NOD2/CARD15 gene variants are linked to failure of antibiotic treatment in perianal fistulating Crohn's disease.
OBJECTIVE
The Crohn's disease (CD) susceptibility gene, nucleotide-binding oligomerizetion domain 2 (NOD2)/caspase recruitment domain 15 (CARD15), is linked to the innate immune response associated with altered epithelial bacterial defense. Its relevance in antibiotic therapy of perianal fistulating CD remains elusive. The aim of the study was to explore systematically the association between NOD2/CARD15 variants and clinical response of perianal fistulas in patients using antibiotic therapy.


METHODS
Fifty-two patients (median age 36 yr) with draining perianal fistulas were treated with ciprofloxacin (N = 49) or metronidazole (N = 3) for a median duration of 7 wk. Complete response was defined as the absence of any draining fistula despite gentle finger compression. Genotyping for NOD2/CARD15 variants and human beta (beta)-defensin 2 (HBD-2) copies was performed by 5' nuclease assays (Applied Biosystems, Foster City, CA). The examiners and laboratory investigators were blinded. The Fisher exact test and Wilcoxon signed rank test were used for statistical analysis.


RESULTS
Ciprofloxacin was discontinued in one patient due to diarrhea after 2 wk. Complete fistula response was observed in 13 of 39 patients with NOD2/CARD15 wild-type (33.3%) compared with none in patients carrying NOD2/CARD15 variants (0%, P= 0.02). The median number of HBD-2 gene copies between responders and partial/nonresponders was similar.


CONCLUSIONS
The study result suggests a substantial contribution of NOD2/CARD15 to the antibiotic treatment outcome of perianal fistulating CD. NOD2/CARD15 variants may predispose to an altered intestinal microflora in perianal fistulas that is less responsive to antibiotic treatment.
Angelberger
Sieglinde
S
Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University Vienna, Vienna, Austria.
Reinisch
Walter
W
Dejaco
Clemens
C
Miehsler
Wolfgang
W
Waldhoer
Thomas
T
Wehkamp
Jan
J
Lichtenberger
Cornelia
C
Schaeffeler
Elke
E
Vogelsang
Harald
H
Schwab
Matthias
M
Teml
Alexander
A
D000328:Adult; D000483:Alleles; D000890:Anti-Infective Agents / Q000009:adverse effects / Q000627:therapeutic use*; D002939:Ciprofloxacin / Q000009:adverse effects / Q000627:therapeutic use*; D003424:Crohn Disease / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics*; D005260:Female; D006580:Genetic Carrier Screening; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D008297:Male; D008795:Metronidazole / Q000009:adverse effects / Q000627:therapeutic use*; D008875:Middle Aged; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011379:Prognosis; D011446:Prospective Studies; D012003:Rectal Fistula / Q000188:drug therapy* / Q000235:genetics*; D017211:Treatment Failure; D023083:beta-Defensins / Q000235:genetics
D000890:Anti-Infective Agents; C106641:DEFB4A protein, human; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; D023083:beta-Defensins; D008795:Metronidazole; D002939:Ciprofloxacin