Clinical predictors at diagnosis of disabling pediatric Crohn's disease†
Guillaume Savoye MD, PhD
Gastroenterology Unit, EPIMAD Registry, Rouen University and Hospital, France
The first two authors contributed equally to this work.
Search for more papers by this authorJulia Salleron MS
Biostatistics Unit, Lille University and Hospital, EA 2694, France
The first two authors contributed equally to this work.
Search for more papers by this authorCorresponding Author
Corinne Gower-Rousseau MD
Epidemiology Unit, EPIMAD Registry, Lille University and Hospital, France
Epidemiology Unit, EPIMAD Registry, Parc Eurasanté, 154 rue du Dr Yersin, CH et U de Lille, 59037 Lille Cedex, FranceSearch for more papers by this authorJean-Louis Dupas MD, PhD
Gastroenterology Unit, EPIMAD Registry, Amiens Hospital and University, France
Search for more papers by this authorGwénola Vernier-Massouille MD
Gastroenterology Unit, EPIMAD Registry, Lille University and Hospital, France
Search for more papers by this authorMathurin Fumery MD
Gastroenterology Unit, EPIMAD Registry, Amiens Hospital and University, France
Search for more papers by this authorVéronique Merle MD, PhD
Epidemiology Unit, EPIMAD Registry, Rouen University and Hospital, France
Search for more papers by this authorEric Lerebours MD, PhD
Gastroenterology Unit, EPIMAD Registry, Rouen University and Hospital, France
Search for more papers by this authorAntoine Cortot MD
Gastroenterology Unit, EPIMAD Registry, Lille University and Hospital, France
Search for more papers by this authorDominique Turck MD, PhD
Pediatric Unit, EPIMAD Registry, Lille University and Hospital, France
Search for more papers by this authorJean-Louis Salomez MD
Epidemiology Unit, EPIMAD Registry, Lille University and Hospital, France
Search for more papers by this authorMarc Lemann MD
Gastroenterology Unit, St Louis Hospital, Paris, France
Search for more papers by this authorJean-Frédéric Colombel MD
Gastroenterology Unit, EPIMAD Registry, Lille University and Hospital, France
Search for more papers by this authorAlain Duhamel MD, PhD
Biostatistics Unit, Lille University and Hospital, EA 2694, France
Search for more papers by this authorGuillaume Savoye MD, PhD
Gastroenterology Unit, EPIMAD Registry, Rouen University and Hospital, France
The first two authors contributed equally to this work.
Search for more papers by this authorJulia Salleron MS
Biostatistics Unit, Lille University and Hospital, EA 2694, France
The first two authors contributed equally to this work.
Search for more papers by this authorCorresponding Author
Corinne Gower-Rousseau MD
Epidemiology Unit, EPIMAD Registry, Lille University and Hospital, France
Epidemiology Unit, EPIMAD Registry, Parc Eurasanté, 154 rue du Dr Yersin, CH et U de Lille, 59037 Lille Cedex, FranceSearch for more papers by this authorJean-Louis Dupas MD, PhD
Gastroenterology Unit, EPIMAD Registry, Amiens Hospital and University, France
Search for more papers by this authorGwénola Vernier-Massouille MD
Gastroenterology Unit, EPIMAD Registry, Lille University and Hospital, France
Search for more papers by this authorMathurin Fumery MD
Gastroenterology Unit, EPIMAD Registry, Amiens Hospital and University, France
Search for more papers by this authorVéronique Merle MD, PhD
Epidemiology Unit, EPIMAD Registry, Rouen University and Hospital, France
Search for more papers by this authorEric Lerebours MD, PhD
Gastroenterology Unit, EPIMAD Registry, Rouen University and Hospital, France
Search for more papers by this authorAntoine Cortot MD
Gastroenterology Unit, EPIMAD Registry, Lille University and Hospital, France
Search for more papers by this authorDominique Turck MD, PhD
Pediatric Unit, EPIMAD Registry, Lille University and Hospital, France
Search for more papers by this authorJean-Louis Salomez MD
Epidemiology Unit, EPIMAD Registry, Lille University and Hospital, France
Search for more papers by this authorMarc Lemann MD
Gastroenterology Unit, St Louis Hospital, Paris, France
Search for more papers by this authorJean-Frédéric Colombel MD
Gastroenterology Unit, EPIMAD Registry, Lille University and Hospital, France
Search for more papers by this authorAlain Duhamel MD, PhD
Biostatistics Unit, Lille University and Hospital, EA 2694, France
Search for more papers by this authorFinancial support: EPIMAD is organized under an agreement between the Institut National de la Santé et de la Recherche Médicale (INSERM) and the Institut National de Veille Sanitaire (InVS) and also received a financial support of the François Aupetit Association, Lion's Club of Northwestern France, Ferring Laboratories, the Société Nationale Française de Gastroentérologie, Lille University Hospital and GIS-Maladies Rares (INSERM 2003). Potential competing interests: none.
