm is not clear. In this study, thoracic aortic aneurysm rat model (thoracic aortic aneurysm model group) was prepared by applying calcium chloride to blood vessels, and normal rats were taken as a sham operation group (sham group), with 10 rats in each group. The changes of angiotensin II content in plasma and left ventricular myocardial tissue were detected. Normal rat thoracic aortic smooth muscle cells were extracted and divided into the control group, angiotensin II group (1 µg/ml angiotensin II), and angiotensin II+angiotensin receptor blocker group (1×10-6 mol/l candesartan+1 µg/ml angiotensin II). The cholecystokinin cell counting kit-8, flow cytometry, Transwell chamber, scratch healing, and Western blot experiments were used to detect cell proliferation, apoptosis, invasion, migration, and the expression changes of Janus kinase/signal transducers and activators of transcription pathway-related proteins. The results showed that angiotensin II content in left ventricular myocardium of thoracic aortic aneurysm group was higher than that of Sham group (p<0.01). Compared with the control group, angiotensin II group showed increased cell proliferative activity, number of invaded cells, mobility, and expression levels of Ras-related C3 botulinum toxin substrate 1, phosphorylated-Janus kinase 2, phosphorylated-signal transducers and activators of transcription 1, and phosphorylated-signal transducers and activators of transcription 3 proteins, and decreased apoptosis rate (p<0.05). Compared with the angiotensin II group, the cell proliferative activity, the number of invaded cells, and mobility as well as the expression levels of Ras-related C3 botulinum toxin substrate 1, phosphorylated-Janus kinase 2, phosphorylated-signal transducers and activators of transcription 1, and phosphorylatedsignal transducers and activators of transcription 3 proteins in the angiotensin II+angiotensin receptor blocker group were decreased, and the apoptosis rate was increased (p<0.05). These results indicated that angiotensin II could induce the proliferation, invasion, and migration of thoracic aortic aneurysm smooth muscle cells, and promote apoptosis. [ABSTRACT FROM AUTHOR]

Objectives Anaemia, a common comorbidity of RA, is related to high disease activity and poor prognosis. It is unknown which biologic/targeted synthetic (b/ts)-DMARDs are optimal for patients with anaemia and RA in regulating anaemia and controlling disease activity. Methods We investigated the change in haemoglobin (Hb) levels, drug retention rates and disease activities after the administration of b/ts-DMARDs with different modes of action [TNF inhibitors (TNFis), immunoglobulin fused with cytotoxic T-lymphocyte antigen (CTLA-4-Ig), IL-6 receptor inhibitors (IL-6Ris) and Janus kinase inhibitors (JAKis)] in patients with RA stratified by baseline Hb levels using the multicentre observational registry for patients with RA in Japan (ANSWER cohort). Results A total of 2093 patients with RA were classified into three groups based on tertiles of the baseline Hb levels (Hblow, anaemic; Hbint, intermediate; Hbhigh, non-anaemic). IL-6Ri increased Hb levels in all groups (the mean change at 12 months in Hblow was +1.5 g/dl, Hbint +0.7 g/dl and Hbhigh +0.1 g/dl). JAKis increased the Hb level in patients with anaemia and RA and retained or decreased the Hb level in non-anaemic patients (the mean change at 12 months in Hblow was +0.6 g/dl, Hbint 0 g/dl and Hbhigh −0.3 g/dl). In patients with anaemia and RA, overall adjusted 3-year drug retention rates were higher in JAKi followed by IL-6Ri, CTLA4-Ig and TNFi (78.6%, 67.9%, 61.8% and 50.8%, respectively). Change of disease activity at 12 months was not different among different b/ts-DMARDs treatments. Conclusion IL-6Ri and JAKi can effectively treat patients with anaemia and RA in a real-world setting. [ABSTRACT FROM AUTHOR]

