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

Abstract

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.

Longitudinal non‐adherence predicts treatment escalation in paediatric ulcerative colitis

“…These findings reflect the complexity of achieving remission in youth with UC, as a number of factors have been shown to contribute to future remission status, including disease activity early in the disease course . Specifically, in the PROTECT main study, lower baseline severity, higher baseline haemoglobin and initial response to therapy (ie clinical remission at week 4) were all significantly associated with steroid‐free remission at week 52 . In adults with UC, electronically monitored adherence to mesalazine was the distinguishing factor between disease relapse and remission.…”

“…Covariates were age, sex and baseline disease characteristics, including PUCAI, haemoglobin, Vitamin D and lower rectal biopsy eosinophil count. Vitamin D level at baseline and lower rectal biopsy eosinophil count were included as additional covariates in the model predicting need for rescue as findings from the PROTECT trial demonstrated individuals with pre‐treatment Vitamin D levels of 25(OH)D <20 ng/mL and pre‐treatment rectal eosinophils <32/hpf were more likely to escalate to anti‐TNFα . Of note, the current study modelled the association between longitudinal adherence and any treatment escalation, therefore our sample was not identical to the previous study predicting only escalation to anti‐TNFα.…”

“…Mild disease presentation was defined using a combination of baseline disease activity (PUCAI < 45) and initial therapy (mesalazine or oral CS with mesalazine prescribed by month 3). The cut‐point of PUCAI < 45 was based upon previous observations of this cohort, in which PUCAI < 45 was identified as a significant predictor of steroid‐free remission at weeks 12 and 52 …”

“…Laboratory data used in the current study included baseline haemoglobin levels, Vitamin D level and lower rectal biopsy eosinophil count. These variables were selected as covariates in the current study based on previous findings from the PROTECT trial, which found higher baseline haemoglobin was associated with steroid‐free remission at week 52, and pre‐treatment Vitamin D <20 ng/mL and rectal eosinophils <32/hpf were associated with treatment escalation to anti‐TNFα …”

“…Control covariates were participant age, sex, need for treatment escalation during the trial, as well as baseline disease characteristics, including disease activity (PUCAI) and haemoglobin levels. PUCAI and haemoglobin levels were included as covariates due to findings from the PROTECT trial demonstrating that lower baseline PUCAI and higher baseline haemoglobin were associated with steroid‐free remission at week 52 . The model was first estimated for all participants (N = 268), then estimated for the subset of participants defined as mild at baseline (n = 99) based on disease activity (PUCAI < 45) and initial treatment.…”