Combination Therapy in Pediatric Inflammatory Bowel Disease: Yes, No, Maybe

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In no population of those afflicted with inflammatory bowel disease (IBD) is the need for tight symptom control, and prevention of disease progression, greater than children whose disease phenotype is often severe and in whom the anticipated duration of disease the greatest. Indeed, it was amply demonstrated in the pre-anti–tumor necrosis factor (TNF) therapy era, that a need for surgery,1 growth failure,2 and impaired quality of life3 were common. Recent data on risk stratification of children newly diagnosed with Crohn's disease (CD) have suggested that the early use of anti-TNF therapy in some patients may change natural history, i.e., less likelihood of penetrating disease.4 In addition, it has been shown that the use of anti-TNF therapy within 90 days of diagnosis is associated not only with a higher likelihood of corticosteroid-free remission at 1 year but also with improved growth.5 However, our enthusiasm for the use of anti-TNF therapy has been tempered by clinical experience showing loss of response over time, the need for dose escalation, or the development of allergy requiring a switch to an alternative anti-TNF agent or a different class of biologic.6–8 Thus, therapeutic maneuvers to increase durability of anti-TNF therapy have been embraced and often focus on whether combination therapy with an immunomodulator (IM) is safe and beneficial.9–11
In this issue of the journal, Cheng et al report a retrospective, single-center experience covering the years 2002 to 2014 focusing on clinical outcomes and safety of infliximab monotherapy versus combination therapy with IM in 148 pediatric patients with IBD (113 CD and 35 ulcerative colitis). Their data demonstrate that combination therapy >6 months significantly lowered secondary loss of response in CD, while insufficient patient numbers were available to conclude similarly in those with ulcerative colitis. Patients were more likely to be in steroid-free remission at 1 and 2 years if they received combination compared with monotherapy. These data are similar to those reported previously in a much larger multicenter pediatric cohort11 and consistent with adult data as well.10 Unfortunately, this study did not include systematic monitoring of thiopurine or infliximab and antibody to infliximab levels, and changes in infliximab dosing were generally done using clinical data only.
From the perspective of the clinician, there are many questions that still remain to be answered, including (1) Why might combination therapy be superior to monotherapy?, (2) How long is combination therapy needed?, (3) Can the concomitant IM be added after the start of monotherapy if there is loss of response?, (4) Does it matter whether the concomitant IM is a thiopurine or methotrexate? (5) Do safety concerns with combination therapy outweigh potential benefits? (6) Can maintenance of therapeutic infliximab levels through close serum monitoring during monotherapy achieve the same results as combination therapy?
It is presumed that there are at least 2 mechanisms by which combination therapy may have added efficacy above monotherapy. First, the IM being used may have value in controlling disease independent of the anti-TNF agent in patients naive to both agents. However, in those patients previously failing IM, data from ACCENT showed no additional value of combination therapy compared with infliximab monotherapy.12 Second, and presumed most important, is the role of the IM in preventing immunogenicity of the anti-TNF, and studies demonstrate higher trough drug levels and less frequent antidrug antibody levels in those patients treated with combination therapy.9,13 A recent meta-analysis of multiple anti-TNF studies confirmed the value of combination therapy in reducing antidrug antibody formation (51% reduction) but cast doubt on the assumption that this is associated with higher trough drug levels.

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