• molecular biology
• structural biology

• Humans
• Janus Kinases/genetics
• Janus Kinases/metabolism
• Janus Kinases/chemistry
• STAT Transcription Factors/genetics
• STAT Transcription Factors/metabolism
• STAT Transcription Factors/chemistry
• Signal Transduction/genetics
• Cytokines/genetics
• Cytokines/metabolism
• Protein Engineering

• 2025931 Department of Health | National Health and Medical Research Council (NHMRC)
• XUST Seeding grant 2050122039

• Crohn’s disease
• Janus kinase inhibitors
• inflammatory bowel disease
• selectivity
• ulcerative colitis

• Crohn’s disease
• biologic therapy
• inflammatory bowel diseases
• liver toxicity
• small molecules
• ulcerative colitis

• Humans
• Non-alcoholic Fatty Liver Disease/complications
• Non-alcoholic Fatty Liver Disease/drug therapy
• Non-alcoholic Fatty Liver Disease/epidemiology
• Cholangitis, Sclerosing/complications
• Cholangitis, Sclerosing/drug therapy
• Hepatitis, Autoimmune/complications
• Inflammatory Bowel Diseases/complications
• Inflammatory Bowel Diseases/drug therapy
• Comorbidity
• Biological Factors/therapeutic use

• JAK inhibitors
• inflammatory bowel diseases
• oral therapies
• small molecules
• treatment

• Crohn’s disease
• Mendelian randomization
• hidradenitis suppurativa
• inflammatory bowel disease
• ulcerative colitis

• Crohn’s disease
• Graves’ disease
• Mendelian randomization
• inflammatory bowel disease
• ulcerative colitis

• ABT-494
• CDAI
• IBD
• JAK inhibitor

• Crohn’s disease
• Janus kinase inhibitors
• effectiveness
• efficacy
• inflammatory bowel diseases
• safety
• tofacitinib
• ulcerative colitis

• Inflammatory bowel disease
• Janus kinase inhibitors
• clinical trials
• small molecules
• ulcerative colitis

• Crohn disease
• Janus kinase inhibitors
• ulcerative colitis

For a significant proportion of patients with inflammatory bowel disease (IBD), primary non-response and secondary loss of response to treatment remain significant issues. Anti-tumor necrosis factor therapies have been licensed for use in IBD. Other disease-related pathways have been targeted as well, including the interleukin 12/23 axis and lymphocyte tracking. However, the need for parenteral administration and the associated costs of dispensing and monitoring all biologics remain a burden on healthcare systems and patients. Janus kinase inhibitors are small-molecule drugs that can be administered orally and are relatively inexpensive, thus offering an additional option for treating IBD. They have been shown to be effective in patients with ulcerative colitis (UC), but they are less effective in those with Crohn’s disease (CD). Nonetheless, given the immune-system-based mechanism of these drugs, their safety profile remains a cause for concern. This article provides an overview of Janus kinase (JAK) inhibitors and new trends in the treatment of IBD.

• inflammatory bowel disease
• janus kinase inhibitor
• small molecule drugs

• Biologicals
• Crohn’s disease
• Inflammatory bowel diseases
• Janus kinase inhibition
• Lymphocyte trafficking
• Small molecules
• Stem cell transplantation
• Ulcerative colitis

Inflammatory bowel diseases (IBDs), mainly represented by Crohn’s disease (CD) and Ulcerative Colitis (UC), are chronic disorders with an unclear pathogenesis. This incurable and iterative intestinal mucosal inflammation requires the life-long use of anti-inflammatory drugs to prevent flares or relapses, which are the major providers of complications, such as small bowel strictures and intestinal perforations. The introduction of tumor necrosis factor (TNF)-alpha inhibitors and other compounds, such as anti-IL12/23 and anti-alpha4/beta7 integrin monoclonal antibodies, has considerably improved the clinical management of IBDs. They are now the standard of care, being the first-line therapy in patients with aggressive disease and in patients with moderate to severe disease with an inadequate response to conventional therapy. However, for approximately one third of all patients, their efficacy remains insufficient by a lack or loss of response due to the formation of anti-drug antibodies or compliance difficulties with parenteral formulations. To address these issues, orally administered Small Molecules Drugs (SMDs) that use a broad range of novel pharmacological pathways, such as JAK inhibitors, sphingosine-1-phosphate receptor modulators, and phosphodiesterase 4 inhibitors, have been developed for CD and UC. This article provides an updated and complete review of the most recently authorized SMDs and SMDs in phase II/III development.

