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

Abstract

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.

Evaluation of anti-TNF therapeutic response in patients with inflammatory bowel disease: Current and novel biomarkers

“…Anti-TNF mAbs could significantly reduce the expression level of TNF-α and suppress the inflammation, therefore the changed mucosal TNF-α transcript level might be used as a promising biomarker to assess the anti-TNF efficacy. More recently, we have validated a correlation between mucosal TNF-α transcript levels and response to anti-TNF mAbs in UC [7] . Validation data demonstrated that baseline mucosal TNF-α transcript level was a better biomarker with a high-test reliability for the prediction of clinical outcomes than other clinical parameters e.g., calprotectin, the UC disease activity index (UCDAI) score, Mayo endoscopic score in patients with UC [7] .…”

“…However, they could not validate such correlation between changed microbiota and anti-TNF therapeutic response [46] . More recently, our group have validated the value of mucosal TNF transcript as a reliable biomarker in the evaluation of anti-TNF therapeutic response in patients with UC [7] . We were able to show that baseline mucosal TNF-α transcript level was a better biomarker than other clinical parameters e.g., calprotectin, the UC disease activity index (UCDAI) score, Mayo endoscopic score in patients with UC [7] .…”

“…However, the level of drugs and ADA are often applied to the monitoring of anti-TNF therapy. Mucosal TNF transcript is a biomarker that not only help in evaluation of therapeutic response, but also help to identify the candidates who should prior to the administration and personation of anti-TNF mAbs in patients with UC [7] . Moreover, the accuracy and power of individual biomarker in the evaluation of therapeutic response in patients with IBD might be low.…”

“…In addition, laboratory biomarkers provide a reproducibly quantifiable tool for the evaluation of disease status and therapeutic efficacy in IBD patients. Therefore, the discovery of reliable biomarkers would be extremely useful in the clinical practice and adds a great help to assess therapeutic efficacy, minimize side-effects, and optimize personalized medicine and strategy for identifying IBD patients who will benefit from anti-TNF therapy [ 7 , 8 ].…”

Improving prediction of disease outcome for inflammatory bowel disease: progress through systems medicine

“…In addition to serological markers, mucosa derived molecular signatures have also been tested for their disease prognostic value. For example, mucosal TNF-alpha expression combined with histological disease activity scores at the point of diagnosis have been reported to be predictive of a severe outcome in UC with a positive and negative predicate values of 0.89 and 0.87 respectively [ 40 ]. However, such parameters are very difficult to implement in routine clinical practice and results are still pending validation in larger, independent patient cohorts.…”