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.

BackgroundFecal calprotectin is widely used to monitor disease activity in patients with inflammatory bowel disease. Multiple commercial kits exist, however, since the analyses are not standardized, these kits cannot be used interchangeably. We aimed to perform a technical evaluation of two kits (Calpro from Calprolab, Norway and Calprest from Eurospital, Italy) and perform a tuning for detection of clinically relevant disease states in ulcerative colitis.Materials and methodsFor tuning against different clinical states a total of 116 patients with ulcerative colitis were recruited (67 of which were part of an earlier publication). For the technical evaluation an additional series of 80 random samples from the hospital lab were included. Technical evaluation was done by correlation and limits of agreement analysis; cut-off levels were explored by ROC analysis against clinically relevant actual states.ResultsThe technical evaluation revealed good correlation between assays, however a non-linear difference was found: At values below 200 mg/kg, no significant bias was found; in the interval 200–1000 mg/kg the Calprest assay measured on average 30% lower than Calpro; and at higher values Calprest measured 60% higher values than Calpro. Both assays predicted Mayo endoscopic score (MES) 0 (cutoff 28: sensitivity 0.38; specificity 0.82 for Calprest; cutoff 28: sensitivity 0.50; specificity 0.77 for Calpro), and MES 2–3 (cutoff 148: sensitivity 0.72; specificity 0.80 for Calprest; cutoff 208: sensitivity 0.64; specificity 0.80 for Calpro), but did not predict normalization of mucosal TNF transcript per se. A combination of calprotectin and MES predicted mucosal TNF transcript values reasonably well (Calpro: sensitivity 0.85, specificity 0.58; Calprest: sensitivity 0.85, specificity 0.61).ConclusionThe Calpro and Calprest assays correlated well, but subtle differences were found, underlining the need for kit-specific cut-off values. Both kits were most precise in predicting active inflammation (MES 2–3), but less so for prediction of mucosal healing (MES 0) and normalization of mucosal TNF gene expression.

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 2004–2014, followed by a validation study from 2014–2018. 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.

Background The long-term outcomes of Ulcerative colitis (UC) after discontinuation of biological therapy are largely unknown. There is also a lack of accurate and validated markers that can predict outcome after withdrawal accurately. The aims of this study were to describe the long-term outcomes in UC patients following cessation of anti-TNF therapy and explore potential biomarkers as an approach towards precision medicine. Methods Seventy-five patients with moderate to severe UC treated to remission with anti-tumor necrosis factor (TNF) were included in the study. This is a follow-up of previously reported UC outcomes. The patients were categorized as either “Remission” or “Relapse”. The “Relapse” group was divided into subgroups determined by the highest treatment level needed to obtain remission the last 3 years of observation: non-biological therapy, biological therapy or colectomy. Remission were divided in long term remission (LTR), those using immunomodulating drugs (LTR + imids) and those using only 5-amino-salicylate (5-ASA) treatment (LTR) for the past 3 years. Analyses of mucosal gene expression by real-time PCR were performed. Results The median (IQR) observation time of all patients included was 121 (111–137) months. Of the 75 patients, 46 (61%) did not receive biological therapy, including 23 (31%) in LTR ± imids. Of these 23 patients, 16 (21%) were defined as LTR with a median observation time of (IQR) 95 (77–113) months. In total 14 patients (19%) underwent colectomy during the 10 years after first remission. Mucosal TNF copies/µg mRNA < 10 000 at anti-TNF discontinuation predicted long-term remission, biological free remission and lower risk of colectomy with a HR 0.36 (0.14–0.92) for long-term remission, HR 0.17 (0.04–0.78) for biological free remission and HR 0.12 (0.01–0.91) for colectomy. IL1RL1 was normalized in LTR phenotype and higher in relapsing UC. Conclusion In this 10-year follow-up of UC of patients with moderate to severe disease, 61% of patients experience an altered phenotype to a milder disease course without need of biological therapy. Twenty-one percent of the patients were LTR without any medication except of 5-ASA. Mucosal TNF gene expression and IL1RL1- transcripts may be of clinical utility for long term prognosis in development of precision medicine in UC.