Abstract
Background:
Identification of children with Crohn's disease (CD) at high risk of disabling disease would be invaluable in guiding initial therapy. Our study aimed to identify predictors at diagnosis of a subsequent disabling course in a population-based cohort of patients with pediatric-onset CD.
Methods:
Among 537 patients with pediatric CD diagnosed at <17 years of age, 309 (57%) with 5-year follow-up were included. Clinical and demographic factors associated with subsequent disabling CD were studied. Three definitions of disabling CD were used: Saint-Antoine and Liège Hospitals' definitions and a new pediatric definition based on the presence at maximal follow-up of: 1) growth delay defined by body mass index (BMI), weight or height lower than −2 SD Z score; and 2) at least one intestinal resection or two anal interventions. Predictors were determined using multivariate analyses and their accuracy using the kappa method considering a relevant value ≥0.6.
Results:
According to the Saint-Antoine definition, the rate of disabling CD was 77% and predictors were complicated behavior and L1 location. According to the Liège definition, the rate was 37% and predictors included behavior, upper gastrointestinal disease, and extraintestinal manifestations. According to the pediatric definition, the rate of disabling CD was 15%, and predictors included complicated behavior, age <14, and growth delay at diagnosis. Kappa values for each combination of predictors were, respectively, 0.2, 0.3, and 0.2 and were nonrelevant.
Conclusions:
Clinical parameters at diagnosis are insufficient to predict a disabling course of pediatric CD. More complex models including serological and genetic biomarkers should be tested. (Inflamm Bowel Dis 2012;)
REFERENCES
- 1 Louis E, Collard A, Oger AF, et al. Behaviour of Crohn's disease according to the Vienna classification: changing pattern over the course of the disease. Gut. 2001; 49: 777–782.
- 2 Cosnes J, Cattan S, Blain A, et al. Long-term evolution of disease behaviour of Crohn's disease. Inflamm Bowel Dis. 2002; 8: 244–250.
- 3 Solberg IC, Vatn MH, Hoie O, et al. Clinical course of Crohn's disease: results of a Norwegian population-based ten-year follow-up study. Clin Gastroenterol Hepatol. 2007; 5: 1430–1438.
- 4 Peyrin-Biroulet L, Loftus EV Jr, Colombel JF, et al. The natural history of adult Crohn's disease in population-based cohorts. Am J Gastroenterol. 2010; 105: 289–297.
- 5 Pariente B, Cosnes J, Danese S, et al. Development of the Crohn's disease digestive damage score, the Lémann score. Inflamm Bowel Dis. 2011; 17: 1415–1422.
- 6 Vernier-Massouille G, Balde M, Salleron J, et al. Natural history of pediatric Crohn's disease: a population-based cohort study. Gastroenterology. 2008; 135: 1106–1113.
- 7 Hyams J, Crandall W, Kugathasan S, et al. Induction and maintenance infliximab therapy for the treatment of moderate-to-severe Crohn's disease in children. Gastroenterology. 2007; 132: 863–873.
