Clinical and biological predictors of response to standardised paediatric colitis therapy (PROTECT): a multicentre inception cohort study

Abstract

Background: Lack of evidence-based outcomes data leads to uncertainty in developing treatment regimens in children who are newly diagnosed with ulcerative colitis. We hypothesised that pretreatment clinical, transcriptomic, and microbial factors predict disease course.

Methods: In this inception cohort study, we recruited paediatric patients aged 4-17 years with newly diagnosed ulcerative colitis from 29 centres in the USA and Canada. Patients initially received standardised mesalazine or corticosteroids, with pre-established criteria for escalation to immunomodulators (ie, thiopurines) or anti-tumor necrosis factor-α (TNFα) therapy. We used RNA sequencing to define rectal gene expression before treatment, and 16S sequencing to characterise rectal and faecal microbiota. The primary outcome was week 52 corticosteroid-free remission with no therapy beyond mesalazine. We assessed factors associated with the primary outcome using logistic regression models of the per-protocol population. This study is registered with ClinicalTrials.gov, number NCT01536535.

Findings: Between July 10, 2012, and April 21, 2015, of 467 patients recruited, 428 started medical therapy, of whom 400 (93%) were evaluable at 52 weeks and 386 (90%) completed the study period with no protocol violations. 150 (38%) of 400 participants achieved week 52 corticosteroid-free remission, of whom 147 (98%) were taking mesalazine and three (2%) were taking no medication. 74 (19%) of 400 were escalated to immunomodulators alone, 123 (31%) anti-TNFα therapy, and 25 (6%) colectomy. Low baseline clinical severity, high baseline haemoglobin, and week 4 clinical remission were associated with achieving week 52 corticosteroid-free remission (n=386, logistic model area under the curve [AUC] 0·70, 95% CI 0·65-0·75; specificity 77%, 95% CI 71-82). Baseline severity and remission by week 4 were validated in an independent cohort of 274 paediatric patients with newly diagnosed ulcerative colitis. After adjusting for clinical predictors, an antimicrobial peptide gene signature (odds ratio [OR] 0·57, 95% CI 0·39-0·81; p=0·002) and abundance of Ruminococcaceae (OR 1·43, 1·02-2·00; p=0·04), and Sutterella (OR 0·81, 0·65-1·00; p=0·05) were independently associated with week 52 corticosteroid-free remission.

Interpretation: Our findings support the utility of initial clinical activity and treatment response by 4 weeks to predict week 52 corticosteroid-free remission with mesalazine alone in children who are newly diagnosed with ulcerative colitis. The development of personalised clinical and biological signatures holds the promise of informing ulcerative colitis therapeutic decisions.

Funding: US National Institutes of Health.

Figure 1.. Time until CS-free Remission (SFR) or Escalation to anti-TNFα by Initial Disease Presentation.

Time until A) CS-free remission (SFR) or B) escalation to anti-TNFa is shown by initial disease presentation of mild (n=178) or moderate-to-severe (n=250). Time until event was censored at last contact. Mild: initiated on mesalazine, or on oral CS with PUCAI < 45. Moderate/Severe: initiated on IV CS, or oral CS with PUCAI ≥ 45. Differences between groups were tested by log-rank test. Data presented represent Kaplan-Meier analysis considering patients lost to follow-up during the first year.

Figure 2.. Biological Predictors of Disease Outcome.

A. Gene set enrichment analyses (GSEA) of the 33 genes differentially expressed in the rectum [18 increased (left), and 15 decreased (right)] in those that did vs. did not achieve WK52 CS-free remission using ToppGene, ToppCluster, and Cytoscape are shown (See Supplemental Appendix). The increased gene sets were associated with cellular transport and channel functions, while the decreased gene sets were associated with antimicrobial responses. The overall 33 gene set signature was associated with need for escalation to anti-TNFα, while the alpha-defensins reactome (biosystem ID: 1269266) antimicrobial peptides pathway showed a stronger association with the W52 SFR outcome. Genes are indicated in red hexagons, GO annotations in blue colors, drug-associations in orange, and pathways, gene family, interactions, and co-expression in green colors. The full list of GSEA results and p-values are in Table S4. B and C. ROC curves are presented for the logistic regression models in patients with clinical data (red) and clinical+biological data (blue) from the imputed dataset with the median CV AUC for the models for B) CS-free Remission and C) Escalation to Anti-TNFα. The cut-point used to define sensitivity and specificity for each model is indicated by the filled circle. See Table 2 and Table 3 for the AUCs and the p-value comparing the AUC of the two ROC curves averaged across the multiple imputations.