AIM: To evaluate the effectiveness of adalimumab in preventing recurrence after intestinal resection for Crohn’s disease in high-risk patients.

METHODS: A multicenter, prospective, observational study was conducted from June 2009 until June 2010. We consecutively included high-risk Crohn’s disease patients who had undergone an ileal/ileocolonic resection. High-risk patients were defined as two or more criteria: smokers, penetrating pattern, one or more previous surgical resections or prior extensive resection. Subcutaneous adalimumab was administered 2 wk (± 5 d) after surgery at a dose of 40 mg eow, with an initial induction dose of 160/80 mg at weeks 0 and 2. Demographic data, previous and concomitant treatments (antibiotics, 5-aminosalicylates, corticosteroids, immunomodulators or biologic therapies), smoking status at the time of diagnosis and after the index operation and number of previous resections (type and reason for surgery) were all recorded. Biological status was assessed with C-reactive protein, erythrocyte sedimentation rate and fecal calprotectin. One year (± 3 mo) after surgery, an ileocolonoscopy and/or magnetic resonance enterography was performed. Endoscopic recurrence was defined as Rutgeerts score ≥ i2. Morphological recurrence was based on magnetic resonance (MR) score ≥ MR1.

RESULTS: Twenty-nine patients (55.2% males, 48.3% smokers at diagnosis and 13.8% after the index operation), mean age 42.3 years and mean duration of the disease 13.8 years were included in the study. A mean of 1.76 (range: 1-4) resections previous to adalimumab administration and in 37.9% was considered extensive resection. 51.7% had previously received infliximab. Immunomodulators were given concomitantly to 17.2% of patients. Four of the 29 (13.7%) developed clinical recurrence, 6/29 (20.7%) endoscopic recurrence and 7/19 (36.8%) morphological recurrence after 1-year. All patients with clinical recurrence showed endoscopic and morphological recurrence. A high degree of concordance was found between clinical-endoscopic recurrence (κ = 0.76, P < 0.001) and clinical-morphological recurrence (κ = 0.63, P = 0.003). Correlation between endoscopic and radiological findings was good (comparing the 5-point Rutgeerts score with the 4-point MR score, a score of i4 was classified as MR3, i3 as MR2, and i2-i1 as MR1) (P < 0.001, r_s = 0.825). During follow-up, five (17.2%) patients needed adalimumab dose intensification (40 mg/wk); Mean time to intensification after the introduction of adalimumab treatment was 8 mo (range: 5 to 11 mo). In three cases (10.3%), a biological change was needed due to a worsening of the disease after the dose intensification to 40 mg/wk. One patient suffered an adverse event.

CONCLUSION: Adalimumab seems to be effective and safe in preventing postoperative recurrence in a selected group of patients who had undergone an intestinal resection for their CD.

Crohn’s disease (CD) is a complex chronic inflammatory bowel disease with an unpredictable course, in most cases accompanied by periodic recurrence and exacerbations[1]. Up to 70% of patients with CD have to undergo surgery due to complications of the disease at least once in their lifetime, frequently resulting in ileocolonic anastomosis[2,3]. Unfortunately, postsurgical recurrence, defined as the appearance of new lesions detected endoscopically, radiologically or pathologically, is common after surgery. One year after intestinal resection, 70%-90% of patients have endoscopic evidence of recurrent disease in the neo-terminal ileum. Despite the high endoscopic recurrence rate, symptomatic recurrence is delayed, with only 20% of patients having symptoms within the first year, increasing to one third after 3 years[4].

Ileocolonoscopy was considered the gold standard in the evaluation of postoperative recurrence, being a useful tool to predict clinical recurrence, CD-related complications and the need for repeat surgery in the future. Rutgeerts et al[4] devised a 5-point score ranging from i0 to i4 to measure the presence and severity of endoscopic lesions in the neoterminal ileum and anastomosis and reported a correlation between endoscopic recurrence and the likelihood of clinical recurrence, especially in those patients with more severe (i3-i4) endoscopic score.

