Efficacy of JAK inhibitors in Crohn’s Disease

Rogler, Gerhard

doi:10.1093/ecco-jcc/jjz186

Cited by 54 publications

(40 citation statements)

References 83 publications

(188 reference statements)

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“…JAK inhibitors influence several inflammatory pathways and are therefore a promising target for inflammatory diseases like IBD. However, blocking JAKs in CD or UC patients showed contradictory results ( 102 ).…”

Section: Janus Kinase (Jak) Inhibitors In Ibdmentioning

confidence: 99%

Role of the IL23/IL17 Pathway in Crohn’s Disease

2021

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Crohn’s disease (CD) is a chronic relapsing disorder of the gastrointestinal tract and represents one of the main entities of inflammatory bowel disease (IBD). CD affects genetically susceptible patients that are influenced by environmental factors and the intestinal microbiome, which results in excessive activation of the mucosal immune system and aberrant cytokine responses. Various studies have implicated the pro-inflammatory cytokines IL17 and IL23 in the pathogenesis of CD. IL23 is a member of the IL12 family of cytokines and is able to enhance and affect the expansion of pathogenic T helper type 17 (Th17) cells through various mechanisms, including maintenance of Th17 signature genes, upregulation of effector genes or suppression of repressive factors. Moreover, IL17 and IL23 signaling is able to induce a cascade of pro-inflammatory molecules like TNF, IFNγ, IL22, lymphotoxin, IL1β and lipopolysaccharide (LPS). Here, IL17A and TNF are known to mediate signaling synergistically to drive expression of inflammatory genes. Recent advances in understanding the immunopathogenetic mechanisms underlying CD have led to the development of new biological therapies that selectively intervene and inhibit inflammatory processes caused by pro-inflammatory mediators like IL17 and IL23. Recently published data demonstrate that treatment with selective IL23 inhibitors lead to markedly high response rates in the cohort of CD patients that failed previous anti-TNF therapy. Macrophages are considered as a main source of IL23 in the intestine and are supposed to play a key role in the molecular crosstalk with T cell subsets and innate lymphoid cells in the gut. The following review focuses on mechanisms, pathways and specific therapies in Crohn’s disease underlying the IL23/IL17 pathway.

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Section: Janus Kinase (Jak) Inhibitors In Ibdmentioning

confidence: 99%

Role of the IL23/IL17 Pathway in Crohn’s Disease

2021

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“…Upadacitinib showed clinical efficacy in phase 2/3 trials for atopic dermatitis [44], ulcerative colitis [44], Crohn's disease [45], psoriatic arthritis [46], and ankylosing spondylitis [47]. Likewise, positive phase 2/3 results have been reported for filgotinib in treating Crohn's disease [44], ulcerative colitis [48], psoriatic arthritis [49], and ankylosing spondylitis [50]. Tofacitinib has received regulatory approval for treating psoriatic arthritis and ulcerative colitis [51], and has positive data in ankylosing spondylitis and also a number of dermatologic conditions.…”

Section: Expert Opinion On Jakinibs (From Us Eu and Japan): A Clinicamentioning

confidence: 99%

Filgotinib, a novel JAK1-preferential inhibitor for the treatment of rheumatoid arthritis: An overview from clinical trials

Tanaka

Kavanaugh

Wicklund

et al. 2021

Modern Rheumatology

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In the treatment of rheumatoid arthritis (RA), Janus kinase inhibitors (jakinibs) represent an emerging class of targeted therapies in addition to biologics. The number of jakinibs has been growing and as of 2020, filgotinib was the latest jakinib to enter the international market for treating RA. Filgotinib has demonstrated preferential inhibition of JAK1-dependent cytokine signaling in in vitro assays. It has been evaluated in the DARWIN (phase 2) and FINCH (phase 3) series of clinical studies for treating patients with moderately-to-severely active RA. Filgotinib received regulatory approval in Japan and Europe in September 2020, while in August 2020 the United States Food and Drug Administration requested additional data from two ongoing clinical studies assessing the potential impact of filgotinib on sperm parameters. This article will review the pharmacological properties, efficacy, and safety of filgotinib as demonstrated in clinical studies. Expert opinion will be provided on jakinibs for RA treatment from the viewpoints of basic research and clinical practice.

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“…However, anti-IL6 therapy had side effects in smaller studies on psoriasis and UC and must be explored carefully (68,69). Tofacitinib, a TYK2 and JAK2 inhibitor developed for RA, is now making way to treatment options in other diseases such as, CD, UC, and psoriasis (70)(71)(72)(73). Plerixafor (drug target: CXCR4) is a drug now used in cancer (lymphoma and multiple myeloma) after stem cell transplantation to initiate migration of stem cells in the bloodstream (74).…”

Section: Common Cell-gene Network Reveal Drug Repurposing Targetsmentioning

confidence: 99%

Integration of Immunome With Disease-Gene Network Reveals Common Cellular Mechanisms Between IMIDs and Drug Repurposing Strategies

Devaprasad

Pandit

2021

Front. Immunol.

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ObjectiveDevelopment and progression of immune-mediated inflammatory diseases (IMIDs) involve intricate dysregulation of the disease-associated genes (DAGs) and their expressing immune cells. Identifying the crucial disease-associated cells (DACs) in IMIDs has been challenging due to the underlying complex molecular mechanism.MethodsUsing transcriptome profiles of 40 different immune cells, unsupervised machine learning, and disease-gene networks, we constructed the Disease-gene IMmune cell Expression (DIME) network and identified top DACs and DAGs of 12 phenotypically different IMIDs. We compared the DIME networks of IMIDs to identify common pathways between them. We used the common pathways and publicly available drug-gene network to identify promising drug repurposing targets.ResultsWe found CD4+Treg, CD4+Th1, and NK cells as top DACs in inflammatory arthritis such as ankylosing spondylitis (AS), psoriatic arthritis, and rheumatoid arthritis (RA); neutrophils, granulocytes, and BDCA1+CD14+ cells in systemic lupus erythematosus and systemic scleroderma; ILC2, CD4+Th1, CD4+Treg, and NK cells in the inflammatory bowel diseases (IBDs). We identified lymphoid cells (CD4+Th1, CD4+Treg, and NK) and their associated pathways to be important in HLA-B27 type diseases (psoriasis, AS, and IBDs) and in primary-joint-inflammation-based inflammatory arthritis (AS and RA). Based on the common cellular mechanisms, we identified lifitegrast as a potential drug repurposing candidate for Crohn’s disease and other IMIDs.ConclusionsExisting methods are inadequate in capturing the intricate involvement of the crucial genes and cell types essential to IMIDs. Our approach identified the key DACs, DAGs, common mechanisms between IMIDs, and proposed potential drug repurposing targets using the DIME network. To extend our method to other diseases, we built the DIME tool (https://bitbucket.org/systemsimmunology/dime/) to help scientists uncover the etiology of complex and rare diseases to further drug development by better-determining drug targets, thereby mitigating the risk of failure in late clinical development.

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Efficacy of JAK inhibitors in Crohn’s Disease

Cited by 54 publications

References 83 publications

Role of the IL23/IL17 Pathway in Crohn’s Disease

Role of the IL23/IL17 Pathway in Crohn’s Disease

Filgotinib, a novel JAK1-preferential inhibitor for the treatment of rheumatoid arthritis: An overview from clinical trials

Integration of Immunome With Disease-Gene Network Reveals Common Cellular Mechanisms Between IMIDs and Drug Repurposing Strategies

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