Data on the safety of Janus kinase inhibitors (JAKis) in patients with renal impairment are lacking. This study aimed to investigate the safety of JAKis compared to biological (b) DMARDs in patients with rheumatoid arthritis (RA) and renal impairment. We used a multi-centre observational registry of patients with RA in Japan (the ANSWER cohort). We assessed the drug retention rates of b/targeted synthetic DMARDs with different modes of action (tumour necrosis factor inhibitors (TNFis), immunoglobulins fused with cytotoxic T-lymphocyte antigen (CTLA-4-Ig), interleukin-6 receptor inhibitors (IL-6Ris), and JAKis) in patients with RA stratified by pre-treatment estimated glomerular filtration rate (eGFR) levels. The time to discontinuation of bDMARDs or JAKis was analysed using a multivariate Cox proportional hazards model This study included 3775 patients, who were classified into three groups (the normal group (eGFR ≥ 60 mL/min/1.73 m2): 2893 patients; CKDa group (eGFR 45–60 mL/min/1.73 m2): 551; and CKDb group (eGFR < 45 mL/min/1.73 m2): 331). In the CKDb group, the 12-month drug retention rate due to adverse events (AE) was the lowest in patients treated with JAKi (TNFi: 93.1%; IL-6Ri: 94.1%; CTLA-4-Ig: 92.3%; JAKi: 75.1%). In the normal and CKDa groups, drug retention rates due to AE were similar among patients treated with bDMARDs and JAKi. In contrast, drug retention rates due to inefficacy were similar between bDMARDs and JAKis in all groups. In the Cox-proportional model, in the CKDb group, TNFi, IL-6Ri, and CTLA-4-Ig showed lower incidence of drug discontinuation due to AE than JAKis (TNFi: hazard ratio = 0.23 (95% confidence interval 0.09–0.61), IL-6Ri: 0.34 (0.14–0.81), CTLA-4-Ig: 0.36 (0.15–0.89)). JAKis showed the lowest drug retention due to AE in patients with moderate-to-severe and severe renal impairment (eGFR < 45 mL/min/1.73 m2). Physicians should pay more attention to renal function when using JAKis than when using bDMARDs. [ABSTRACT FROM AUTHOR]

Rising number of inflammatory bowel disease (IBD) cases in developing countries necessitate clear guidance for clinicians for the appropriate use of advanced therapies. An expert consensus document was generated to guide the usage of tofacitinib, a Janus kinase inhibitor, in ulcerative colitis. Tofacitinib is a useful agent for the induction and maintenance of remission in ulcerative colitis. It can be used in the setting of biological failure or even steroid-dependent and thiopurine refractory disease. Typically, the induction dose is 10 mg BD orally. Usually, clinical response is evident within eight weeks of therapy. In those with clinical response, the dose can be reduced from 10 mg BD to 5 mg BD. Tofacitinib should be avoided or used cautiously in the elderly, patients with cardiovascular co-morbidity, uncontrolled cardiac risk factors, previous thrombotic episodes and those at high risk for venous thrombosis or previous malignancy. Baseline evaluation should include testing for and management of hepatitis B infection and latent tuberculosis. Where feasible, it is prudent to ensure complete adult vaccination, including Herpes zoster, before starting tofacitinib. The use of tofacitinib may be associated with an increased risk of infections such as herpes zoster and tuberculosis reactivation. Maternal exposure to tofacitinib should be avoided during pre-conception, pregnancy, and lactation. There is emerging evidence of tofacitinib in acute severe colitis, although the exact positioning (first-line with steroids or second-line) is uncertain. [ABSTRACT FROM AUTHOR]

The introduction of biologic agents for the treatment of psoriasis has revolutionized the current treatment landscape, targeting cytokines in the interleukin (IL)-23/IL-17 pathway and demonstrating strong efficacy and safety profiles in clinical trials. These agents however are costly, are associated with a risk of immunogenicity, and require administration by intravenous or subcutaneous injection, limiting their use among patients. Oral therapies, specifically small molecule and microbiome therapeutics, have the potential to be more convenient and cost-effective agents for patients and have been a focus of development in recent years, with few targeted oral medications available for the disease. In this manuscript, we review pipeline oral therapies for psoriasis identified through a search of ClinicalTrials.gov (30 June 2022–1 October 2023). Available preclinical and clinical trial data on each therapeutic agent are discussed. Small molecules under development include tumor necrosis factor inhibitors, IL-23 inhibitors, IL-17 inhibitors, phosphodiesterase-4 inhibitors, Janus kinase inhibitors, A3 adenosine receptor agonists, and sphingosine-1-phosphate receptor 1 agonists, several of which are entering phase III trials. Oral microbials have also demonstrated success in early phase studies. As new oral therapies emerge for the treatment of psoriasis, real-world data and comparative trials are needed to better inform their use among patients. [ABSTRACT FROM AUTHOR]

