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Background: Accumulating evidence has demonstrated that arcuate nucleus (ARC) of the hypothalamus is likely responsible for the close association between chronic stress, depression, and diabetes. Xiaoyaosan (XYS), a Chinese herbal formula, remarkably improves depressive-like behavior and glucose intolerance, but the mechanism remains unclear. Leptin receptor (LepR) regulates energy expenditure and depression by mediating the action of leptin on the ARC. Therefore, we hypothesized that XYS may regulate depressive-like behavior and glucose intolerance via the leptin and its cascade LepR-STAT3/PI3K pathway in the ARC. Methods: A rat model of depressive-like behavior and susceptibility to glucose intolerance was induced by exposure to chronic unpredictable mild stress (CUMS) for six weeks. XYS (2.224 g/kg) was orally gavaged for six weeks, and fluoxetine (2.0 mg/kg) was administrated to the positive control group. Depressive-like behaviors were assessed using the open field test (OFT), sucrose preference test (SPT) and forced swim test (FST). Fasting blood glucose (FBG) and oral glucose tolerance test (OGTT) were performed to evaluate the effects of XYS on blood glucose. Peripheral leptin and blood lipids were detected using enzyme-linked immunosorbent assay and an automatic biochemical analyzer, respectively. The effects of XYS on the LepR-STAT3/PI3K pathway were detected by quantitative real-time PCR and western blotting. Results: XYS ameliorated CUMS-induced depressive-like behaviors and elevated blood glucose. XYS improved the food intake but have no significant effects on the body weight. Peripheral leptin and its central receptor were also suppressed by XYS, accompanied by the downregulation of JAK2/STAT3 and PI3K/AKT pathway in the ARC. Additionally, XYS increased AGRP and NPY expression but inhibited POMC in the ARC. Conclusions: XYS improves depressive-like behaviors and susceptibility to glucose intolerance induced by CUMS, which may be achieved by the downregulation of the LepR-STAT3/PI3K signaling pathway in the ARC. [ABSTRACT FROM AUTHOR]

Objectives Excessive and inappropriate production of pro-inflammatory cytokines plays a key role in Still's disease. Janus kinase inhibitor (JAKi) agents mainly block pro-inflammatory cytokine pathways, notably IL-6 and IFN. The objective was to assess the efficacy and safety of JAKi agents in difficult-to-treat systemic JIA or adult-onset Still's disease (AOSD). Methods This retrospective study was based on a national survey conducted in the departments of rheumatology, paediatric rheumatology and internal medicine of French hospitals regarding systemic JIA and AOSD patients who received JAKi agents. The data were collected with a standardized questionnaire and analysed at different times (treatment initiation, months 1, 3 and 6 and the end of follow-up). Results Nine patients (seven adults) were included. All patients showed inadequate response to CS or conventional synthetic or biologic DMARDs. Baricitinib was used in five patients, ruxolitinib in two, tofacitinib in two and upadacitinib in one. A JAKi was used combined with CS in all but two patients. A JAKi was associated with anakinra and CS in one patient, and with MTX, anakinra and CS in another. The median (range) follow-up was 16 (1–33) months. Two cases out of nine showed complete remission, 3/9 partial response and 4/9 treatment failure. At the last visit, CS could be decreased but not stopped. Tolerance of the JAKi was acceptable (no severe adverse events). Conclusion JAKi agents may be a therapeutic option for some patients with difficult-to-treat Still's disease, especially those with partial response to medium- or high-dose CS or biologics. [ABSTRACT FROM AUTHOR]

Simple Summary: Targeted therapies have revolutionized the management of hematological malignancies and solid organ cancers. These new treatments present numerous infectious complications. We aim to present the main infectious complications related to immune checkpoint inhibitors, Bruton's tyrosine kinase (BTK) inhibitors, phosphatidylinositol 3-kinase inhibitors (PI3K), antiapoptotic protein BCL-2 inhibitors, Janus kinase inhibitors and CAR-T cell infusion treatments. The knowledge of complications allows the physician to better identify patients at risk in order to implement diagnostic and therapeutic strategies, or to discuss the implementation of preventive measures. Background: Infections are well known complications of some targeted drugs used to treat solid organ cancer and hematological malignancies. Furthermore, Individual patient risk factors are associated with underlying pathologies, concomitant immunosuppressive treatment, prior treatment and use of anti-infective prophylaxis. Immune-related adverse events (irAEs) are frequent among patients treated with new targeted drugs. Objectives: In this narrative review, we present the current state of knowledge concerning the infectious complications occurring in patients treated with immune checkpoint inhibitors (ICIs), Bruton's tyrosine kinase (BTK) inhibitors, phosphatidylinositol 3-kinase (PI3K) inhibitors, antiapoptotic protein BCL-2 inhibitors, Janus kinase inhibitors or CAR-T cell infusion. Sources: We searched for studies treating infectious complications of ICIs, BTK inhibitors, PI3K inhibitors, antiapoptotic protein BCL-2 inhibitors and CAR-T cell therapy. We included randomized, observational studies and case reports. Content: Immune-related adverse events (irAEs) are frequent among patients treated with new targeted drugs. Treatment of irAEs with corticosteroids and other immunosuppressive agents can lead to opportunistic infections. Bruton's tyrosine kinase (BTK) inhibitors are associated with higher rate of infections, including invasive fungal infections. Implications: Infections, particularly fungal ones, are common in patients treated with BTK inhibitors even though most of the complications occurring among patients treated by ICIs or CART-cells infusion are associated with the treatment of side effects related to the use of these new treatments. The diagnosis of these infectious complications can be difficult and may require extensive investigations. [ABSTRACT FROM AUTHOR]

Background/Aim: Tuberculosis is a disease involving many systems, such as the lung, gastrointestinal system, genitourinary system, etc. Detecting this disease in its latency significantly reduces the morbidity and mortality associated with tuberculosis. One of the tests used in latent TB screening is the interferon gamma release test. In rheumatology practices, it is routinely used to screen for latent tuberculosis infections before treatment with biological agents and Janus kinase (JAK) inhibitors, and it can also be used to exclude tuberculosis infection in clinical practice. In our study, we aimed to evaluate the reasons for requesting interferon gamma release tests and the results of this test in patients who requested it. Methods: Patients admitted to internal medicine and rheumatology outpatient clinics were retrospectively screened within the retrospective cohort study. In total, 364 patients who requested interferon gamma release testing were included in the study. Nine patients with unclear test results were excluded. Laboratory results, demographic data, reasons for requesting the interferon gamma release test, and results were evaluated. Results: The interferon gamma release test was requested by 355 patients. Of these, 266 patients (74.9%) asked for latent tuberculosis screening before treatment with biological agents and JAK inhibitors. This was followed by patients with peripheral lymphadenopathy-lung nodules, patients with unexplained elevated acute phase reactants, and patients with constitutional symptoms, respectively. Ten out of 107 patients (9.3%) had an active tuberculosis infection, while six out of ten patients (60%) had pulmonary tuberculosis, and four (40%) had extrapulmonary tuberculosis. Conclusion: The most common reason for requesting the interferon gamma release test in internal medicine and rheumatology clinics was screening for latent tuberculosis before treatment with biologic agents and JAK inhibitors. In internal medicine, it has been observed that this test can also be requested by patients with constitutional symptoms, unexplained elevated acute phase reactants, and a preliminary diagnosis of tuberculosis in order to rule out or strengthen the preliminary diagnosis. [ABSTRACT FROM AUTHOR]

