How to improve the safety of biologic therapy in Crohn's disease.

Short- and long-term anti tumor necrosis factor-alpha (TNF-alpha) therapy in Crohn's disease is generally well tolerated. However, clinicians must be vigilant for the occurrence of infrequent but serious events. Antibodies to infliximab interfere with the safety and efficacy of the drug and may lead to infusion reactions, loss of response, and delayed serum sickness-like reactions. The optimal strategy to overcome the production of antibodies is systematic maintenance treatment. The most effective way to minimize the risk of opportunistic infection is to vaccinate the patients and to avoid the use of corticosteroids. All patients should receive varicella vaccination, annual influenza vaccination (also pandemic influenza A - H1N1), and pneumococcal vaccination every 3 to 5 years. In addition, HPV vaccine should be administered to young females, and hepatitis B vaccine to HBV seronegative patients. Unlike corticosteroids, infliximab does not pose an increased risk for serious infection. Treatment with anti TNF-alpha agents increases the risk of activation of latent TB. Therefore, all patients should be screened for TB infection before starting with therapy. The use of anti TNF-alpha agents in combination with immunomodulators is associated with an increased risk of non-Hodgkin's lymphoma, but the absolute rate remains low. There is no evidence that other malignancies and death rates in patients treated with anti TNF-alpha strategies are increased. Reported data from 300 pregnant women treated with infliximab have not shown any untoward effects of treatment on pregnancy outcome.

Polymorphisms in multidrug resistance 1 (MDR1) gene are associated with refractory Crohn disease and ulcerative colitis.

We used coding and noncoding polymorphisms evenly spaced across the ABCB1/MDR1 gene to perform association analysis in Slovenian patients with inflammatory bowel diseases and to obtain haplotype structure and patterns of linkage disequilibrium (LD) in the MDR1 gene. A disease association study was performed in 307 IBD patients, including 144 patients with ulcerative colitis (UC) and 163 patients with Crohn's disease (CD), and 355 healthy controls. Here we report an association between MDR1 alleles, polymorphisms and haplotypes and refractory CD patients, who do not respond to standard therapy, including patients who develop fistulas. We also report an association with UC and MDR1 polymorphisms in a Slovenian population. Haplotypes significantly associated with diseases were defined by single-nucleotide polymorphisms (SNPs) in exons 12 (1236 C>A), 21(A893S), and 26 (3435 C>T). In addition, two intronic SNPs in LD with the disease haplotype, one in intron 13 (rs2235035) and another in intron 16 (rs1922242), were significantly associated with refractory Crohn (P=0.026, odds ratio (OR) 2.7 and P=0.025, OR 2.8, respectively), as well as with UC (P=0.006, OR 1.8 and P=0.026, OR 1.9, respectively). Our results suggest that MDR1 is a potential target for therapy in refractory CD patients and in patients with UC.