Background-The lack of evidence-based outcomes data leads to uncertainty in developing treatment regimens in children newly diagnosed with Ulcerative Colitis (UC). We hypothesized that pre-treatment clinical, transcriptomic, and microbial factors predict disease course. Methods-We performed an inception cohort study of 428 paediatric UC patients receiving standardised mesalazine or corticosteroids (CS), with pre-established criteria for escalation to thiopurines or anti-TNFα. RNA sequencing (n=206) defined pre-treatment rectal gene expression. 16S sequencing (n=343) characterized rectal/fecal microbiota. The primary outcome was Week 52 CS-free remission (SFR) with no therapy beyond mesalazine. Findings-Week 52 SFR was achieved in 150/400 (38%) participants; 74/400 (19%) received thiopurines alone, 12¾00 (31%) received anti-TNFα, and 25/400 (6%) colectomy. Lower baseline clinical severity, higher baseline hemoglobin, and Week 4 clinical remission were associated with achieving Week 52 SFR (logistic model AUC:0.70 (95% CI 0.65-0.75), specificity 77% (CI 71-82), n=386). Baseline severity and week 4 remission were validated inan independent cohort of 274 participants. An antimicrobial peptide gene signature (OR:0.6, p=0.002) and Ruminococcaceae (OR:1.4, p=0.04) and Sutterella (OR: 0.8, p=0.05) abundance were independently associated with SFR after adjusting for the clinical predictors. Amongst moderateto-severe patients, escalation to anti-TNFα was associated with increased baseline clinical severity and decreased hemoglobin, serum 25 (OH) D, and rectal eosinophils (logistic model AUC:0.78 (95% CI 0.72-0.84), specificity 85% (CI 78-93), n=232). A rectal transportgene signature (OR: 0.3, p=0.0006) and Oscillospira abundance (OR:0.6, p=0.02) were independently associated with escalation to anti-TNFα after adjusting for the clinical predictors. Interpretation-Our findings support the utility of using initial clinical activity and treatment response by 4 weeks to predict Week 52 CS-free remission with mesalazine alone in children newly diagnosed with UC. The development of personalized clinical and biological signatures holds the promise of informing UC therapeutic decisions.

Background Previous retrospective pediatric ulcerative colitis (UC) studies had limited ability to describe disease progression and identify predictors of treatment response. The PROTECT multicentre inception cohort aimed to identify characteristics associated with outcomes following standardized therapy after initial diagnosis. Methods We completed a prospective multicentre inception cohort study at 29 centres in the USA and Canada of paediatric patients aged 4–17 years newly diagnosed with UC who received initial standardized treatment with mesalamine or corticosteroids (CS) guided by the Pediatric UC Activity Index (PUCAI). The key outcomes for this analysis were week 12 CS-free remission, defined as PUCAI<10 and taking only mesalamine, and treatment escalation to anti-TNFα, immunomodulators or colectomy among those initially treated with intravenous (IV) CS. Independent predictors were identified through multivariable logistic regression using a per-protocol approach. Registered with clinicaltrials.gov: NCT01536535 Findings 428 children initiated mesalamine (n=136), oral CS (n=144), or IV CS (n=148) with initial mean ± standard deviation PUCAI of 31±13, 50±14, and 67±14, respectively (p<0.001). By week 12, CS-free remission taking mesalamine only was achieved by 48% (64/132) initiating with mesalamine, 33% (47/141) with oral CS, and 21% (30/143) with IV CS (p<0.001). Treatment escalation was required in 7% (9/132), 15% (21/141), and 36% (52/143), respectively (p<0.001); 8 patients, all initially treated with IV CS, received colectomy. Predictors of week 12 CS-free remission were baseline PUCAI <35 (odds ratio (OR) 2.4, 95% CI 1.4–4.2; p=0.002), higher baseline albumin by 1 g/dL increments among age < 12 years (4.1, 1.9–8.6; p=0.0003), and week 4 remission (6.3, 3.8–10.4; p<0.0001). Predictors of treatment escalation by week 12 in those initially treated with IV CS included baseline total Mayo score ≥11 (2.6, 0.9–7.2; p=0.068), rectal biopsy eosinophil count ≤32/high power field (4.6, 1.6–12.8; p=0.004), rectal biopsy surface villiform changes (3.1, 1.1–8.6; p=0.034) and not achieving week 4 remission (30.2, 6.4–144.2; p<0.0001). Interpretation Our findings provide guidelines to assess response of children newly diagnosed with UC to standardized initial therapy and identify predictors of treatment response and failure. These data suggest that additional therapeutic interventions may be warranted to improve early outcomes, especially in those presenting with severe disease and requiring intravenous corticosteroids.

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