Summary Background Stricturing and penetrating complications account for substantial morbidity and health-care costs in paediatric and adult onset Crohn’s disease. Validated models to predict risk for complications are not available, and the effect of treatment on risk is unknown. Methods We did a prospective inception cohort study of paediatric patients with newly diagnosed Crohn’s disease at 28 sites in the USA and Canada. Genotypes, antimicrobial serologies, ileal gene expression, and ileal, rectal, and faecal microbiota were assessed. A competing-risk model for disease complications was derived and validated in independent groups. Propensity-score matching tested the effect of anti-tumour necrosis factor α (TNFα) therapy exposure within 90 days of diagnosis on complication risk. Findings Between Nov 1, 2008, and June 30, 2012, we enrolled 913 patients, 78 (9%) of whom experienced Crohn’s disease complications. The validated competing-risk model included age, race, disease location, and antimicrobial serologies and provided a sensitivity of 66% (95% CI 51–82) and specificity of 63% (55–71), with a negative predictive value of 95% (94–97). Patients who received early anti-TNFα therapy were less likely to have penetrating complications (hazard ratio [HR] 0·30, 95% CI 0·10–0·89; p=0·0296) but not stricturing complication (1·13, 0·51–2·51; 0·76) than were those who did not receive early anti-TNFα therapy. Ruminococcus was implicated in stricturing complications and Veillonella in penetrating complications. Ileal genes controlling extracellular matrix production were upregulated at diagnosis, and this gene signature was associated with stricturing in the risk model (HR 1·70, 95% CI 1·12–2·57; p=0·0120). When this gene signature was included, the model’s specificity improved to 71%. Interpretation Our findings support the usefulness of risk stratification of paediatric patients with Crohn’s disease at diagnosis, and selection of anti-TNFα therapy. Funding Crohn’s and Colitis Foundation of America, Cincinnati Children’s Hospital Research Foundation Digestive Health Center.

Tumor necrosis factor-alpha (TNFα) antagonists including antibodies and soluble receptors have shown remarkable efficacy in various immune-mediated inflammatory diseases (IMID). As experience with these agents has matured, there is an emerging need to integrate and critically assess

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Tumor necrosis factor-alpha (TNFα) antagonists have shown remarkable efficacy in a variety of immune-mediated inflammatory diseases (IMIDs). Therapeutic scope and limitations of these agents are reviewed in a recently published article in the Journal. In spite of their therapeutic popularity, little is known about their modes of action in vivo and factors that limit their scope of therapeutic use. Intriguingly, while all TNFα antagonists including blocking antibodies and soluble receptors are effective in certain IMIDs, only anti-TNFα antibodies are effective in other IMIDs. Early efforts at understanding how TNFα antagonists act in IMIDs centered on their ability to neutralize soluble TNFα or to block TNF receptors from binding to their ligands. Subsequent studies suggested a role of complement-mediated lysis or antibody-dependent cell cytotoxicity in their therapeutic effects. More recent models postulate that TNFα blockers may act by affecting intracellular signaling, with the end result being a hastened cell cycle arrest, apoptosis, suppression of cytokine production, or improved Treg cell function. TNFα antagonists can also modulate the functions of myofibroblasts and osteoclasts, which might explain how TNFα antagonists reduce tissue damage in chronic IMIDs. Focusing on the human therapeutic experience, this analytical review will review the biology of mechanisms of action, the limiting factors contributing to disease restriction in therapeutic efficacy, and the mechanism and frequency of treatment-limiting adverse responses of TNFα antagonists. It is hoped that the overview will address the needs of clinicians to decide on optimal use, spur clinical innovation, and incite translational researchers to set priorities for in vivo human investigations.

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.