Secukinumab, a human anti-IL-17A monoclonal antibody, for moderate to severe Crohn's disease: unexpected results of a randomised, double-blind placebo-controlled trial

Hueber, Wolfgang; Sands, Bruce E.; Lewitzky, Steve; Vandemeulebroecke, Marc; Reinisch, Walter; Higgins, Peter; Wehkamp, Jan; Feagan, Brian G.; Yao, Michael; Karczewski, Marek; Karczewski, Jacek; Pezous, Nicole; Bek, Stephan; Bruin, Gerard; Mellgard, Bjoern; Berger, C; Londei, Marco; Bertolino, Arthur P.; Tougas, Gervais; Travis, Simon

doi:10.1136/gutjnl-2011-301668

Cited by 1,303 publications

(941 citation statements)

References 38 publications

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“…For instance, the anti IFNγ anti body fontolizumab showed low efficacy in patients for treatment of active Crohn's disease 80 . Moreover, the anti IL 17A antibody secukinumab resulted in aggrav ation of Crohn's disease in many patients, possibly owing to the protective effects of IL 17A on gut epi thelial cells [81][82][83] . Consistently, IL 17A inactivation did not result in amelioration of experimental colitis in mice 84,85 .…”

Section: T Cellmentioning

confidence: 99%

Current and emerging therapeutic targets for IBD

Neurath

2017

Nat Rev Gastroenterol Hepatol

484

368

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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

484

368

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“…54 Further, STAT3 was shown to be required to drive both colitis and systemic inflammation not only by modulating T H 17-cell differentiation but also by promoting T-cell activation and survival. 41 However, targeted therapies against IL-17A in Crohn's disease have been proven ineffective 55,56 and recent studies have shown that IL-17A is important for maintaining intestinal barrier integrity and has a protective role in regard to the development of colitis. 57,58 Further, it is becoming more apparent that the T H 17-cell lineage has a degree of heterogeneity with regards to pathogenicity.…”

Section: Hic1 Is Required To Limit Stat3 Signaling In T H 17 Cellsmentioning

confidence: 99%

The transcriptional repressor HIC1 regulates intestinal immune homeostasis

et al. 2017

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“…Conversely, because Th17 cells express stem cell markers and appear to have greater capacity for self-renewal than Th1-like cells (42), and might therefore serve as a reservoir of nonpathogenic cells able to transition into pathogenic, IFN-γ producing cells, therapies that deplete Th17 cells are also warranted. In this regard, antibody-based therapies that block IL-12p40 (and thus both IL-23 and IL-12) (43, 44) and IFN-γ (45) have shown promise in IBD trials, whereas blockade of IL-17A has not (46), despite promising results in clinical trials of other Th17-driven autoimmune disorders, such as psoriasis, rheumatoid arthritis, and uveitis (47). Thus, although the rationale for targeting the Th17 pathway remains promising in IBD, strategies that target both the Th17 and Th1 arms should be considered.…”

Section: Wt Th17pmentioning

confidence: 99%

Th17 cells give rise to Th1 cells that are required for the pathogenesis of colitis

Harbour¹,

Maynard²,

Zindl³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

342

274

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Th17 cells reactive to the enteric microbiota are central to the pathogenesis of certain types of inflammatory bowel disease. However, Th17 cells display substantial developmental plasticity, such that some progeny of Th17 cell precursors retain a predominantly IL-17A+ phenotype, whereas others extinguish IL-17 expression and acquire expression of IFN-γ, giving rise to “Th1-like” cells. It remains unclear what role these subsets play in inflammatory bowel disease. Using a Th17 transfer model of colitis, we found that IFN-γ–deficient Th17 cells retained an IL-17A+ phenotype and were unable to induce colitis in recipients. Development of disease required the transition of a subset of Th17 precursors to Th1-like cells and was contingent on the expression of both Stat4 and T-bet, but not the IL-12 or IFN-γ receptors. Moreover, Th17 cells could provide “help” for the development of pathogenic Th1 cells from naïve precursors. These results indicate that Th17 cells are potent mediators of colitis pathogenesis by dual mechanisms: by directly transitioning to Th1-like cells and by supporting the development of classic Th1 cells.

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Secukinumab, a human anti-IL-17A monoclonal antibody, for moderate to severe Crohn's disease: unexpected results of a randomised, double-blind placebo-controlled trial

Cited by 1,303 publications

References 38 publications

Current and emerging therapeutic targets for IBD

Current and emerging therapeutic targets for IBD

The transcriptional repressor HIC1 regulates intestinal immune homeostasis

Th17 cells give rise to Th1 cells that are required for the pathogenesis of colitis

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