JAK2 Research Articles

Assessment of the Safety of Tofacitinib Among Patients With Psoriasis: A Systematic Review and Meta-Analysis.

Psoriasis is a clinically heterogeneous, lifelong skin condition. Novel medications such as Janus kinase (JAK) inhibitors have emerged as a promising class of agents that modulate the immune response. Tofacitinib could reduce skin lesions and boost patient-reported clinical outcomes, but its immunosuppressive effects might also increase patients' risk of infections and other adverse effects. To assess the safety outcomes of using Tofacitinib in comparison to placebo in terms of the incidence of serious infections, herpes zoster infection (HZ), upper respiratory tract infections (URTI), nasopharyngitis, and serious adverse events (SAE), this systematic review and meta-analysis followed the Cochrane Handbook for Systematic Reviews and Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The search strategy involved five databases. Two authors independently screened and selected studies. Only randomized controlled trials (RCTs) were eligible for inclusion. Data on baseline patient characteristics and outcomes such as serious infections, HZ infections, nasopharyngitis, and URTIs were extracted. The risk of bias was assessed using the revised version of the Cochrane risk of bias (ROB2) tool, and meta-analysis was conducted using Cochrane's Revman web. The ORwas employed to estimate outcomes. A probability value of less than 0.05 was considered statistically significant. The search strategy initially identified 998 studies; of these, six RCTs were included with a total of 2516 participants having moderate-to-severe psoriasis and treated with either Tofacitinib or placebo. The meta-analysis results revealed increases in the risks of HZ, URTIs, serious infections, nasopharyngitis, and SAE, but no significant difference was found between the intervention and placebo groups. The risk of bias was assessed using the ROB2 tool, revealing low bias across most domains, with some concerns in certain studies related to deviations from intended interventions and missing outcome data. In conclusion, while Tofacitinib is effective against moderate-to-severe psoriasis with non-significant risks, there are some safety concerns regarding the measured outcomes. Future research is needed concerning the assessment of safety outcomes with long-term use of Tofacitinib among larger populations.

Systematic review of Janus kinases inhibitors for rheumatoid arthritis: methodology, reporting, and quality of evidence evaluation.

To evaluate the methodological, reporting and evidence quality of systematic reviews or meta-analyses of Janus kinases (JAK) inhibitors for the treatment of rheumatoid arthritis (RA). Our study systematically retrieved reviews from various databases, spanning from inception to June 2024. Two evaluators independently assessed the methodological, reporting, and evidence quality of each review using the AMSTAR-2 and PRIAMA2020 tools. The evidence quality was evaluated according to GRADE criteria. Six aspects were evaluated: publication year, study type, homogeneity, risk of publication bias, AMSTAR-2 methodology, and PRIAMA2020 reporting quality. Excel 2016 facilitated conversion of scores into radar plots. Following stringent selection criteria, a total of 18 relevant studies were identified. The AMSTAR-2 scores ranged from 4 to 13 points, with five studies rated as low quality and the remaining 13 as critically low quality. All studies encompassed populations, interventions, controls, and outcome measures, demonstrating commendable integrity. However, there is room for improvement in study protocol development and registration, comprehensive search strategies, inclusion and exclusion criteria, conflict of interest disclosure, and discussion of heterogeneity. PRIAMA2020 assessments ranged from 14.5 to 21 points, with two studies scoring below 15 points due to increased bias risk from data transformation and sensitivity analysis. Notably, all reviews (100%) adhered to PRIAMA2020 guidelines for certain items but none met all criteria. GRADE evaluation included 446 outcome measures, with 158 of moderate, 156 of low, and 132 of very low quality, indicating JAK inhibitors is effective in improving RA. According to radar chart, the average rank score was 13.13. One study achieved a balanced score across all dimensions, while 11 exceeded the average, five showed significant differences in PRIAMA2020 scores, and four in AMSTAR two scores. Despite summarizing the efficacy and safety of JAK inhibitors in treating RA, the included studies exhibited poor methodological and reporting quality, along with low-quality evidence overall. Therefore, caution is warranted among decision-makers regarding the use of JAK inhibitors in RA treatment. Urgent requirements include high-quality, multicenter studies investigating JAK inhibitors for RA. https://www.crd.york.ac.uk/PROSPERO, identifier 413415.

