Update on Janus Kinase Antagonists in Inflammatory Bowel Disease

Boland, Brigid S.; Sandborn, William J.; Chang, John T.

doi:10.1016/j.gtc.2014.05.011

Cited by 75 publications

(43 citation statements)

References 47 publications

(78 reference statements)

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“…Thus, blockade of JAK kinases might be used to suppress cytokine signalling in mucosal immune cells. As individual JAKs mediate cell activation via sev eral cytokines (for example, JAK3 is activated via IL 2, IL 4, IL 7, IL 9, IL 15 and IL 21) with proposed pro inflammatory roles in colitis [110][111][112][113] , this approach opens the possibility to block the activity of several pro inflammatory cytokines simultaneously. Indeed, several JAK inhibitors (tofacitinib, ABT494 and filgo tinib) have been developed for clinical therapy 114,115 .…”

Section: T Cellmentioning

confidence: 99%

Current and emerging therapeutic targets for IBD

Neurath

2017

Nat Rev Gastroenterol Hepatol

518

403

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Inflammatory bowel diseases (including IBD, exempli fied by Crohn's disease and ulcerative colitis) are chronic relapsing disorders affecting the gastrointestinal tract. IBD has a progressive and destructive nature and, there fore, can cause various complications including steno ses, abscesses, fistulas, extraintestinal manifestations and colitis associated neoplasias and cancer 1,2 . Thus, effective therapeutic approaches are of high clinical rele vance in patients with IBD. This Review summarizes current therapeutic strategies and highlights emerging new treatment approaches for IBD with special refer ence to the proposed molecular mechanisms of action of anti inflammatory drugs. Current IBD therapiesClassic anti-inflammatory drugs. 5 Aminosalicylates (5 ASAs) are important anti inflammatory drugs that are frequently used for anti inflammatory therapy in patients with ulcerative colitis 3 . By contrast, 5 ASA based drugs show little or no efficacy in inducing res olution of clinical symptoms and tissue inflammation in patients with Crohn's disease 4 .5 ASAs are effective for induction and mainten ance of remission in ulcerative colitis and might also reduce the risk of developing colitis associated tumours in these patients 5 . Several mechanisms of action for 5 ASAs have been proposed, including reduction of prostaglandin synthesis via inhibition of cyclooxygenase, suppression of proinflammatory cytokine production and oxygen free radicals, inhib ition of lipoxygenase, blockade of neutrophil chemo taxis and mast cell activation, and impairment of nuclear factor κB activation (NF κB) in immune cells 3 . Moreover, studies in mice revealed that 5 ASA based drugs augment peroxisome proliferator activated receptor γ (PPARγ) expression and promote PPARγ translocation from the cytoplasm to the nucleus where they result in activation of peroxisome proliferator hormone response element driven genes to suppress colitis activity 6,7 .In addition to 5 ASAs, corticosteroids (systemically or topically delivered) have been used for remission induction in ulcerative colitis 2 . Although cortico steroids favour induction of remission in both ulcer ative colitis and Crohn's disease, they are not suitable for mainten ance of remission in IBD 1,2 . Mechanistically, gluco corticoids bind to a specific cytosolic receptor fol lowed by translocation of the complex to the nucleus to either activate or repress gene transcription (via bind ing to DNA corticosteroid response elements) 8,9 . Additionally, the glucocorticoid-receptor complex can inactivate pro inflammatory transcription factors such as NF κB and activator protein 1 (AP1) via proteinprotein inter actions, thereby preventing their activation of inflammatory mediators (for example, leukotrienes and cytokines such as IL 1 and IL 6). REVIEWS© 2 0 1 7 M a c m i l l a n P u b l i s h e r s L i m i t e d , p a r t o f S p r i n g e r N a t u r e . A l l r i g h t s r e s e r v e d .

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Section: T Cellmentioning

confidence: 99%

Current and emerging therapeutic targets for IBD

Neurath

2017

Nat Rev Gastroenterol Hepatol

518

403

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“…The drug is currently being investigated for the treatment of psoriasis and IBD (12)(13)(14)(15) . TOFA (CP-690,550) is an oral small-molecule drug (SMD) with a molecular weight of 312.3 Da.…”

Section: Discussionmentioning

confidence: 99%

“…This inhibition ends up blocking signals for several inflammatory cytokines such as interleukin (IL)-2, IL-4, IL-6, IL-7, IL-9, IL-15, IL-21 and interferon-gama, among others (13)(14)(15) . These cytokines are involved in the pathogenesis of IBD and play a role in many immune signaling routes including lymphocyte activation, function, and proliferation (12)(13)(14)(15) . The initial favorable results of TOFA in a phase II multicenter randomized trial in UC, prompted a phase III program (OCTAVE) investigating the efficacy and safety of induction and maintenance therapy in patients with moderately to severely active UC (8,9) .…”

Section: Discussionmentioning

confidence: 99%

Tofacitinib in the Management of Ulcerative Colitis Refractory to Anti-TNF and Anti-Integrin Therapies

Teixeira

Damião

Kotze

2018

Arq. Gastroenterol.

