Clinical and biological predictors of response to standardised paediatric colitis therapy (PROTECT)

a multicentre inception cohort study

Jeffrey S. Hyams, Sonia Davis Thomas, Nathan Gotman, Yael Haberman, Rebekah Karns, Melanie Schirmer, Angela Mo, David R. Mack, Brendan Boyle, Anne M. Griffiths, Neal S. LeLeiko, Cary G. Sauer, David J. Keljo, James Markowitz, Susan S. Baker, Joel Rosh, Robert N. Baldassano, Ashish Patel, Marian Pfefferkorn, Anthony Otley & 30 others Melvin Heyman, Joshua Noe, Maria Oliva-Hemker, Paul A. Rufo, Jennifer Strople, David Ziring, Stephen L. Guthery, Boris Sudel, Keith Benkov, Prateek Wali, Dedrick Moulton, Jonathan Evans, Michael D. Kappelman, M. Alison Marquis, Francisco A. Sylvester, Margaret H. Collins, Suresh Venkateswaran, Marla Dubinsky, Vin Tangpricha, Krista L. Spada, Bradley Saul, Jessie Wang, Jose Serrano, Kevin Hommel, Urko M. Marigorta, Greg Gibson, Ramnik J. Xavier, Subra Kugathasan, Thomas Walters, Lee A. Denson

Research output: Contribution to journalArticle

5 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1708-1720
Number of pages13
JournalThe Lancet
Volume393
Issue number10182
DOIs
StatePublished - Apr 27 2019

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Colitis
Cohort Studies
Pediatrics
Mesalamine
Adrenal Cortex Hormones
Ulcerative Colitis
Logistic Models
Odds Ratio
Immunologic Factors
Therapeutics
Tumor Necrosis Factor-alpha
RNA Sequence Analysis
Colectomy
Microbiota
National Institutes of Health (U.S.)
Uncertainty
Area Under Curve
Canada
Hemoglobins
Gene Expression

All Science Journal Classification (ASJC) codes

  • Medicine(all)

Cite this

Hyams, J. S., Davis Thomas, S., Gotman, N., Haberman, Y., Karns, R., Schirmer, M., ... Denson, L. A. (2019). Clinical and biological predictors of response to standardised paediatric colitis therapy (PROTECT): a multicentre inception cohort study. The Lancet, 393(10182), 1708-1720. https://doi.org/10.1016/S0140-6736(18)32592-3
Hyams, Jeffrey S. ; Davis Thomas, Sonia ; Gotman, Nathan ; Haberman, Yael ; Karns, Rebekah ; Schirmer, Melanie ; Mo, Angela ; Mack, David R. ; Boyle, Brendan ; Griffiths, Anne M. ; LeLeiko, Neal S. ; Sauer, Cary G. ; Keljo, David J. ; Markowitz, James ; Baker, Susan S. ; Rosh, Joel ; Baldassano, Robert N. ; Patel, Ashish ; Pfefferkorn, Marian ; Otley, Anthony ; Heyman, Melvin ; Noe, Joshua ; Oliva-Hemker, Maria ; Rufo, Paul A. ; Strople, Jennifer ; Ziring, David ; Guthery, Stephen L. ; Sudel, Boris ; Benkov, Keith ; Wali, Prateek ; Moulton, Dedrick ; Evans, Jonathan ; Kappelman, Michael D. ; Marquis, M. Alison ; Sylvester, Francisco A. ; Collins, Margaret H. ; Venkateswaran, Suresh ; Dubinsky, Marla ; Tangpricha, Vin ; Spada, Krista L. ; Saul, Bradley ; Wang, Jessie ; Serrano, Jose ; Hommel, Kevin ; Marigorta, Urko M. ; Gibson, Greg ; Xavier, Ramnik J. ; Kugathasan, Subra ; Walters, Thomas ; Denson, Lee A. / Clinical and biological predictors of response to standardised paediatric colitis therapy (PROTECT) : a multicentre inception cohort study. In: The Lancet. 2019 ; Vol. 393, No. 10182. pp. 1708-1720.
@article{0f8bc7c42ff14a4981e789d0a3b8b762,
title = "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.",
author = "Hyams, {Jeffrey S.} and {Davis Thomas}, Sonia and Nathan Gotman and Yael Haberman and Rebekah Karns and Melanie Schirmer and Angela Mo and Mack, {David R.} and Brendan Boyle and Griffiths, {Anne M.} and LeLeiko, {Neal S.} and Sauer, {Cary G.} and Keljo, {David J.} and James Markowitz and Baker, {Susan S.} and Joel Rosh and Baldassano, {Robert N.} and Ashish Patel and Marian Pfefferkorn and Anthony Otley and Melvin Heyman and Joshua Noe and Maria Oliva-Hemker and Rufo, {Paul A.} and Jennifer Strople and David Ziring and Guthery, {Stephen L.} and Boris Sudel and Keith Benkov and Prateek Wali and Dedrick Moulton and Jonathan Evans and Kappelman, {Michael D.} and Marquis, {M. Alison} and Sylvester, {Francisco A.} and Collins, {Margaret H.} and Suresh Venkateswaran and Marla Dubinsky and Vin Tangpricha and Spada, {Krista L.} and Bradley Saul and Jessie Wang and Jose Serrano and Kevin Hommel and Marigorta, {Urko M.} and Greg Gibson and Xavier, {Ramnik J.} and Subra Kugathasan and Thomas Walters and Denson, {Lee A.}",
year = "2019",
month = "4",
day = "27",
doi = "10.1016/S0140-6736(18)32592-3",
language = "English (US)",
volume = "393",
pages = "1708--1720",
journal = "The Lancet",
issn = "0140-6736",
publisher = "Elsevier Limited",
number = "10182",

