“Lies, damned lies, and statistics” –Mark Twain (who attributed this quote to Benjamin Disraeli)
Using statistics, the recent COMMIT study (Gastroenterol 2014; 146: 681-88) showed that the combination therapy of methotrexate (MTX) and infliximab (IFX) was not more effective than IFX alone. Does this result makes sense? No.
Before getting back to that question, here’s the background: this 50-week study was a randomized, double-blind, placebo-controlled trial with patients assigned to either methotrexate at dose escalated gradually to 25 mg/week (n=63) or placebo (n=62); both groups received a prednisone induction (with tapering starting at week 1) along with IFX (5 mg/kg) at weeks 1, 3, 7, 14, 22, 30, 38, and 46. Remission was considered to be a CD Activity Index (CDAI) of <150 in individuals off prednisone. The patients enrolled in this study were on average about 40 years of age and had similar baseline characteristics, including disease duration of more 9 years.
Amazing to me was the fact that nearly 40% of both the treatment and control group included current smokers (since smoking clearly worsens CD).
- Combination therapy resulted in fewer antibodies to IFX (ATIs): 4% vs. 20% (P=.01)
- Combination therapy resulted in higher IFX trough levels: 6.35 mcg/mL vs. 3.75 mcg/mL (P=.08); the proportion with detectable trough levels was also higher in the combination group: 52% compared with 46%.
- Safety was similar. “No clinically relevant hepatotoxicity was identified.” However, 14 patients did experience an increase in liver enzymes. Infusion-related reactions were infrequent: 1 in combination group, and 3 in IFX monotherapy.
- At week 14, 76% of combination group achieved prednisone-free remission and 78% of IFX monotherapy. At week 50, these numbers were 56% and 57% respectively.
Getting back to the question about why this does not add up as a negative study –the combination group had lower ATIs and better IFX drug levels, this usually translates into better response. As such, the limitations of this study deserve to be scrutinized:
- Relatively small numbers of patients
- Objective markers like colonoscopy were not included
- Short duration of study period. While a 1 year study is not really all that short, some benefits of medications can take a longer time to appreciate
- Prednisone induction may have obscured MTX benefit
- Treatment group had long duration of disease. Those with shorter disease duration may have a more inflammatory component to their disease and respond more favorably.
Bottomline: this study showed that the combination of MTX/IFX was not statistically-superior to IFX alone. Given the favorable benefit on ATIs and IFX drug levels, MTX combination may still be useful, particularly in those with more recent onset of IBD.
Plus One More Reference:
Clin Gastroenterol Hepatol 2014; 12: 434-42. This retrospective study of 425 patients (1975-2012) examined features associated with failure of medical treatment. “Patients prescribed thiopurine or anti-TNF therapy when they have a complicated stage of CD are more likely to require surgery. Better patient outcomes are achieved by treating CD at early inflammation stages.”
Related blog entries:
- Switching to methotrexate therapy
- Drug levels for inflammatory bowel disease
- Adding Methotrexate to Anti-TNFs
- Methotrexate and liver toxicity