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


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

In This Article


Prevention of postsurgical recurrence of CD is a fundamental task in the practical management of patients with this condition. Indeed, available literature data documented that the large majority of affected individuals will undergo surgery within a few years of diagnosis.[23] Histologic recurrence of CD was reported as early as 1 week after surgery.[24] At 1 year after intestinal resection, 70–90% of patients have endoscopic evidence of recurrent CD,[1,25] and clinical recurrence occurs in one third of patients at 3 years after surgery and in 60% after 10 years.[26] Until recently, such a complication appeared almost unavoidable because the most effective traditional drugs—AZA/6-MP—only reduce recurrence, at best, by ~25% and are associated with a high rate of adverse events.[13] Therefore, search for different effective approaches to this emerging problem has become mandatory in order to modify the natural history of CD.

To date, only one placebo-controlled study of anti-tumor necrosis factor antibodies as prophylactic postoperative therapy has been published.[15] In particular, very limited data are present in medical literature evaluating the efficacy of ADA in a similar setting of patients.[20,21] Therefore, we observed, for the first time in a randomized controlled trial, that ADA is effective and safe in preventing postsurgical endoscopic and clinical relapse of CD at 2 years after surgery. The proportion of patients with endoscopic recurrence was only 6.3% in the ADA group as compared with 64.7% in the AZA group and 83.3% in the mesalamine group. In addition, the proportions of patients with clinical recurrence at 2 years were much lower in the ADA group (12.5%) than in the AZA and mesalamine groups (64.7% and 50%, respectively). The efficacy of postsurgical ADA treatment was also reinforced by the higher quality of life, assessed by IBD-Q, reported by patients in the ADA group compared with those in the AZA and mesalamine groups. Finally, there were no apparent safety concerns identified in this study and the rates of adverse events were similar among our three study groups.

We opted to use both endoscopic and clinical recurrence as the primary study end points and measure of CD relapse. As to the endoscopic relapse, it is well known that severity of endoscopic recurrence is associated with the worst prognosis, and then high rates of clinical recurrence.[1] In our study, all but three patients in the ADA group had completely normal ileal mucosa, defined as an endoscopic score of i0. Among the AZA-treated patients, using the same endoscopic score, only one patient had normal mucosa as well as among the mesalamine-treated patients. Conversely, severe endoscopic recurrence, defined as an endoscopic score of i3 or i4, occurred in none of the ADA-treated patients compared with more than half of those who received AZA or mesalamine. These data are in agreement with those observed by Regueiro et al.,[15] who found that all but 2 of the 12 IFX-treated patients had completely normal ileal mucosa (score of i0) compared with only 1 of the placebo-treated patients. Moreover, severe endoscopic recurrence (score of i3 or i4), occurred in only 1 IFX-treated patient compared with more than half of those who received placebo. Most published postoperative studies evaluating the efficacy of traditional drugs have reported 1-year endoscopic recurrence rates between 40% and 60% with active treatment. Therefore, to date, our study represents the second trial, and the only randomized one using ADA, to report high endoscopic remission rates.

Considering the clinical relapse, we decided to define clinical recurrence in case of a score of 2 on the clinical recurrence grading scale proposed by Hanauer et al.,[9] as CDAI had not been validated for study of postoperative recurrence. However, we also measured CDAI scores to give a full and more complete outcome evaluation of our treated patients. We documented lower rates of clinical recurrence, using both clinical indexes, in the ADA-treated patients than in the AZA- and mesalamine-treated patients. Our findings are in contrast with those observed by Regueiro et al.,[15] showing nonsignificant higher proportion of patients in clinical remission in the IFX group (80.0%) compared with the placebo group (53.8%). However, differently from our investigation, they opted to define clinical recurrence based only on the CDAI score that, as also acknowledged by them, has an imperfect nature. Indeed, four of the five placebo-treated patients with clinical recurrence had increased CDAI scores shortly after surgery, whereas two IFX-treated patients had increased CDAI scores at the same time point and none of these patients had increased CDAI scores at the end of the follow-up period. Our data on clinical recurrence rates are notably higher than those observed by Hanauer et al.[9] and Reinisch et al.[8] using 6-MP/AZA or by Rutgeers et al.[7] using antibiotics, thus confirming the efficacy of ADA in preventing CD recurrence compared with AZA or mesalamine also from a clinical point of view.

It is well known that there are several risk factors associated with postoperative endoscopic, clinical, and surgical CD recurrence. They include cigarette smoking, penetrating/fistulizing behavior disease, young age, short disease duration before first surgery, early administration of immunomodulators, and ileocolonic disease.[27,28,29,30] Among our groups, no significant differences in terms of frequency of these risk factors have been observed, although active smoking was more common in the ADA group. Thus, it is interesting to stress that, despite the presence of cigarette smokers at baseline and throughout the study in our ADA-treated patients, the endoscopic and clinical recurrence rates were significantly lower in the ADA group than in the AZA and mesalamine groups. This finding suggests that, although smoking cessation remains of paramount importance in prevention of CD recurrence, ADA may effectively contrast the effect of cigarette smoking on postoperative disease relapse, as already reported in patients treated with immunosuppressive drugs.[31]