Primary myelofibrosis (PMF) is the least common of all myeloproliferative neoplasms (MPNs), characterized by a neoplastic transformation of early hematopoietic stem cells, predominantly megakaryocytes and granulocytes. The disease shows gradual evolution from an initial prefibrotic stage to an overt fibrotic stage. Janus kinase (JAK) 2, CALR, and MPL mutations are most common in nonchronic myeloid leukemia MPNs but are not always present. Ineffective marrow hematopoiesis leads to extramedullary hematopoiesis and associated symptoms such as splenomegaly, hepatomegaly, anemia, and pro-inflammatory cytokines-induced constitutional symptoms. The WHO criteria, 2016, consider the combination of clinical, morphological, and molecular genetics features for the diagnosis of the condition. Currently, Dynamic International Prognostic Scoring System is most widely used to predict the prognosis. Here, we report the case of a 63-year-old male diagnosed with the rare disease PMF with extramedullary hematopoiesis and bleeding gastric varices. PMF was diagnosed by bone marrow biopsy showing diffuse fibrosis, positive JAK2-V617F mutation in genetic analysis, negative Philadelphia chromosome, pancytopenia, splenomegaly, and raised leukocyte dehydrogenase. [ABSTRACT FROM AUTHOR]

Objective To evaluate the use of Janus kinase inhibitor (JAKi) in treating JDM and develop cytokine biomarkers of active disease. Methods This study involved a retrospective cohort study that evaluated JAKi in 101 JDM patients as well as a cross-sectional study of cytokines in 128 JDM patients and 30 controls between November 2017 and December 2021 in the Affiliated Children's Hospital of Capital Institute of Pediatrics (China). Results During the median follow-up period of 19 months, 65.5% of the patients had improved rashes, and CAT-BM scores decreased. Overall, 39.6% of JDM patients eliminated glucocorticoids. Muscle strength was improved in all patients who had abnormal muscle strength before JAKi use. Patients and parents provided positive subjective reviews of JAKi, and no serious adverse events were reported. Potential side effects of JAKi included abnormal leukopoenia (14/95) and cough (16/83), which affected over 10% of the JDM patients. In the cytokine analysis, 12/34 cytokines were significantly elevated in active JDM patients. Compared with active JDM patients with multiple phenotypes, active JDM patients with only rashes demonstrated lower cytokine levels. Anti-NXP2-positive active patients had lower cytokine levels compared with those without positive anti-NXP2 antibodies. Among all increased cytokines, IL-1RA changed most dramatically, reaching over 793 times the mean of normal values. We developed a panel composed of six cytokines to differentiate active or stable status in our cohort (area under the curve = 0.8486, P   <  0.05). Conclusion The preliminary evidence suggested that JAKi is a relatively safe and effective alternative for JDM patients. Cytokine profiles could well reflect the inflammatory status of JDM patients. [ABSTRACT FROM AUTHOR]

In recent years, better knowledge of the pathophysiology of inflammatory bowel diseases (IBD) has led to a relevant expansion of the therapeutic arsenal for these conditions. Janus kinase (JAK) inhibitors are a family of small molecules that block one or more of the intracellular tyrosine kinases, including JAK-1, JAK-2, JAK-3 and TYK-2. Tofacitinib, a non-selective small molecule JAK inhibitor, and upadacitinib and filgotinib, which are selective JAK-1 inhibitors, have been approved by the US Food and Drug Administration (FDA) for moderate-to-severe active ulcerative colitis. Compared to biological drugs, JAK inhibitors have a short half-life, rapid onset of action, and no immunogenicity. Both clinical trials and real-world evidence support the use of JAK inhibitors in the treatment of IBD. However, these therapies have been linked with multiple adverse events (AEs) including infection, hypercholesterolemia, venous thromboembolism, major adverse cardiovascular events, and malignancy. While early studies recognized several potential AEs, post-marketing trials have shown that tofacitinib may increase the risk of thromboembolic diseases and major cardiovascular events. The latter are seen in patients aged 50 years or older with cardiovascular risk factors. Hence, the benefits of treatment and risk stratification need to be considered when positioning tofacitinib. Novel JAK inhibitors with a more selective effect on JAK-1 have proven to be effective in both Crohn's disease and ulcerative colitis, offering a potentially safer and efficacious therapeutic option to patients, including those with previous non-response to other therapies such as biologics. Nevertheless, long-term effectiveness and safety data are required. [ABSTRACT FROM AUTHOR]

Simple Summary: EF-24 has exhibited many anti-cancer properties and enhanced bioavailability over curcumin. We demonstrated that through interfering with the nuclear translocation of NF-κB and the activation of JNK, EF-24 inhibited MMP-9 gene transcription, repressing NPC invasion. These findings provide potential avenues for the use of curcumin analogs with increased bioavailability in managing this devastating disease. Cancer metastasis is a main cause of failure in treating subjects with nasopharyngeal carcinoma (NPC) and is frequently linked to high death rates. EF-24, an analog of curcumin, has exhibited many anti-cancer properties and enhanced bioavailability over curcumin. Nevertheless, the effects of EF-24 on the invasiveness of NPC are poorly understood. In this study, we demonstrated that EF-24 effectively inhibited TPA-induced motility and invasion responses of human NPC cells but elicited very limited cytotoxicity. In addition, the TPA-induced activity and expression of matrix metalloproteinase-9 (MMP-9), a crucial mediator of cancer dissemination, were found to be reduced in EF-24-treated cells. Our reporter assays revealed that such a reduction in MMP-9 expression by EF-24 was transcriptionally mediated by NF-κB via impeding its nuclear translocation. Further chromatin immunoprecipitation assays displayed that the EF-24 treatment decreased the TPA-induced interaction of NF-κB with the MMP-9 promoter in NPC cells. Moreover, EF-24 inhibited the activation of JNK in TPA-treated NPC cells, and the treatment of EF-24 together with a JNK inhibitor showed a synergistic effect on suppressing TPA-induced invasion responses and MMP-9 activities in NPC cells. Taken together, our data demonstrated that EF-24 restrained the invasiveness of NPC cells through the transcriptional suppression of MMP-9 gene expression, implicating the usefulness of curcumin or its analogs in controlling the spread of NPC. [ABSTRACT FROM AUTHOR]

Acanthus ilicifolius var. xiamenensis is a traditional herbal medicine in China. In this study, the anti-inflammatory activities of active ingredients of A. ilicifolius var. xiamenensis were investigated in RAW 264.7 cells and Freund's complete adjuvant-induced arthritic rats. Results showed that n-butanol extract exerted antiarthritic potential by reducing paw edema, arthritis score, and altered hematological and biochemical parameters in experimental rats. Phytochemical studies on n-butanol extract resulted in the isolation of five alkaloids (1–5) and five phenylethanoids (6–10). The anti-inflammatory assay of compounds 1–10 on lipopolysaccharide (LPS)-treated RAW 264.7 cells indicated that phenylethanoids 9 and 10 exhibited notable inhibitory activities. The result indicated that compounds 9 and 10 attenuated inflammation by decreasing the production of nuclear factor kappa-B (NF-κB) p65, inhibitory subunit of NF kappa B alpha, Janus kinase 2 (JAK2), signal transducer and activator of transcription 3 (STAT3), and inducible nitric oxide synthase in LPS-mediated RAW 264.7 macrophages. Phenylethanoids 9 and 10 increased the expression of interleukin-10 and endothelial nitric oxide synthase. Therefore, compounds 9 and 10 showed anti-inflammatory activity by regulation of NF-κB and JAK/STAT signaling pathways. [ABSTRACT FROM AUTHOR]