- 8 Crombé V, Salleron J, Savoye G, et al. Long-term outcome of treatment with infliximab in pediatric-onset Crohn's disease: a population-based study. Inflamm Bowel Dis. 2011; 17: 2144–2152.
- 9 Colombel JF, Sandborn WJ, Reinisch W, et al. Infliximab, azathioprine, or combination therapy for Crohn's disease. N Engl J Med. 2010; 362: 1383–1395.
- 10 Schnitzler F, Fidder H, Ferrante M, et al. Long-term outcome of treatment with infliximab in 614 patients with Crohn's disease: results from a single-centre cohort. Gut. 2009; 58: 492–500.
- 11 Colombel JF, Sandborn WJ, Rutgeerts P, et al. Adalimumab for maintenance of clinical response and remission in patients with Crohn's disease: the CHARM trial. Gastroenterology. 2007; 132: 52–65.
- 12 Hanauer SB, Feagan BG, Lichtenstein GR, et al. Maintenance infliximab for Crohn's disease: the ACCENT I randomised trial. Lancet. 2002; 359: 1541–1549.
- 13 Sands BE, Anderson FH, Bernstein CN, et al. Infliximab maintenance therapy for fistulizing Crohn's disease. N Engl J Med. 2004; 350: 876–885.
- 14 Lichtenstein GR, Yan S, Bala M, et al. Infliximab maintenance treatment reduces hospitalizations, surgeries, and procedures in fistulizing Crohn's disease. Gastroenterology. 2005; 128: 862–869.
- 15 Rutgeerts P, Diamond RH, Bala M, et al. Scheduled maintenance treatment with infliximab is superior to episodic treatment for the healing of mucosal ulceration associated with Crohn's disease. Gastrointest Endosc. 2006; 63: 433–442.
- 16 D'Haens G, Geboes K, Rutgeerts P. Endoscopic and histologic healing of Crohn's (ileo-) colitis with azathioprine. Gastrointest Endosc. 1999; 50: 667–671.
- 17 Feagan BG, Panaccione R, Sandborn WJ, et al. Effects of adalimumab therapy on incidence of hospitalization and surgery in Crohn's disease: result from the CHARM study. Gastroenterology. 2008; 135: 1493–1499.
- 18 Baert F, Moortgat L, Van Assche G, et al. Mucosal healing predicts sustained clinical remission in patients with early-stage Crohn's disease. Gastroenterology. 2010; 138: 463–468.
- 19 D'Haens G, Baert F, van Assche G, et al. Early combined immunosuppression or conventional management in patients with newly diagnosed Crohn's disease: an open randomized trial. Lancet. 2008; 371: 660–667.
- 20 Bathon JM, Martin RW, Fleischmann RM, et al. Comparison of etanercept and methotrexate in patients with early rheumatoid arthritis. N Engl J Med. 2000; 343: 1586–1593.
- 21 Genovese MC, Bathon JM, Martin RW, et al. Etanercept versus methotrexate in patients with early rheumatoid arthritis: two-year radiographic and clinical outcomes. Arthritis Rheum. 2002; 46: 1443–1450.
- 22 St Clair EW, van der Heijde DM, Smolen JS, et al. Active-controlled study of patients receiving infliximab for the treatment of rheumatoid arthritis of early onset study group. Combination of infliximab and methotrexate therapy for early rheumatoid arthritis: a randomized, controlled trial. Arthritis Rheum. 2004; 50: 3432–3443.
- 23 Breedveld FC, Weisman MH, Kavanaugh AF, et al. The PREMIER study: a multicenter, randomized, double-blind clinical trial of combination therapy with adalimumab plus methotrexate versus methotrexate alone or adalimumab alone in patients with early, aggressive rheumatoid arthritis who had not had previous methotrexate treatment. Arthritis Rheum. 2006; 54: 26–37.
- 24 Schreiber S, Reinisch W, Colombel JF, et al. Early Crohn's disease shows high levels of remission to therapy with adalimumab. Subanalysis of CHARM. Gastroenterology. 2007; 132: A147.
