103when adding an immunosuppressive agent to adalimumab [ 20 ]. Within this second
meta-analysis, an interesting observation was that the use of concomitant immuno-
suppressive therapy was associated with a trend toward improved rates of remission
at 6 months for infliximab (OR 1.73, 95% CI 0.97–3.07), but not adalimumab (OR
0.88, 95% CI 0.58–1.35) or certolizumab (OR 0.93, 95% CI 0.65–1.34) [ 20 ]. When
interpreting these data, we must remember that a significant proportion of the adali-
mumab and certolizumab patients enrolled had failed infliximab therapy, and thus
the use of concomitant immunosuppressive agents represents the continuation of an
immunosuppressive agent when switching TNF-antagonists as opposed to starting
an immunosuppressive agent de novo in these patients. Furthermore, this meta-anal-
ysis excluded patients naïve to immunosuppressive therapy and thus represents a
step-up approach to combination therapy as opposed to the more efficacious top-
down approach. These variations in observations help to highlight the fact that the
timing of adding an immunosuppressive agent to TNF-antagonist is as important as
the potential impact it has on TNF-antagonist pharmacokinetics. This concept is
further supported by two RCTs showing that early combined immunosuppression is
superior to traditional step-up algorithms.
The “top-down” trial is a randomized trial where 133 patients were randomized
to either early combined immunosuppression with infliximab (ECI; n = 67) or con-
ventional management (CM; n = 66) where patients received steroids followed in
sequence by azathioprine and infliximab [ 21 ]. At 26 weeks, a higher proportion of
patients in the ECI group were in steroid-free clinical remission without surgical
resection as compared to the CM group (60% vs. 35.9%, p = 0.006), and this differ-
ence continued through week 52 (61.5% vs. 42.2%, p = 0.0278). At week 104, the
rates of mucosal healing (absence of ulcers) were significantly higher in the ECI
group as compared to the CM group (73% vs. 30.4%, p = 0.0028). Notably, the rates
of serious adverse events were similar between both groups (30.8% vs. 25.3%,
p = 1.0). This study was the first to demonstrate that the early use of combined
immunosuppressive therapy impacted treatment outcomes. Although they were able
to demonstrate statistically significant differences in outcomes that correlate with
long-term disease-related complications (i.e., mucosal healing), the small size of the
study precludes its ability to directly quantify the impact on outcomes of interest
such as hospitalization, surgery, and overall complications.
The REACT trial is a cluster randomization trial in which community practices
in Canada (n = 34) and Belgium (n = 5) were randomly assigned in a 1:1 ratio to
either ECI with a TNF-antagonist (ECI; n = 21 centers, n = 1084 patients) or CM
where immunosuppression and TNF-antagonist use were determined by the pri-
mary provider (CM; n = 18 centers, n = 898 patients) [ 22 ]. The primary outcome
(remission as defined by a Harvey-Bradshaw score (HBS) ≤4 in the absence of
steroids) was achieved in a similar proportion of the ECI and CM groups at 12 (66%
vs. 62%, p = 0.65) and 24 months (73% vs. 65%, p = 0.35). Within this study, how-
ever, a significantly higher proportion of patients in the ECI group received combi-
nation immunosuppressive/TNF-antagonist combination therapy at 12 months
(15.1% vs. 6.5%, p < 0.001) and 24 months (19.7% vs. 9.6%, p < 0.001), and the
ECI group had highly significant and clinically important reductions in the rates of
7 Concomitant Use of Immunosuppressive Therapy with Tumor Necrosis Factor (TNF)