As noted in recent posts (see links below), there is increased interest in showing direct mucosal healing and achieving optimal drug levels in controlling Crohn disease (CD).
- Clin Gastroenterol Hepatol 2014: 12: 414-422.
- Clin Gastroenterol Hepatol 2014: 12: 423-431.
The first study examines the rates of deep remission induced by adalimumab. Deep remission is “defined as the absence of mucosal ulceration and CD Activity Index scores less than 150.”
Design: The data is derived from the EXTEND (EXTend the Safety and Efficacy of Adalimumab Through ENDoscopic Healing) trial. EXTEND was a 52-week randomized, double-blind, placebo-controlled trial of adalimumab (ADA) for adults (n=135) with moderate to severe ileocolonic CD. All patients received open-label induction with ADA (160/80 mg at weeks 0/2), then were randomized to ongoing ADA 40 mg every other week or placebo.
Results: Rates of DR were 16% in ADA patients compared with 10% of placebo-treated patients at week 12. By week 52, 19% of ADA patients were in DR compared with 0% of placebo-treated patients.
- Analysis showed that shorter disease duration was associated with DR. One-third of patients with CD for <2 years achieved DR.
- Patients with DR had better outcomes than those with only mucosal healing (n=8); those with isolated clinical remission (n=19, no mucosal healing), but not DR, had similar outcomes to those with DR. The associated editorial (pg 432) notes “symptoms will still make patients go to the emergency department, or miss work, or feel miserable, regardless of how good their mucosa looks.”
- The authors state that during the 40 weeks after early CR, “estimated savings were $6117 for direct medical costs and $4243 for indirect costs” (total $10,360). This monetary savings may not be offset in clinical practice by ileocolonoscopy which is not only invasive but also expensive.
Conclusion (from the authors): “Before any recommendation to adopt DR as a treatment target, establishing a clear association between achievement of DR and better long-term prognosis is necessary.” The editorial advises against adopting DR as a treatment goal: “combining symptoms and mucosal healing into 1 end-point should be reconsidered as a measure of response to anti-inflammatory therapies.”
The second study, referenced above, examined plasma concentrations of certolizumab pegol (CZP) and endoscopic outcomes of patients with Crohn disease.
Design: The authors analyzed data (post hoc analysis) from the MUSIC (The Endoscopic MUcoSal Improvement in Patients with Active CD Treated with CZP) study. Adult patients received subcutaneous CZP (400 mg) at weeks 0, 2, and 4 followed by every 4 week treatment for 52 weeks. Endoscopic evaluation took place at weeks 0, 10, and 54 and CZP concentrations were measured at weeks 8 and 54. At week 10, there were 45 patients analyzed and at week 54, 18 patients.
- Mean CZP concentrations: 11.1 mcg/mL at week 8 (4 weeks after previous dosing) and 14.9 mcg/mL at week 54 (2 weeks after previous dosing).
- Higher CZP concentration (by quartile values) correlated with endoscopic response (P=.0016) and remission (P=.0302) at week 10.
- Among those with the highest CZP values, their 8-week CDEIS (CD Endoscopic Index of Severity) remission rate was 75% (12/16). Overall, CDEIS remission was noted in 56% (25/45) at week 8.
- At week 54, endoscopic remission correlated with plasma CZP values (P=.0206).
- Both high CRP and high body weight inversely correlated with CZP concentrations.
Conclusion from this study: As with other anti-TNF agents, higher serum levels were associated with mucosal healing. However, the data do not prove causality. “It is possible that higher trough concentrations at week 8 may be a consequence of mucosal healing” rather than the reverse.
Bottomline: These two studies together show that achieving optimal long-term response correlates with therapeutic drug levels and mucosal healing. At the same time, these studies along with many other indicate that we have along way to go in order for us to achieve these objectives consistently.
Related blog posts:
- CCFA 2014 Meeting Notes (Part 1)
- Superiority of AntiTNFs in Children
- AGA Guidelines for the Use of AntiTNFs/Thiopurines