Selected Summary

Summary: In a randomised, double-blind, placebo-controlled, multicentre trial, Colombel et al evaluated the efficacy of adalimumab, a fully human, anti–tumour necrosis factor-α (TNF-α) monoclonal antibody administered subcutaneously for the maintenance of response and remission in adults with moderate to severe Crohn disease (CD). At the time of randomisation, patients who had previously been through an open-label induction study and had achieved clinical response with adalimumab were randomised to receive placebo (n = 170), adalimumab 40 mg every other week (n = 172), or adalimumab 40 mg weekly (n = 157). Patients were followed up for a total of 56 weeks. The primary endpoint was the proportion of patients who were maintained in clinical remission (Crohn's Disease Activity Index score <150) after 56 weeks. Both alternate-week adalimumab and weekly adalimumab were significantly more effective than placebo in maintaining remission through 56 weeks. At week 56, 65 of 157 patients who received weekly subcutaneous adalimumab (40 mg) were in remission compared with 20 of 170 patients receiving placebo (relative risk, 3.5; 95% confidence interval [CI], 2.2–5.5). The number needed to treat for that population was 4 (95% CI, 3–5). There was no statistically significant difference between patients receiving adalimumab weekly or every other week. Serious adverse events occurred in a greater percentage of placebo-treated patients (15.3%) versus those randomised to adalimumab (9.2% and 8.2% for 40 mg every other week and 40-mg weekly groups, respectively; P < 0.05 vs placebo). Infectious adverse events occurred in 36.8% of patients in the placebo group versus 46.2% of patients in the adalimumab 40 mg every other week group (P < 0.05 vs. placebo) and 44.4% of those treated with adalimumab 40 mg weekly (P = 0.089). Serious infectious adverse events were infrequent, occurring in 2.7% of patients in each of the adalimumab groups compared with 3.4% of patients in the placebo group. There were 2 cases of tuberculosis reported, both in the adalimumab-treated groups (1 in the weekly group and 1 in the every other week group). One case of breast cancer was reported in the placebo group. Comment: Crohn disease is a chronic inflammatory disorder of the gastrointestinal tract of unknown aetiology. Patients usually experience recurrent attacks, with acute flares of disease interspersed with periods of remission. The disease can be complicated by the development of intestinal obstructions, perianal disease, and fistulae (1). It also has a number of extraintestinal manifestations including arthritis, uveitis, hepatitis, and skin rashes. There is no cure for CD and treatment is aimed at inducing remission, maintaining remission, and promoting growth in children and improving their quality of life. Enteral nutrition, corticosteroids, aminosalicylates, and immunomodulators such as azathioprine or 6-mercaptopurine form the mainstay of treatment for active CD. Tumour necrosis factor-α is an important cytokine in the pathogenesis of CD, with elevated concentrations playing a role in pathogenic inflammation (2,3). Clinical trials have shown that infliximab, a chimeric monoclonal antibody to TNF-α, given as intravenous infusion, is effective for induction and maintenance of remission in moderate to severe CD including fistulising disease (4,5). Antibody formation, which leads to subsequent infusion reactions, loss of efficacy, and delayed hypersensitivity reactions, has been observed with the use of infliximab. Adalimumab (Humira, Abbott Laboratories), which in contrast to infliximab is a fully human immunoglobulin G1 anti-TNF-α monoclonal antibody, is less immunogenic and is believed to have fewer of these hypersensitivity reactions (6). Adalimumab can be given subcutaneously and binds with high affinity and specificity to human TNF-α, and modulates biological responses regulated by TNF-α (6). Its efficacy has been demonstrated in rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis (7). Adalimumab has also been found to be effective in inducing remission in CD (8,9). In 2006 Hanauer et al showed that adalimumab was superior to placebo for the induction of remission in patients with moderate to severe CD naïve to anti-TNF-α therapy (8). In another study, Sandborn et al investigated the role of adalimumab in inducing remission in patients who could not tolerate infliximab or had symptoms despite receiving infliximab therapy. A total of 21% of patients receiving adalimumab versus 7% of those receiving placebo achieved remission at week 4 (P < 0.001) (10). The first large randomised controlled trial to be published in full on the use of adalimumab for the maintenance of remission in CD is that of Colombel and colleagues. Their results clearly show that for patients who had initially experienced clinical response to adalimumab, the medication was effective at maintaining remission through 56 weeks. Adalimumab was generally well tolerated and its safety profile was consistent with previous experience with the drug. In a more recently published but smaller study, Sandborn et al also showed that adalimumab was effective at maintaining remission through 56 weeks (11) In a recent open-label study, Peyrin-Beraulet et al showed that adalimumab could be effective in maintaining remission in patients with CD who had initially responded but lost response to infliximab (12). This study by Colombel et al clearly shows that adalimumab can be used to maintain remission in patients with moderate to severe CD whose remission had (at least) been induced with adalimumab. Because it can be given subcutaneously and is potentially less immunogenic than infliximab, it can also be considered in patients who either do not tolerate infliximab or develop a tolerance to it. It was also noted to be safe because the frequency of adverse events was no worse in the adalimumab groups than in the placebo group. Although there are no formal studies of adalimumab use in the paediatric population, at least 1 case report has been published. Mian et al reported the successful use of adalimumab in a 15-year-old girl with refractory CD who initially responded but later developed hypersensitivity to infliximab (13). Adalimumab (40 mg) was given subcutaneously every other week. The child showed significant improvement in symptoms, laboratory values, and endoscopic findings without any adverse events. She remained in remission and had received 12 doses by the time the report was written. Formal clinical trials of the use of adalimumab in paediatric CD are required to establish efficacy, safety, and optimum dosing regimen in this population.