Introduction: Atherosclerosis is common CHD caused by accumulation of oxidized LDL-c forming foam cell with macrophage that narrowing blood vessels. It increased risk of CVD. Green vegetables rich with PUFA is important to maintain healthy status. This study investigated the mechanistic pathway mediate combination of Decosapentanoic acid (DPA) and linoleic acid (LA) as anti-atherothengic effect in rats fed high fat diet. Materials and Methods: Seventy-five male albino rats were divided into five groups (15 rats each) were fed high fat diet (40% Saturated fat) for 3 months: Group (I): Rats given 10 % DPA. Group (II): Rats given 10 % LA. Group (III): Rats given 10 % DPA+10% LA. Group (IV): Rats treated with atorvastatin (10 mg/kg BW) and Group (v) Untreated. In addition, Group (VI): 15 rats fed normal diet. Results: Data obtained showed that, plasma cholesterol and LDL-c levels were highly significant reduced in group III (p < 0.001) versus other groups compared with untreated. Level of triglycerides was reduced but still high than normal (p=0.05) and atherogenic index. The activity of HMG-CoA reductase was reduced while apo-A, apo-c elevated, JAK was upregulated in combination therapy (p< 0.001). The elevated Apo-A, apo-c activate clearing factor and decreased triglycerides. Conclusion: It was concluded that, upregulated of JAK by combination therapy mediate inhibition of HMG-CoA reductase that decreased endogenous synthesis of cholesterol and reduced its level in circulation. [ABSTRACT FROM AUTHOR]

The Janus kinases (JAK) are crucial targets in drug development for several diseases. However, accounting for the impact of possible structural rearrangements on the binding of different kinase inhibitors is complicated by the extensive conformational variability of their catalytic kinase domain (KD). The dynamic KD contains mainly four prominent mobile structural motifs: the phosphate-binding loop (P-loop), the αC-helix within the N-lobe, the Asp-Phe-Gly (DFG) motif, and the activation loop (A-loop) within the C-lobe. These distinct structural orientations imply a complex signal transmission path for regulating the A-loop’s flexibility and conformational preference for optimal JAK function. Nevertheless, the precise dynamical features of the JAK induced by different types of inhibitors still remain elusive. We performed comparative, microsecond-long, Gaussian accelerated molecular dynamics simulations in triplicate of three phosphorylated JAK2 systems: the KD alone, type-I ATP-competitive inhibitor (CI) bound KD in the catalytically active DFG-in conformation, and the type-II inhibitor (AI) bound KD in the catalytically inactive DFG-out conformation. Our results indicate significant conformational variations observed in the A-loop and αC helix motions upon inhibitor binding. Our studies also reveal that the DFG-out inactive conformation is characterized by the closed A-loop rearrangement, open catalytic cleft of N and C-lobe, the outward movement of the αC helix, and open P-loop states. Moreover, the outward positioning of the αC helix impacts the hallmark salt bridge formation between Lys882 and Glu898 in an inactive conformation. Finally, we compared their ligand binding poses and free energy by the MM/PBSA approach. The free energy calculations suggested that the AI’s binding affinity is higher than CI against JAK2 due to an increased favorable contribution from the total non-polar interactions and the involvement of the αC helix. Overall, our study provides the structural and energetic insights crucial for developing more promising type I/II JAK2 inhibitors for treating JAK-related diseases. [ABSTRACT FROM AUTHOR]

Alopecia areata (AA) is an autoimmune disease characterized by damage to hair follicles and hair loss. Cell-free DNA (cfDNA) has recently received attention as a biomarker of various disorders including inflammatory skin diseases. In this study, we aimed to investigate the clinical significance of cfDNA and the circulating DNAs of disease-associated cytokines in AA patients. Serum samples were obtained from 63 patients with AA and 32 healthy controls (HC). Using droplet digital polymerase chain reaction, circulating C-X-C motif chemokine ligand (CXCL) 9, CXCL10, CXCL11, C-X-C motif chemokine receptor 3, interferon (IFN)-γ, interleukin (IL) -7, IL-15, and Janus kinase (JAK) 2 were detectable in both HC and AA patients. Among the detectable DNAs, copies of circulating CXCL9, CXCL11, IL-15, IFN-γ, and JAK2 were significantly higher in AA patients than in HC. These results suggest that increased circulating DNA levels may reflect damage to hair follicles in AA patients. [ABSTRACT FROM AUTHOR]

