In recent years, Janus kinase (JAK) inhibitors have been gradually approved for the treatment of immune-mediated inflammatory diseases (IMIDs), including rheumatoid arthritis, axial spondyloarthritis, psoriatic arthritis, juvenile idiopathic arthritis, giant cell arteritis, atopic dermatitis, alopecia areata, psoriasis, and inflammatory bowel disease. To standardize the application of JAK inhibitors in IMIDs, the expert group of this consensus has formulated the Chinese expert consensus on the treatment of immune-mediated inflammatory diseases with Janus kinase inhibitors, based on the latest research data, relevant guidelines, domestic and international literature, and clinical practice experience of the experts. This consensus provides a comprehensive introduction to treatment regimens, safety management, and medication use in specific populations, aiming to assist clinicians in making reasonable clinical decisions.
Humans ; Janus Kinase Inhibitors/therapeutic use* ; Consensus ; Inflammation/drug therapy* ; Inflammatory Bowel Diseases/drug therapy* ; East Asian People

INTRODUCTION: Since 2016, several therapies have been approved for treating atopic dermatitis (AD) in Singapore, including biologics, oral Janus kinase (JAK) inhibitors and topical crisaborole. This study supplements the 2016 Singapore treatment guidelines for AD, focusing on newer therapies for moderate-to-severe disease, while revisiting older treatment regimens to accommodate changes in knowledge and practice. METHOD: A modified Delphi panel was held, led by 2 co-chairs. The voting expert panel consisted of 12 dermatologists experienced in managing AD in Singapore. Delphi survey rounds were conducted between 24 July and 27 October 2023. Panellists indicated their agreement with drafted statements using a 5-point Likert scale. Consensus was defined as ≥80% agreement. An expert meeting was held to facilitate the consensus process between rounds 1 and 2 of voting. RESULTS: All expert panellists participated in both survey rounds, with a 100% response rate. Thirty-nine statements, classified into general principles, conventional treatments, biologics and JAK inhibitors, were proposed. Of these, 27 statements reached consensus at the end of round 1. After the expert meeting, 17 statements were included in round 2, of which 16 statements reached consensus. One statement did not reach consensus. Key updates are the inclusion of dupilumab and JAK inhibitors as potential first-line treatments for moderate-to-severe AD, in certain populations. CONCLUSION This modified Delphi study generated consensus among Singapore dermatology experts, to update treatment guidelines in moderate-to-severe atopic dermatitis. The consensus statements developed are intended to supplement the 2016 Singapore treatment guidelines for AD. Further revisions may be required when new evidence and/or treatments become available.
Dermatitis, Atopic/drug therapy* ; Humans ; Singapore ; Janus Kinase Inhibitors/therapeutic use* ; Biological Products/therapeutic use* ; Delphi Technique ; Consensus ; Antibodies, Monoclonal, Humanized/therapeutic use* ; Severity of Illness Index ; Bridged Bicyclo Compounds, Heterocyclic/therapeutic use* ; Dermatologic Agents/therapeutic use* ; Practice Guidelines as Topic ; Pyrimidines/therapeutic use* ; Boron Compounds

Humans ; Janus Kinase Inhibitors/therapeutic use* ; Vitiligo/drug therapy* ; Psoriasis ; Protein Kinase Inhibitors

Classical myeloproliferative neoplasm (MPN) related thrombosis mainly affects elderly patients and often involves arterial circulation, while, MPN-visceral venous thrombosis (SVT) mainly affects young women, and is closely associated with JAK2V617F mutation but not closely with CALR mutation. The pathogenesis of MPN-SVT is not only related to JAK2V617F mutation and vascular endothelial damage, but also needs further research to determine the machanism. JAK2V617F mutation is the most common in MPN-SVT clinically. Patients with non-cirrhotic SVT need to detect MPN mutation, while the detection of CALR or MPL mutation needs to be combined with clinical judgment. At present, the main treatment strategies of MPN-SVT are JAK inhibitors, supplementation of anticoagulants and treatment of portal hypertension. This article reviews the latest research progress on the epidemiology, pathogenesis, diagnosis and treatment strategies of MPN-SVT.
Aged ; Anticoagulants ; Female ; Humans ; Janus Kinase 2/genetics* ; Janus Kinase Inhibitors ; Mutation ; Myeloproliferative Disorders/genetics* ; Neoplasms ; Thrombosis ; Venous Thrombosis