- 25 Schreiber S, Colombel JF, Bloomfield R, et al. Increased response and remission rates in short-duration Crohn's disease with subcutaneous certolizumab pegol: an analysis of PRECiSE 2 randomized maintenance trial data. Am J Gastroenterol. 2010; 105: 1574–1582.
- 26 Beaugerie L, Seksik P, Nion-Larmurier I, et al. Predictors of Crohn's disease. Gastroenterology. 2006; 130: 650–656.
- 27 Loly C, Belaiche J, Louis E. Predictors of severe Crohn's disease. Scand J Gastroenterol. 2008; 43: 948–954.
- 28 Gower-Rousseau C, Salomez JL, Dupas JL, et al. Incidence of inflammatory bowel disease in northern France (1988–1990). Gut. 1994; 35: 1433–1438.
- 29 Molinie F, Gower-Rousseau C, Yzet T, et al. Opposite evolution in incidence of Crohn's disease and ulcerative colitis in northern France (1988–1999). Gut. 2004; 53: 843–848.
- 30 Satsangi J, Silverberg MS, Vermeire S, et al. The Montreal classification of inflammatory bowel disease: controversies, consensus, and implications. Gut. 2006; 55: 749–753.
- 31 Vasseur F, Gower-Rousseau C, Vernier-Masouille G, et al. Nutrional status and growth in pediatric Crohn's disease: a population based study. Am J Gastroenterol. 2010; 105: 1893–1900.
- 32 Sachs L. Applied Statistics, 2nd ed. A Handbook of Techniques. New York: Springer; 1982. p 333–337.
- 33 Landis JR, Koch GG, The measurement of observer agreement for categorical data. Biometrics. 1977; 33: 159–174.
- 34 Markowitz J, Hyams J, Mack D, et al Corticosteroid therapy in the age of infliximab: acute and 1-year outcomes in newly diagnosed children with Crohn's disease. Clin Gastroenterol Hepatol. 2006; 1124–1129.
- 35 Veloso FT, Ferreira JT, Barros L, et al. Clinical outcome of Crohn's disease: analysis according to the Vienna classification and clinical activity. Inflamm Bowel Dis. 2001; 7: 306–313.
- 36 Sands BE, Arsenault JE, Rosen MJ, et al. Risk of early surgery for Crohn's disease: implications for early treatment strategies. Am J Gastroenterol. 2003; 98: 2712–2718.
- 37 Wolters FL, Russel MG, Sijbrandij J, et al. Phenotype at diagnosis predicts recurrence rates in Crohn's disease. Gut. 2006; 55: 1124–1130.
- 38 Latakos PL, Czegledi Z, Szamosi T, et al. Perianal disease, small bowel disease, smoking, prior steroid or early azathioprine/biological therapy are predictors of disease behaviour change in patients with Crohn's disease. World J Gastroenterol. 2009; 15: 3504–3510.
- 39 Thia KT, Sandborn WJ, Harmsen WS, et al. Risk factors associated with progression to intestinal complications of Crohn's disease in a population based cohort. Gastroenterology. 2010; 139: 1147–1155.
- 40 Latella G, Cocco A, Angelucci E, et al. Clinical course of Crohn's disease first diagnosed at surgery for acute abdomen. Dig Dis Sci. 2009; 269–276.
- 41 Boualit M, Julia Salleron J, Savoye G, et al. Early surgery is not associated with poor prognosis in pediatric Crohn's disease: a population-based study. Gastroenterology. 2011; 140( Suppl 1): S–38.
- 42 Punati J, Markowitz J, Lerer T, et al. Effect of early immunomodulator use in moderate to severe pediatric Crohn's disease. Inflamm Bowel Dis. 2008; 14: 949–954.
- 43 Levine A, Griffiths A, Markowitz J, et al Pediatric modification of the Montreal classification for inflammatory bowel disease: the Paris classification. Inflamm Bowel Dis. 2011; 17: 1314–1321.