The gastrointestinal (GI) tract, home to the largest microbial population in the human body, plays a crucial role in overall health through various mechanisms. Recent advancements in research have revealed the potential implications of gut-brain and vice-versa communication mediated by gut-microbiota and their microbial products in various diseases including type-2 diabetes and Alzheimer’s disease (AD). AD is the most common type of dementia where most of cases are sporadic with no clearly identified cause. However, multiple factors are implicated in the progression of sporadic AD which can be classified as non-modifiable (e.g., genetic) and modifiable (e.g. Type-2 diabetes, diet etc.). Present review focusses on key players particularly the modifiable factors such as Type-2 diabetes (T2D) and diet and their implications in microbiota-gut-brain (MGB) and brain-gut (BG) communication and cognitive functions of healthy brain and their dysfunction in Alzheimer’s Disease. Special emphasis has been given on elucidation of the mechanistic aspects of the impact of diet on gut-microbiota and the implications of some of the gut-microbial products in T2D and AD pathology. For example, mechanistically, HFD induces gut dysbiosis with driven metabolites that in turn cause loss of integrity of intestinal barrier with concomitant colonic and systemic chronic low-grade inflammation, associated with obesity and T2D. HFD-induced obesity and T2D parallel neuroinflammation, deposition of Amyloid β (Aβ), and ultimately cognitive impairment. The review also provides a new perspective of the impact of diet on brain-gut and microbiota-gut-brain communication in terms of transcription factors as a commonly spoken language that may facilitates the interaction between gut and brain of obese diabetic patients who are at a higher risk of developing cognitive impairment and AD. Other commonality such as tyrosine kinase expression and functions maintaining intestinal integrity on one hand and the phagocytic clarence by migratory microglial functions in brain are also discussed. Lastly, the characterization of the key players future research that might shed lights on novel potential pharmacological target to impede AD progression are also discussed.

Atopic dermatitis (AD) is a prevalent chronic inflammatory skin disease. The Janus kinase (JAK) has been identified as a target in AD, as it regulates specific inflammatory genes and adaptive immune responses. However, the efficacy of topically applied JAK inhibitors in AD is limited due to the unique structure of skin. We synthesized JAK1/JAK2 degraders (JAPT) based on protein degradation targeting chimeras (PROTACs) and prepared them into topical preparations. JAPT exploited the E3 ligase to mediate ubiquitination and degradation of JAK1/JAK2, offering a promising AD therapeutic approach with low frequency and dosage. In vitro investigations demonstrated that JAPT effectively inhibited the release of pro-inflammatory cytokines and reduced inflammation by promoting the degradation of JAK. In vivo studies further confirmed the efficacy of JAPT in degrading JAK1/JAK2, leading to a significant suppression of type I, II, and III adaptive immunity. Additionally, JAPT demonstrated a remarkable reduction in AD severity, as evidenced by improved skin lesion clearance and AD severity scores (SCORAD). Our study revealed the therapeutic potential of JAPT, surpassing conventional JAK inhibitors in the treatment of AD, which suggested that JAPT could be a promising topically applied anti-AD drug targeting the JAK-STAT signaling pathway.

Clinical trials and real-world studies have shown the effectiveness of upadacitinib for treating rash and pruritus in patients with atopic dermatitis (AD). This study aimed to determine whether the early reduction in rash or pruritus at week 12 of upadacitinib treatment could be maintained at later treatment stages. This retrospective study involved 227 and 73 patients with moderate-to-severe AD treated with 15 and 30 mg upadacitinib daily, respectively. The eczema area and severity index (EASI) scores, peak pruritus numerical rating scale (PP-NRS), and investigator’s global assessment (IGA) were analyzed. At week 12, patients were divided into achievers and non-achievers of EASI 75, 90, 100, absolute EASI ≤ 2, IGA0/1, PP-NRS4, or absolute PP-NRS ≤ 1. Achievement rates for each endpoint were assessed at later time points (weeks 24, 36, and 48) in both groups. Week 12 achievers largely maintained their endpoint achievements until week 48, regardless of dosage (15 mg or 30 mg). Week 12 non-achievers saw an increasing achievement rate of EASI 75 until week 48. The initial reduction in rash and pruritus at week 12 persisted until week 48 with upadacitinib treatment, suggesting potential benefits for patients requiring prolonged treatment despite not achieving EASI 75 at week 12.