Abstract Atopic eczema (AE) is a complex, chronic and recurrent inflammatory pruritic skin condition that impacts the quality of life and exerts an economic toll on patients and their families. One of the factors contributing to AE is the immune dysregulation of the Janus kinase-signal transducers and activators of transcription (JAK-STAT) inflammatory pathway. This has prompted the conduct of various large clinical trial programs to evaluate the efficacy and safety of Janus kinase inhibitors (JAK-i) for AE. The overall and significant benefit of these drugs from clinical studies resulted in regulatory approvals for JAK-i to treat moderate-to-severe atopic eczema. The objective of this position paper was to evaluate the safety, efficacy and role of upadacitinib, baricitinib and abrocitinib in managing AE and update the current recommended treatment algorithm within the 2018 Malaysian Clinical Practice Guidelines for the Management of Atopic Eczema. The Persatuan Dermatologi Malaysia recommends that these JAK-i can be considered as an option for systemic therapy in severe AE.
Dermatitis, Atopic--therapy ; Janus Kinase Inhibitors

Tofacitinib is a Janus kinase inhibitor and can block the Janus kinase-signal transducer and activator of transcription signal transduction pathway and reduce the production and release of a variety of cytokines. It has great potential in the treatment of various rheumatic diseases with a rapid onset of action and can reduce corticosteroid dependence and related adverse events. The therapeutic effect of tofacitinib in adult patients has been confirmed, and it has been increasingly used in pediatric patients in recent years. This article reviews the clinical application of tofacitinib in the treatment of pediatric autoimmune diseases.
Adult ; Child ; Humans ; Janus Kinases/metabolism* ; Piperidines/therapeutic use* ; Protein Kinase Inhibitors/therapeutic use* ; Pyrimidines/therapeutic use* ; Rheumatic Diseases/drug therapy*

Macrophages show significant heterogeneity in function and phenotype, which could shift into different populations of cells in response to exposure to various micro-environmental signals. These changes, also termed as macrophage polarization, of which play an important role in the pathogenesis of many diseases. Numerous studies have proved that Hesperidin (HDN), a traditional Chinese medicine, extracted from fruit peels of the genus citrus, play key roles in anti-inflammation, anti-tumor, anti-oxidant and so on. However, the role of HDN in macrophage polarization has never been reported. Additional, because of its poor water solubility and bioavailability. Our laboratory had synthesized many hesperidin derivatives. Among them, hesperidin derivatives-12 (HDND-12) has better water solubility and bioavailability. So, we evaluated the role of HDND-12 in macrophage polarization in the present study. The results showed that the expression of Arginase-1 (Arg-1), interleukin-10 (IL-10), transforming growth factor β (TGF-β) were up-regulated by HDND-12, whereas the expression of inducible Nitric Oxide Synthase (iNOS) was down-regulated in LPS- and IFN-γ-treated (M1) RAW264.7 cells. Moreover, the expression of p-JAK2 and p-STAT3 were significantly decreased after stimulation with HDND-12 in M1-like macrophages. More importantly, when we taken AG490 (inhibitor of JAK2/STAT3 signaling), the protein levels of iNOS were significantly reduced in AG490 stimulation group compare with control in LPS, IFN-γ and HDND-12 stimulation cells. Taken together, these findings indicated that HDND-12 could prevent polarization toward M1-like macrophages, at least in part, through modulating JAK2/STAT3 pathway.
Animals ; Cytokines ; genetics ; metabolism ; Enzyme Inhibitors ; pharmacology ; Gene Expression Regulation ; drug effects ; Hesperidin ; chemistry ; pharmacology ; Inflammation ; genetics ; metabolism ; Janus Kinase 2 ; antagonists & inhibitors ; metabolism ; Macrophages ; drug effects ; immunology ; metabolism ; Medicine, Chinese Traditional ; Mice ; Molecular Structure ; Phosphorylation ; drug effects ; RAW 264.7 Cells ; STAT3 Transcription Factor ; antagonists & inhibitors ; metabolism ; Signal Transduction ; drug effects