Objectives Whether naive CD4+ T cells are dysregulated and associated with the overactivation of CD4+ T cells in primary SS (pSS) remains unclear. We aimed to explore the role and underlying mechanism of naive CD4+ T cells in pSS. Methods We examined the activation, proliferation and differentiation of naive CD4+ T cells from pSS patients and healthy controls. Differentially expressed genes were identified using RNA sequencing, and were overexpressed or silenced to determine the gene regulating follicular helper T (Tfh) cells. Assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) with chromatin immunoprecipitation with high-throughput sequencing (ChIP-seq) was performed to explore the epigenetic mechanism. Naive CD4+ T cells were treated with pSS-related cytokines to explore the upstream signalling pathway. Results pSS naive CD4+ T cells had higher potentials of activation, proliferation and differentiation towards Tfh cells. Thymocyte selection-associated high mobility group box protein (TOX) was upregulated in pSS naive CD4+ T cells and promoted T cell activation and Tfh cell polarization. TOX silencing in pSS naive CD4+ T cells downregulated B cell lymphoma 6 (BCL6) expression and altered levels of multiple Tfh-associated genes. ChIP-seq analysis implied that TOX bound to the BCL6 locus, where there were accessible regions found by ATAC-seq. IFN-α induced TOX overexpression, which was attenuated by Janus kinase (JAK) and signal transducer and activator of transcription 1 (STAT1) inhibitors. Conclusion Our data suggest that TOX in pSS naive CD4+ T cells is upregulated, which facilitates Tfh cell differentiation. Mechanistically, IFN-α induces TOX overexpression in naive CD4+ T cells through JAK–STAT1 signalling and TOX regulates BCL6 expression. Therefore, IFN-α-JAK–STAT1 signalling and TOX might be potential therapeutic targets in pSS. [ABSTRACT FROM AUTHOR]

Background This study was designed to evaluate if patients with high risk for severe coronavirus disease 2019 (COVID-19) would benefit from treatment with tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) followed by baricitinib in case of hypoxemia and systemic inflammation. Methods PANCOVID is an open-label, double-randomized, phase 3 pragmatic clinical trial including adults with symptomatic COVID-19 with ≥2 comorbidities or aged ≥60 years and was conducted between 10 October 2020 and 23 September 2021. In the first randomization, patients received TDF/FTC or no TDF/FTC. In the second randomization, patients with room air oxygen saturation <95% and at least 1 increased inflammatory biomarker received baricitinib plus dexamethasone or dexamethasone alone. The primary endpoint was 28-day mortality. Main secondary endpoint was 28-day disease progression or critical care unit admission or mortality. The trial was stopped before reaching planned sample size due to the decrease in the number of cases and a mortality rate substantially lower than expected. Results Of the 355 included participants, 97% were hospitalized at baseline. Overall, 28-day mortality was 3.1%. The 28-day mortality relative risk (RR) for participants treated with TDF/FTC was 1.76 (95% confidence interval [CI],.52–5.91; P =.379); it was 0.42 (95% CI,.11–1.59; P =.201) for those treated with baricitinib. The 28-day RR for the main secondary combined endpoint for participants treated with TDF/FTC was 0.95 (95% CI,.66–1.40; P =.774); it was 0.90 (95% CI,.61–1.33; P =.687) for those treated with baricitinib. Conclusions Our results do not suggest a beneficial effect of TDF/FTC; nevertheless, they are compatible with the beneficial effect of baricitinib already established by other clinical trials. Clinical Trials Registration EudraCT: 2020-001156-18. [ABSTRACT FROM AUTHOR]

The article provides an overview of the recent World Congress of Dermatology held in Singapore with the theme "Dermatology Beyond Borders.It mentions the notable studies discussed at the congress include the results of clinical trials for novel treatments for psoriasis, atopic dermatitis, and alopecia areata, showcasing advancements in dermatological research and potential treatment options.

The article describes five cases of demartomyositis (DM) with bullous periorbital oedema identified at the Johns Hopkins Myositis Center, who were all positive for anti-p155/140, suggesting a novel clinical manifestation of this subgroup. Topics discussed include an overview of the case of each patient, condition which prompted concern for angioedema in two participants, and finding on bullous periorbital oedema.

The article describes the case of ankylosing spondylitis (AS) initially requiring anti-tumor necrosis factor (TNF) therapy until undergoing a bone marrow allograft for acute myeloid leukaemia (AML), following which the patient's AS symptoms are in remission. Topics discussed include treatment for ankylosing spondylitis, possible reason for the remission of symptoms, and reason that the AML was unlikely the trigger for the flare.

The article presents a multistakeholder perspective on issues facing managed care professionals in the disease burden and management of vitiligo, a skin disease characterized by selective loss of melanocytes followed by depigmentation in the affected areas of the skin. Topics covered include the epidemiology and pathogenesis of the disease, diagnosis and assessment and the emerging therapies and unmet needs in vitiligo.

Objectives JAK Inhibitors (JAKi) are recommended DMARDs for patients with moderate-to-severe RA who failed first-line therapy with methotrexate. There is a lack of data allowing an evidence-based choice of subsequent DMARD therapy for patients who had discontinued JAKi treatment. We aimed to compare the effectiveness of TNF inhibitor (TNFi) therapy vs JAKi vs other mode of action (OMA) biologic DMARD (bDMARD) in RA patients who were previously treated with a JAKi. Methods RA patients who discontinued JAKi treatment within the Swiss RA registry SCQM were included for this observational prospective cohort study. The primary outcome was drug retention for either TNFi, OMA bDMARD or JAKi. The hazard ratio for treatment discontinuation was calculated adjusting for potential confounders. A descriptive analysis of the reasons for discontinuation was performed. Results Four hundred treatment courses of JAKi were included, with a subsequent switch to either JAKi, TNFi or OMA bDMARD. The crude overall drug retention was higher in patients switching to another JAKi as compared with TNFi and comparable to OMA. A significant difference of JAKi vs TNFi persisted after adjusting for potential confounders. Conclusion In a real-world population of RA patients who discontinued treatment with a JAKi, switching to another JAKi resulted in a higher drug retention than switching to a TNFi. A switch to a second JAKi seems an effective therapeutic option. [ABSTRACT FROM AUTHOR]

