Distinct blood protein profiles associated with the risk of short-term and mid/long-term clinical relapse in patients with Crohn's disease stopping infliximab: when the remission state hides different types of residual disease activity.
[en] OBJECTIVE: Despite being in sustained and stable remission, patients with Crohn's disease (CD) stopping anti-tumour necrosis factor α (TNFα) show a high rate of relapse (~50% within 2 years). Characterising non-invasively the biological profiles of those patients is needed to better guide the decision of anti-TNFα withdrawal.
DESIGN: Ninety-two immune-related proteins were measured by proximity extension assay in serum of patients with CD (n=102) in sustained steroid-free remission and stopping anti-TNFα (infliximab). As previously shown, a stratification based on time to clinical relapse was used to characterise the distinct biological profiles of relapsers (short-term relapsers: <6 months vs mid/long-term relapsers: >6 months). Associations between protein levels and time to clinical relapse were determined by univariable Cox model.
RESULTS: The risk (HR) of mid/long-term clinical relapse was specifically associated with a high serum level of proteins mainly expressed in lymphocytes (LAG3, SH2B3, SIT1; HR: 2.2-4.5; p<0.05), a low serum level of anti-inflammatory effectors (IL-10, HSD11B1; HR: 0.2-0.3; p<0.05) and cellular junction proteins (CDSN, CNTNAP2, CXADR, ITGA11; HR: 0.4; p<0.05). The risk of short-term clinical relapse was specifically associated with a high serum level of pro-inflammatory effectors (IL-6, IL12RB1; HR: 3.5-3.6; p<0.05) and a low or high serum level of proteins mainly expressed in antigen presenting cells (CLEC4A, CLEC4C, CLEC7A, LAMP3; HR: 0.4-4.1; p<0.05).
CONCLUSION: We identified distinct blood protein profiles associated with the risk of short-term and mid/long-term clinical relapse in patients with CD stopping infliximab. These findings constitute an advance for the development of non-invasive biomarkers guiding the decision of anti-TNFα withdrawal.
Disciplines :
Gastroenterology & hepatology
Author, co-author :
Pierre, Nicolas ; Université de Liège - ULiège > GIGA > GIGA I3 - Translational gastroenterology
Huynh-Thu, Vân Anh ; Université de Liège - ULiège > Département d'électricité, électronique et informatique (Institut Montefiore) > Algorithmique des systèmes en interaction avec le monde physique
Allez, Matthieu ; Service d'Hépato-Gastroentérologie, Hôpital Saint Louis, APHP, Université de Paris, Paris, France
Bouhnik, Yoram; Service de Gastroentérologie et Assistance Nutritive, Hôpital Beaujon, Clichy, France
Laharie, David ; Service d'Hépato-Gastroentérologie, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France
Bourreille, Arnaud; Institut des maladies de l'appareil digestif, Centre Hospitalier Universitaire de Nantes, Nantes, France
Colombel, Jean-Frédéric; Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
Meuwis, Marie-Alice ; Centre Hospitalier Universitaire de Liège - CHU > > Service de gastroentérologie, hépatologie, onco. digestive
Louis, Edouard ; Centre Hospitalier Universitaire de Liège - CHU > > Service de gastroentérologie, hépatologie, onco. digestive
GETAID (Groupe d’Etude Thérapeutique des Affections Inflammatoires du tube Digestif)
Language :
English
Title :
Distinct blood protein profiles associated with the risk of short-term and mid/long-term clinical relapse in patients with Crohn's disease stopping infliximab: when the remission state hides different types of residual disease activity.