To investigate the role of Janus kinase (JAK) inhibitor AG490 in the anti-proliferation and cell cycle in human retinoblastoma HXO-RB44 cell lines in vitro, and to explore its effect on the expression of JAK2/signal transducer and activator of transcription 3 (STAT3).
 Methods: Cells were divided into an experiment group and a control group, and the experiment group was further divided into 6 sub-groups according to different AG490 concentrations (6.25, 12.50, 25.00, 50.00 or 100.00 μmol/L). Cell proliferation in the different groups was analyzed by cell vitality determination. Cell cycle distribution and apoptosis rate were examined by flow cytometry. The protein levels of STAT3, p-STAT3 and vascular endothelial growth factor (VEGF) were detected by Western blot.
 Results: After 48 h treatment with AG490, the viability of HXO-RB44 cells was reduced in a concentration-dependent manner. Compared with the control group, there was no significant difference in the experiment groups except the 6.25 μmol/L group (all P>0.05). The apoptosis rates in the experiment groups were significantly increased with increase in concentration of AG490 compared with that in the control group (all P<0.05). The cell ratio in the G1 phase in 50 or 100 μmol/L group was increased, whereas the cell ratio in the S phase was decreased. Western blot results showed that the expressions of STAT3 and p-STAT3 in the experiment groups were dramatically reduced with the increase in concentration of AG490 compared with that in the control group (all P<0.05). VEGF expression didn't obviously change in the experiment groups with AG490 concentration less than 12.5 μmol/L compared with that in the control group (both P>0.05), but there were significant differences in the other experiment groups (all P<0.05). 
 Conclusion: JAK inhibitor AG490 can inhibit proliferation and promote apoptosis of the retinoblastoma HXO-RB44 cells through down-regulation of JAK2/STAT3 signaling pathway.
Apoptosis ; drug effects ; Cell Line, Tumor ; Cell Proliferation ; drug effects ; Cell Survival ; drug effects ; Enzyme Inhibitors ; pharmacology ; Gene Expression Regulation, Neoplastic ; drug effects ; Humans ; Janus Kinase 2 ; genetics ; metabolism ; Retinoblastoma ; STAT3 Transcription Factor ; genetics ; metabolism ; Signal Transduction ; drug effects ; Tyrphostins ; pharmacology ; Vascular Endothelial Growth Factor A ; metabolism

Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by inflammation and joint destruction that causes significant morbidity and mortality. However, the combined use of methotrexate, a synthetic disease-modifying antirheumatic drug (DMARD), and biologic DMARD has revolutionized treatment of RA. Clinical remission is now realistic targets, achieved by a large proportion of RA patients, and rapid and appropriate induction of remission by intensive treatment with biological DMARD and methotrexate is prerequisite to halt joint damage and functional disabilities. However, biological DMARD is limited to intravenous or subcutaneous uses and orally available small but strong molecules have been developed. Oral administration of tofacitinib targeting the Janus kinase (JAK) is significantly effective than placebo in active patients with methotrexatenaive, inadequately responsive to methotrexate or tumor necrosis factor (TNF)-inhibitors. The efficacy was rapid and as strong as adalimumab, a TNF-inhibitor. Meanwhile, association of tofacitinib on carcinogenicity and malignancy is under debate and further investigation on post-marketing survey would be warranted. On the other hand, discontinuation of a biological DMARD without disease flare is our next goal and desirable from the standpoint of risk reduction and cost effectiveness, especially for patients with clinical remission. Recent reports indicate that more than half of early RA patients could discontinue TNF-targeted biological DMARD without clinical flare and functional impairment after obtaining clinical remission. Contrarily, for established RA, fewer patients sustained remission after the discontinuation of biological DMARD and "deep remission" at the discontinuation was a key factor to keep the treatment holiday of biological DMARD.
Administration, Oral ; Antirheumatic Agents/*administration & dosage/adverse effects ; Arthritis, Rheumatoid/diagnosis/*drug therapy/metabolism/physiopathology ; Biological Products/administration & dosage ; Disability Evaluation ; Drug Administration Schedule ; Humans ; Janus Kinases/antagonists & inhibitors/metabolism ; Molecular Targeted Therapy ; Predictive Value of Tests ; Protein Kinase Inhibitors/administration & dosage ; Recovery of Function ; Remission Induction ; Signal Transduction/drug effects ; Treatment Outcome ; Tumor Necrosis Factor-alpha/antagonists & inhibitors/metabolism

To study the preventive effect of sophocarpine (Soc) on dextran sulfate sodium (DSS)-induced colitis in mice, in order to analyze the influence of Soc on toll like receptor 4 (TLR4)/mitogen-activated protein kinases (MAPKs) and janus tyrosine kinase 2 signal transducer and activator of transcription 3 (JAK2/STAT3) signal pathways in mice intestinal tissues. The mice was given 2.5% DSS for 6 days to induce the acute colitis model. The Soc-treated group was intraperitoneally injected with sophocarpine 30 mg · kg(-1) · d(-1) since the day before the experiment to the end. The disease activity index (DAI) was assessed everyday, and the colonic morphology and histological damage were observed with HE staining. The mRNA expressions of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6) were detected by real-time RT-PCR. The changes in key protein kinase p38 mitogen-activated protein kinase (p38MAPK), c-Jun NH2-terminal protein kinase1/2 (JNK1/2), extracellular signal-regulated kinase1/2 (ERK1/2), JAK2, STAT3 in TLR4/MAPKs and JAK2/STAT3 signaling pathways were detected by western blot. The result showed that the model group showed statistical significance in body weight, DAI, colon length and histopathological changes compared with the normal group (P <0.05); however, the Soc-treated group showed significant improvements in the above indexes compared with the model group (P <0.05). TNF-α, IL-1β and IL-6 in the model group was significantly higher than that in the normal group (P <0.05), but lowered in the Soc-treated group to varying degrees (P <0.05). In the normal group, the expressions of TLR4 and the phosphorylation of P38, JNK1/2, JAK2, STAT3 were at low levels; in the model group, the phosphorylation of P38, JNK1/2, JAK2, STAT3 increased; the Soc-treated group showed a decrease in TLR4 expression compared with the model group, with notable declines in the phosphorylation of TLR4, P38, JNK1/2, JAK2, STAT3. These findings indicate that Soc can inhibit TLR4/MAPKs, K2/STAT3 signaling pathway activation, reduce the expression of proinflammatory cytokines TNF-α, IL-1β and IL-6 and relieve inflammatory reactions, so as to effectively prevent experimental colitis.
Alkaloids ; pharmacology ; therapeutic use ; Animals ; Colitis ; drug therapy ; immunology ; pathology ; Cytokines ; genetics ; Janus Kinase 2 ; antagonists & inhibitors ; physiology ; Male ; Mice ; Mice, Inbred BALB C ; Phosphorylation ; STAT3 Transcription Factor ; antagonists & inhibitors ; physiology ; Toll-Like Receptor 4 ; antagonists & inhibitors ; physiology