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


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Vermeire
Severine
S
Department of Gastroenterology, UZ Gasthuisberg, Leuven, Belgium.
Louis
Edouard
E
Rutgeerts
Paul
P
De Vos
Martine
M
Van Gossum
Andre
A
Belaiche
Jacques
J
Pescatore
Paul
P
Fiasse
Rene
R
Pelckmans
Paul
P
Vlietinck
Robert
R
Merlin
Françoise
F
Zouali
Habib
H
Thomas
Gilles
G
Colombel
Jean-Frederic
JF
Hugot
Jean-Pierre
JP
D000328:Adult; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D002352:Carrier Proteins / Q000235:genetics*; D015331:Cohort Studies; D003424:Crohn Disease / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005765:Gastrointestinal Agents / Q000627:therapeutic use*; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D000069285:Infliximab; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D053473:Nod2 Signaling Adaptor Protein; D011237:Predictive Value of Tests; D012016:Reference Values; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D000911:Antibodies, Monoclonal; D002352:Carrier Proteins; D005765:Gastrointestinal Agents; D047908:Intracellular Signaling Peptides and Proteins; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab