Homozygosity for the NOD2 p.Leu1007fsX1008 variant is the main genetic predictor for fibrostenotic Crohn's disease.

To the Editor: It is with great interest that I read the review of Rieder et al on ‘‘Predictors of fibrostenotic Crohn’s disease’’ in Inflammatory Bowel Diseases. The authors mentioned the role of genetic factors, in particular NOD2, which was the only gene significantly associated with intestinal stenosis in the recent European ImmunoChip study. There are three additional points worth mentioning regarding the role of NOD2 mutations in the development of fibrostenotic Crohn’s disease (CD). First, while two NOD2 mutations have a high specificity for predicting complicated CD, a single NOD2 mutation has relatively little sensitivity and only moderate specificity for predicting fibrostenotic and complicated CD. In a very recent meta-analysis, which included 49 studies with 8893 subjects including 2897 carriers of NOD2 mutations, the presence of a single NOD2 mutation predicted only an 8% increase in the risk for complicated disease (defined as stricturing phenotype B2 or penetrating phenotype B3). The authors of this meta-analysis therefore concluded that the presence of only one mutated NOD2 allele has a very limited prognostic value predicting complicated CD behavior. However, there was a 41% increase for the risk for complicated disease with two NOD2 mutations. Moreover, the presence of two NOD2 mutations had 98% specificity for complicated disease. The pooled relative risk (RR) of stricturing disease with the presence of any (one or more) NOD2 mutations was 1.33 (95% confidence interval [CI] 1.15–1.55; P < 0.001). Although other NOD2 mutations may contribute to a complicated disease behavior, the three main CDassociated NOD2 mutations (p.R702W, p.G908R, p.Leu1007fsX1008) are also considered the three main NOD2 mutations modifying CD behavior and were included into this meta-analysis. Second, we provided evidence that homozygosity especially for the NOD2 variant p.Leu1007fsX1008 results in ileal fibrostenosis. The recent NOD2 meta-analysis was limited by the fact that only 12 studies had sufficient data to analyze for individual NOD2 mutations and this meta-analysis did not have enough data to differentiate between heterozygous and homozygous carriers of individual mutations to analyze for fibrostenotic CD. Given these limitations, only an association of fibrostenotic CD with NOD2 p.G908R carrier status was found in this meta-analysis (RR: 1.90, 95% CI 1.17–3.07; P 1⁄4 0.009). In contrast, in one of the most detailed phenotypic analysis of CD patients with NOD2 mutations, including 19 CD patients with two p.Leu1007fsX1008 mutations (identified among 445 IBD patients), we show that all homozygous carriers of the p.Leu1007fsX1008 NOD2 mutation with CD develop fibrostenotic disease in the terminal ileum (Table 1). 73.7% of these patients had to undergo stricture-related surgery. Of these patients, 78.6% developed restenoses after surgical resection. We confirmed these data in a prospective study in which the p.Leu1007fsX1008 variant was associated with an increased risk of intestinal stenosis (odds ratio [OR] 1⁄4 12.00, CI 3.47–41.54, P 1⁄4 0.00042, Bonferroni corrected). After publication of these studies, we observed the same phenotype in a similar-sized replication CD cohort of homozygous carriers of the p.Leu1007fsX1008 mutation (unpubl. obs.), suggesting that these patients would be a primary target group for a personalized early top-down therapeutic strategy to prevent surgical interventions. Third, we recently demonstrated that fibrostenosis is an important risk factor for fistulizing CD. Therefore, CD patients with fistulas not improving under efficacious therapy such as antitumor necrosis factor (TNF) antibodies should be screened for intestinal stenosis. In our retrospective study of 333 CD patients, concomitant stenosis was diagnosed in 125 patients with fistulas. In this study, the positive predictive value (PPV) was 86.2% for fistulas predicting intestinal stenosis. In logistic regression analysis, the presence of fistulas (OR 4.51; 95% CI 2.54–8.01, P 1⁄4 2.68 10 ) and disease duration (OR 1.09; 95% CI 1.05– 1.13; P 1⁄4 3.19 10 ) were strongly associated with intestinal stenosis. TABLE 1. Phenotypic Characteristics.