[Display omitted] • Using HTS, we optimized a potent and selective JAK1/TYK2 dual inhibitor series. • We used structural information to improve JAK1/TYK2 potency. • We confirmed the potency and selectivity of our lead compound in vitro and in vivo. Janus kinase (JAK) inhibitors have gathered interest as treatments for several inflammatory and autoimmune diseases. The four first marketed inhibitors target JAK1, with varying selectivity towards other JAK family members, but none inhibit tyrosine kinase-2 (TYK2) at clinically relevant doses. TYK2 is required for the signaling of the interleukin (IL)-12 and IL-23 cytokines, which are key to the polarization of T H 1 and T H 17 cells, respectively; two cell subtypes that play major roles in inflammatory diseases. Herein, we report our effort towards the optimization of a potent and selective dual JAK1/TYK2 inhibitor series starting from a HTS hit. Structural information revealed vectors required to improve both JAK1 and TYK2 potency as well as selectivity towards JAK2. The potent inhibition of both JAK1 (3.5 nM) and TYK2 (5.7 nM) in biochemical assays by our optimized lead compound, as well as its notable selectivity against JAK2, were confirmed in cellular and whole blood assays. Inhibition of TYK2 by the lead compound was demonstrated by dose-dependent efficacy in an IL-23-induced psoriasis-like inflammation mouse model. [ABSTRACT FROM AUTHOR]

• The study first elucidated the protective effect of transdermal administration of Tetrastigma hemsleyanum polysaccharides in IMQ-induced psoriasis-like mice. • Tetrastigma hemsleyanum polysaccharides acted by blocking the keratinocyte-Th17 cell cycle. • Therapeutic effects of Tetrastigma hemsleyanum polysaccharides on psoriasis may be related to the JAK/STAT3 signaling pathway. The pathogenesis of psoriasis involves the interaction between keratinocytes and immune cells, leading to immune imbalance. While most current clinical treatment regimens offer rapid symptom relief, they often come with significant side effects. Tetrastigma hemsleyanum polysaccharides (THP), which are naturally nontoxic, possess remarkable immunomodulatory and anti-inflammatory properties. In this study, we utilized an imiquimod (IMQ)-induced psoriasis mouse model and a LPS/IL-6-stimulated HaCaT model. The potential and mechanism of action of THP in psoriasis treatment were assessed through methods including Psoriasis Area Severity Index (PASI) scoring, histopathology, flow cytometry, immunoblotting, and reverse transcription-polymerase chain reaction (RT-PCR). Percutaneous administration of THP significantly alleviated symptoms and manifestations in IMQ-induced psoriatic mice, including improvements in psoriatic skin appearance (erythema, folds, scales), histopathological changes, decreased PASI scores, and spleen index. Additionally, THP suppressed abnormal proliferation of Th17 cells and excessive proliferation and inflammation of keratinocytes. Furthermore, THP exhibited the ability to regulate the JAK/STAT3 signaling pathway. Findings from in vivo and in vitro studies suggest that THP can inhibit abnormal cell proliferation and excessive inflammation in lesional skin, balance Th17 immune cells, and disrupt the interaction between keratinocytes and Th17 cells. This mechanism of action may involve the modulation of the JAK/STAT3 signaling pathway, offering potential implications for psoriasis treatment. [Display omitted] [ABSTRACT FROM AUTHOR]

Objectives: To describe safety and efficacy of filgotinib 200 or 100 mg (FIL200/FIL100) in Japanese patients with rheumatoid arthritis in a long-term extension (LTE; NCT03025308)., Methods: Patients who completed any of three parent studies (NCT02889796: inadequate response [IR] to methotrexate [MTX]; NCT02873936: IR to biologic disease-modifying antirheumatic drugs; NCT02886728: MTX-naïve) without rescue therapy could enter the LTE; patients taking FIL continued their dosage, and those who received comparators were rerandomised to FIL200 or FIL100. This analysis includes week 156 interim results., Results: Among Japanese patients, 110 received FIL200, and 97 received FIL100. Mean (SD) FIL200 and FIL100 exposure was 157.0 (51.49) and 156.0 (52.45) weeks. The exposure-adjusted incidence rates (95% CI) for FIL200/FIL100 were 2.7 (1.4, 5.2)/2.4 (1.2, 5.1) for herpes zoster, 0.9 (0.3, 2.8)/1.0 (0.3, 3.2) for malignancy (excluding nonmelanoma skin cancer), and 0.6 (0.2, 2.4)/0.3 (0.0, 2.4) for major adverse cardiovascular events. More patients receiving FIL200 with prior FIL200 exposure achieved clinical remission vs other groups (including Clinical Disease Activity Index remission in 40% vs 27% or less at week 156)., Conclusions: FIL200 and FIL100 were generally well tolerated by Japanese patients, without new, unexpected adverse events., (© Japan College of Rheumatology 2024. Published by Oxford University Press.)