Ruxolitinib cream 1.5% (OPZELURA™) is a topical formulation of ruxolitinib, a potent, selective inhibitor of Janus kinase (JAK)1 and JAK2. The targeting of these kinases is associated with therapeutic benefits in patients with atopic dermatitis (AD). In two identically designed, multinational, phase III studies in patients aged ≥ 12 years with mild to moderate AD, ruxolitinib cream 1.5% improved measures of disease severity, pruritus and sleep disturbance relative to vehicle cream when applied twice daily for 8 weeks. Disease severity was controlled for the next 44 weeks when applied as needed to active lesions. Ruxolitinib cream 1.5% was well tolerated in this patient population; its safety profile was similar to that of vehicle cream over the short term, with the types of treatment-emergent adverse events typical of those seen in the vehicle-controlled period over the longer term. Moreover, application site treatment-emergent adverse events indicative of skin tolerability issues (e.g. stinging/burning sensation) were infrequent and no safety findings suggestive of systemic JAK inhibition were identified. Although further longer-term data would be of use, ruxolitinib cream 1.5% provides an alternative to established topical agents (e.g. corticosteroids and calcineurin inhibitors) for the treatment of mild to moderate AD in adults and adolescents. Plain Language Summary: Atopic dermatitis (AD; also known as atopic eczema) is a chronic, relapsing, inflammatory skin disease that most commonly occurs in children but may also affect adults. Ruxolitinib cream 1.5% (OPZELURA™) is a topical therapy that inhibits Janus kinase (JAK)1 and JAK2, which are enzymes that can modify the inflammatory pathways involved in AD. It is approved in the USA for short-term and non-continuous longer-term treatment of mild to moderate AD in non-immunocompromised patients aged ≥ 12 years whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable. Patients experienced clearer skin and a reduction in itch and disturbed sleep when treated with ruxolitinib cream 1.5% twice daily compared with a non-medicated cream for 8 weeks. Moreover, clearer skin was maintained for a further 44 weeks when using the treatment as needed. The safety profile of ruxolitinib cream 1.5% was similar to that of the non-medicated cream, and stinging/burning sensations following application were infrequent. Thus, ruxolitinib cream 1.5% offers an alternative to established topical agents (e.g. corticosteroids and calcineurin inhibitors) for the treatment of adults and adolescents with mild to moderate AD. [ABSTRACT FROM AUTHOR]

Background: Abrocitinib, an oral Janus kinase 1 inhibitor, provided significant itch relief by week 2 in patients with moderate-to-severe atopic dermatitis (AD) in the phase III JADE COMPARE trial. Objectives: This post-hoc analysis of JADE COMPARE aimed to further characterize itch response and determined whether early itch relief could predict subsequent improvements in AD severity. Methods: JADE COMPARE was a randomized, double-blind, double-dummy, placebo-controlled trial. Adult patients (aged ≥ 18 years) with moderate-to-severe AD were randomly assigned to receive oral abrocitinib 200 mg or 100 mg once daily, subcutaneous dupilumab 300 mg every other week (after a 600-mg loading dose), or placebo, plus medicated topical therapy for 16 weeks. Assessments were ≥ 4-point improvement in Peak Pruritus Numerical Rating Scale (PP-NRS4) from days 2 to 15, Eczema Area and Severity Index (EASI), Investigator's Global Assessment (IGA) response, and Dermatology Life Quality Index (DLQI) scores at week 12. Association between week 2 PP-NRS4 and efficacy at week 12 was evaluated by chi-squared tests. The predictive value of early response for later efficacy was assessed by area under the receiver operating characteristic curve. Results: As early as day 4 after treatment, a significantly greater proportion of patients achieved PP-NRS4 response with abrocitinib 200 mg (18.6%) versus dupilumab (5.6%; p < 0.001) and placebo (6.0%; p < 0.003). A similar trend was observed with abrocitinib at the 100-mg dose, with significantly greater PP-NRS4 response rates versus placebo as early as day 9. With both doses of abrocitinib, week 12 IGA 0/1, EASI-75, EASI-90, and DLQI 0/1 response rates were greater in week 2 PP-NRS4 responders than nonresponders; no differences were observed between week 2 PP-NRS4 responders and nonresponders in the dupilumab and placebo groups. Early improvement in PP-NRS at week 2 was associated with skin clearance at week 12 in abrocitinib-treated patients. Conclusions: Abrocitinib resulted in rapid relief from itch in patients with moderate-to-severe AD, with significant improvement in itch as early as day 4 after treatment with abrocitinib 200 mg compared with dupilumab and placebo. Abrocitinib-induced itch relief by week 2 was associated with subsequent improvements at week 12. [Video abstract available.] Trial registration: ClinicalTrials.gov identifier: NCT03720470. 2fQ_82bhGurT9XTD9WAh-8 Early itch response with abrocitinib is associated with later efficacy outcomes in patients withmoderate-to-severe atopic dermatitis: subgroup analysis of the randomized phase III JADE COMPARE trial (MP4 335,375kb) Plain Language Summary: An investigation into whether quick relief from itch with abrocitinib, a new medicine for atopic dermatitis, leads to later improvements in skin rash Atopic dermatitis (AD), also called atopic eczema, is a skin disease that affects people throughout their lives. About 10% of adults worldwide have AD. Itch is the most bothersome symptom reported by people with AD and scratching this itch can damage the skin, resulting in painful sores. It is unknown if relief from itch can influence other symptoms of AD. We analyzed data from the JADE COMPARE study, which included 837 people who received treatment with abrocitinib, dupilumab or placebo. We studied how fast itch relief occurred after people received these treatments. We also wanted to study if rapid itch relief was associated with improvement in other signs of AD later on with continued treatment. We found that as early as 4 days after treatment, abrocitinib 200 mg provided significant relief from itch compared with dupilumab or placebo. People who had rapid itch relief within 2 weeks of treatment with abrocitinib were more likely to have clear or almost clear skin and improved quality of life after 12 weeks of continued treatment with abrocitinib. Rapid itch relief did not appear to increase the likelihood of clear skin at week 12 in people who received dupilumab. Larger studies are needed to confirm this result. This study provides important evidence for physicians as they analyze itch relief and determine treatment options for people with AD. [ABSTRACT FROM AUTHOR]

Background: Atopic dermatitis is a chronic inflammatory skin disease that can negatively impact work productivity and daily activities. Ruxolitinib cream, a Janus kinase inhibitor, demonstrated efficacy and safety in patients with atopic dermatitis in two phase III studies (TRuE-AD1 and TRuE-AD2). Objective: This post hoc analysis sought to describe the effects of ruxolitinib cream on work productivity and activity impairment from pooled data from the phase III studies, to estimate indirect costs due to atopic dermatitis, and to estimate the incremental cost savings with ruxolitinib cream versus vehicle cream. Methods: Patients in both studies were ≥ 12 years old with atopic dermatitis for ≥ 2 years, an Investigator's Global Assessment score of 2 or 3, and a 3–20% affected body surface area at baseline. Patients were randomized 2:2:1 to receive ruxolitinib cream (0.75% or 1.5%) or vehicle cream for 8 weeks. Patient self-reported productivity in the efficacy-evaluable population was assessed at weeks 2, 4, and 8 using the Work Productivity and Activity Impairment Questionnaire-Specific Health Problem version 2.0. Statistical significance for the two doses versus vehicle was calculated using an analysis of covariance. Work Productivity and Activity Impairment overall work impairment scores were converted to a model of costs per employed patient due to lost productivity and incremental cost savings from ruxolitinib cream treatment using a human capital approach. Results: Of 1249 patients enrolled (median age, 32 years; female sex, 61.7%), 1208 were included in the efficacy-evaluable population. Patients applying 0.75% or 1.5% ruxolitinib cream had significant changes in overall work impairment (− 17.9% [0.75% strength] and − 15.0% [1.5% strength] vs − 5.7% for vehicle; p < 0.0001 for both) and daily activity impairment (− 20.6% [0.75% strength] and − 21.5% [1.5% strength] vs − 10.6% for vehicle; p < 0.0001 for both). These corresponded to estimated lost productivity costs in 2021 US dollars of $1313 (0.75% strength) and $1242 (1.5% strength) versus $2008 (vehicle) over the 8-week trial period. Compared with a patient receiving vehicle, incremental annual indirect cost savings were estimated to be $5302 with 0.75% ruxolitinib cream and $4228 with 1.5% ruxolitinib cream. Conclusions: Ruxolitinib cream therapy is associated with improved work productivity and daily activity compared with vehicle and is estimated to reduce the indirect cost burden on the patient. Clinical trial registration: ClinicalTrials.gov identifiers: NCT03745638 (registered 19 November, 2018) and NCT03745651 (registered 19 November, 2018) [ABSTRACT FROM AUTHOR]

