Treatment of Inflammatory Bowel Disease with Biologics

102

on treatment success [ 10 ], the use of high-dose steroids and recruitment of a popula-
tion with a milder disease course and increased propensity to respond to therapy may
have obscured the clinical benefit of concomitant methotrexate therapy [ 11 , 12 ]. The
measurable impact of methotrexate on antidrug antibodies and infliximab drug con-
centrations would suggest that a therapeutic benefit does exist when using this immu-
nosuppressive agent.
No comparative effectiveness studies are currently available comparing TNF-
antagonist monotherapy versus TNF-antagonist combination therapy for other
TNF-antagonists such as adalimumab, certolizumab, and golimumab. In post hoc
analyses, when stratifying RCTs by baseline immunosuppressive use, the concomi-
tant use of an immunosuppressive appears to impact the pharmacokinetics of these
TNF-antagonists, but this did not directly translate to improved treatment outcomes
within these trials [ 6 , 13 – 18 ] (Table 7.2).
Pooled analyses of RCTs and observational data for adalimumab have suggested
that the use of concomitant immunosuppressive therapy results in improved rates of
remission at 12 weeks compared to adalimumab monotherapy (OR 0.78, 95% 0.64–
0.95). Although this would suggest that a clinical benefit may exist, this improved
efficacy at 12 weeks did not translate to improved rates of remission at 52 weeks
within this meta-analysis (OR 1.08, 95% CI 0.87–1.33) [ 19 ]. A second meta- analysis
that pooled patient level data from three TNF-antagonist RCTs in CD (infliximab,
adalimumab, certolizumab) similarly observed that no clinical benefit was present

Table 7.1 Comparative effectiveness randomized controlled trials of infliximab monotherapy
versus combination therapy with an immunosuppressive agent

Crohn’s disease Ulcerative colitis

SONIC [ 7 ] COMMIT [ 9 ] UC-SUCCESS [ 8 ]

IFX IFX + AZA IFX IFX + MTX IFX IFX + AZA

Clinical

remission (%)

44 57 78 76 22 40

Mucosal

healing (%)

30 44 – – 55 63

Antidrug

antibody (%)

14.6 0.9 20.4 4.0 19.0 3.0

IFX

concentration

1.6 μg/mL 3.5 μg/mL 3.8 μg/

mL

6.4 μg/mL – –

IFX infliximab, AZA azathioprine, MTX methotrexate

Table 7.2 Stratified analysis of randomized controlled trials for TNF-antagonists according to
baseline immunosuppressive use

Agent

Antidrug antibody Clinical remission

TNF-antagonist

monotherapy

Combination

therapy

TNF-antagonist

monotherapy

Combination
therapy
PRECISE 2 CTZ 12% 2% 64% 61%
CLASSIC II ADA 3.8% 0 45% 48%
PURSUIT GOL 3.8% 1.1% 50% 44%
IFX infliximab, CTZ certolizumab, ADA adalimumab, GOL golimumab

P.S. Dulai and C.A. Siegel