Normalization of mucosal tumor necrosis factor-α: A new criterion for discontinuing infliximab therapy in ulcerative colitis

Olsen, Trine; Rismo, Renathe; Gundersen, Mona D.; Paulssen, Eyvind J.; Johnsen, Knut; Kvamme, Jan-Magnus; Goll, Rasmus; Florholmen, Jon

doi:10.1016/j.cyto.2015.12.021

Cited by 22 publications

(19 citation statements)

References 32 publications

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“…Unresolved questions include when therapy can be successfully discontinued following achievement of disease remission. Based on previous findings we propose that clinical and endoscopic criteria are not sufficient for determining disease remission, and that evidence of mucosal normalisation of inflammatory mediators is also needed 26 32 .…”

Section: Discussionmentioning

confidence: 93%

“…IL33 mucosal gene expression was increased in acute UC, alongside other known mediators of acute inflammation including TNF. The normalisation of mucosal TNF-expression has previously been associated with long-term disease remission in UC 32 . Interestingly, we found a more pronounced downregulation of inflammatory cytokines in the subgroup of patients (n = 10) whom achieved normalisation of mucosal TNF levels, including a significant reduction of IL-33 (p = 0.02).…”

Section: Discussionmentioning

confidence: 93%

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Loss of interleukin 33 expression in colonic crypts - a potential marker for disease remission in ulcerative colitis

Gundersen

Goll

Hol

et al. 2016

Sci Rep

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Interleukin 33 (IL-33) is a cytokine preferentially elevated in acute ulcerative colitis (UC), inferring a role in its pathogenesis. The role of IL-33 in intestinal inflammation is incompletely understood, with both pro-inflammatory and regulatory properties described. There are also conflicting reports on cellular sources and subcellular location of IL-33 in the colonic mucosa, justifying a closer look at IL-33 expression in well-defined clinical stages of UC. A total of 50 study participants (29 UC patients and 21 healthy controls) were included from a prospective cohort of inflammatory bowel disease patients treated to disease remission with infliximab, a tumour necrosis factor alpha (TNF) inhibitor. To our knowledge this is the first study examining mucosal IL-33 expression before and after anti-TNF therapy. In colonic mucosal biopsies we found a 3-fold increase in IL-33 gene expression comparing acute UC to healthy controls (p < 0.01). A significant reduction of IL33 between acute UC and disease remission was observed when TNF normalised in the mucosa (p = 0.02). Immunostaining revealed IL-33 in the nuclei of epithelial cells of scattered colonic crypts in acute disease, while at disease remission, IL-33 was undetectable, a novel finding suggesting that enterocyte-derived IL-33 is induced and maintained by inflammatory mediators.

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Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 93%

Loss of interleukin 33 expression in colonic crypts - a potential marker for disease remission in ulcerative colitis

Gundersen

Goll

Hol

et al. 2016

Sci Rep

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“…In human pathology, among inflammatory cytokines, TNF-α and IL-17 are the most important for progression of UC towards chronic inflammation. 1 , 47 Reduction of serum levels of TNF-α predicts long-term remission of UC 48 and the use of anti-TNF-α biological agents represents the most effective therapeutic approach for inducing mucosal healing in patients with UC. 49 Accordingly, downregulation of serum and fecal levels of TNF-α, followed by decreased levels of IL-17, are associated with achievement of mucosal healing in patients with UC who receive anti-TNF-α biologics.…”

Section: Discussionmentioning

confidence: 99%

Indoleamine 2,3-dioxygenase-dependent expansion of T-regulatory cells maintains mucosal healing in ulcerative colitis

