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.
Bibliographical noteFunding Information:
JSH has served on an advisory board for Janssen and is acting as a consultant for AbbVie, Takeda, Lilly, Boehringer-Ingelheim, Allergan, Pfizer, Receptos, and AstraZeneca. SDT has been a member of an independent data monitoring committee for Lycera Corporation. AMG has received research support from AbbVie; been a consultant for AbbVie, Celgene, Janssen, Lilly, Pfizer, and Takeda; and been a speaker for AbbVie, Janssen, and Shire. NSL has been a consultant for AbbVie. CGS has been a consultant for AbbVie. DJK has received research support from Genentech and Takeda. JM has been a consultant for Janssen, Celgene, and Lilly. JR has been a consultant for AbbVie, Celgene, Janssen, Luitpold, and Pfizer, and received grant funding from Janssen and AbbVie. AP has participated in speakers bureaus AbbVie and Janssen. AO has been a member of an advisory board for Janssen and AbbVie, and received research support from Lilly, AbbVie, Janssen, Takeda, and Celgene. MH has received research grants from Genentech, AbbVie, Shire, Takeda, Mallinkrodt, Janssen, and Gilead. MO-H has received research grants from Abbott Immunology and Janssen and been a consultant for Hoffman LaRoche. PAR has been a consultant for Shire and Leutpold; been a speaker for AbbVie; and received research support from TechLab. JSt has been a consultant and speaker for AbbVie. DZ has participated on speakers bureaus for AbbVie and been a consultant for 11 Health and Technologies and Vitality Biopharma. MDK has been a consultant for AbbVie, Janssen, GlaxoSmithKline, and Pfizer. MHC has been a consultant for Shire, Regeneron, Receptos, and Allakos, and has research contracts with Shire and Regeneron. MD has been a consultant for Prometheus Laboratories, AbbVie, Janssen, Takeda, Pfizer, Celgene, UCB, Boehringer Ingelheim, Lilly, Gilead, and Allergan. SK has been a consultant for Janssen and UCB. LAD has received grant support from AbbVie and Janssen. All other authors declare no competing interests.
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