• Crohn’s disease
• inflammatory bowel diseases
• small molecule drugs
• ulcerative colitis

Blocking interferon-function by therapeutic intervention of the JAK-STAT-axis is a novel promising treatment option for inflammatory bowel disease (IBD). Although JAK inhibitors have proven efficacy in patients with active ulcerative colitis (UC), they failed to induce clinical remission in patients with Crohn's disease (CD). This finding strongly implicates a differential contribution of JAK signaling in both entities. Here, we dissected the contribution of different STAT members downstream of JAK to inflammation and barrier dysfunction in a mouse model of Crohn's disease like ileitis and colitis (Casp8^ΔIEC mice). Deletion of STAT1 in Casp8^ΔIEC mice was associated with reduced cell death and a partial rescue of Paneth cell function in the small intestine. Likewise, organoids derived from the small intestine of these mice were less sensitive to cell death triggered by IBD-key cytokines such as TNFα or IFNs. Further functional in vitro and in vivo analyses revealed the impairment of MLKL-mediated necrosis as a result of deficient STAT1 function, which was in turn associated with improved cell survival. However, a decrease in inflammatory cell death was still associated with mild inflammation in the small intestine. The impact of STAT1 signaling on gastrointestinal inflammation dependent on the localization of inflammation, as STAT1 is essential for intestinal epithelial cell death regulation in the small intestine, whereas it is not the key factor for intestinal epithelial cell death in the context of colitis. Of note, additional deletion of STAT2 was not sufficient to restore Paneth cell function but strongly ameliorated ileitis. In summary, we provide here compelling molecular evidence that STAT1 and STAT2, both contribute to intestinal homeostasis, but have non-redundant functions. Our results further demonstrate that STATs individually affect the distinct pathophysiology of inflammation in the ileum and colon, respectively, which might explain the diverse outcome of JAK inhibitors on inflammatory bowel diseases.

• Paneth cells
• STAT signaling
• cell death
• inflammation
• inflammatory bowel disease

• Cell death
• Gastrointestinal infection
• IBD
• Interferons

• Crohn’s disease
• Inflammatory bowel disease
• JAK/STAT inhibition
• JAK/STAT pathway
• Janus kinase
• Signal transducer and activator of transcription
• Tofacitinib
• Ulcerative colitis

• Colitis, Ulcerative/drug therapy
• Crohn Disease/drug therapy
• Humans
• Janus Kinase Inhibitors/pharmacology
• Janus Kinase Inhibitors/therapeutic use
• Janus Kinases
• Transducers

• 6-Aminopyridin-3-ol
• Adhesion
• Angiogenesis
• Inflammatory bowel disease
• Ring modification
• Structure-activity relationship
• TNF-α

Currently, there is a growing interest in Janus kinase (JAK) intracellular signalling since targeted inhibitors against these pathways are proving effective in the treatment of a range of immune-mediated diseases, such as rheumatoid arthritis (RA), psoriasis, psoriatic arthritis (PsA), inflammatory bowel disease and atopic dermatitis. In particular, post marketing experience and the increasing development of new pharmacological inhibitors of broad and increasingly selective JAK pathways provide new insights into the JAK pathway role in viral infections as well as their pathogenic role in immune-mediated inflammatory diseases. Herein we provide an overview of the biological role of JAK signalling and its role in immunity against viruses, with particular regard to herpes zoster reactivation. Thereafter, we will discuss the evidence currently available on the principal JAK inhibitors and their association with viral infections.

• AK
• JAK inhibitors
• herpes zoster
• immune-mediated diseases
• inflammatory arthritis
• rheumatoid arthritis

• IBD
• Immunosuppression
• NMSC
• Small Molecule

Despite the development of novel therapies, inflammatory bowel diseases remain an innovative treatment challenge. Helminth therapy is a new promising approach, and a key issue is the identification of helminth-derived anti-inflammatory mediators. P28 glutathione-S-transferase (P28GST), a protein derived from schistosomes, a trematode parasitic helminth, was shown to reduce intestinal inflammation in experimental colitis by down-regulating the Th1/Th17 response. In this multicenter, open-label, pilot Phase 2a study, we evaluated the safety of P28GST administered to patients with mild Crohn’s disease (CD). We enrolled 10 patients with a baseline Crohn’s disease activity index (CDAI) value <220. Eight patients received two to three subcutaneous injections of recombinant P28GST with adjuvant. This three-month treatment was followed by a nine-month monitoring period. The primary endpoints were the monthly rate and seriousness of adverse events (AEs). Secondary endpoints were clinical recurrence, assessed with the CDAI as well as the levels of immunologic and inflammatory blood and tissue markers. The most common AEs were local or regional events at the injection site and gastrointestinal disorders. At three months after the first injection, CDAI scores and blood calprotectin levels decreased in parallel. These results indicate that P28GST showed promise as a safe and new therapeutic option for treating CD.

• Crohn’s disease
• Crohn’s disease activity index
• P28GST
• calprotectin
• helminth protein
• safety

• IBD clinical
• crohn’s disease
• drug development
• inflammatory bowel disease
• ulcerative colitis