Anti–TNF- antibodies have important limitations in treating Crohn disease. Although the commercially available anti–TNF- antibodies—infliximab and adalimimab—are effective when disease is refractory to other conventional therapies, up to 40% of patients with Crohn disease do not respond to the treatment initially (1, 2). In addition, whereas infliximab can significantly decrease rates of hospitalization and surgery in the short term (3, 4), its long-term effect is not clear (a result critical to the advocacy of anti–TNF- as first-line therapy and perhaps its earlier use in children). Standard maintenance dosing of infliximab (5 mg/kg of body weight every 8 weeks) can sustain remissions for up to 1 year, but only for 20% of patients overall (60% of all patients with Crohn disease are primary responders, and only 30% of them achieve a 54-week remission) (1). Finally, "infliximab-refractory" has become a veritable category of Crohn disease status. Therefore, despite the anti–TNF- antibody revolution, we still need new therapies and strategies to treat Crohn disease.

Infliximab maintenance therapy is a successful strategy for sustaining clinical improvement in patients who respond to initial therapy; however, up to 60% of patients worsen within a year either because the drug becomes less effective or because of intolerable side effects (1). To make progress, we must understand the biology of these events. Are induced anti-infliximab antibodies (ATIs) one such mechanism? Patients who receive infliximab on an episodic, as-needed basis frequently develop ATIs, which in turn correlate with lower postinfusion infliximab concentrations, increased risk for infusion reactions, and shorter responses (5, 6). Of interest, ATIs seem unimportant in patients taking infliximab maintenance therapy on a fixed-dosage schedule. In the ACCENT I trial (A Crohn's Disease Clinical Trial Evaluating Infliximab in a New Long-Term Treatment Regimen) of infliximab maintenance therapy (6), ATIs did not affect the rates of clinical response, remission, or serious infusion reactions. Furthermore, only few (5%) patients with worsening disease while receiving maintenance infliximab had ATIs before dosage escalation to reestablish control of disease. Since ATIs are less common when immunomodulators are used concomitantly with infliximab (5–7), some people advocate using immunomodulators with maintenance infliximab to suppress ATI formation (8). Because ATIs are less common with scheduled maintenance therapy, immunomodulators may have less benefit than use with episodic infliximab therapy.

This issue contains a report of the GAIN (Gauging Adalimumab Efficacy in Infliximab Nonresponders) trial by Sandborn and colleagues (9). The trial tested the hypothesis that treatment with a fully human anti–TNF- antibody, adalimumab, for patients with infliximab-refractory Crohn disease would reduce disease activity (9). People have hypothesized that preexisting ATIs induced by infliximab, which is a hybrid human–murine antibody, would not affect adalimumab. Alternatively, adalimumab may be less immunogenic in humans because it is a fully human antibody. The trial involved 311 patients with Crohn disease who responded to infliximab therapy and then lost responsiveness or developed intolerance to infliximab. The study patients were randomly assigned to receive adalimumab (n = 155) or placebo (n = 156). Patients received subcutaneous injections of adalimumab, 160 mg at week 0 and 80 mg at week 2, at the same schedule as placebo. Investigators assessed disease activity at week 0 (pretreatment) and weeks 1, 2, and 4. At 4 weeks, the rates of clinical responses and remission for adalimumab and placebo significantly differed: 52% versus 34% (70-point decrease in the Crohn's Disease Activity Index [CDAI] score); 38% versus 25% (100-point decrease in CDAI score); and 21% versus 7% (remission; CDAI score <150 points). The effect of adalimumab on fistulas was indistinguishable from that of placebo. The clinical improvement with adalimumab did not depend on the reason for stopping infliximab therapy and was unaffected by ATIs. Sandborn and colleagues did not compare the response to adalimumab in patients with a history of episodic infliximab exposure or regular maintenance dosing.