High-dose dexamethasone regulates microglial polarization via the GR/JAK1/STAT3 signaling pathway after traumatic brain injury.

Although microglial polarization and neuroinflammation are crucial cellular responses after traumatic brain injury, the fundamental regulatory and functional mechanisms remain insufficiently understood. As potent anti-inflammatory agents, the use of glucocorticoids in traumatic brain injury is still controversial, and their regulatory effects on microglial polarization are not yet known. In the present study, we sought to determine whether exacerbation of traumatic brain injury caused by high-dose dexamethasone is related to its regulatory effects on microglial polarization and its mechanisms of action. In vitro cultured BV2 cells and primary microglia and a controlled cortical impact mouse model were used to investigate the effects of dexamethasone on microglial polarization. Lipopolysaccharide, dexamethasone, RU486 (a glucocorticoid receptor antagonist), and ruxolitinib (a Janus kinase 1 antagonist) were administered. RNA-sequencing data obtained from a C57BL/6 mouse model of traumatic brain injury were used to identify potential targets of dexamethasone. The Morris water maze, quantitative reverse transcription-polymerase chain reaction, western blotting, immunofluorescence and confocal microscopy analysis, and TUNEL, Nissl, and Golgi staining were performed to investigate our hypothesis. High-throughput sequencing results showed that arginase 1, a marker of M2 microglia, was significantly downregulated in the dexamethasone group compared with the traumatic brain injury group at 3 days post-traumatic brain injury. Thus dexamethasone inhibited M1 and M2 microglia, with a more pronounced inhibitory effect on M2 microglia in vitro and in vivo. Glucocorticoid receptor plays an indispensable role in microglial polarization after dexamethasone treatment following traumatic brain injury. Additionally, glucocorticoid receptor activation increased the number of apoptotic cells and neuronal death, and also decreased the density of dendritic spines. A possible downstream receptor signaling mechanism is the GR/JAK1/STAT3 pathway. Overactivation of glucocorticoid receptor by high-dose dexamethasone reduced the expression of M2 microglia, which plays an anti-inflammatory role. In contrast, inhibiting the activation of glucocorticoid receptor reduced the number of apoptotic glia and neurons and decreased the loss of dendritic spines after traumatic brain injury. Dexamethasone may exert its neurotoxic effects by inhibiting M2 microglia through the GR/JAK1/STAT3 signaling pathway.

Review of Janus Kinase Inhibitors as Therapies for Noninfectious Uveitis.

Uveitis remains one of the leading causes of blindness worldwide, with different etiologies requiring separate approaches to treatment. For over a decade, oral, topical, and local injection of corticosteroids as well as systemic conventional disease-modifying antirheumatic drugs (DMARDs) have remained the most effective treatment for noninfectious uveitis (NIU). Systemic administration of antitumor necrosis factor-α and other biological DMARDs have been used for treating cases that responded inadequately to conventional treatments. Unfortunately, some refractory patients still suffer from frequent attacks despite the combination of multiple treatments. Recently, there has been promising evidence for Janus kinase (JAK) inhibitors as the next-generation therapy for NIU. The JAK/signal transducers and activators of the transcription (STAT) signaling pathway mediate the downstream events involved in immune fitness, tissue repair, inflammation, apoptosis, and adipogenesis by binding various ligands, such as cytokines, growth hormones, and growth factors. The mutation or loss of JAK/STAT components is implicated in autoimmune diseases, thus inhibition of such pathways has been an important area of research in therapeutic development.1 In this review, we provide a comprehensive overview of the efficacy and safety of JAK inhibitors for the management of NIU, with evidence from current trials and case reports.

Time-course analysis of antibody and cytokine response after the third SARS-CoV-2 vaccine dose