- 44 Allez M, Lemann M, Bonnet J, et al. Long term outcome of patients with active Crohn's disease exhibiting extensive and deep ulcerations at colonoscopy. Am J Gastroenterol. 2002; 97: 947–953.
- 45 Arnott ID, Landers CJ, Nimmo EJ, et al. Sero-reactivity to microbial components in Crohn's disease is associated with disease severity and progression, but not NOD2/CARD15 genotype. Am J Gastroenterol. 2004; 99: 2376–2384.
- 46 Dubinski MC, Kugathasan S, Mei L, et al. Increased immune reactivity predicts aggressive complicating Crohn's disease in children. Clin Gastroenterol Hepatol. 2008; 6: 1105–1111.
- 47 Amre DK, Lu SE, Costea F, et al. Utility of serological markers in predicting the early occurrence of complications and surgery in pediatric Crohn's disease patients. Am J Gastroenterol. 2006; 101: 645–652.
- 48 Papp M, Altorjay I, Dotan N, et al. New serological markers for inflammatory bowel disease are associated with earlier age at onset, complicated disease behaviour, risk for surgery, and NOD2/CARD15 genotype in a Hungarian IBD cohort. Am J Gastroenterol. 2008; 103: 665–681.
- 49 Abreu MT, Taylor KD, Lin YC, et al. Mutations in NOD2 are associated with fibrostenosing disease in patients with Crohn's disease. Gastroenterology. 2002; 123: 679–688.
- 50 Annese V, Lombardi G, Perri F, et al. Variants of CARD15 are associated with an aggressive clinical course of Crohn's disease—an IG-IBD study. Am J Gastroenterol. 2005; 100: 84–92.
- 51 Alvarez-Lobos M, Arostegui JI, Sans M, et al. Crohn's disease patients carrying Nod2/CARD15 gene variants have an increased and early need for first surgery due to structuring disease and higher rate of surgical recurrence. Ann Surg. 2005; 242: 693–700.
- 52 Seiderer J, Schnitzler F, Brand S, et al. Homozygosity for the CARD15 frameshift mutation 1007fs is predictive of early onset of Crohn's disease with ileal stenosis, entero-enteral fistulas, and frequent need for surgical intervention with high risk of restonosis. Scand J Gastroenterol. 2006; 41: 1421–1432.
- 53 Economou M, trikalinos TA, Loizou KT, et al. Differential effects of NOD2 variants on Crohn's disease risk and phenotype in diverse populations: a metaanalysis. Am J Gastroenterol. 2004; 99: 2393–2404.
- 54 Vermeire S, Pierik M, Hlavaty T, et al. Association of organic cation transporter risk haplotype with perianal penetrating Crohn's disease but not with susceptibility to IBD. Gastroenterology. 2005; 129: 1845–1853.
- 55 Henckaerts L, Van Steen K, Verstreken I, et al. Genetic profiling and prediction of disease course in Crohn's disease patients. Clin Gastroenterol Hepatol. 2009; 7: 972–980.
- 56 Weersma RK, Stokkers PC, van Bodegraven AA, et al. Molecular prediction of disease risk and severity in a large Dutch Crohn's disease cohort. Gut. 2009; 58: 388–395.
- 57 Ferrante M, Henckaerts L, Joossens M, et al. New serological markers in inflammatory bowel disease are associated with complicated disease behaviour. Gut. 2007; 56: 1394–1403.
- 58 Siegel CA, Siegel LS, Hyams JS, et al. Real-time tool to display the predicted disease course and treatment response for children with Crohn's disease. Inflamm Bowel Dis. 2011; 17: 30–38.
- 59 Peyrin-Biroulet L, Cieza A, Sandborn WJ, et al. Disability in inflammatory bowel disease: developing Icf core sets for patients with IBD based on the WHO international classification of functioning, disability and health. Gastroenterology. 2011; 140( Suppl 1): S424.