Hanauer SB, Feagan BG, Lichtenstein GR, et al. Maintenance infliximab for Crohn's disease: the ACCENT I randomised trial. Lancet 2002; 359: 1541-9. doi:10.1016/S0140-6736(02)08512-4 http://www.ncbi.nlm.nih.gov/pubmed/12047962
Cottone M, Criscuoli V. Infliximab to treat Crohn's disease: an update. Clin Exp Gastroenterol 2011; 4: 227-38. doi:10.2147/CEG.S6440 http://www.ncbi.nlm.nih.gov/pubmed/22016584
Burmester GR, Panaccione R, Gordon KB, et al. Adalimumab: long-term safety in 23 458 patients from global clinical trials in rheumatoid arthritis, juvenile idiopathic arthritis, ankylosing spondylitis, psoriatic arthritis, psoriasis and Crohn's disease. Ann Rheum Dis 2013; 72: 517-24. doi:10.1136/annrheumdis-2011-201244 http://www.ncbi.nlm.nih.gov/pubmed/22562972
Siegel CA, Marden SM, Persing SM, et al. Risk of lymphoma associated with combination anti-tumor necrosis factor and immunomodulator therapy for the treatment of Crohn's disease: a meta-analysis. Clin Gastroenterol Hepatol 2009; 7: 874-81. doi:10.1016/j.cgh.2009.01.004 http://www.ncbi.nlm.nih.gov/pubmed/19558997
Long MD, Martin CF, Pipkin CA, et al. Risk of melanoma and nonmelanoma skin cancer among patients with inflammatory bowel disease. Gastroenterology 2012; 143: 390-9. doi:10.1053/j.gastro.2012.05.004 http://www.ncbi.nlm.nih.gov/pubmed/22584081
van der Valk ME, Mangen M-JJ, Leenders M, et al. Healthcare costs of inflammatory bowel disease have shifted from hospitalisation and surgery towards anti-TNFalpha therapy: results from the COIN study. Gut 2014; 63: 72-9. doi:10.1136/gutjnl-2012-303376 http://www.ncbi.nlm.nih.gov/pubmed/23135759
Kennedy NA, Warner B, Johnston EL, et al. Relapse after withdrawal from anti-TNF therapy for inflammatory bowel disease: an observational study, plus systematic review and meta-analysis. Aliment Pharmacol Ther 2016; 43: 910-23. doi:10.1111/apt.13547 http://www.ncbi.nlm.nih.gov/pubmed/26892328
Pierre N, Baiwir D, Huynh-Thu VA, et al. Discovery of biomarker candidates associated with the risk of short-term and mid/long-term relapse after infliximab withdrawal in Crohn's patients: a proteomics-based study. Gut 2021; 70: 1450-7. doi:10.1136/gutjnl-2020-322100
Lundberg M, Eriksson A, Tran B, et al. Homogeneous antibody-based proximity extension assays provide sensitive and specific detection of low-abundant proteins in human blood. Nucleic Acids Res 2011; 39: e102. doi:10.1093/nar/gkr424 http://www.ncbi.nlm.nih.gov/pubmed/21646338
Assarsson E, Lundberg M, Holmquist G, et al. Homogenous 96-plex PEA immunoassay exhibiting high sensitivity, specificity, and excellent scalability. PLoS One 2014; 9: e95192. doi:10.1371/journal.pone.0095192 http://www.ncbi.nlm.nih.gov/pubmed/24755770
Louis E, Mary J-Y, Vernier-Massouille G, et al. Maintenance of remission among patients with Crohn's disease on antimetabolite therapy after infliximab therapy is stopped. Gastroenterology 2012; 142: 63-70. doi:10.1053/j.gastro.2011.09.034 http://www.ncbi.nlm.nih.gov/pubmed/21945953
Davidson-Pilon C. Lifelines: survival analysis in python. J Open Source Softw 2019; 4: 1317. doi:10.21105/joss.01317
Wickham H. Ggplot2: elegant graphics for data analysis. 2nd edn.
Casanova MJ, Chaparro M, García-Sánchez V, et al. Evolution after anti-TNF discontinuation in patients with inflammatory bowel disease: a multicenter long-term follow-up study. Am J Gastroenterol 2017; 112: 120-31. doi:10.1038/ajg.2016.569 http://www.ncbi.nlm.nih.gov/pubmed/27958281
Couper KN, Blount DG, Riley EM. IL-10: the master regulator of immunity to infection. J Immunol 2008; 180: 5771-7. doi:10.4049/jimmunol.180.9.5771 http://www.ncbi.nlm.nih.gov/pubmed/18424693
Chapman KE, Coutinho AE, Zhang Z, et al. Changing glucocorticoid action: 11β-hydroxysteroid dehydrogenase type 1 in acute and chronic inflammation. J Steroid Biochem Mol Biol 2013; 137: 82-92. doi:10.1016/j.jsbmb.2013.02.002 http://www.ncbi.nlm.nih.gov/pubmed/23435016
Remaley AT. Apolipoprotein A-II: still second fiddle in high-density lipoprotein metabolism? Arterioscler Thromb Vasc Biol 2013; 33: 166-7. doi:10.1161/ATVBAHA.112.300921 http://www.ncbi.nlm.nih.gov/pubmed/23325471
