ABSTRACT
AIM: To investigate genetic factors that might help define which Crohn's disease (CD) patients are likely to benefit from anti-tumor necrosis factor (TNF) therapy. METHODS: This was a prospective cohort study. Patients were recruited from a university digestive disease practice database. We included CD patients who received anti-TNF therapy, had available medical records (with information on treatment duration and efficacy) and who consented to participation. Patients with allergic reactions were excluded. Patients were grouped as ever-responders or non-responders. Genomic DNA was extracted from peripheral blood, and 7 single nucleotide polymorphisms (SNPs) were assessed. The main outcome measure (following exposure to the drug) was response to therapy. The patient genotypes were assessed as the predictors of outcome. Possible confounders and effect modifiers included age, gender, race, and socioeconomic status disease, as well as disease characteristics (such as Montreal criteria). RESULTS: 121 patients were included. Twenty-one were non-responders, and 100 were ever-responders. Fas ligand SNP (rs763110) genotype frequencies, TNF gene -308 SNP (rs1800629) genotype frequencies, and their combination, were significantly different between groups on multivariable analysis controlling for Montreal disease behavior and perianal disease. The odds of a patient with a Fas ligand CC genotype being a non-responder were four-fold higher as compared to a TC or TT genotype (P = 0.009, OR = 4.30, 95%CI: 1.45-12.80). The presence of the A (minor) TNF gene -308 allele correlated with three-fold higher odds of being a non-responder (P = 0.049, OR = 2.88, 95%CI: 1.01-8.22). Patients with the combination of the Fas ligand CC genotype and the TNF -308 A allele had nearly five-fold higher odds of being a non-responder (P = 0.015, OR = 4.76, 95%CI: 1.35-16.77). No difference was seen for the remaining SNPs. CONCLUSION: The Fas-ligand SNP and TNF gene -308 SNP are associated with anti-TNF treatment response in CD and may help select patients likely to benefit from therapy.
Subject(s)
Crohn Disease/drug therapy , Crohn Disease/genetics , Fas Ligand Protein/genetics , Gastrointestinal Agents/therapeutic use , Tumor Necrosis Factor-alpha/genetics , Adalimumab/therapeutic use , Adult , Alleles , Certolizumab Pegol/therapeutic use , Colonoscopy , Crohn Disease/diagnostic imaging , Female , Genotype , Humans , Infliximab/therapeutic use , Male , Middle Aged , Polymorphism, Single Nucleotide , Prospective Studies , Tumor Necrosis Factor-alpha/antagonists & inhibitorsABSTRACT
BACKGROUND: Crohn's disease (CD) therapy is rapidly evolving. Recent and ongoing clinical trials using immunologically active stem cells (SC) for the treatment of CD demonstrate the potential for this novel therapy to induce complete and long-lasting remission of symptoms in settings where 'standard' therapies have been unsuccessful. OBJECTIVE/METHODS: This review of SC, including mesenchymal stem cell (MSC) therapy for CD discusses how the immunological effects of MSC may correct some of the pathophysiological defects underpinning CD, and examines the latest clinical trial data providing evidence of their efficacy in the treatment of Crohn's disease. RESULTS/CONCLUSIONS: Given the beneficial effects on mucosal healing seen in animal models of inflammation and results from early clinical trials, MSC may serve as a candidate therapy for patients who have failed to respond to biological therapy.