Background: Baricitinib, an oral selective Janus kinase inhibitor, is approved to treat adults with severe alopecia areata (AA)., Objective: To report the week 152 efficacy results from the phase 3 trial BRAVE-AA2 down-titration substudy., Methods: BRAVE-AA2 enrolled 546 adults with severe AA (Severity of Alopecia Tool [SALT] score ≥50). Baricitinib 4-mg-treated patients achieving a clinical response (SALT score ≤20) at week 52 were rerandomized 1:1 to stay on 4-mg or down-titrate to 2-mg. The last observation carried forward was used to impute missing or censored data., Results: At week 52, 86/234 (36.8%) baricitinib 4-mg-treated patients were eligible for down-titration; 44 remained on 4-mg while 42 down-titrated to 2-mg. At week 152, 39/44 (88.6%) 4-mg-treated patients had maintained clinical response, compared to 24/41 (58.5%) down-titrated patients. Among down-titrated patients, loss of treatment benefit was less frequent in those with sustained response and SALT score ≤5 at week 52., Limitations: Method and timing of down-titration were prespecified in the protocol based on week 52 responder status and not on other clinical factors., Conclusion: More than half of down-titrated patients maintained response. Sustained treatment response and/or near-total regrowth may be associated with a greater likelihood of response maintenance after down-titration., Competing Interests: Conflicts of interest Dr King is a clinical trial investigator for Abbvie, Eli Lilly and Company, Incyte, Pfizer Inc, Regeneron, and Sanofi Genzyme; is a consultant or is on the advisory board for Abbvie, AltruBio Inc, Almirall, AnaptysBio, Arena Pharmaceuticals, Aslan Pharmaceuticals, BiologicsMD, Bristol Meyers Squibb, Concert Pharmaceuticals Inc, Equillium, Horizon Therapeutics, Eli Lilly and Company, Incyte Corp, Janssen Pharmaceuticals, LEO Pharma, Merck, Otsuka/Visterra Inc, Pfizer Inc, Q32 Bio Inc, Regeneron, Sanofi Genzyme, Sun Pharmaceutical Industries, TWi Biotechnology Inc; is on the data monitoring committee for Incyte Corp, Ventyx Biosciences Inc; is on speakers bureaus for Abbvie, Eli Lilly and Company, Incyte, Pfizer Inc, Regeneron, Sanofi Genzyme; and receives travel support from Pfizer, Eli Lilly and Company, Sun Pharmaceuticals. Dr Ohyama is a consultant or is on the advisory board for AbbVie GK, Bristol Myers Squibb Japan, Eli Lilly and Company, Maruho Pharmaceutical Co, Pfizer Inc, ROHTO Pharmaceutical Co, Taisho Pharmaceutical Co; is an editor at The Journal of Dermatology; reports honoraria/speakers bureaus for Eli Lilly and Company, Pfizer Inc; receives research grant from Shiseido Co, Maruho Co, Advantest Corp., Sun Pharma Japan Ltd; and receives travel support from Pfizer Inc. Dr Senna is a consultant or is on the advisory board for Abbvie, Eli Lilly and Company, Pfizer Inc, Arena, Cassiopia, Inmagene, Kintor, LOreal; is on the data monitoring committee for Abbvie, Eli Lilly and Company, Pfizer Inc; reports honoraria/speakers bureaus for Eli Lilly and Company, Pfizer Inc; receives travel support from Eli Lilly and Company, Pfizer Inc. Dr Shapiro is a consultant or is on the advisory board for Pfizer Inc, Eli Lilly and Company; Drs Dutronc, Durand, Yu, Kolodsick, and Chiasserini are employees and shareholders of Eli Lilly and Company. Dr Liu is an employee of Tigermed-BDM, Inc. Dr Piraccini is a consultant or is on the advisory board for Difa Cooper, Ducrey, Eli Lilly and Company, LOreal, Pfizer, Inc; reports honoraria/speakers bureaus for Difa Cooper, Ducrey, Eli Lilly and Company, LOreal, Pfizer, Inc. Dr Somani has no conflicts of interest to declare., (Copyright © 2024. Published by Elsevier Inc.)