The main limitations of ileocolonoscopy are its restriction to the level of intestinal mucosa and to the colon and neoterminal ileum area due to stenosis at the ileocolonic anastomosis site. Recently, magnetic resonance (MR) enteroclysis, a safe and non-invasive new imaging technique for small bowel, has proven to be a useful tool for detecting unsuspected penetrating disease, reaching areas restricted to ileocolonoscopy. A 4-point MR-enteroclysis-based score (MR0-MR3) has been validated by Sailer et al[5] and studies comparing ileocolonoscopy and MR enteroclysis suggest that they are of similar value in terms of predicting the risk of clinical recurrence in postoperative CD patients[6].

Different studies have assessed the efficacy of the available medications in the prevention of postoperative CD recurrence. Mesalamine, nitroimidazole antibiotics, azathioprine and 6-mercaptopurine have been reported to be effective treatments but have shown limited efficacy in reducing postoperative recurrence[7-12]. Recent results from a randomized placebo-controlled trial and a prospective pilot study with the chimeric anti-tumor necrosis factor alpha (TNF-α) antibody infliximab (IFX) support the utility of biologic therapies for the prevention of postoperative CD recurrence[13-15].

Adalimumab is a fully human anti-TNF-α monoclonal antibody that has been shown to be highly effective in inducing and maintaining remission in patients with moderate-to-severe CD. Adalimumab is effective not only in naïve patients but also in patients with loss of response or intolerance to IFX[16-19]. However, its efficacy in preventing postoperative recurrence has yet to be assessed.

The aim of this study is to evaluate the effectiveness and safety of adalimumab in preventing endoscopic and morphological recurrence at 12 mo after intestinal resection for CD in patients at high risk of recurrence, as well as to assess the influence of different risk factors associated with recurrence in CD patients treated with adalimumab. Additionally, we investigated the effectiveness of adalimumab in preventing clinical CD recurrence 1 year after surgery and compared endoscopic and radiological findings for predicting clinical recurrence in CD patients who had undergone intestinal resection.

In this study, we found adalimumab to be effective and safe in preventing recurrence after surgery for CD in a special subgroup of patients at high risk of recurrence. Intestinal resection is not curative and the majority of patients develop endoscopic recurrence even before clinical symptoms become apparent. Early detection and treatment of endoscopic lesions is essential to improve the long-term outcome for these patients and thus, to improve their quality of life. One year after intestinal resection, 70%-90% of patients have endoscopic recurrence and clinical recurrence occurs in nearly 20%[4]. A number of studies have evaluated the efficacy of active treatment (mesalamine, nitroimidazole antibiotics and immunomodulators) for prevention of postoperative CD recurrence and most of them reported endoscopic recurrence to be between 40% and 60% at 12 mo after surgery[22]. Recently, the anti-TNF-α antibody, IFX, has been associated with a significant reduction in postoperative recurrence in CD[14,15,23,24]. However, to date, there have been no published results with adalimumab, only a case series of six patients who underwent resection for an ileocecal stricture in which adalimumab was successfully used to prevent postsurgical recurrence of CD[25]. For this reason, we decided to evaluate the effectiveness and safety of adalimumab in preventing postoperative endoscopic and morphological recurrence as the primary study endpoint. This cohort of patients developed clinical recurrence in 13.7% of cases, endoscopic recurrence in 20.7% and MRE recurrence in 36.8%, although MRE was only evaluated in 19 patients and could be overestimated. In the clinical trial conducted by Regueiro et al[14], 9.1% of patients in the IFX-treated group had endoscopic recurrence and 84.6% in the placebo group. In our study, the rate of endoscopic recurrence was higher, at 24.1%. It is important to take into account that our results refer to a special subgroup of patients with high risk factors for recurrence (two or more of: smoker, penetrating pattern, prior extensive resection and one or more previous surgical resections), so higher percentages are expected. In addition, there were several differences between the two studies in terms of design. In our cohort, only 5 of the 29 patients (17.2%) were on concomitant immunomodulator treatment whereas this applied to 4 of the 11 (36.4%) patients in the IFX-treated group in the Regueiro study. Also, in the clinical trial with IFX, only one (9.1%) patient had previously undergone more than two intestinal resections compared to 7 (24.1%) patients in this study.

