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Approach to loss of response to advanced therapies in inflammatory bowel disease

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World Journal of Gastroenterology 2024年第22期30卷 2902-2919页

作者： Nikil Vootukuru Abhinav Vasudevan Department of Gastroenterology and Hepatology Eastern HealthVictoriaBox Hill 3128Australia Eastern Health Clinical School Monash UniversityVictoriaBox Hill 3128Australia

BACKGROUND Remarkable progress over the last decade has equipped clinicians with many options in the treatment of inflammatory bowel disease.Clinicians now have the unique opportunity to provide individualized treatment that can achieve and sustain remission in many patients.However,issues of primary non-response(PNR)and secondary loss of response(SLOR)to non-tumour necrosis factor inhibitor(TNFi)therapies remains a common problem.Specific issues include the choice of optimization of therapy,identifying when dose optimization will recapture response,establishing optimal dose for escalation and when to switch therapy.AIM To explores the issues of PNR and SLOR to non-TNFi therapies.METHODS This review explores the current evidence and literature to elucidate management options in cases of PNR/SLOR.It will also explore potential predictors for response following SLOR/PNR to therapies including the role of therapeutic drug monitoring(TDM).RESULTS In the setting of PNR and loss of response to alpha-beta7-integrin inhibitors and interleukin(IL)-12 and IL-23 inhibitors dose optimization is a reasonable option to capture response.For janus kinase inhibitors dose optimization can be utilized to recapture response with loss of response.CONCLUSION The role of TDM in the setting of advanced non-TNFi therapies to identify patients who require dose optimization and as a predictor for clinical remission is not yet established and this remains an area that should be addressed in the future.

关键词： Inflammatory bowel disease Ulcerative colitis Crohn Biologics Interleukin-12 and interleukin-23 inhibitors Alpha-beta7-integrin inhibitors janus kinase inhibitors Sphingosine-1-phosphate receptor modulators

Treatment with a JAK1/2 inhibitor ameliorates murine autoimmune cholangitis induced by IFN overexpression

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Cellular & Molecular Immunology 2022年第10期19卷 1130-1140页

作者： Tihong Shao Patrick S.C.Leung Weici Zhang Koichi Tsuneyama William M.Ridgway Howard A.Young Zongwen Shuai Aftab A.Ansari M.Eric Gershwi Department of Rheumatology and Immunology The First Affiliated Hospital of Anhui Medical UniversityHefeiChina Division of Rheumatology Allergyand Clinical ImmunologySchool of MedicineUniversity of CaliforniaDavisCAUSA Department of Pathology and Laboratory Medicine Institute of Biomedical SciencesTokushima University Graduate SchoolTokushimaJapan Center for Cancer Research National Cancer Institute-FrederickFrederickMDUSA

The interferon(IFN)signaling pathways are major immunological checkpoints with clinical significance in the pathogenesis of autoimmunity.We have generated a unique murine model named ARE-Del,with chronic overexpression of IFNγ,by altering IFNγmetabolism.Importantly,these mice develop an immunologic and clinical profile similar to patients with primary biliary cholangitis,including high titers of autoantibodies and portal inflammation.We hypothesized that the downregulation of IFN signaling pathways with a JAK1/2 inhibitor would inhibit the development and progression of cholangitis.To study this hypothesis,ARE-Del^(+/−)mice were treated with the JAK1/2 inhibitor ruxolitinib and serially studied.JAK inhibition resulted in a significant reduction in portal inflammation and bile duct damage,associated with a significant reduction in splenic and hepatic CD4^(+)T cells and CD8^(+)T cells.Functionally,ruxolitinib inhibited the secretion of the proinflammatory cytokines IFNγand TNF from splenic CD4^(+)T cells.Additionally,ruxolitinib treatment also decreased the frequencies of germinal center B(GC B)cells and T follicular helper(Tfh)cells and led to lower serological AMA levels.Of note,liver and peritoneal macrophages were sharply decreased and polarized from M1 to M2 with a higher level of IRF4 expression after ruxolitinib treatment.Mechanistically,ruxolitinib inhibited the secretion of IL-6,TNF and MCP1 and the expression of STAT1 but promoted the expression of STAT6 in macrophages in vitro,indicating that M1 macrophage polarization to M2 occurred through activation of the STAT6-IRF4 pathway.Our data highlight the significance,both immunologically and clinically,of the JAK/STAT signaling pathway in autoimmune cholangitis.