The widespread administration of an additional dose of the SARS-CoV-2 vaccine has been promoted across adult populations, demonstrating a robust immune response against COVID-19. Longitudinal studies provide crucial data on the durability of immune response after the third vaccination. This study aims to explore the antibody response, neutralizing activity, and cytokine response against the SARS-CoV-2 ancestral strain (wild-type) and its variants during the timeline before and after the administration of the third vaccine dose. Anti-spike antibody titers and neutralizing antibodies blocking ACE2 binding to spike antigens were measured in 62 study participants at baseline, and on days 7, 21, and 180 post-vaccination. Cytokine levels were assessed at the same points except for day 180, with an additional measurement on day 3 post-vaccination. The analysis revealed no substantial variation in anti-spike antibody titer against the SARS-CoV-2 ancestral strain between the pre-vaccination phase and three days following the third dose. However, a significant nine-fold increase in these titers was observed by day 7, maintained until day 21. Although a decrease was observed by day 180, all participants still had detectable antibody levels. A similar trend was noted for neutralizing antibodies, with a four-fold rise by day 7 post-vaccination. At day 180, a diminution of neutralizing antibody titers was evident for both wild-type and all variants, including Omicron subvariant. A transient increase in cytokine activity, notably involving components of the Janus kinase (JAK)/signal transducers and activators of transcription (STAT) pathway, such as CXCL10 and IL-10, was observed within three days after the third dose. This study underscores a distinct amplification of humoral immune response seven days following the third SARS-CoV-2 vaccine dose and observes a decline in neutralizing antibody titers 180 days following the third dose, thus indicating the temporal humoral effectiveness of booster vaccination. A short-term cytokine surge, notably involving the JAK/STAT pathway, highlights the dynamic immune modulation post-vaccination.

Safety and Efficacy of Upadacitinib in Crohn's Disease: An Updated Systematic Review.

Crohn's disease (CD) is a chronic inflammatory bowel disease that significantly impacts patient quality of life. This systematic review evaluates the safety and efficacy of upadacitinib, a selective Janus kinase (JAK) inhibitor, in the treatment of CD. A comprehensive literature search was conducted across multiple databases, yielding seven studies published between 2020 and 2024, encompassing 1,481 patients. The review includes randomized controlled trials, post hoc analyses of phase 3 trials, and observational studies. Findings consistently demonstrate upadacitinib's superiority over placebo in inducing and maintaining clinical remission, achieving endoscopic response, and normalizing inflammatory markers. Notably, upadacitinib showed rapid symptom relief, with clinical remission observed as early as five to six days after treatment initiation. Efficacy was observed across various patient populations, including those with prior biologic failure. Long-term studies indicated sustained clinical and endoscopic improvements, with remission rates maintained for up to 30 months. Upadacitinib also demonstrated effectiveness in real-world, treatment-refractory cohorts. Safety profiles were generally consistent with those of other JAK inhibitors. Common adverse events included infections, particularly herpes zoster, and laboratory abnormalities such as neutropenia and elevated creatine kinase. Serious adverse events were infrequent, although careful monitoring is warranted. This review suggests that upadacitinib is a promising treatment option for moderate to severe CD, offering rapid and sustained efficacy with an acceptable safety profile.

Role of HPV E7/miR-143-3p/SH2D3A pathway in regulating the occurrence and development of cervical cancer.

This study aims to explore the role of SH2D3A in cervical cancer, as well as its potential interaction with human papillomavirus (HPV) E7 and microRNA (miRNA). Quantitative reverse transcription polymerase chain reaction (qRT-PCR) and immunohistochemistry were used to compare the expressions of SH2D3A in tissues. To assess the effects of SH2D3A on cervical cancer cell phenotypes, SH2D3A was knocked down in SiHa and HeLa cells, followed by cell proliferation (Cell Counting Kit-8 assay), apoptosis (flow cytometry), and invasion (Transwell assay) analyses. A transplantation tumor model was established to compare the tumorigenic ability of cervical cancer cells before and after SH2D3A silencing. Bioinformatics analysis predicted and dual-luciferase reporter assays verified the sponge adsorption effect of SH2D3A on miRNA. Western blot and qRT-PCR analyses were conducted to examine the impact on target genes following the downregulation of HPV E7 and SH2D3A. SH2D3A expression was significantly elevated in cervical cancer tissues. SH2D3A silencing inhibited cell proliferation and invasion, induced apoptosis, and reduced tumorigenesis in nude mice. Bioinformatics tools identified a binding relationship between SH2D3A and miR-143-3p, confirmed by the luciferase reporter assays. Western blot analysis revealed that SH2D3A knockdown led to decreased levels of Janus kinase 1 (JAK1) and signal transducer and activator of transcription 3 (STAT3) proteins. Additionally, qRT-PCR showed that SH2D3A mRNA levels decreased after HPV E7 silencing, whereas miR-143-3p levels significantly increased. HPV E7 influences SH2D3A expression through miR-143-3p, thereby regulating the JAK1/STAT3 pathway. This mechanism promotes the occurrence and development of cervical cancer.

