Adalimumab Is More Effective Than Azathioprine and Mesalamine at Preventing Postoperative Recurrence of Crohn's Disease

A Randomized Controlled Trial

Edoardo Savarino MD; PhD; Giorgia Bodini MD; Pietro Dulbecco MD; Lorenzo Assandri MD; Linda Bruzzone MD; Fabrizio Mazza MD; Anna Chiara Frigo MSc; Valentina Fazio MD; Elisa Marabotto MD; Vincenzo Savarino MD

Disclosures

Am J Gastroenterol. 2013;8(11):1731-1742. 

In This Article

Abstract and Introduction

Abstract

Objectives: Postsurgical recurrence of Crohn's disease (CD) is very frequent and, to date, only infliximab has been shown to be useful in preventing it. The efficacy of adalimumab (ADA) is poorly known. We evaluated whether the administration of ADA after resective intestinal surgery reduces postoperative CD recurrence.

Methods: We randomly assigned 51 patients with CD who had undergone ileocolonic resection to receive after 2 weeks from surgery ADA at the dose of 160/80/40 mg every two weeks, azathioprine (AZA) at 2 mg/kg/day, or mesalamine at 3 g/day, and they were followed up for 2 years. The primary end point was the proportion of patients with endoscopic and clinical recurrence. Secondary end point was the assessment of quality of life by means of a previously validated questionnaire.

Results: The rate of endoscopic recurrence was significantly lower in ADA (6.3%) compared with the AZA (64.7%; odds ratio (OR)=0.036 (95% confidence interval (CI) 0.004–0.347)) and mesalamine groups (83.3%; OR=0.013 (95% CI 0.001–0.143)). There was a significantly lower proportion of patients in clinical recurrence in the ADA group (12.5%) compared with the AZA (64.7%; OR=0.078 (95% CI 0.013–0.464)) and mesalamine groups (50%; (OR=0.143 (95% CI 0.025–0.819)). The quality of life was higher in the ADA (202) than in the AZA (90; OR=0.028 (95% CI 0.004–0.196)) and mesalamine groups (98; OR=0.015 (95% CI 0.002–0.134)).

Conclusions: The administration of ADA after intestinal resective surgery was greatly effective in preventing endoscopic and clinical recurrence of CD. Further larger studies are necessary to confirm the therapeutic advantage and to show the economic implications of biologic therapy in this field.

Introduction

Postsurgical recurrence of Crohn's disease (CD) is a very frequent event. At 1 year, reported rates of endoscopic relapse range from 30 to 80%.[1,2] It has been shown that endoscopic recurrence correlates with the likelihood of future clinical recurrence, and predicts the development of CD-related complications and need for reoperation. At least 50% of patients experience clinical recurrence, which lags behind endoscopic recurrence.[1,2] Up to 70% of patients require repeat surgery within 20 years.[3,4] Thus, the prevention of postsurgical recurrence of CD is mandatory in order to prevent both disease relapse and a second negative outcome such as surgery. However, up to now, traditional drugs that have been used to treat the naturally occurring disease are either ineffective (mesalamine, steroids, antibiotics) or poorly effective (azathioprine (AZA) or 6-mercaptopurine (6-MP)).[5,6,7,8,9,10,11,12] In particular, five controlled trials have examined the efficacy of immunomodulators in postoperative CD, with two studies demonstrating a generally favorable effect,[9,10] two studies showing no benefit,[8,11] and one, more recent study, failing to show superiority of AZA over mesalamine because of AZA-related adverse events.[12] Moreover, a recent meta-analysis by Peyrin-Biroulet et al.[13] documented that AZA or 6-MP were more effective than control arms (placebo or mesalamine) in preventing moderate to severe (i2–i4 according to Rutgeerts' score) endoscopic recurrence, but they were not effective in the prevention of very severe (i3–i4) recurrence and were associated with a high rate of adverse events, leading to drug withdrawal.[13] On the other hand, three recent studies demonstrated that infliximab (IFX, Remicade, Janssen Biotech, Horsham, PA), a monoclonal antibody anti-tumor necrosis factor-α, has a remarkable efficacy in preventing this complication, although data in this field are still limited.[14,15,16] Sorrentino et al.[14] reported in 2007 a case series of 7 CD patients treated with IFX plus oral methotrexate 10 mg/week immediately after surgery who were compared with a control group given mesalamine 2.4 g/day. This study showed the complete absence of endoscopic and clinical recurrence at 2 years in all IFX-treated patients as opposed to a combined clinical/endoscopic recurrence rate of 75% in the mesalamine-treated group.[14] Regueiro et al.[15] confirmed these findings in a small randomized controlled trial that included 11 IFX-treated patients and 13 placebo-treated controls:[15] endoscopic recurrence at 1 year was prevented in 91% of IFX-treated patients vs. 15% of controls. More recently, Sorrentino et al.[16] showed in a prospective cohort study of 12 consecutive patients, who were treated immediately after surgery with maintenance IFX (5 mg/kg) for 24 months and then discontinued, that a dose of 3 mg/kg is sufficient to avoid endoscopic disease recurrence at 1 year in all patients who had endoscopic evidence of disease reactivation after stopping the medication.[16] Although these data need confirmation from further large placebo-controlled trials, they seem to indicate that therapy with IFX—initiated immediately after surgery—is able to prevent endoscopic and clinical recurrence of CD in the large majority of patients.

ADA (Humira; Abbott Laboratories, Abbott Park, Chicago, IL) is a recombinant, fully human, immunoglobulin G1 monoclonal antibody. This anti-tumor necrosis factor agent was found to be effective in treatment of refractory luminal CD, both in patients who were naive to IFX and in those who had already been treated with IFX.[17,18,19] Given the recent application of this drug in clinical practice, its efficacy in preventing the postsurgical recurrence of CD has still little evidence. In particular, only one open-label study and one case series report have been published up to now.[20,21]

Taking into account the above aspects, we planned a prospective, randomized study aimed at assessing whether this new medication is more effective than the traditional ones in preventing postsurgical recurrence of the disease in a group of patients who underwent resection for ileocecal stricture caused by CD. Secondary aim was the assessment of quality of life by means of a previously validated questionnaire for inflammatory bowel disease evaluation.

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