Different risk factors have been associated with postoperative CD recurrence. However, cigarette smoking is the only modifiable risk factor to be identified to date, and the most significant, with twice the risk of presenting a clinical recurrence compared with non-smokers[26,27]. We found an increased clinical recurrence risk in patients who reported smoking at the time of the index operation compared with non-smokers. When we evaluated patients who were smokers at the time of diagnosis, no differences in risk were found. This was consistent with other studies that found no increased risk in ex-smokers[26,27] or reported a reduction in the recurrence rate after stopping[28,29] and suggests that the effect of smoking disappears some time after giving up the habit. These results support the fact that physicians should advise, encourage and assist CD patients to stop smoking. Another factor to consider is the length of the previous intestinal resection. In our study, the clinical and endoscopic recurrence rate was higher in patients with prior extensive resection (> 100 cm) and with more than two previous resections, consistent results with those obtained from the study about the impact of azathioprine on the prevention of postoperative CD recurrence[9]. Other risk factors for postoperative CD recurrence, such as penetrating pattern, duration of CD or complex perianal disease, did not influence the proportion of patients with endoscopic and/or morphological recurrence.

Clinical postoperative recurrence was defined as the presence of symptoms, such as diarrhea, abdominal pain or decreased well-being, or complications which led to changes in medical or surgical management. All patients with clinical recurrence showed endoscopic and morphological recurrence 1 year after intestinal resection.

We avoided using the clinical activity index because it is difficult to perform in this setting. Some studies in which clinical postoperative recurrence was measured with the Crohn’s Disease Activity Index did not correlate with endoscopic recurrence one year after ileocolonic resection, while inflammatory parameters, such as CRP values, showed good correlation with endoscopic recurrence at one year[30,31]. We decided to use serum and fecal biological markers because they represent objective and quantifiable estimates of inflammatory activity. The main advantages are its simplicity and reproducibility; they can be repeated frequently to monitor changes in inflammatory activity, whether spontaneous or induced by treatment. We found that two or more elevated inflammatory parameters showed good correlation with endoscopic and morphological recurrence, especially in those scores indicating more severe lesions (i3-i4 or MR2-MR3). These techniques have been compared previously and our results are consistent with available data[5,6].

The incidence of side effects (3.4%) was no different from other published series. The patient that developed an adverse event also had to discontinue treatment with IFX previously. This is consistent with a recent study that concluded that elective switching from IFX to adalimumab may be associated with loss of tolerance within one year, and the recommendation is therefore to adhere to the first anti-TNF agent[32].

We are aware of the potential limitations of our study. The main one is that there was no control group, so we cannot accurately compare our results with those obtained in other studies such as Regueiro et al[14]. Secondly, the number of patients included in this cohort study was small, which may compromise statistical validity and not allow differences to be established in some of the variables measured. Lastly, five patients were treated concomitantly with immunomodulators, although there was no change in the dose regimen for these drugs before or during the study. It is difficult to assess the added benefit of co-treatment in preventing postoperative recurrence. In fact, in the Regueiro clinical trial, with a higher percentage of patients on immunomodulators, the concomitant use of immunomodulators did not appear to influence postoperative recurrence.

In summary, a significant percentage of CD patients require intestinal resection surgery over the course of their disease, and almost all show endoscopic recurrence one year after resection. This is the first published study on the effectiveness of adalimumab in preventing endoscopic and morphological recurrence after intestinal resection for CD. Our results strongly suggest that adalimumab is effective in patients with several risk factors associated with postoperative recurrence, such as smokers, penetrating pattern, or previous and extensive intestinal resections. Obviously, further randomized, controlled trials with better design and a larger number of patients are needed to confirm our conclusions and determine the duration of adalimumab maintenance treatment after surgery.