Stegk JP, Ebert B, Martin H-J, et al. Expression profiles of human 11beta-hydroxysteroid dehydrogenases type 1 and type 2 in inflammatory bowel diseases. Mol Cell Endocrinol 2009; 301: 104-8. doi:10.1016/j.mce.2008.10.030 http://www.ncbi.nlm.nih.gov/pubmed/19022342
Ahmed A, Schwaderer J, Hantusch A, et al. Intestinal glucocorticoid synthesis enzymes in pediatric inflammatory bowel disease patients. Genes Immun 2019; 20: 566-76. doi:10.1038/s41435-019-0056-1 http://www.ncbi.nlm.nih.gov/pubmed/30686824
Lim LG, Neumann J, Hansen T, et al. Confocal endomicroscopy identifies loss of local barrier function in the duodenum of patients with Crohn's disease and ulcerative colitis. Inflamm Bowel Dis 2014; 20: 892-900. doi:10.1097/MIB.0000000000000027 http://www.ncbi.nlm.nih.gov/pubmed/24691113
Kiesslich R, Duckworth CA, Moussata D, et al. Local barrier dysfunction identified by confocal laser endomicroscopy predicts relapse in inflammatory bowel disease. Gut 2012; 61: 1146-53. doi:10.1136/gutjnl-2011-300695 http://www.ncbi.nlm.nih.gov/pubmed/22115910
Liu JJ, Madsen KL, Boulanger P, et al. Mind the gaps: confocal endomicroscopy showed increased density of small bowel epithelial gaps in inflammatory bowel disease. J Clin Gastroenterol 2011; 45: 240-5. doi:10.1097/MCG.0b013e3181fbdb8a http://www.ncbi.nlm.nih.gov/pubmed/21030873
Marin ML, Greenstein AJ, Geller SA, et al. A freeze fracture study of Crohn's disease of the terminal ileum: changes in epithelial tight junction organization. Am J Gastroenterol 1983; 78: 537-47. http://www.ncbi.nlm.nih.gov/pubmed/6613965
Söderholm JD, Olaison G, Peterson KH, et al. Augmented increase in tight junction permeability by luminal stimuli in the non-inflamed ileum of Crohn's disease. Gut 2002; 50: 307-13. doi:10.1136/gut.50.3.307 http://www.ncbi.nlm.nih.gov/pubmed/11839706
Vivinus-Nébot M, Frin-Mathy G, Bzioueche H, et al. Functional bowel symptoms in quiescent inflammatory bowel diseases: role of epithelial barrier disruption and low-grade inflammation. Gut 2014; 63: 744-52. doi:10.1136/gutjnl-2012-304066 http://www.ncbi.nlm.nih.gov/pubmed/23878165
Castell JV, Gómez-Lechón MJ, David M, et al. Interleukin-6 is the major regulator of acute phase protein synthesis in adult human hepatocytes. FEBS Lett 1989; 242: 237-9. doi:10.1016/0014-5793(89)80476-4 http://www.ncbi.nlm.nih.gov/pubmed/2464504
Chiffoleau E. C-Type lectin-like receptors as emerging orchestrators of sterile inflammation represent potential therapeutic targets. Front Immunol 2018; 9: 227. doi:10.3389/fimmu.2018.00227 http://www.ncbi.nlm.nih.gov/pubmed/29497419
Arimura K, Takagi H, Uto T, et al. Crucial role of plasmacytoid dendritic cells in the development of acute colitis through the regulation of intestinal inflammation. Mucosal Immunol 2017; 10: 957-70. doi:10.1038/mi.2016.96 http://www.ncbi.nlm.nih.gov/pubmed/27848952
Baumgart DC, Metzke D, Guckelberger O, et al. Aberrant plasmacytoid dendritic cell distribution and function in patients with Crohn's disease and ulcerative colitis. Clin Exp Immunol 2011; 166: 46-54. doi:10.1111/j.1365-2249.2011.04439.x http://www.ncbi.nlm.nih.gov/pubmed/21762123
Baumgart DC, Metzke D, Schmitz J, et al. Patients with active inflammatory bowel disease lack immature peripheral blood plasmacytoid and myeloid dendritic cells. Gut 2005; 54: 228-36. doi:10.1136/gut.2004.040360 http://www.ncbi.nlm.nih.gov/pubmed/15647187
Ramspek CL, Steyerberg EW, Riley RD, et al. Prediction or causality? A scoping review of their conflation within current observational research. Eur J Epidemiol 2021; 36: 889-98. doi:10.1007/s10654-021-00794-w http://www.ncbi.nlm.nih.gov/pubmed/34392488
Louis E, Belaiche J, van Kemseke C, et al. A high serum concentration of interleukin-6 is predictive of relapse in quiescent Crohn's disease. Eur J Gastroenterol Hepatol 1997; 9: 939-44. doi:10.1097/00042737-199710000-00004 http://www.ncbi.nlm.nih.gov/pubmed/9391781
Demšar J, Zupan B. Hands-on training about overfitting. PLoS Comput Biol 2021; 17: e1008671. doi:10.1371/journal.pcbi.1008671 http://www.ncbi.nlm.nih.gov/pubmed/33661899
Price WN. Big data and black-box medical algorithms. Sci Transl Med 2018; 10: aao5333. doi:10.1126/scitranslmed.aao5333 http://www.ncbi.nlm.nih.gov/pubmed/30541791