Two major bovine milk whey proteins induce distinct responses in IEC-6 intestinal cells

Abstract α-Lactalbumin (α-LA) and β-lactoglobulin (β-LG) are major whey proteins in bovine milk. We studied the effects of these molecules on the intestinal cell response by comparing the native form with the denatured form containing oligomers obtained by treatment with 2,2,2-trifluoroethanol (TFE). We previously reported that proteins in native and TFE-treated forms exhibited cell growth stimulation and cytotoxicity, respectively, in undifferentiated rat crypt IEC-6 and human colon Caco-2 cells. However, neither whey protein showed cytotoxicity even in the TFE-treated form in differentiated Caco-2 cells. Only undifferentiated immature intestinal cells can distinguish between these native and denatured proteins. Moreover, α-LA and β-LG exhibited different oligomer formation characteristics during the TFE treatment. In the present study, we compared the effects of native and TFE-treated whey proteins on IEC-6 cells in more detail. The native forms of both whey proteins exhibited cell proliferative effects in a concentration-dependent manner. For the TFE-treated forms, α-LA showed rapid and potent cytotoxicity, whereas β-LG altered cell responses depending on its concentration and exposure time; lower concentration/shorter exposure and higher concentration/longer exposure induced cell growth stimulation and cytotoxicity, respectively. Pre-treatment of the cell membrane with cholesterol suppressed the effects on the cell response only in TFE-treated β-LG (TFE-β-LG). In a preliminary examination using inhibitors of signal transduction, TFE-treated α-LA acted on the intrinsic apoptosis pathway via Bcl-2-associated X and p53, whereas the action of TFE-LG did not require this pathway. Tyrosine phosphorylation is necessary for the cell proliferation effect of both native whey proteins; however, native α-LA, but not native β-LG, also required activation of the pathway with selective epidermal growth factor receptor tyrosine kinase and Janus kinase 2/3. In summary, the two major bovine milk whey proteins induced similar yet discrete responses in undifferentiated intestinal cells. Even when oligomers are formed, β-LG may be much less hazardous to immature intestinal cells than α-LA.

Marine Bioactive Molecules as Inhibitors of the Janus Kinases: A Comparative Molecular Docking and Molecular Dynamics Simulation Approach.

A treasure trove of naturally occurring biomolecules can be obtained from sea living organisms to be used as potential antioxidant and anti-inflammatory agents. These bioactive molecules can target signaling molecules involved in the severity of chronic autoimmune diseases such as rheumatoid arthritis (RA). The intracellular tyrosine kinases family, Janus kinases (JAKs, includes JAK1, JAK2, and JAK3), is implicated in the pathogenesis of RA through regulating several cytokines and inflammatory processes. In the present study, we conducted molecular docking and structural analysis investigations to explore the role of a set of bioactive molecules from marine sources that can be used as JAKs' specific inhibitors. Around 200 antioxidants and anti-inflammatory molecules out of thousands of marine molecules found at the Comprehensive Marine Natural Products Database (CMNPD) website, were used in that analysis. The details of the interacting residues were compared to the recent FDA approved inhibitors tofacitinib and baricitinib for data validation. The shortlisted critical amino acids residues of our pharmacophore-based virtual screening were LYS905, GLU957, LEU959, and ASP1003 at JAK1, GLU930 and LEU932 at JAK2, and GLU905 and CYS909 of JAK3. Interestingly, marine biomolecules such as Sargachromanol G, Isopseudopterosin E, Seco-Pseudopterosin, and CID 10071610 showed specific binding and significantly higher binding energy to JAK1 active/potential sites when being compared with the approved inhibitors. In addition, Zoanthoxanthin and Fuscoside E bind to JAK2's critical residues, GLU930 and LEU932. Moreover, Phorbaketal and Fuscoside E appear to be potential candidates that can inhibit JAK3 activity. These results were validated using molecular dynamics simulation for the docked complexes, JAK1(6sm8)/SG, JAK2 (3jy9)/ZAX, and JAK3 (6pjc)/Fuscoside E, where stable and lower binding energy were found based on analyzing set of parameters, discussed below (videos are attached). A promising role of these marine bioactive molecules can be confirmed in prospective preclinical/clinical investigations using rheumatoid arthritis models.

