Background: Recently, we reported the result of a randomized clinical trial to compare the clinical efficacy of adalimumab (ADA) monotherapy with the combination of ADA with azathioprine (AZA) in induction of remission for Japanese patients with Crohn's Disease (CD) naïve to tumor necrosis factor (TNF) antagonists (DIAMOND trial). However, whether ADA trough levels and anti-ADA antibodies (AAA) were relevant to disease outcome remains unclear. The aim of this study is to evaluate the impact of ADA trough levels and AAA at 26weeks on clinical activity at 52 weeks and to examine the effect of AZA on ADA trough level in CD patients enrolled in DIAMOND trial.
Methods: In the preceding DIAMOND trial, 176 patients with active CD naïve to TNF antagonists were randomly assigned to either have ADA monotherapy or the combination therapy. The clinical efficacy was evaluated at Week 26 and 52. Clinical remission was defined as a CDAI score of less than 150 points. Serum samples from the patients in both groups at Week 26 were collected and trough levels of ADA and AAA were measured by using ELISA system. Also, blood samples were collected from patients in the combination group at Week 12, and processed to measurement of 6-TGN in red blood cells (RBCs). A multiple regression model was performed to identify factors independently related to trough levels of ADA and AAA at Week 26. Covariates included in the model were age, sex, body weight, the duration of the disease, disease location, previous surgery, presence of internal fistula, presence of anal fistula, smoking status and medication at entry.
Results: One hundred and fifty-one serum samples were analyzed from 176 patients enrolled in the study. Patients with clinical remission at 52 weeks had significantly higher trough level of ADA (7.7 μg/ml) at 26 weeks than those with active disease (5.4 μg/ml: p<0.001). Development of AAA at 26 weeks was significantly and positively associated with disease activity at 52weeks (p=0.021). A multivariate logistic regression model revealed that sex and low body weight were factors independently associated with high ADA trough level, and that male sex was associated with occurrence of AAA. There was a trend towards a higher 6TG level at 12 weeks in CD patients negative for AAA at 26 weeks (322 pmol/8×108 RBCs) than in those positive for it (137 pmol/8×108 RBCs), despite no significant difference of mean dose of AZA between AAA negative and positive group.
Conclusions: Higher trough levels of ADA and absence of AAA at 26 weeks obviously affected clinical activity at 52 Weeks in CD patients treated with ADA monotherapy or the combination therapy. A high 6TG concentration might be required for suppression of AAA.