Simple Summary: At present, the immunotherapy and immune microenvironment of bladder cancer have attracted more and more attention from clinicians and researchers. In this study, the high expression of SULF2 by RNA sequencing of tissues from 90 bladder cancer patients was associated with poor prognosis in patients. We further found that a high expression of SULF2 can promote the polarization of macrophages to M2. In mechanistic studies, we found that SULF2 can promote the secretion of IL-8 through Wnt/β-catenin. IL-8 promotes the transcription of CD163 and CD206 in the microenvironment, ultimately leading to the polarization of macrophages to M2 macrophages. This study elucidates the effect of SULF2 on the polarization of macrophages in the tumor microenvironment. Sulfatase 2 (SULF2) affects the occurrence and development of cancer by regulating HSPG-binding factors. However, the mechanism of SULF2 in bladder cancer (BCa) is unknown. To determine this, we analyzed the RNA sequencing of 90 patients with BCa. The results showed that the expression of SULF2 was closely related to the prognosis of BCa. Moreover, in vivo and in vitro experiments revealed that SULF2 promotes tumor proliferation and invasion. Furthermore, using a mouse orthotopic BCa model and flow cytometric analysis, we identified that SULF2 affects the polarization of macrophages. Mechanism studies clarified that SULF2 promoted the release of HSPG-binding factors, such as IL-8, in the microenvironment through β-catenin. Meanwhile, IL-8 activated the JAK2/STAT3 pathway of macrophages to promote the expression of CD163 and CD206, thereby regulating the polarization of macrophages to the M2-type. Conclusively, these results indicate that SULF2 plays an important role in regulating the microenvironment of BCa and promotes the polarization of macrophages to the M2-type by secreting IL-8, which further deepens the malignant progression of BCa. [ABSTRACT FROM AUTHOR]

Background: Atopic dermatitis (AD) is a prevalent pruritic chronic relapsing inflammatory skin condition that predominantly manifests before the age of 5 years. Physical, mental, and financial burdens of AD are substantial and can adversely reflect on patients, carers, and society. Objective: This article purpose is to review available systemic treatments for moderate-severe AD in children and adolescents and present the evidence behind it. Methods: A thorough search was performed on PubMed. Keywords used were systemic treatment, atopic dermatitis, moderate-severe, and children and adolescents, in addition to search for individual systemic agents. English-published data were utilized exclusively. Results and recommendations drawn from elected studies and guidelines are displayed in this review. Results: Treating patients with moderate-severe AD has proved to be challenging. Not long ago, the available systemic treatments were restricted to conventional immunosuppressants including ciclosporin and methotrexate among others. However, recent years have witnessed impressive advancement in the understanding of AD pathogenesis at the molecular level that resulted in the emergence of multiple promising targeted biologic therapy options including interleukin (IL)-4 and IL-13 inhibitors, IL-13 inhibitors, and JAK inhibitors. Conclusion: Although the new biologic agents have been proposed to be more effective and possibly safer than the traditionally used conventional wide-spectrum immunosuppressive agents for moderate-severe AD, head-to-head comparative studies are limited and long-term data to ascertain the safety of these biologic agents are lacking. Moreover, the cost of biologic agents is far greater than conventional immunosuppressant agents which could contribute to its limited availability in some institutions. [ABSTRACT FROM AUTHOR]

Treatment of inflammatory bowel disease (IBD) during the early phase of the disease is important so as to avoid long-term damage from chronic inflammation. There are now multiple treatments available for moderate-to-severe IBD which when used appropriately should reduce the rate of complications. [ABSTRACT FROM AUTHOR]

The article presents summaries of safety labeling changes approved by the U.S. Food and Drug Administration (FDA) from July to September 2022. These include the additions and revisions to the labeling of Arthrotec (diclofenac sodium/misoprostol), opzelura (ruxolinitib phosphate), and ultomiris (ravulizumab-cwvz).

Purpose: JAK-inhibitors (JAK-i) might be associated with venous (VTE) and arterial thromboembolic events (ATE). To evaluate the association between JAK-i and the risk of VTE and ATE. Methods: A self-controlled case series was performed using data from the nationwide French healthcare insurance system database SNDS. We included all patients treated with JAK-i (baricitinib or tofacitinib), and having presented at least one VTE or ATE between November 1, 2017 and June 30, 2019. Associations were estimated using the incident rate ratio (IRR). Two post-exposure periods (until day 30 and until day 60) were individualized. Results: Among 5870 patients with JAK-i dispensing, 92 had an incident VTE or ATE within the study period. Their median age at JAK-i initiation was 65.7 years [IQR: 56.1–75.8] and 65.2% were female (n = 60). Before event incidence, 65.2% (n = 60) received baricitinib, 32.6% (n = 30) tofacitinib and 2.2% (n = 2) had both medications. Moreover, 41.3% (n = 38) presented a VTE and 58.7% (n = 54) an ATE. The median time-to-onset after JAK-i initiation was 4.6 months [IQR: 2.5–9.2] for VTE and 6.1 months [IQR: 3.0–8.5] for ATE. An IRR of 8.27 (95% CI 3.41–20.04) for VTE was detected during JAK-i treatment and remained increased over the 30-day period of post-exposure (6.52 [2.02–21.11]). An IRR of 9.27 (3.68–23.34) was also found for ATE, which remained increased over the 30-day period of post-exposure (10.12 [3.27–31.37]). No increased risk was detected during long-term post-exposure for either VTE or ATE. Conclusions: This study shows evidence of an increased risk of VTE and ATE associated with the use of baricitinib and tofacitinib. [ABSTRACT FROM AUTHOR]

Purpose: Janus kinase (JAK) inhibitors have been developed to treat moderate to severe atopic dermatitis, but there is little evidence comparing the safety profile of these drugs. The aim of this study is to compare the relative safety of the different systemic JAK inhibitors in atopic dermatitis. Methods: Medline, EMBASE, and clinicaltrials.gov were searched to identify phase 2/3, clinical trials (RCTs) designed to evaluate the efficacy and safety of systemic JAK inhibitors in atopic dermatitis. Outcomes were the risk of any adverse event (AE), serious AEs, AEs leading to treatment discontinuation, any infection, serious infections, herpes zoster infection, and any cardiac or vascular event. Results: Eighteen RCTs were included. Compared with placebo, baricitinib (odds ratio [OR] 1.25, 95% credible interval [CrI] 1.03–1.55), abrocitinib (OR 1.54, 95% CrI 1.25–1.90), and upadacitinib (OR 1.46, 95% CrI 1.19–1.81) increase the risk of any adverse event. Abrocitinib (OR 1.62, 95% CrI 1.7–2.72), upadacitinib (OR 1.67, 95% CrI 1.19–2.43), and dupilumab (OR 1.69, 95% CrI 1.02–2.79) increase the risk of infections when compared with placebo. Dupilumab has a reduced risk of herpes zoster infection when compared with upadacitinib (OR 0.23; 95% CrI 0.08–0.81) No further statistically significant risk differences between treatments were identified. Conclusions: The results suggest systemic JAK inhibitors for atopic dermatitis have a similar safety profile. However, as current data present limitations, postmarketing safety evidence will be crucial to draw definitive conclusions regarding the safety of JAK inhibitors. [ABSTRACT FROM AUTHOR]