Diagnosis and Management of Inflammatory Bowel Disease-Associated Spondyloarthritis.

Inflammatory bowel disease (IBD)-associated spondyloarthritis (SpA) is common but remains poorly understood. In this review article, we aimed to provide guidance regarding the diagnosis and management of this condition. For diagnosis of IBD-associated peripheral SpA (IBD-pSpA), we recommend collaboration with rheumatology for incorporation of clinical symptoms, physical examination findings, joint imaging if applicable, and available diagnostic criteria. For the management of IBD-pSpA, we first recommend assessment and treatment of underlying luminal IBD disease activity. We provide guidance regarding positioning of advanced therapies for IBD in patients with IBD-pSpA based on the limited available literature. For diagnosis of IBD-associated axial SpA, we recommend rheumatology referral to make the diagnosis based on incorporation of symptoms, laboratory data, imaging findings (sacroiliitis), and available diagnostic criteria. For the management of axial SpA, we recommend comanagement with rheumatology and use of either antitumor necrosis factor agents or Janus kinase inhibitors, when applicable.

Chronicles of A.I. Pospelov Moscow Society of Dermatovenerologists and Cosmetologists (MSDС was founded on October 4, 1891) Bulletin of the MSDС № 1157

On April 16th we held our last meeting of A.I. Pospelov Moscow Society of Dermatologists and Cosmetologists in person. There were 102 participants and 5 applicants. Our agenda included two clinical cases: the first one was a clinical case of fulminant acne (Miderm Clinic); the second one was about gangrenous pyoderma as a possible marker or paraneoplasia in intestinal oncological diseases (Sechenov University). We present clinical cases of patients with fulminant acne and periorbital oedema in the first report, and ascending colon tumour and T3N0M0 rectal cancer in the second report. Three reports were presented in the scientific part of the meeting: the effectiveness of therapy for severe psoriasis (Sechenov University), the effectiveness of Janus kinase inhibitors in atopic dermatitis (Sechenov University), the molecular genetic aspects of the fungal mycosis pathogenesis (State Scientific Center of Dermatovenerology and Cosmetology). The authors presented the results of their own clinical studies of the effectiveness of therapy of diseases, including in the report on molecular-genetic aspects of the pathogenesis of mycosis fungoides the author assessed the changes in the expression levels of genes of the JAK-STAT signalling pathway and transcription factors both in visually unaffected skin and in the focus of clinically detectable lesions.

Experience of abrocitinib in atopic dermatitis

Atopic dermatitis is an autoinflammatory, genetically determined, itchy disease characterized by a long, relapsing course and a sharp decrease in the patient’s quality of life. Atopic dermatitis is caused by a complex interaction of immune dysregulation, epidermal gene mutations, and multi-environmental factors that affect the skin, causing intense itchy rashes. The disease often occurs among young children and subsequently has age-related clinical features. Currently, the treatment of atopic dermatitis has a wide range of options, including drugs from the group of small molecules recently registered in the Russian Federation. The drugs are intended for patients with moderate to severe atopic dermatitis. Baricitinib, abrocitinib and upadacitinib as Janus kinase inhibitors from the small molecule group have already demonstrated good tolerability, safety and a pronounced clinical effect in the vast majority of patients with atopic dermatitis in available clinical trials. The first clinical experience with the use of abrocitinib in adult patients with atopic dermatitis is presented. The interest of the presented clinical cases lies in the demonstration of high clinical efficacy and safety of mono- and combination therapy with the Janus kinase inhibitor abrocitinib. Despite the short period of treatment and observation (4 weeks), objective severity of atopic dermatitis manifestations (SCORAD index 60 points) and sharp decrease in the patients' quality of life (DLQI index 20 points), a reduction of clinical parameters exceeding 60% was achieved at a dose of 200 mg daily. During the whole observation period no adverse clinical reactions or changes in laboratory parameters were registered against the background of abrocitinib administration. The pilot results of abrocitinib use are encouraging and provide grounds for conducting longer and larger-scale studies to investigate the efficacy of the drug for its inclusion in the combination therapy of patients with moderate to severe atopic dermatitis.