关键词： Primary biliary cholangitis Autoimmunity Interferons janus kinase inhibitors Ruxolitinib

Role of JAK-STAT signaling pathway in pathogenesis and treatment of primary Sjögren’s syndrome

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中华医学杂志（英文版） 2023年第19期136卷 2297-2306页

作者： Mucong Li Mengtao Li Lin Qiao Chanyuan Wu Dong Xu Yan Zhao Xiaofeng Zeng China 100730

Primary Sjögren’s syndrome (pSS) is a systemic autoimmune disease with high prevalence and possible poor prognosis. Though the pathogenesis of pSS has not been fully elucidated, B cell hyperactivity is considered as one of the fundamental abnormalities in pSS patients. It has long been identified that janus kinases-signal transducer and activator of transcription (JAK-STAT) signaling pathway contributes to rheumatoid arthritis and systemic lupus erythematosus. Recently, increasing numbers of studies have provided evidence that JAK-STAT pathway also has an important role in the pathogenesis of pSS via direct or indirect activation of B cells. Signal transducer and activator of transcription 1 (STAT1), STAT3, and STAT5 activated by various cytokines and ribonucleic acid contribute to pSS development, respectively or synergically. These results reveal the potential application of janus kinase inhibitors for treatment of pSS, which may fundamentally improve the quality of life and prognosis of patients with pSS.

关键词： Primary Sjögren’s syndrome JAK-STAT pathway janus kinase inhibitors Disease-modifying antirheumatic drugs

Toward a better understanding of typeⅠinterferonopathies:a brief summary,update and beyond

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World Journal of Pediatrics 2020年第1期16卷 44-51页

作者： Zhong-Xun Yu Hong-Mei Song Department of Pediatrics Peking Union Medical College HospitalChinese Academy of Medical SciencesBeijingChina

Backgrounds TypeⅠinterferonopathy is a group of autoinflammatory disorders associated with prominent enhanced typeⅠinterferon signaling.The mechanisms are complex,and the clinical phenotypes are diverse.This review briefly summarized the recent progresses of typeⅠinterferonopathy focusing on the clinical and molecular features,pathogeneses,diagnoses and potential therapies.Data sources Original research articles and literature reviews published in PubMed-indexed journals.Results TypeⅠinterferonopathies include Aicardi-Goutières syndrome,spondyloenchondro-dysplasia with immune dysregulation,stimulator of interferon genes-associated vasculopathy with onset in infancy,X-linked reticulate pigmentary disorder,ubiquitin-specific peptidase 18 deficiency,chronic atypical neutrophilic dermatitis with lipodystrophy,and Singleton-Merten syndrome originally.Other disorders including interferon-stimulated gene 15 deficiency and DNAseⅡdeficiency are believed to be interferonopathies as well.Intracranial calcification,skin vasculopathy,interstitial lung disease,failure to thrive,skeletal development problems and autoimmune features are common.Abnormal responses to nucleic acid stimuli and defective regulation of protein degradation are main mechanisms in disease pathogenesis.First generation janus kinase inhibitors including baricitinib,tofacitinib and ruxolitinib are useful for disease control.Reverse transcriptase inhibitors seem to be another option for Aicardi-Goutières syndrome.Conclusions Tremendous progress has been made for the discovery of typeⅠinterferonopathies and responsible genes.janus kinase inhibitors and other agents have potential therapeutic roles.Future basic,translational and clinical studies towards disease monitoring and powerful therapies are warranted.

关键词： Hereditary autoinflammatory diseases Interferon typeⅠ janus kinase inhibitors

Role of baricitinib in COVID-19 patients:A systematic review and meta-analysis

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World Journal of Meta-Analysis 2023年第4期11卷 125-133页

作者： Manisha Thakur Akhil Babu Gopal Lal Khatik Ashok Kumar Datusalia Ramchander Khatri Anoop Kumar Department of Regulatory Toxicology National Institute of Pharmaceutical Education and ResearchRaebareliRaebareli 226002India Department of Medicinal Chemistry National Institute of Pharmaceutical Education and ResearchRaebareliRaebareli 226002India Department of Pharmacognosy Delhi Pharmaceutical Sciences and Research UniversityNew Delhi 110017India Department of Pharmacology and Clinical Research Delhi Pharmaceutical Sciences and Research UniversityNew Delhi 110017DelhiIndia

BACKGROUND Recent studies have indicated the use of baricitinib in coronavirus disease 2019(COVID-19)patients.However,the use of baricitinib in COVID-19 patients is unclear so far.AIM To determine the precise role of baricitinib in the mortality of COVID-19 patients.METHODS The relevant studies were searched in PubMed,Google scholar,and Clinical trials registries till July 13,2021 and sorted out based on inclusion and exclusion criteria.The quality of studies was assessed using Newcastle-Ottawa Scale.A random-effect model was used,and the pooled estimate was calculated as the odds ratio with a 95%confidence interval using Rev Man 5.RESULTS A total of 11 studies(4 observational and 7 clinical trials)were found relevant for analysis.The overall estimate measure in terms of odds ratio for observational studies was 0.42[0.11,1.67],whereas for clinical trials it was 0.37[0.09,1.46],indicating a non-significant reduction in COVID-19 patient deaths in the baricitinib group versus the non-baricitinib group.CONCLUSION More studies are required to confirm the role of baricitinib in the deaths of COVID-19 patients.

关键词： janus kinase inhibitors Baricitinib COVID-19 Mortality Systematic Review Meta-analysis