A new analysis supports a strategy of aggressive adalimumab treatment in moderately ill patients with Crohn disease who have a CRP of 10 ml/L or greater.
Data from existing randomized clinical trials (CLASSIC-1 to study induction of remission, and the CHARM and EXTEND trials to study maintenance therpy) were used in this UC San Diego analysis to explore the safety and efficacy of adalimumab in moderate Crohn disease (CD). This post hoc analysis of incidentally collected data in randomized controlled trials will be cited by those who have favored switching to a “top-down” approach in the treatment of inflammatory bowel diseases. Guidelines have continued to favor the “step-up” strategy, where anti–tumor necrosis factor (anti-TNF) agents are reserved for those with severe disease, or for patients who do not respond well to first-line agents. This study suggests that in moderately ill patients, anti-TNF agents can be safely started as first-line therapy (at least when measured over slightly less than 5 years). And further-that using anti-TNF agents in those with elevated C-reactive protein (CRP) levels at baseline prevents complications and hospitalizations.
Why assess CRP? Experts have recently begun suggesting a customized approach in the decision to use anti-TNF agents, based on aggressive therapeutic monitoring (for more on that see my review of an expert panel’s discussion at the 2012 Advances in Inflammatory Bowel Diseases, the Crohn’s & Colitis Foundation’s Clinical & Research Conference). The San Diego study suggests that CRP, a nonspecific marker of chronic inflammation, is a good place to start with aggressive therapeutic monitoring-it appeared to identify a cohort with only moderate symptoms but who had the potential for rapid development of stricturing or perforating disease.
Patients were classified as “moderate CD” if their score on the Crohn’s Disease Activity Index (CDAI) was 300 or less; “severe CD” was classified by a score greater than 300. In the CLASSIC-1 study, moderate and severe CD patients (anti-TNF–naive) were randomized to receive subcutaneous placebo or one of several adalimumab doses scheduled over a 2-week induction period. Patients were further classified into baseline “low-CRP” and “high-CRP” groups (a cutoff of 10 mg/L qualified the patient as “severe”).
The paper is complex, blending discussions of induction and remission-maintenance data from 3 different clinical trials. But several conclusions can be gleaned from the statistical analysis. Moderate CD patients had the highest clinical remission rate and the largest treatment effect compared with placebo at week 4 following high-dose induction, and within that group, the highest efficacy was seen among those with high CRP. Adalimumab maintenance treatment achieved superior remission versus placebo at 1 year. Most important, the moderate CD cohort with elevated CRP levels who received placebo experienced disease activity and hospitalization rates comparable to those of patients who were severe at baseline. Moderate patients had a lower treatment-related adverse-effect rate than the severe group, measured over nearly a 5-year follow-up period.
In summary: this analysis supports a strategy of aggressive adalimumab treatment in moderately ill CD patients who have a CRP level of 10 mg/L or greater. Additional study is needed, particularly a prospective, randomized, controlled trial rather than this post hoc analysis of existing data. Without that, guideline writers are not likely to move away from the “step-up” approach.
Sandborn WJ, Colombel J, Panes J, et al. Exploring the use of adalimumab for patients with moderate Crohn’s disease: subanalyses from induction and maintenance trials. J Crohn's Colitis 2013 (March).