Crohn's disease genotypes of patients in remission vs relapses after infliximab discontinuation.

AIM: To investigate genetic differences between Crohn's disease (CD) patients with a sustained remission vs relapsers after discontinuing infliximab while in corticosteroid-free remission. METHODS: Forty-eight CD patients received infliximab and were in full corticosteroid-free clinical remission but then discontinued infliximab for reasons other than a loss of response, were identified by review of an electronic database and charts. Infliximab-associated remission was defined as corticosteroid-free plus normalization of clinical disease activity [CD activity index (CDAI) < 150] during follow-up visits based on physician global assessments. A CD relapse (loss of infliximab-induced remission) was clinically defined as a physician visit for symptoms of disease activity (CDAI > 220) and a therapeutic intervention with CD medication(s), or a hospitalization with complications related to active CD. Genetic analyses were performed on samples from 14 patients (n = 6 who had a sustained long term remission after stopping infliximab, n = 8 who rapidly relapsed after stopping infliximab). Nucleotide-binding oligomerization domain 2 (NOD2)/caspase activation recruitment domain 15 (CARD15) polymorphisms (R702W, G908R and L1007fs) and the inflammatory bowel disease 5 (IBD5) polymorphisms (IGR2060a1 and IGR3081a1) were analyzed in each group. RESULTS: Five single nucleotide polymorphisms of IBD5 and NOD2/CARD15 genes were successfully analyzed for all 14 subjects. There was no significant increase in frequency of the NOD2/CARD15 polymorphisms (R702W, G908R and L1007fs) and the IBD5 polymorphisms (IGR2060a1 and IGR3081a1) in either group of patients; those whose disease relapsed rapidly or those who remained in sustained long term remission following the discontinuation of infliximab. Nearly a third of patients in full clinical remission who stopped infliximab for reasons other than loss of response remained in sustained clinical remission, while two-thirds relapsed rapidly. There was a marked difference in the duration of clinical remission following discontinuance of infliximab between the two groups. The patients who lost remission did so after 1.0 years ± 0.6 years, while those still in remission were at the time of this study, 8.1 years ± 2.6 years post-discontinuation of infliximab, P < 0.001. The 8 patients who had lost remission after discontinuing infliximab had a mean number of 5 infusions (range 3-7), with a mean treatment time of 7.2 mo (range 1.5 mo-15 mo). The mean duration of time from the last infusion of infliximab to the time of loss of remission was 382 d (range 20 d-701 d). The 6 patients who remained in remission after discontinuing infliximab had a mean number of 6 infusions (range 3-12), with a mean treatment duration of 12 mo (range 3.6 mo-32 mo) (P = 0.45 relative to those who lost remission). CONCLUSION: There are no IBD5 or NOD2/CARD15 mutations that predict which patients might have sustained remission and which will relapse rapidly after stopping infliximab.

Drug-disease interaction: Crohn's disease elevates verapamil plasma concentrations but reduces response to the drug proportional to disease activity.

AIM: Inflammation is involved in the pathogenesis of cardiovascular diseases that includes reduced response to pharmacotherapy due to altered pharmacokinetics and pharmacodynamics. It is not known if these effects exist in general in all inflammatory conditions. It also remains unknown whether in a given population the effect is a function of disease severity. We investigated whether pharmacokinetics and pharmacodynamics of a typical calcium channel inhibitor are influenced by Crohn's disease (CD), a disease for which the disease severity can be readily ranked. METHODS: We administered 80 mg verapamil orally to (i) healthy control subjects (n= 9), (ii) patients with clinically quiescent CD (n= 22) and (iii) patients with clinically active CD (n= 14). Serial analysis of verapamil enantiomers (total and plasma unbound), blood pressure and electrocardiograms were recorded over 8 h post dose. The severity of CD was measured using the Harvey-Bradshaw Index. RESULTS: CD substantially and significantly increased plasma verapamil concentration and in a stereoselective fashion (S, 9-fold; R, 2-fold). The elevated verapamil concentration, however, failed to result in an increased verapamil pharmacodynamic effect so that the patients with elevated verapamil concentration demonstrated no significant increase in response measured as PR interval and blood pressure. Instead, the greater the disease severity, the lower was the drug potency to prolong PR interval (r= 0.86, P < 0.0006), CONCLUSIONS: CD patients with severe disease may not respond to cardiovascular therapy with calcium channel blockers. Reducing the severity increases response despite reduced drug concentration. This observation may have therapeutic implication beyond the disease and the drug studies herein.