Objectives Whether patients with RA benefit from repeated trials of biologic or targeted synthetic DMARDs (b/tsDMARDs) after three or more attempts is unknown. We aimed to describe treatment outcomes in each line of b/tsDMARD therapy. Methods Using data from the British Society for Rheumatology Biologics Register for RA from 2001 to 2020, change to a new b/tsDMARD (except biosimilar switches) was defined as a new line of therapy. Treatment outcomes were compared across lines of therapy, including DAS28 remission (≤2.6), low disease activity (LDA, ≤3.2) at 6 months and median time to drug discontinuation. Multiple imputation was used for missing data. Results A total of 22 934 individuals starting a first b/tsDMARD were included (mean age 56 years, 76% female), among whom 10 823 commenced a second-line drug, 5056 third, 2128 fourth, 767 fifth and 292 sixth. Most (71%) had sufficient data for DAS28-derived outcome analyses. TNF inhibitors were the most common first-line drug, but choice of subsequent-line drugs changed over time. Seventeen percent achieved DAS28 remission following first-line, 13% second and 8–13% with third through sixth. LDA was achieved in 29% of first-line, 23% second, 17–22% through to the sixth. Patients stayed on first-line therapy for a median of 2.6 years, ranging from 1.0–1.4 years for lines two to six. Conclusion Many patients will eventually benefit after repeated trials of b/tsDMARD. Further research to improve treatment selection are needed to prevent prolonged trial and error approaches in some patients. [ABSTRACT FROM AUTHOR]

Objective The aim of this study was to characterize the safety and efficacy of filgotinib, lanraplenib and tirabrutinib in patients with active SS. Methods This multicentre, double-blind study randomized patients with active primary or secondary SS [EULAR SS disease activity index (ESSDAI) ≥5) to receive filgotinib 200 mg (Janus kinase-1 inhibitor), lanraplenib 30 mg (spleen tyrosine kinase inhibitor), tirabrutinib 40 mg (Bruton's tyrosine kinase inhibitor), or placebo. The composite primary end point was the week-12 proportion of patients fulfilling protocol-specified improvement criteria (based on CRP and SS-related symptoms). The EULAR SS patient-reported index (ESSPRI) and the ESSDAI change from baseline (CFB) were secondary end points. Exploratory end points included disease-related biomarkers. Treatment-emergent adverse events (AEs) represented safety outcomes. Results The mean of the baseline ESSDAI was 10.1, and of ESSPRI was 6.2 in the 150 patients who were treated; 125 completed the 24-week placebo-controlled treatment period. At week 12, 43.3% of the filgotinib group achieved the primary end point (P   =  0.17 vs placebo) vs 42.3% (P   =  0.16), 34.7% (P   =  0.33), and 26.7% of lanraplenib, tirabrutinib, and placebo groups, respectively. Neither secondary end point was met. Biomarker reductions included immunoglobulins classically associated with SS disease activity. Filgotinib ESSDAI CFB appeared more pronounced in subgroups with baseline ESSDAI ≥14 or without DMARDs/CSs. Most AEs were Grade 1 or 2. Conclusion Three drugs with disparate mechanisms were tested, but no significant differences vs placebo in primary or secondary end points were observed. These results may be considered hypothesis-generating, given the drug tolerability, subgroup analysis, and biomarker findings. Trial registration ClinicalTrials.gov, https://clinicaltrials.gov , NCT03100942. [ABSTRACT FROM AUTHOR]

Pregnant people have an elevated risk of severe COVID-19-related complications compared to their non-pregnant counterparts, underscoring the need for safe and effective therapies. In this review, we summarize published data on COVID-19 therapeutics in pregnancy and lactation to help inform clinical decision-making about their use in this population. Although no serious safety signals have been raised for many agents, data clearly have serious limitations and there are many important knowledge gaps about the safety and efficacy of key therapeutics used for COVID-19. Moving forward, diligent follow-up and documentation of outcomes in pregnant people treated with these agents will be essential to advance our understanding. Greater regulatory push and incentives are needed to ensure studies to obtain pregnancy data are expedited. [ABSTRACT FROM AUTHOR]

Psoriasis is an immune-mediated disease, with the interleukin (IL)-23/IL-17 axis currently considered its main pathogenic pathway. Tyrosine kinase 2 (TYK2) is responsible for mediating immune signalling of IL-12, IL-23 and type I interferons, without interfering with other critical systemic functions as other JAK proteins do. This article aims to review the current knowledge on deucravacitinib, a new oral drug that selectively inhibits TYK2, granting it a low risk of off-target effects. After good efficacy and safety results in a phase II, placebo-controlled trial, two phase III, 52-week trials evaluated deucravacitinib 6 mg against placebo and apremilast—an active comparator. POETYK PSO-1 and PSO-2 involved 1688 patients with moderate-to-severe psoriasis. After 16 weeks, in both studies, over 50% of patients treated with deucravacitinib reached PASI75, which was significantly superior to placebo and apremilast. In POETYK PSO-1, these results improved until week 24 and were maintained through week 52, with over 65% of patients achieving PASI75 at this point. A reduction in signs and symptoms was also reported by patients, with greater impact on itch. Deucravacitinib was well tolerated and safe. There were no reports of serious infections, thromboembolic events, or laboratory abnormalities, which are a concern among other JAK inhibitors. Persistent efficacy and consistent safety profiles were reported for up to 2 years. Despite advances in the treatment of psoriasis, namely among biologic agents, an oral, effective and safe new drug can bring several advantages to prescribers and patients. Further investigation is required to understand where to place deucravacitinib among current psoriasis treatment options. [ABSTRACT FROM AUTHOR]

Radix scutellariae (the root of Scutellaria baicalensis Georgi) is a traditional Chinese medicine (TCM) used to treat a wide range of inflammation-related diseases, such as obesity, diabetes, diabetic kidney disease, and COVID-19-associated inflammatory states in the lung and kidney. Baicalin is the major anti-inflammatory component of Radix scutellariae and has shown the potential to inhibit inflammation in metabolic disorders. In this study, we explored the ability and underlying mechanisms of baicalin to modulate the macrophage to mitigate insulin resistance in obesity. Obese mice were administered baicalin (50 mg/kg/day) intraperitoneally for 3 weeks. RAW264.7 and BMDM cells were stimulated with LPS and treated with baicalin for 24 h, while 3T3-L1 and primary white adipocytes were treated with the supernatants from baicalin-treated RAW264.7 cells for 24 h. The results showed that baicalin significantly improved glucose and insulin tolerance as well as decreased fat and adipose tissue macrophage levels in obese mice. Besides, baicalin significantly reduced serum and adipose tissue IL-1β, TNF-α and IL-6 levels in obese mice, as well as suppressed LPS-induced IL-1β, TNF-α and IL-6 expression and release in macrophages. Furthermore, treatment with the supernatant from baicalin-treated RAW264.7 cells increased the levels of PGC-1α, SIRT1, p-IRS-1 and p-AKT in adipocytes. Moreover, baicalin treatment dramatically downregulated macrophage p-p38, p-JNK, and Ac-p65Lys310 levels while increasing SIRT1 both in vivo and in vitro. Importantly, JNK inhibitor SP600125 blocked most of the effects of baicalin on SIRT1, Ac-p65Lys310 and pro-inflammatory factors in macrophages. Therefore, these results demonstrated for the first time that baicalin exerts its anti-inflammatory effects in obese adipose tissue macrophages mainly through suppressing JNK/SIRT1/p65 signaling. These findings amplified the mechanisms of baicalin and its potential to attenuate insulin resistance. [Display omitted] • Baicalin alleviates insulin resistance and inflammation in the adipose tissue of obese mice. • Baicalin mitigates insulin resistance by inhibiting adipose macrophage inflammatory effects. • Baicalin exerts anti-inflammatory activity in macrophages through suppressing JNK/SIRT1/p65 signaling. [ABSTRACT FROM AUTHOR]

