I read with interest the study by Reenaers et al., on adalimumab (ADA) in Crohn's disease, and whether co-therapy with immunosuppressants (IS) enhances the outcomes. The authors have mirrored the methodology of Sokol et al. in an attempt to determine whether a benefit can be shown in using IS with ADA. This is a widely debated area, with only poorly controlled retrospective and post hoc data to guide us. Yet, it is of great clinical concern, as we wish to get the most out of biologics, but without unnecessary excess risk to patients.
As always, with retrospective observational studies, the devil is in the detail. Their data appear to show some benefit with combination (ADA + IS) therapy, but only for certain outcomes or in subsets of patients. Fewer semesters with flare were seen in those receiving both drugs at initiation of ADA, although only in those in whom combination therapy was continued; yet, the overall ADA failure rate was lower in those with combination therapy in the first trimester (regardless of whether IS was continued or ceased). Thus, we get intriguing hints, but not clear-cut proof, that combination therapy does give better efficacy when using ADA as appears to be the case for infliximab.
However, what we do not know is how much the results were influenced by unreported factors. In particular, we do not know how many patients were IS-naïve at ADA onset, whether this was a selected group in some way (as weight is generally low considering the ~40% proportion of male subjects), whether any compliance/adherence assessment was made (as noncompliance would lead to convergence between groups) and what the power of the study was to detect various (negative) potential outcomes. In addition, we do not know much about methotrexate use (route, dose), nor are we told whether there was a standard approach taken at each centre thus potentially confounding interpretation.
Allowing for these provisos, the data are interesting, and appear to suggest that in those in whom there are compelling reasons to use ADA, greatest efficacy, and smallest failure rate, results from early combination therapy. In addition, this approach may save money (with a lower rate of ADA weekly dosing), which is important as all healthcare funding is under pressure and therefore a costs analysis would be of interest using their data. What is not yet clear is whether ongoing combination is justified. As discussed by the authors, there is a small extra risk (infectious, malignant) of this approach, and until more robust data emerge, the choice between gaining the benefit or avoiding the risk must be taken after consideration of each case and discussion with the patient. It is doubtful whether we will ever get an RCT evaluating this issue; however, a discontinuation study as done for Infliximab may help clarify things further.