The Anti-Vitiligo Effects of Feshurin In Vitro from Ferula samarcandica and the Mechanism of Action.

Vitiligo is a complex disorder characterized by skin depigmentation; the canonical Wnt signaling pathway that involves β-catenin plays a crucial role in promoting the melanin production in melanocytes. Targeted inhibition of the Janus kinase JAK-STAT pathway can effectively diminish the secretion of the chemokine C-X-C motif ligand CXCL10, thereby safeguarding melanocytes. Ferula has been applied as a treatment regimen for a long period; however, its use for the treatment of vitiligo has not been previously documented. CCK-8 assay, Intracellular melanin content assay, Tyrosinase activity assay, Western blotting, qRT-PCR, and ELISA methods were employed. Using molecular docking verified the inhibitory effects of feshurin on the JAK1. The sesquiterpene coumarin feshurin was separated from Ferula samarcandica. Feshurin was shown to induce GSK-3β phosphorylation, resulting in the translocation of β-catenin into the nucleus. This translocation subsequently upregulated the transcription of microphthalmia-associated transcription factor (MITF), leading to increased tyrosinase activity and melanin production. In addition, feshurin inhibited the production of chemokine CXCL10 via the JAK-STAT signaling pathway, which was verified by molecular docking. Based on these findings, it can be concluded that feshurin exhibits significant potential for the development of novel anti-vitiligo therapeutics.

Effect of AML-exosomes on the cellular and molecular properties of bone marrow mesenchymal stromal cells: Expression of JAK/STAT signaling genes

Purpose of studyDespite the various therapeutic options introduced for AML treatment, therapy resistance and relapse are still the main obstacles. It is well known that alterations in the bone marrow microenvironment (BMM) play a crucial role in leukemia growth and the treatment failure of AML. Evidence shows that exosomes alter the components of BMM in a way that support leukemia survival, leading to chemoresistance. In this study, we evaluated the effect of AML exosomes on the biological functions of human bone marrow mesenchymal stromal cells (h BM-MSCs), especially alteration in the expression of the JAK/STAT signaling genes, as a leukemia-favoring pathway. MethodExosomes were isolated from the HL-60 cell line and characterized using flow cytometry, Transmission Electron Microscopy (TEM), and Dynamic Light Scattering (DLS) technique. The exosome protein content was assessed using a bicinchoninic acid (BCA) protein assay kit in order to determine the concentration of exosomes. Subsequently, MSCs were treated with varying concentrations of AML exosomes, and data was obtained using MTT, cell cycle, apoptosis, and ki67 assays. Additionally, gene expression analysis was conducted through qRT-PCR. ResultAML exosomes regulated the viability and survival of MSCs in a concentration-dependent manner. The qRT-PCR data revealed that treatment with AML exosomes at a concentration of 50 μg/mL led to a significant upregulation of JAK2, STAT3, and STAT5 genes in MSCs. ConclusionBecause the JAK/STAT signaling pathway has been shown to play a role in the proliferation and survival of leukemic cells, our results suggest that AML exosomes stimulate MSCs to activate this pathway. This activation may impede AML cell apoptosis, potentially leading to chemoresistance and relapse.

Comparative early effectiveness across 14 PsA drugs and 5 classes of PsA treatment: 3-month results from the PRO-SPIRIT study

BackgroundThe psoriatic arthritis (PsA) Observational Study of Persistence of Treatment (PRO-SPIRIT) assesses effectiveness and persistence of real-world PsA treatments. Ixekizumab (IXE) is an interleukin (IL)-17A inhibitor (i) (IL-17Ai), approved for...

Development of a Robust Pd-Catalyzed C–S Coupling for the Synthesis of Janus Kinase Inhibitor GDC-9918

Development of a Robust Pd-Catalyzed C–S Coupling for the Synthesis of Janus Kinase Inhibitor GDC-9918

Exploring new horizons: angiotensin II, angiotensin II type 1 receptor, and renal outer medullary potassium channel interaction in distal convoluted tubule.