Acović

Marković

Gazdic

et al. 2018

Therap Adv Gastroenterol

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Background:Dendritic cell (DC)-derived indolamine 2,3-dioxygenase (IDO) degrades tryptophan to kynurenine, which promotes conversion of inflammatory T cells in immunosuppressive regulatory T cells (Tregs). We analyzed the significance of the IDO:Treg axis for inducing and maintaining mucosal healing in ulcerative colitis (UC).Methods:Dextran sodium sulphate (DSS)-induced colitis in BALB/c mice (model for mucosal healing) and C57BL/6 mice (model for persistent disease) was used. Serum, fecal samples and colon-infiltrating immune cells of 65 patients with UC with mucosal healing or persistent colitis were analyzed.Results:Significantly higher serum levels of kynurenine and downregulated inflammatory cytokines were noticed in DSS-treated BALB/c mice compared with C57BL/6 mice. Increased IDO activity and attenuated capacity for antigen presentation and production of inflammatory cytokines, observed in BALB/c DCs, was followed by a significantly lower number of inflammatory T helper 1 (Th1) and Th17 cells and a notably increased number of Tregs in the colons of DSS-treated BALB/c mice. DCs and Tregs were crucially important for the maintenance of mucosal healing since their depletion aggravated colitis. Mucosal healing, followed by an increase in kynurenine and intestinal Tregs, was re-established when BALB/c DCs were transferred into DC-depleted or Treg-depleted DSS-treated BALB/c mice. This phenomenon was completely abrogated by the IDO inhibitor. Significantly higher serum and fecal levels of kynurenine, accompanied by an increased presence of intestinal Tregs, were noticed in patients with UC with mucosal healing and negatively correlated with disease severity, fecal calprotectin, colon-infiltrating interferon γ and interleukin-17-producing cells, serum and fecal levels of inflammatory cytokines.Conclusion:IDO-dependent expansion of endogenous Tregs should be further explored as a new approach for the induction and maintenance of mucosal healing in patients with UC.

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“…No: 205314; Qiagen, Hilden, Germany). Mucosal TNF gene transcript was measured by real-time PCR procedures previously described in detail [30][31][32][33].…”

Section: Cytokine Transcript Measurementsmentioning

confidence: 99%

Discovery and validation of mucosal TNF expression combined with histological score - a biomarker for personalized treatment in ulcerative colitis

et al. 2020

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Background There are no accurate markers that can predict clinical outcome in ulcerative colitis at time of diagnosis. The aim of this study was to explore a comprehensive data set to identify and validate predictors of clinical outcome in the first year following diagnosis. Methods Treatment naive-patients with ulcerative colitis were included at time of initial diagnosis from 2004 to 2014, followed by a validation study from 2014 to 2018. Patients were treated according to clinical guidelines following a standard step-up regime. Patients were categorized according to the treatment level necessary to achieve clinical remission: mild, moderate and severe. The biopsies were assessed by Robarts histopathology index (RHI) and TNF gene transcripts. Results We included 66 patients in the calibration cohort and 89 patients in the validation. Mucosal TNF transcripts showed high test reliability for predicting severe outcome in UC. When combined with histological activity (RHI) scores the test improved its diagnostic reliability. Based on the cut-off values of mucosal TNF and RHI scores from the calibration cohort, the combined test had still high reliability in the validation cohort (specificity 0.99, sensitivity 0.44, PPV 0.89, NPV 0.87) and a diagnostic odds-ratio (DOR) of 54. Conclusions The combined test using TNF transcript and histological score at debut of UC can predict severe outcome and the need for anti-TNF therapy with a high level of precision. These validated data may be of great clinical utility and contribute to a personalized medical approach with the possibility of top-down treatment for selected patients.

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Normalization of mucosal tumor necrosis factor-α: A new criterion for discontinuing infliximab therapy in ulcerative colitis

Cited by 22 publications

References 32 publications

Loss of interleukin 33 expression in colonic crypts - a potential marker for disease remission in ulcerative colitis

Loss of interleukin 33 expression in colonic crypts - a potential marker for disease remission in ulcerative colitis

Indoleamine 2,3-dioxygenase-dependent expansion of T-regulatory cells maintains mucosal healing in ulcerative colitis

Discovery and validation of mucosal TNF expression combined with histological score - a biomarker for personalized treatment in ulcerative colitis

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