How should immunomodulators be optimized when used as combination therapy with anti-tumor necrosis factor agents in the management of inflammatory bowel disease?

Abstract

In the last 15 years the management of inflammatory bowel disease has evolved greatly, largely through the increased use of immunomodulators and, especially, anti-tumor necrosis factor (anti-TNF) biologic agents. Within this time period, confidence in the use of anti-TNFs has increased, whilst, especially in recent years, the efficacy and safety of thiopurines has been questioned. Yet despite recent concerns regarding the risk: benefit profile of thiopurines, combination therapy with an immunomodulator and an anti-TNF has emerged as the recommended treatment strategy for the majority of patients with moderate-severe disease, especially those who are recently diagnosed. Concurrently, therapeutic drug monitoring has emerged as a means of optimizing the dosage of both immunomodulators and anti-TNFs. However the recommended therapeutic target levels for both drug classes were largely derived from studies of monotherapy with either agent, or studies underpowered to analyze outcomes in combination therapy patients. It has been assumed that these target levels are applicable to patients on combination therapy also, however there are few data to support this. Similarly, the timing and duration of treatment with immunomodulators when used in combination therapy remains unknown. Recent attention, including post hoc analyses of the pivotal registration trials, has focused on the optimization of anti-TNF agents, when used as either monotherapy or combination therapy. This review will instead focus on how best to optimize immunomodulators when used in combination therapy, including an evaluation of recent data addressing unanswered questions regarding the optimal timing, dosage and duration of immunomodulator therapy in combination therapy patients.

Keywords: Inflammatory bowel disease; Thiopurines; Drug monitoring; Tumor necrosis factor-alpha; Combination therapy

Core tip: Clinicians managing inflammatory bowel disease frequently have to decide whether to use anti-tumor necrosis factor (anti-TNF) therapy alone or in combination with immunomodulators (IM), which requires an assessment of patient factors and the risk/benefit profile of each treatment strategy. Once a decision is made to use combination therapy, questions on how best to optimize IMs must be addressed. Thiopurines, rather than methotrexate, (MTX) are more efficacious and easier to administer, whereas in certain population groups, MTX may be safer. The effective dose of IM may be lower in combination therapy and combination therapy is probably most important in the first 12 mo of treatment. Withdrawing IMs is best done when the patient is in deep remission, ideally supported by the use of therapeutic drug monitoring of anti-TNFs.