Louis E, Vermeire S, Rutgeerts P, De Vos M, Van Gossum A, Pescatore P, Fiasse R, Pelckmans P, Reynaert H, D'Haens G, Malaise M, Belaiche J
Dept of Gastroenterology, CHU of Liège, Belgium.
Scand J Gastroenterol. 2002 Jul;37(7):818-24.
Two-thirds to three-fourths of patients with either refractory luminal or fistulizing Crohn disease respond to infliximab treatment. The ability or inability to respond seems to persist over time. Biological characteristics and/or genetic background can influence the response to treatment. The aim was to assess the value of C-reactive protein and TNF-alpha serum levels before treatment as well as the TNF -308 gene polymorphism in the prediction of response to infliximab treatment in Crohn disease.
Two-hundred-and-twenty-six Crohn disease patients treated in the setting of an expanded access programme to infliximab in Belgium were studied. There were 136 refractory luminal diseases and 90 refractory fistulizing diseases. Luminal diseases were treated with one single infusion; fistulizing diseases with three infusions at weeks 0, 2 and 6. A clinical response to treatment was defined as either a Crohn disease activity index <150 (complete) or a drop of 70 points (partial) at week 4, for luminal disease, and as either complete fistula healing (complete) or a decrease of at least 50% of the number of draining fistulas on two consecutive visits between weeks 0 and 18, for fistulizing disease. CRP and serum TNF-alpha levels were measured at week 0 before treatment and were compared between responders and non-responders. Patients were genotyped for the -308 TNF gene polymorphism, and allelic as well as genotype frequencies were compared between responders and non-responders.
There were 73.2% responders (46.4% complete and 26.8% partial) and 26.8% non-responders. Response rates were similar in luminal and fistulizing diseases. CRP level before treatment was significantly higher in responders than in non-responders (16.8 mg/l (5-160) versus 9.6 mg/l (5-143); P = 0.02). Furthermore, response rate was significantly higher in patients with elevated CRP (>5 mg/l) than in patients with a normal CRP value (<5 mg/l) before treatment (76% versus 46%; P=0.004; OR: 0.26 (0.11-0.63)). Allelic and genotype frequencies for -308 TNF gene polymorphism were not significantly different between responders and non-responders--with the exception of a slightly higher TNF2 frequency in non-responders in luminal disease (22.1 % versus 11.6%; P = 0.04). However, this was not associated with a significant difference in genotype frequencies.
A positive clinical response to infliximab was associated with a higher CRP level before treatment in our population of Crohn disease patients, but there was no relevant association with -308 TNF gene polymorphism. We therefore suggest that CRP level may help to identify better candidates for infliximab treatment.
三分之二至四分之三的难治性管腔型或瘘管型克罗恩病患者对英夫利昔单抗治疗有反应。反应能力或无反应能力似乎会随时间持续存在。生物学特征和/或基因背景可影响治疗反应。目的是评估治疗前C反应蛋白和肿瘤坏死因子-α血清水平以及肿瘤坏死因子-308基因多态性在预测克罗恩病患者对英夫利昔单抗治疗反应中的价值。
研究了在比利时英夫利昔单抗扩大准入项目中接受治疗的226例克罗恩病患者。其中136例为难治性管腔型疾病，90例为难治性瘘管型疾病。管腔型疾病采用单次输注治疗；瘘管型疾病在第0、2和6周进行三次输注。治疗的临床反应定义为：对于管腔型疾病，在第4周时克罗恩病活动指数<150（完全缓解）或下降70分（部分缓解）；对于瘘管型疾病，在第0至18周期间连续两次就诊时瘘管完全愈合（完全缓解）或引流瘘管数量至少减少50%。在治疗前第0周测量C反应蛋白和血清肿瘤坏死因子-α水平，并在反应者和无反应者之间进行比较。对患者进行肿瘤坏死因子-308基因多态性基因分型，并比较反应者和无反应者之间的等位基因及基因型频率。
反应者占73.2%（完全缓解46.4%，部分缓解26.8%），无反应者占26.8%。管腔型和瘘管型疾病的反应率相似。治疗前反应者的C反应蛋白水平显著高于无反应者（16.8mg/L（5-160）对9.6mg/L（5-143）；P=0.02）。此外，治疗前C反应蛋白升高（>5mg/L）的患者反应率显著高于C反应蛋白值正常（<5mg/L）的患者（76%对46%；P=0.004；OR：0.26（0.11-0.63））。反应者和无反应者之间肿瘤坏死因子-308基因多态性的等位基因及基因型频率无显著差异——管腔型疾病中无反应者的肿瘤坏死因子2频率略高除外（22.1%对11.6%；P=0.04）。然而，这与基因型频率无显著差异无关。
在我们的克罗恩病患者群体中，对英夫利昔单抗的阳性临床反应与治疗前较高的C反应蛋白水平相关，但与肿瘤坏死因子-308基因多态性无相关联系。因此，我们建议C反应蛋白水平可能有助于识别更适合英夫利昔单抗治疗的患者。