}

Hyams, JS, Davis Thomas, S, Gotman, N, Haberman, Y, Karns, R, Schirmer, M, Mo, A, Mack, DR, Boyle, B, Griffiths, AM, LeLeiko, NS, Sauer, CG, Keljo, DJ, Markowitz, J, Baker, SS, Rosh, J, Baldassano, RN, Patel, A, Pfefferkorn, M, Otley, A, Heyman, M, Noe, J, Oliva-Hemker, M, Rufo, PA, Strople, J, Ziring, D, Guthery, SL, Sudel, B, Benkov, K, Wali, P, Moulton, D, Evans, J, Kappelman, MD, Marquis, MA, Sylvester, FA, Collins, MH, Venkateswaran, S, Dubinsky, M, Tangpricha, V, Spada, KL, Saul, B, Wang, J, Serrano, J, Hommel, K, Marigorta, UM, Gibson, G, Xavier, RJ, Kugathasan, S, Walters, T & Denson, LA 2019, 'Clinical and biological predictors of response to standardised paediatric colitis therapy (PROTECT): a multicentre inception cohort study', The Lancet, vol. 393, no. 10182, pp. 1708-1720. https://doi.org/10.1016/S0140-6736(18)32592-3

Clinical and biological predictors of response to standardised paediatric colitis therapy (PROTECT) : a multicentre inception cohort study. / Hyams, Jeffrey S.; Davis Thomas, Sonia; Gotman, Nathan; Haberman, Yael; Karns, Rebekah; Schirmer, Melanie; Mo, Angela; Mack, David R.; Boyle, Brendan; Griffiths, Anne M.; LeLeiko, Neal S.; Sauer, Cary G.; Keljo, David J.; Markowitz, James; Baker, Susan S.; Rosh, Joel; Baldassano, Robert N.; Patel, Ashish; Pfefferkorn, Marian; Otley, Anthony; Heyman, Melvin; Noe, Joshua; Oliva-Hemker, Maria; Rufo, Paul A.; Strople, Jennifer; Ziring, David; Guthery, Stephen L.; Sudel, Boris; Benkov, Keith; Wali, Prateek; Moulton, Dedrick; Evans, Jonathan; Kappelman, Michael D.; Marquis, M. Alison; Sylvester, Francisco A.; Collins, Margaret H.; Venkateswaran, Suresh; Dubinsky, Marla; Tangpricha, Vin; Spada, Krista L.; Saul, Bradley; Wang, Jessie; Serrano, Jose; Hommel, Kevin; Marigorta, Urko M.; Gibson, Greg; Xavier, Ramnik J.; Kugathasan, Subra; Walters, Thomas; Denson, Lee A.

In: The Lancet, Vol. 393, No. 10182, 27.04.2019, p. 1708-1720.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Clinical and biological predictors of response to standardised paediatric colitis therapy (PROTECT)

T2 - a multicentre inception cohort study

AU - Hyams, Jeffrey S.

AU - Davis Thomas, Sonia

AU - Gotman, Nathan

AU - Haberman, Yael

AU - Karns, Rebekah

AU - Schirmer, Melanie

AU - Mo, Angela

AU - Mack, David R.

AU - Boyle, Brendan

AU - Griffiths, Anne M.

AU - LeLeiko, Neal S.

AU - Sauer, Cary G.

AU - Keljo, David J.

AU - Markowitz, James

AU - Baker, Susan S.

AU - Rosh, Joel

AU - Baldassano, Robert N.

AU - Patel, Ashish

AU - Pfefferkorn, Marian

AU - Otley, Anthony

AU - Heyman, Melvin

AU - Noe, Joshua

AU - Oliva-Hemker, Maria

AU - Rufo, Paul A.

AU - Strople, Jennifer

AU - Ziring, David

AU - Guthery, Stephen L.

AU - Sudel, Boris

AU - Benkov, Keith

AU - Wali, Prateek

AU - Moulton, Dedrick

AU - Evans, Jonathan

AU - Kappelman, Michael D.

AU - Marquis, M. Alison

AU - Sylvester, Francisco A.

AU - Collins, Margaret H.

AU - Venkateswaran, Suresh

AU - Dubinsky, Marla

AU - Tangpricha, Vin

AU - Spada, Krista L.

AU - Saul, Bradley

AU - Wang, Jessie

AU - Serrano, Jose

AU - Hommel, Kevin

AU - Marigorta, Urko M.

AU - Gibson, Greg

AU - Xavier, Ramnik J.

AU - Kugathasan, Subra

AU - Walters, Thomas

AU - Denson, Lee A.

PY - 2019/4/27

Y1 - 2019/4/27

N2 - 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.

AB - 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.

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