The 4-week follow-up in the GAIN trial seems short, but it is adequate to detect early improvement. In infliximab-naive patients with Crohn disease (CLASSIC I [Clinical Assessment of Adalimumab Safety and Efficacy Studies as Induction Therapy in Crohn's Disease I] study [2]), the same adalimumab induction regimen and follow-up, compared with placebo, resulted in a CDAI score decrease of 70 points or more and remission rates of 59% versus 37% and 36% versus 12%, respectively. Adalimumab on the same schedule but at a lower dose caused a primary response in 58% of patients at 4 weeks in a study of adalimumab maintenance dosing (10). On the other hand, we lack important information about the infliximab-experienced patients in the GAIN trial. We do not know the dosing schedule of infliximab; disease activity before infliximab treatment began, at the time of response, and at the time of loss of response; and the cumulative dose of infliximab before the loss of response or the development of intolerable side effects. Without this knowledge, we are left to wonder whether the GAIN trial investigators introduced a bias against adalimumab by enrolling patients who otherwise would have been classified as primary nonresponders. Conversely, the authors might have included patients who would have responded well to infliximab if treatment had not been stopped because of otherwise manageable infusion reactions, which could introduce a bias favoring adalimumab. Finally, the investigators did not compare adalimumab responses in patients with larger or smaller cumulative infliximab doses. Without this subgroup analysis, we are uncertain about the generalizability of the GAIN trial results.

Despite the study's limitations, we can draw the following conclusions. The GAIN trial data support the use of adalimumab in infliximab-refractory or -intolerant patients but suggest that once patients lose responsiveness to an anti–TNF- antibody, they don't fully regain it, even with a less immunogenic anti–TNF- antibody. An earlier study hinted at this lower rate of response to adalimumab in infliximab-exposed patients with Crohn disease. The investigators of CHARM (Crohn's Trial of the Fully Human Antibody Adalimumab for Remission Maintenance) included primary responders to infliximab. The investigators found a statistically nonsignificant trend toward lower response and remission rates to adalimumab in infliximab-experienced patients compared with infliximab-naive patients (10).

Some investigators are questioning the conventional step-up treatment for Crohn disease and have begun to test it against a more aggressive regimen ("top-down" treatment), which uses anti–TNF- antibodies and immunomodulators as first-line therapy (11). Regardless of the outcome of these experiments, we can expect that Crohn disease will still become refractory to anti–TNF- antibodies in many patients. Moreover, we are early in the evaluation of adalimumab, and whether it offers clinically significant advantages over infliximab (beyond subcutaneous administration) is not yet clear. Even fully human antibody drugs can elicit antidrug antibodies, and we do not know whether they are important clinically (12–14). In addition, refractoriness to infliximab may be a class effect, perhaps because treatment with infliximab changes the fundamental processes in Crohn disease.

The GAIN trial data raise an important question: Do patients with infliximab-refractory Crohn disease have the same inflammatory disease that they had before taking infliximab? Infliximab induces apoptosis in lamina propria lymphocytes in patients with Crohn disease (15). We do not know whether these lymphocytes are T_H1, T_H17, or even regulatory T cells. Whether changes in the proinflammatory and anti-inflammatory activities of effector cell populations after infliximab treatment persist or return when clinical benefits diminish is not known. We also do not know whether infliximab interacts predominantly with soluble TNF-, receptor-bound soluble TNF-, or membrane-bound TNF-. Interaction with different forms of TNF- could induce different effects on cell survival or apoptotic signaling in specific cell populations (16, 17). Comparing the immunologic characteristics of patients with infliximab-refractory disease to those of primary nonresponders may provide some clues to the immunologic changes that predict anti–TNF- drug resistance. Our cumulative experience with the clinical effects of anti–TNF- antibodies should stimulate more basic investigation into the mechanisms of treatment failure.

The message of the GAIN trial is that clinicians can use adalimumab as a treatment for patients who were previously responsive to infliximab but now are refractory to or intolerant of it. However, fewer patients will respond than those who responded to infliximab initially and only a minority will achieve remission. The medical management of Crohn disease after the patient becomes refractory to anti–TNF- antibodies is a major challenge for the inflammatory bowel disease research community. We will succeed only when we more fully understand the biological mechanisms at play in resurgent inflammatory disease.