NOD2/CARD15 does not influence response to infliximab in Crohn's disease

• Published in: Gastroenterology (New York, N.Y. 1943) Vol. 123; no. 1; p. 106
• Main Authors: Vermeire, Severine, Louis, Edouard, Rutgeerts, Paul, De Vos, Martine, Van Gossum, Andre, Belaiche, Jacques, Pescatore, Paul, Fiasse, Rene, Pelckmans, Paul, Vlietinck, Robert, Merlin, Françoise, Zouali, Habib, Thomas, Gilles, Colombel, Jean-Frederic, Hugot, Jean-Pierre
• Format: Journal Article
• Language: English
• Published: United States 01.07.2002
• Subjects: Adult; Antibodies, Monoclonal - therapeutic use; Carrier Proteins - genetics; Cohort Studies; Crohn Disease - drug therapy; Crohn Disease - genetics; Crohn Disease - metabolism; Female; Gastrointestinal Agents - therapeutic use; Gene Frequency; Genotype; Humans; Infliximab; Intracellular Signaling Peptides and Proteins; Male; Nod2 Signaling Adaptor Protein; Predictive Value of Tests; Reference Values; Treatment Outcome; Tumor Necrosis Factor-alpha - biosynthesis
• ISSN: 0016-5085
• DOI: 10.1053/gast.2002.34172

NOD2/CARD15 was recently identified as the first gene underlying Crohn's disease (CD) susceptibility. Monoclonal antibodies to tumor necrosis factor (TNF)-alpha (infliximab) are a potent treatment for CD, with about 70% of patients responding. It is not clear which factors influence treatment outcome. We assessed whether variants in NOD2/CARD15 are predictive for differences in clinical response. Two hundred forty-five CD patients (86 fistulizing, 159 luminal) receiving infliximab in an expanded access program were genotyped for the 3 main associated variants of NOD2/CARD15, without knowledge of the treatment response. Short-term clinical response was assessed at 4 weeks (refractory) or 10 weeks (fistulizing) after first infliximab infusion, and the mean duration of response was calculated. In a subgroup of patients, production of TNF in response to lipopolysaccharide (LPS) in mucosal biopsy tissue was also determined by means of immunoassay, and results were related to the different NOD2/CARD15 genotypes. In total, 32.6% of patients carried mutations in NOD2/CARD15 (18.8% R702W, 8.6% G908R, and 10.2% 1007fs) compared with 15% in controls (P < 0.001). Despite observed differences in TNF production in mucosal biopsy tissue, there was no relationship between the overall presence of a mutation in NOD2/CARD15 or of any of the mutations separately and short-term infliximab response or response duration. Furthermore, multivariate analysis could not identify clinical characteristics that, in combination with NOD2/CARD15 mutations, were associated with response to infliximab. In this cohort of CD patients, the frequency of NOD2/CARD15 mutations was significantly greater than that of healthy controls. However, NOD2/CARD15 was not predictive of treatment outcome with infliximab in CD.