Immune factors such as interferon‑ɣ and interleukin 4 belong to the group of cytokines that are dependent on type I/II receptors for their signal transmission. Upon activation, these receptors transmit their signal to the cell nucleus and, thus, modulate gene transcription via a signaling cascade consisting of Janus kinases (JAK). This family of four kinases (JAK 1, JAK 2, JAK 3, and tyrosine kinase 2 (TYK2)) subsequently activate members of the signal transducer and activator of transcription (STAT). This finding turned the JAK/STAT signaling pathway into a pharmacological target for the treatment of inflammatory diseases in which cytokines using type I/II receptors play a pathogenic role. In 2018, the European Medicines Agency (EMA) approved tofacitinib for the treatment of psoriatic arthritis. This was the first approval of a JAK/STAT pathway inhibitor for patients treated by dermatologists and rheumatologists. Since then, several new JAK inhibitors have been approved for dermatologic diseases such as atopic dermatitis, alopecia areata, vitiligo, and plaque-type psoriasis. In addition, JAK inhibitors are being investigated for the treatment of many other skin diseases. Thus, systemic JAK inhibitors complete the spectrum of immunotherapeutics with a broader immunological approach compared to monoclonal antibodies. The low molecular weight of JAK inhibitors enables the preparation of these drugs for both systemic and topical administration. Their utilization could represent a valuable alternative to topical steroids. The safety profile of JAK inhibitors must be taken into account. Possible long-term effects may become apparent in the next few years. This article describes both approved JAK inhibitors and relevant new JAK inhibitors that are promising candidates for approval as therapeutics in dermatology., (© 2024. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Superficial plaque erosion causes many acute coronary syndromes. However, mechanisms of plaque erosion remain poorly understood, and we lack directed therapeutics for thrombotic complication. Human eroded plaques can harbor neutrophil extracellular traps (NETs) that propagate endothelial damage at experimental arterial lesions that recapitulate superficial erosion. Clonal Hematopoiesis of Indeterminate Potential (CHIP) denotes age-related clonal expansion of bone marrow-derived cells harboring somatic mutations in the absence of overt hematological disease. CHIP heightens the risk of cardiovascular disease, with the greatest increase seen in individuals with JAK2 V617F. Neutrophils from mice and humans with JAK2 V617F undergo NETosis more readily than Jak2 WT (wild-type) cells. We hypothesized that JAK2 V617F, by increasing propensity to NETosis, exacerbates aspects of superficial erosion. We generated Jak2 V617F and Jak2 WT mice with heterozygous Jak2 V617F in myeloid cells. We induced areas of denuded endothelium that recapitulate features of superficial erosion and assessed endothelial integrity, cellular composition of the erosion, thrombosis rates, and response to ruxolitinib, a clinically available JAK1/2 inhibitor, in relation to genotype. Following experimental erosion, Jak2 V617F mice have greater impairment of endothelial barrier function and increased rates of arterial thrombosis. Neointimas in Jak2V617F mice exhibit increased apoptosis, NETosis, and platelet recruitment. Jak2 V617F mice treated with ruxolitinib show increased endothelial continuity and reduced apoptosis in the neointima comparable to levels in Jak2 WT. These observations provide new mechanistic insight into the pathophysiology of superficial erosion, the heightened risk for myocardial infarction in JAK2 V617F CHIP, and point the way to personalized therapeutics based on CHIP status. • Mechanisms of plaque erosion remain poorly understood. • Clonal hematopoiesis due to mutant JAK2 predisposes to myocardial infarction. • Mice bearing mutant myeloid Jak2 show increased liability to endothelial damage. • A JAK kinase inhibitor can mitigate superficial intimal damage due to Jak2 mutation. [ABSTRACT FROM AUTHOR]

Competing Interests: None disclosed.

Competing Interests: None disclosed.