Combination Therapy with Adalimumab -Is it Helpful?

A recent study (JM Chalbhoub et al. Inflamm Bowel Dis 2017; 23: 1316-27) performed a systematic review and meta-analysis to examine the effectiveness of Adalimumab (ADA) combination therapy compared with monotherapy.  With infliximab (IFX), the SONIC study, showed that combination therapy with an immunomodulator (IMM) (azathioprine) improved response; combination therapy resulted in reduced immunogenicity, lower rates of infusion reactions, and higher IFX levels.

With the advent of widespread use of therapeutic drug monitoring, some have questioned the need for combination therapy with IFX.  The need for combination therapy for ADA is also a matter of debate.  ADA has less immunogenicity than IFX and it is unclear if combination therapy will improve outcomes. There have been conflicting studies regarding combination therapy with ADA, prompting the current meta-analysis.

The authors identified 24 articles for inclusion from an initial pool of 1194. Key findings:

  • No significant difference between combination therapy and monotherapy was noted for induction of remission (OR 0.86) or response (OR 1.01). The induction of remission is based on data from 3096 patients (1400 on combination treatment).
  • No difference was noted for maintenance of remission (OR 0.97) or response (OR 0.91). The maintenance of remission is based on data from 1885 patients (859 on combination treatment).
  • Patients receiving combination therapy had lower odds of developing antidrug antibodies (OR 0.24)
  • Subgroup analysis in anti-TNF experienced patients showed improved successful induction of remission (OR 1.26) but also more frequent opportunistic infections (OR 2.44)

Overall, the authors conclude that “combination of ADA and immunomodulators does not seem superior to ADA monotherapy for induction and maintenance of remission and response to Crohn’s disease.” They do comment on the recent DIAMOND study which was a randomized open-label top-down strategy trial in anti-TNF-naive and IMM-naïve patients.  While no overall advantage of combination therapy was evident, better endoscopic response (84% vs. 64% with monotherapy) was seen at 26 weeks (but not at 52 weeks).

This study has several limitations.  Overall, there were a small number of randomized trials and the trials had significant heterogeneity.

My take (borrowed from authors): “It is unclear whether the addition of IMM impacts the efficacy of a less immunogenic anti-TNF biologic such as ADA in CD.” Though, in the subgroup of anti-TNF exposed patients, “combination therapy was associated with higher odds of induction of remission.”

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