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-Janus kinases inhibitors have already been incorporated into the management of immune-mediated diseases, such as rheumatoid arthritis, and are being investigated for the treatment of psoriasis and inflammatory bowel diseases, both ulcerative colitis and Crohn's disease. Tofacitinib is an oral small-molecule drug that inhibits Janus kinases 1, Janus kinases 3, and, to a lesser extent, Janus kinases 2. This inhibition ends up blocking signals for several inflammatory cytokines that are involved in the pathogenesis of inflammatory bowel diseases and play a role in many immune signaling routes, including lymphocyte activation, function, and proliferation. We report a patient with active ulcerative colitis with primary non-response to three biologics (infliximab, adalimumab and vedolizumab), with different mechanisms of action, who refused surgical treatment and had a favorable response to tofacitinib with clinical and endoscopic remission. No adverse events were observed with the use of the agent. This case illustrates the difficulties we may face regarding the identification of the expression of proper mechanism of action involved in the pathogenesis of ulcerative colitis patients and the importance of having another treatment option with different mechanism of action, like tofacitinib. HEADINGS -Proctocolitis, therapy. Biological factors. Monoclonal antibodies. Janus kinase inhibitors, therapeutic use.Declared conflict of interest of all authors: Teixeira FV is a speaker and consultant for Janssen, Ferring, Abbvie and Takeda; advisory board for Ferring and Janssen. Damião AOMC is a speaker and consultant for Abbvie, Janssen, Pfizer and Takeda. He is also an employee of Nestle. Kotze PG is a speaker and consultant of Abbvie, Janssen, Takeda and Pfizer. Disclosure of funding: no funding received Studied carried out at Gastrosaúde,

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“…The orally delivered substance filgotinib is an inhibitor of Janus-kinase 1 (JAK1) [64]. In a randomized, double-blinded phase II trial, filgotinib was effective in the induction of clinical remission, but it failed to reach an endoscopic improvement ( n = 174).…”

Section: New Substances In the Pipeline – Reason To Hopementioning

confidence: 99%

Treatment Perspectives in Crohn’s Disease

Vetter¹

2018

Digestion

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Background: Crohn’s disease (CD) is a chronic immune-mediated disorder of the gastrointestinal tract. The pathophysiological understanding of this disease is limited and no curative therapy is available so far. Therefore, most patients require long-lasting or even life-long immunosuppressive therapies for the suppression of symptoms to improve quality of life and reduction of long-term risks. However, in a relevant subgroup of patients, these therapeutic goals cannot be sufficiently attained. Summary: Clinically established therapies in active CD comprise corticosteroids and immunosuppressants such as azathioprine. After the introduction of anti-TNFα (Tumor necrosis factor alpha) antibodies, other biologicals (e.g., vedolizumab and ustekinumab) have also been approved. New drugs in the pipeline like filgotinib, upadacitinib, risankizumab or rifaximin could improve the therapy of CD in the near future. Thus, an individualized therapy management, based on optimal selection of therapeutic agents will become more important. Additionally, the local application of mesenchymal stem cells might be helpful in the management of fistulas. Key Messages: The targeted biological therapeutic agents (anti-TNFα antibodies, vedolizumab, ustekinumab) are well established for therapy in CD. There are several new substances in the pipeline with promising results in phase II trials (filgotinib, rifaximin, risankizumab, upadacitinib). The upcoming extension of the therapeutic arsenal will require methods for an optimized selection of substances, thus enabling a more individualized therapy.

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Update on Janus Kinase Antagonists in Inflammatory Bowel Disease

Cited by 75 publications

References 47 publications

Current and emerging therapeutic targets for IBD

Current and emerging therapeutic targets for IBD

Tofacitinib in the Management of Ulcerative Colitis Refractory to Anti-TNF and Anti-Integrin Therapies

Treatment Perspectives in Crohn’s Disease

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