NOD2 polymorphism predicts response to treatment in Crohn's disease--first steps to a personalized therapy.

BACKGROUND AND AIMS: Great efforts have been made to predict disease behavior over time and the response to treatment in Crohn's disease (CD). Such understanding could personalize therapy. Early introduction of more aggressive therapies to patients at high risk and no introduction of predictable refractory treatments could become possible. We hence tested the influence of the NOD2 carrier status on treatment response. PATIENTS AND METHODS: In 185 CD patients (age 45 ± 9.8 years, female n = 108, minimum disease duration 10 years), the three most common polymorphisms (p.Arg702Trp, p.Gly908Arg, p.Leu1007fsX1008) of NOD2 were tested by polymerase chain reaction and sequencing. Detailed clinical and medical history were obtained with a standardized questionnaire and by reviewing the medical charts. Treatments introduced were chosen by physicians blinded to genotype data. RESULTS: The frequency of the NOD2 variant allele was about one-third (67, 30.2%) of CD patients. NOD2 carriers were more often treated with systemic and locally active steroids and with an immunosuppressant (Azathioprine/6-MP). NOD2 mutation carrier status was more often associated with systemic steroid [8.9% vs. wild-type (WT) 1.2%, P = 0.0086] and local-steroid refractory (14.9% vs. WT 3.5%; P = 0.001). The WT patients were significantly higher refractory to immunosuppressant (12.8% vs. NOD2 carriers, 0.5%, P = 0.03). Most WT patients were treated with TNF-α antagonists and remission rates were significantly higher in this group after 1 year of treatment (84% vs. NOD2 carriers, 33%, P = 0.07). CONCLUSIONS: The study presents first hints for the NOD2 carrier status to be predictive for response to therapy. A higher percentage of CD patients with NOD2 mutation carrier status was steroid refractory but could be treated well with immunosuppressants. The WT status showed a higher response to steroids and remission rates within 1 year of anti-TNF-α therapy. On the way to personalized medicine, this approach should be further investigated in larger studies.

The endothelin axis influences enteric glia cell functions.

BACKGROUND: The biologic effects of endothelin-1 (ET-1) are not limited to its vasoconstricting activity. A new and highly interesting role of the endothelin axis is its involvement in immune functions. As ET-1 is highly increased during gut inflammation, the aim of this study was to see if the endothelin axis influences enteric glia cell (EGC) functions, and through them, the immune response, during gut inflammation. MATERIAL/METHODS: Cultured EGCs were treated with interleukin-1 beta (IL-1 beta), tumor necrosis factor-alpha (TNFalpha), IL-4, interferon-gamma, and ET-1. Secretion of ET-1 was detected by ELISA. Cultured EGCs were labeled with anti-glial fibrillary acidic protein (GFAP), endothelin-A (ETA), and endothelin-B (ETB), antibodies. The expression of ETA and ETB receptors was evaluated using reverse transcription PCR. Glial fibrillary acidic protein expression was determined by Western blot. RESULTS: ET-1 secretion of EGCs could be stimulated by IL-1 beta and TNFalpha in a time and dose-dependent manner, whereas IL-4 and interferon-gamma showed no effect on ET-1 production. Cultured EGCs expressed ETA and ETB-receptors. Endothelin B mRNA expression was increased after incubation with IL-1 beta. Incubation of cells with IL-1 beta, TNFalpha, and ET-1 led to a significant increase of GFAP in EGCs. CONCLUSIONS: Enteric glia cells express functional ETA and ETB receptors and produce huge amounts of ET-1 during gut inflammation, which increase GFAP expression in EGCs. These ET-1/ET receptors autocrine or paracrine loops might provide a new means to modulate EGC function, such as change in gut motility, cytokine production, and regulating gut homeostasis.