Leonurus japonicus Houtt. (Labiatae), commonly known as Chinese motherwort, is a herbaceous flowering plant that is native to Asia. It is widely acknowledged in traditional medicine for its diuretic, hypoglycemic, antiepileptic properties and neuroprotection. Currently, Leonurus japonicus (Leo) is included in the Pharmacopoeia of the People's Republic of China. Traditional Chinese Medicine (TCM) recognizes Leo for its myriad pharmacological attributes, but its efficacy against ICH-induced neuronal apoptosis is unclear. This study aimed to identify the potential targets and regulatory mechanisms of Leo in alleviating neuronal apoptosis after ICH. The study employed network pharmacology, UPLC-Q-TOF-MS technique, molecular docking, pharmacodynamic studies, western blotting, and immunofluorescence techniques to explore its potential mechanisms. Leo was found to assist hematoma absorption, thus improving the neurological outlook in an ICH mouse model. Importantly, molecular docking highlighted JAK as Leo's potential therapeutic target in ICH scenarios. Further experimental evidence demonstrated that Leo adjusts JAK1 and STAT1 phosphorylation, curbing Bax while augmenting Bcl-2 expression. Leo showcases potential in mitigating neuronal apoptosis post-ICH, predominantly via the JAK/STAT mechanism. [Display omitted] • Exploration of Leo's role in ICH treatment. • Leo promotes hematoma absorption. • Identification of JAK as a potential target. • Leo modulates JAK1 and STAT1 activity. • Inhibition of neuronal apoptosis via JAK/STAT. [ABSTRACT FROM AUTHOR]

The article describes the case of a 34-year-old Chinese woman who was diagnosed with adult-onset Still's disease (AOSD) according to the Yamaguchi criteria at the age of 31. Topics discussed include clinical symptoms, reason for the delay in the 14th dose of tocilizumab (TCZ) infusion, and clinical manifestation in the patient presented in the study.

Objectives: Results of the ORAL Surveillance safety trial have indicated that there is an increased risk for the development of malignancies with tofacitinib therapy when compared to treatment with tumor necrosis factor inhibitors (TNFi). This study was undertaken to further examine this safety concern in rheumatoid arthritis (RA) patients in a real‐world setting. Methods: Using US insurance claims data from Optum Clinformatics (2012–2020), IBM MarketScan Research Databases (2012–2018), and Medicare (parts A, B, and D, 2012–2017), we created 2 cohorts of RA patients who had initiated treatment with tofacitinib or TNFi. The first cohort, designated the real‐world evidence (RWE) cohort, included RA patients from routine care. For the second cohort, designated the randomized controlled trial (RCT)–duplicate cohort, we emulated the inclusion and exclusion criteria that were applied in the ORAL Surveillance trial of tofacitinib, which allowed us to assess the comparability of our results with the results of that trial. Cox proportional hazards models with propensity score fine‐stratification weighting were used to estimate hazard ratios (HRs) and 95% confidence intervals (95% CIs) for the risk of any malignancy (excluding nonmelanoma skin cancer). Database‐specific estimates were meta‐analyzed using fixed‐effects models with inverse‐variance weighting. Results: The RWE cohort consisted of 83,295 patients, including 10,504 patients (12.6%) who received treatment with tofacitinib. The pooled weighted HR for the primary outcome of any malignancy associated with tofacitinib treatment compared to any malignancy associated with TNFi therapy was 1.01 (95% CI 0.83, 1.22) in the RWE cohort and 1.17 (95% CI 0.85, 1.62) in the RCT‐duplicate cohort (compared to the ORAL Surveillance trial HR of 1.48 [95% CI 1.04, 2.09]). Conclusion: We did not find evidence of an increased risk of malignancy development with tofacitinib therapy, in comparison with TNFi therapy, in RA patients treated in a real‐world setting. However, our results cannot rule out the possibility of an increase in risk that may accrue with a longer duration of treatment with tofacitinib. [ABSTRACT FROM AUTHOR]

Objectives To describe the use of baricitinib and tofacitinib by Swedish RA patients and to compare their effectiveness with that of biologic DMARDs (bDMARDs). Methods RA patients who initiated baricitinib (n  = 1420), tofacitinib (n  = 316), abatacept (n  = 1050), IL-6 inhibitors (IL-6is; n  = 849), rituximab (n  = 1101) or TNF inhibitors (TNFis; n  = 6036) between January 2017 and November 2019 were followed for a minimum of 1 year using data from several linked Swedish national registers. Proportions reaching a good EULAR 28-joint DAS (DAS28) response, HAQ Disability Index (HAQ-DI) improvement >0.2 units and Clinical Disease Activity Index (CDAI) remission were compared at 1 year, imputing discontinued treatments as 'non-response'. Additionally, we compared drug retention and changes in DAS28, HAQ-DI and CDAI from baseline to 3 months after treatment initiation. Results On average, baricitinib, and particularly tofacitinib, were initiated as later lines of therapy and more frequently as monotherapy compared with rituximab and TNFi. Adjusted 1 year response proportions were consistently lower on TNFi compared with baricitinib, with differences of −4.3 percentage points (95% CI −8.7, 0.1) for good EULAR response, −9.9 (−14.4 to −5.4) for HAQ-DI improvement and −6.0 (−9.8 to −2.2) for CDAI remission. Comparisons with non-TNFi bDMARDs also favoured baricitinib, but not consistently. Treatment responses for tofacitinib were only marginally lower than those for baricitinib and generally similar to those of bDMARDs, with precision limited by low power. Comparisons of drug retention and changes in disease activity from baseline to 3 months supported the 1 year findings. Conclusions Baricitinib and tofacitinib showed at least equivalent effectiveness compared with bDMARDs after exploring several different effectiveness measures. [ABSTRACT FROM AUTHOR]

Simple Summary: ROS and JAK/Stat3 cooperatively upregulate the expression of HIF-1α in bone marrow-derived mesenchymal stem cells under normoxic conditions in response to breast tumor cells. The upregulation of HIF-1α contributes in part to the increase in VEGF expression in the bone marrow-derived mesenchymal stem cells. Bone marrow-derived mesenchymal stem cells improve the angiogenic sprouting capacity of mature endothelial cells in a VEGF-dependent manner. Breast tumor cells recruit bone marrow-derived mesenchymal stem cells (BM-MSCs) and alter their cellular characteristics to establish a tumor microenvironment. BM-MSCs enhance tumor angiogenesis through various mechanisms. We investigated the mechanisms by which BM-MSCs promote angiogenesis in response to breast tumor. Conditioned media from MDA-MB-231 (MDA CM) and MCF7 (MCF7 CM) breast tumor cells were used to mimic breast tumor conditions. An in vitro spheroid sprouting assay using human umbilical vein endothelial cells (HUVECs) was conducted to assess the angiogenesis-stimulating potential of BM-MSCs in response to breast tumors. The ROS inhibitor N-acetylcysteine (NAC) and JAK inhibitor ruxolitinib attenuated increased HIF-1α in BM-MSCs in response to MDA CM and MCF7 CM. HIF-1α knockdown or HIF-1β only partially downregulated VEGF expression and, therefore, the sprouting capacity of HUVECs in response to conditioned media from BM-MSCs treated with MDA CM or MCF7 CM. Inactivation of the VEGF receptor using sorafenib completely inhibited the HUVECs' sprouting. Our results suggest that increased HIF-1α expression under normoxia in BM-MSCs in response to breast tumor cells is mediated by ROS and JAK/Stat3, and that both HIF-1α-dependent and -independent mechanisms increase VEGF expression in BM-MSCs to promote the angiogenic sprouting capacity of endothelial cells in a VEGF-dependent manner. [ABSTRACT FROM AUTHOR]