There was a high endoscopic recurrence rate in our AZA-treated (64.7) and mesalamine-treated (83.3%) groups. These data confirm previous postoperative natural history studies and randomized placebo-controlled trials showing inefficacy of traditional drugs in preventing CD relapse.[32,33] Sulfasalazine and mesalamine have been studied most extensively and only one out of three placebo-controlled sulfasalazine studies showed a mild reduction of radiographic and surgical recurrence at 1 year, whereas only one out of four placebo-controlled and several uncontrolled mesalamine studies observed a statistically significant decrease in clinical recurrence at 72 months.[33,34,35,36,37,38,39,40] Two placebo-controlled studies documented a modest efficacy of nitroimidazole antibiotics in the prevention of clinical and endoscopic postoperative recurrence of CD, although their effect decreases over time and important medication intolerance reduces their long-term use.[7,41] Five controlled trials have examined the efficacy of immunomodulators in postoperative CD, with two studies demonstrating a generally favorable effect,[9,10] two studies no benefit,[8,11] and one more recent study documenting that the superiority of AZA over mesalamine could not be demonstrated because of therapeutic failure due to AZA-related adverse events. Our data seem to support the latter investigation reporting no superiority of AZA over mesalamine in this particular setting. More recently, a combination of azathioprine and a 3-month course of metronidazole were found to be more effective than antibiotic alone in preventing endoscopic recurrence (i2–i4) at 12 months.[10] Although 6-MP/AZA and nitroimidazole antibiotics may have modest benefit in the prevention of postoperative CD recurrence, endoscopic recurrence rates remained significant, ranging from 37.5% to 52%.

The decision to use a 3-g dose of mesalamine in our study was based on the prior maintenance trials using mesalamine,[8,9,10,11] whereas the rationale for using AZA at 2 mg/kg dose was based on the data showing maintenance benefits from the purine analogs for maintenance therapy of CD[42] and from previous maintenance studies using purine analogs such as 6-MP[8] and AZA.[11] Indeed, in the latter studies, 6-MP (50 mg daily) and AZA (2 mg/kg daily) have been used at lower dosages than those recommended by current guidelines. Although there are no dose-ranging data to predict response, we selected a dosage that was likely to be tolerated without inducing adverse events in a large proportion of patients who were "disease free" undergoing "prophylactic" therapy.

It is worth of noting that, in contrast to Regueiro et al.[15] and Sorrentino et al.,[14] all patients included in our study were also evaluated regarding their quality of life using a previously validated questionnaire,[22] before and after surgery, throughout the 2-year follow-up period. We found that before surgery no differences were present in terms of mean IBD-Q value among our groups and this underlines the similar characteristics of our patients randomized in the three groups. Moreover, we observed that at 1 and 2 years after surgery, patients in the ADA group (87.5) reported a better quality of life than patients in the AZA (11.8) and mesalamine (16.7) groups, indicating that prophylactic postsurgical therapy by ADA is strongly associated with high quality of life maintenance, at least up to 2 years after surgery, compared with the AZA- and mesalamine-treated patients.

Some potential limitations of our study should be discussed. First, patients enrolled in this investigation have not been compared with a placebo-controlled group. However, we included in our study a third arm, as control arm, in whom patients have been treated with standard doses of mesalamine, a medication reported in the largest available meta-analysis to give a nonsignificant benefit over placebo in the setting of postoperative prevention of CD.[43] Therefore, we can assume that the efficacy of mesalamine in the prevention of postoperative recurrence can be considered as similar to placebo. Moreover, this study had a long follow-up period (2 years), during which only one of the ADA-treated patients developed endoscopic recurrence, thus limiting a potential placebo effect in the short time period. Indeed, a recent meta-analysis of the related literature[44] indicated that the placebo effect, as expected, rapidly fades with time and that endoscopic recurrence rates in placebo-treated patients after 1 year are up to 80%, as also observed by Regueiro et al. in their investigation,[4] and by us in this study. It is also relevant to note that a hypothetical placebo effect in this study could not explain why important mucosal lesions, assessed by an independent blinded endoscopist, were present only in the AZA and mesalamine groups and why the latter strongly correlated with ESR and CRP levels. A limitation of our study may also be the decision to include patients who had previously received immunomodulator therapy or IFX. Previous immunomodulator or IFX use, however, did not appear to affect recurrence. A final point is regarding the relatively small number of patients enrolled in this study. We are aware that confirmation of our data by a larger, multicenter trial would be desirable. Anyway, the single-center design of the study permitted us to reduce potential bias because of different operators performing endoscopy scoring, different physicians completing clinical evaluation, and IBD-Q. Moreover, although our sample size was small, the a priori power calculation considered a potential large endoscopic (80% recurrence in the mesalamine group and 15% in the ADA group) and clinical difference (65% recurrence in the mesalamine group and 5% in the ADA group). Thus, despite the small sample size, statistical significance was achieved with the observed endoscopic recurrence rate of 83.3% in the mesalamine group vs. only 6.3% in the ADA group and with the observed clinical recurrence rate of 50% in the mesalamine group vs. only 12.5% in the ADA group. Finally, although 5 out of 51 patients (9.8%) withdrew early from the study, they pertained to all treatment groups (1 patient from the ADA group, 2 patient from the AZA group, and 2 patients from the mesalamine group). Furthermore, imputed analyses were based on at least 36 weeks of observed data carried forward. Thus, incomplete and imputed study data are unlikely to be an appreciable source of bias.

In conclusion, our study provides strong evidence that ADA is much more effective than the traditional medications (AZA or mesalamine) in preventing endoscopic and clinical postoperative recurrence of CD and provides a rationale for aggressive postoperative chemoprevention with biologic therapy. To our knowledge, this is the first randomized controlled trial in which ADA has been successfully used to prevent postoperative CD recurrence, an event considered almost mandatory in the natural history of this disorder. We are aware that larger postoperative controlled trials are needed to establish the actual impact of this drug on the rate of disease recurrence. In our practice, based on previous positive data on IFX and our results on the success of ADA in preventing postoperative relapses, we should consider that patients at high risk of CD recurrence, such as ileal penetrating disease and recurrent resective surgery, can benefit from postsurgical prophylaxis with either IFX or ADA. The duration of postoperative ADA maintenance and the appropriate endoscopic follow-up evaluation as well as the economic impact of this approach remain a matter for future studies.