Patient-Specific Approach to Combination Versus Monotherapy with the Use of Antitumor Necrosis Factor α Agents for Inflammatory Bowel Disease

There is little debate that monoclonal antibodies directed against tumor necrosis factor-α (anti-TNFα) represent important tools in our armamentarium in the management of inflammatory bowel disease (IBD). However, the beneficial effects of systemic therapy for IBD, including immunosuppressive (IS) agents such as azathioprine/6-mercaptopurine (AZA/6-MP), methotrexate (MTX), corticosteroids, and anti-TNFα therapy must be countered against established risks. Because of the wealth of data now supporting the use of anti-TNFα–based therapy, the debate has switched from whether or not to use such treatments to how to optimize their use in individual patients. The debate over the use of concomitant anti-TNFα and IS therapy (combination therapy) versus anti-TNFα monotherapy is central to this question and represents a point of significant consternation for clinicians. This review provides an overview and historical perspective on this question and also discusses a clinically useful approach for individualizing treatment decisions.

The History of the Combination Therapy Versus Monotherapy Debate (How Did We Get Here Anyway?)

With the advent of anti-TNFα therapy in the 1990s with infliximab (IFX), practitioners had at their disposal a rapidly acting and highly efficacious therapy for both luminal and perianal Crohn disease (CD). However, because of the significant cost of these therapies and a less clear understanding of the benefits of scheduled maintenance therapy, episodic use of IFX was common both in clinical practice and in clinical trials. It soon became apparent that the episodic use of IFX was associated with increased immunogenicity as measured by higher levels of antibodies to IFX (ATI) ( Table 1 ). Rates of ATI were as high as 75% in one study. In a study by Maser and colleagues, episodic use of IFX was associated with ATI in 39% of patients versus only 16% in those treated with scheduled maintenance therapy with IFX. These data are highly relevant when considering the debate regarding combination versus monotherapy, because it was clear that administration of a concomitant IS reduced the development of ATI and was associated with higher IFX drug levels in patients receiving episodic IFX ( Table 2 ; also see Table 1 ).

Table 1

Incidence of antibodies to IFX stratified by concomitant use of immunosuppressants and by IFX treatment strategy

Study	CON-IS/ATI Pos (%)	No CON-IS/ATI Pos (%)	P Value
Episodic Therapy
Baert	43	75	<.01
Farrell	24	63	.007 ^a
Hanauer	16	38	.003
Maser	0	60	.018
Vermeire	46	73	<.001
Scheduled Maintenance Therapy
Hanauer (5mg/kg)	7	11	.42
Hanauer (10mg/kg)	4	8	.42
Maser	13	15	.9
Van Assche	5	12.5	.43
Colombel (SONIC)	0.9	14.6	NR
Feagan (COMMIT)	4	20.4	.01

Abbreviations: ATI: antibodies to IFX; CON-IS, concomitant immunosuppressant used; No CON-IS, no concomitant immunosuppressant used; NR, not reported; Pos, positive.

a In observational cohort.

Table 2

IFX levels stratified by concomitant use of immunosuppressants and by IFX treatment strategy

Study	IFX Level/CON-IS	IFX Level/No CON-IS	P Value
Episodic Therapy
Baert ^a	RR 1.93 for IFX >12 μg/mL ^b	Reference	<.001
Vermeire ^a	6.45 μg/mL (3–11.6)	2.42 (1–10.8)	.065
Scheduled Maintenance Therapy
Maser ^c	Reported as similar but no data provided		NA
Van Assche ^c	2.87 μg/mL (1.35–4.72)	1.65 μg/mL (0.54–3.68)	<.0001
Colombel (SONIC) ^c	3.5 μg/mL	1.6 μg/mL	<.001
Feagan (COMMIT) ^c	6.35 μg/mL	3.75 μg/mL	P = NS