Objective: Janus kinase (JAK) inhibition effectively treats immune‐mediated inflammatory diseases (IMIDs); however, concern over the risk of major adverse cardiac events (MACE) and venous thromboembolism (VTE) remains. We aimed to evaluate the safety (VTE and MACE outcomes) of JAK inhibitors in the treatment of IMIDs. Methods: A search in PubMed, Embase, and ClinicalTrials.gov databases was conducted for randomized clinical trials (RCTs) of JAK inhibitors across IMIDs. Primary outcomes were VTE and MACE with JAK inhibitors compared with placebo and active comparator arms stratified by follow‐up time. Results: Sixty‐six RCTs enrolled 38,574 patients with a mean age of 48.8 years and a mean follow‐up of 10.5 months. JAK inhibitors had a numerically higher rate of VTE when compared with controls (odds ratio [OR] 1.65; 95% confidence interval [CI]: 0.97‐2.79), driven by trials with a follow‐up duration of 12 or more months (OR 2.17; 95% CI: 1.16‐4.05; Pinteraction = 0.05). When compared with active comparators, JAK inhibitors increased VTE in clinical trials with 12 or more months' versus less than 12 months' follow‐up time (OR 2.38 [95% CI: 1.24‐4.57] vs 0.30 [95% CI: 0.07‐1.26], respectively; Pinteraction = 0.01). No increased risk of VTE was seen when comparing JAK inhibitors with placebo arms. For the outcome of MACE, the results were largely similar but did not reach statistical significance (OR 1.19; 95% CI: 0.86‐1.64). Conclusion: JAK inhibitors when compared with active comparator arms increased the risk of VTE, which was dependent on duration of exposure. Future clinical trials with extended follow‐up are needed to clarify the safety profiles of JAK inhibitors. [ABSTRACT FROM AUTHOR]

Objectives: The treatment goal for rheumatoid arthritis has undergone a dramatic change over recent years with the advent of biologic and targeted synthetic disease‐modifying antirheumatic drugs (b/tsDMARDs). This systematic review aims to discuss the comparative efficiency of new drugs versus the standard of care methotrexate. Methods: Pubmed, Google Scholar, and Science Direct were searched, and 7072 records were retrieved. Randomized controlled trials published in the last five years with full‐text papers, blinded studies, and studies with an open‐label extension were included. Studies with a high risk of bias as calculated by the Cochrane risk of bias (RoB2) tool were excluded. The last database search was conducted on 21 August 2021. Results: Fifteen studies were identified and analyzed by categorizing drugs into Janus kinase (JAK) inhibitors, tumour necrosis factor (TNF) inhibitors, and monoclonal antibodies with other targets (anti‐GM‐CSF receptor, anti‐IL6 receptor, anti‐IL‐17 monoclonal antibodies), with a total of 7963 participants. Data were synthesized with tables and the PRISMA flow diagram. Our analysis included baricitinib, filgotinib, peficitinib, infliximab, certolizumab, sarilumab, tocilizumab namilumab, mavrilimumab, golimumab, and CNT06785. Conclusions: These studies showed that except for CNT 06785 (anti‐Interleukin 17A monoclonal antibody), biologic and targeted synthetic disease‐modifying drugs combined with methotrexate or as monotherapy yield better clinical and radiographical outcomes. This systematic review does not discuss biosimilars and the adverse effects of biologic drugs in detail. Infections remain a significant adverse drug reaction of monoclonal antibodies. However, these drugs play a crucial role in adequately managing this disease for patients with severe arthritis. [ABSTRACT FROM AUTHOR]

Atopic dermatitis (AD) is a chronic inflammatory skin condition that can have tremendous impact on quality of life for affected children and adults. First-line therapy for acute management of AD includes topical therapies such as corticosteroids, calcineurin inhibitors, and, more recently, the phosphodiesterase inhibitor crisaborole. Topical agents have remained the mainstay therapy for decades; however, there has been a longstanding need for topical therapies with high efficacy and low risk of adverse effects with long-term use. Given the ongoing advances in understanding the pathogenesis of AD, there are novel targets for pharmacological intervention. We are now in an unprecedented time with more than 40 topical treatments in the pipeline for AD in addition to many developments and treatments on the horizon. This review summarizes selected therapeutic topical agents in later phases of development that target various aspects in the pathogenesis of AD such as Janus kinase inhibition (ruxolitinib and delgocitinib), phosphodiesterase-4 inhibition (roflumilast and difamilast), aryl hydrocarbon modulation (tapinarof), and modulation of the microbiome. We also review novel targeted therapies that are in early phase clinical trials, including AMTX-100, BEN-2293, and PRN473. Preliminary findings on efficacy and tolerability of most of these agents are promising, but further studies are warranted to evaluate the long-term safety and efficacy of these novel agents against the current standard of care. [ABSTRACT FROM AUTHOR]

Objective: Despite a wealth of studies evaluating rheumatoid arthritis (RA) therapies, it remains difficult to compare efficacies across trials due to heterogeneous study populations. We sought to identify patient/trial characteristics associated with clinical response to enable fairer comparisons. Methods: We reviewed 565 disease‐modifying antirheumatic drug studies compiled for American College of Rheumatology (ACR) management guidelines. Seventy‐two articles on randomized controlled phase II/III trials from 1995 to 2018 reporting the proportion of patients achieving 20%, 50% or 70% improvement in the ACR's RA disease score (ACR20/50/70) or Disease Activity Score‐28 with erythrocyte sedimentation rate or C‐reactive protein (DAS28‐ESR or DAS28‐CRP) with follow‐up more than 3 months were included. We explored associations between 34 patient/trial characteristics and ACR responses. We constructed multivariable models using these factors to compute expected response rates and to compare observed with expected response rates across therapies. Results: Among eligible clinical trials, later publication year, baseline DAS28‐CRP score, methotrexate/biologic naivety, baseline ESR, follow‐up of 52 weeks or more, number of subjects enrolled, and anticitrullinated peptide antibody seropositivity were associated with greater ACR response. Greater age, longer disease duration, higher baseline Sharp score, and steroid use were associated with lower response rates. Predictive models incorporating these factors explained 29%, 37%, and 53% of variance in ACR20, ACR50, and ACR70, respectively. Overall, comparing observed versus expected rates of response across trials more closely approximated results of head‐to‐head trials. For example, although observed responses numerically favored adalimumab to tofacitinib, comparison of observed versus expected results across trials more closely approximated the results from a head‐to‐head trial ("Oral Rheumatoid Arthritis triaL [ORAL] Strategy"). Conclusion: We identified factors associated with ACR response in RA trials. Adjusting for expected outcomes yielded therapy comparisons somewhat more similar to head‐to‐head trials. These findings could inform other across‐trial comparisons, particularly when head‐to‐head trials are lacking. [ABSTRACT FROM AUTHOR]