This study investigates angiotensin II (Ang II)'s regulatory mechanism on renal outer medullary potassium channel (ROMK) activity in the distal convoluted tubule (DCT) during low potassium intake, focusing on the Janus kinase 2 (JAK2) pathway activation mediated by the Ang II type 1 receptor (AT1R). Utilizing a low potassium diet mouse model, various methods including patch clamping, reverse transcription-quantitative polymerase chain reaction, Western blotting, and immunohistochemical staining were applied to analyze ROMK channel activity and the expression of related proteins. The findings reveal that Ang II inhibits ROMK activity in the DCT2 membrane through AT1R activation, with the JAK2 pathway playing a central role. Further, inhibiting JAK2 reverses this effect, indicating its potential in hypertension treatment. This study provides novel insights into the role of Ang II in renal potassium excretion and hypertension pathophysiology.

Severe exacerbation of facial dermatitis with swelling following introduction of abrocitinib in a patient with atopic dermatitis

BackgroundAbrocitinib, an oral small-molecule Janus kinase 1 (JAK1) inhibitor, has been widely accepted for the treatment of moderate-to-severe atopic dermatitis (AD). Currently there is a paucity of data on the adverse events (AEs) after abrocitinib treatment, especially on rare events such as exacerbation of facial dermatitis, and their causal relationship and subsequent management remains poorly elucidated.Case presentationA 43-year-old female patient with moderate AD received dupilumab after failure of topical treatments. Facial dermatitis persisted and became refractory after dupilumab treatment, and the patient changed treatment to oral abrocitinib. Fifteen hours after the first dose of abrocitinib, she developed exacerbation of facial dermatitis with swelling. The patient was initially diagnosed as abrocitinib-induced hypersensitivity. However, a score of 3 of the Naranjo adverse drug reaction assessment indicates week correlation between abrocitinib therapy and exacerbation of facial dermatitis, and negative results from subsequent drug provocation test further suggests no causal relationship.ConclusionsThe present case report highlights the necessity of careful determination of abrocitinib-induced hypersensitivity, which should not be diagnosed simply based on the time sequence between drug exposure and symptom occurrence. In addition, caution should be exercised for drug withdrawal, especially when confirmative evidence is absent. Drug provocation test can be helpful and effective treatments could be continued unless severe AEs occur.

Golidocitinib: First Approval.

Golidocitinib (®) is an oral, potent, selective Janus kinase 1 (JAK1) inhibitor being developed by Dizal (Jiangsu) Pharmaceutical Co., Ltd for the treatment of cancer, including peripheral T cell lymphoma (PTCL). In June 2024, golidocitinib received conditional approval in China for the treatment of adult patients with relapsed or refractory (r/r) PTCL who have received at least one line of systemic treatment. This article summarizes the milestones in the development of golidocitinib leading to this first approval for the treatment of adults with PTCL.

Long-Term Safety and Efficacy of Janus kinase (JAK) Inhibitors in the Treatment of Rheumatoid Arthritis

Background: Janus kinase (JAK) inhibitors are a new class of drugs for the treatment of rheumatoid arthritis (RA); however, the long-term consequences of using these drugs are still not well understood. Objective: The primary objective of this research was to examine the effectiveness and safety of JAK inhibitors for the management of rheumatoid arthritis (RA) patients. Methodology: Clinical raw data of 150 RA patients receiving JAK inhibitors was collected in different tertiary care hospitals in Lahore, Pakistan from March 2023 to June 2024. till were conducted. The anti-inflammatory effect was evaluated by the Disease Activity Score in 28 joints (DAS28) and the safety profile through adverse events, laboratory markers, and patients self-reported outcomes. The SPSS version 27 applied for raw data analysis which used the paired t-tests and multiple regression models to establish the factors that determine favorable outcomes and complications. Results: JAK inhibitors also reduced the DAS28 scores from baseline to 24 months by a mean of 3. 2 ± 1. 1 (p<0. 001). The findings stated that 12 percent of the patients at baseline and 45 percent of the patients at 24 months had achieved remission. The reported side effects were infections, 25%; gastrointestinal problems, 18%; and abnormal liver function tests, 10%. Severe adverse reactions were noted in 5% of the patients and no new safety issues were observed over the course of the treatment. Conclusion: JAK inhibitors have been shown to be useful in decreasing the activity of RA for the long-term use with reasonable side effects. The results provided evidence that JAK inhibitors were best treatment of rheumatoid arthritis (RA) but for best efficacy results closely monitoring and specific approach should be applied.