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- Materials and Methods
Background: The efficacy of infliximab for endoscopic recurrence after resection of Crohn's disease (CD) has not yet been reported. The aim of this prospective study was to investigate the impact of infliximab on early endoscopic lesions after resection for CD.
Methods: Twenty-six patients maintaining clinical remission (CD activity index [CDAI] score <150) with mesalamine (3 g/day) after resection showed endoscopic recurrence in the neoterminal ileum at 6 months postoperatively (=baseline). Over the following 6 months, 10 patients were treated with continuous mesalamine (3 g/day), 8 patients were treated with azathioprine therapy (50 mg/day), and the other 8 patients were treated with infliximab therapy (5 mg/kg, every 8 weeks). During ileocolonoscopy at baseline and 6 months later, mucosal biopsies were taken for cytokine assays.
Results: During 6-month observation, no patients in the infliximab group, 3 (38%) in the azathioprine group, and 7 (70%) in the mesalamine group developed clinical recurrence (CDAI ≥150) (P = 0.01). At 6 months, endoscopic inflammation was improved in 75% of patients in the infliximab group, 38% in the azathioprine group, and 0% in the mesalamine group (P = 0.006). The mucosal interleukin (IL)-1β, IL-6, and tumor necrosis factor-α levels significantly decreased in the infliximab group, while they significantly increased in the mesalamine group, and they did not change significantly in the azathioprine group.
Conclusions: Infliximab therapy showed clear suppressive effects on clinical and endoscopic disease activity, and mucosal cytokine production in patients with early endoscopic lesions after resection. To confirm our conclusions, randomized controlled trials with a larger number of patients are necessary.
Crohn's disease (CD) is a chronic relapsing, remitting inflammatory bowel disease, the cause of which remains unknown. The primary goals of treating patients with CD are to induce a clinical remission quickly and maintain the remission as long as possible. Various medications are used in the management of active and quiescent CD. The effects of prophylactic medications for maintenance of remission after surgery have been reported in many studies. On the basis of current evidence, mesalamine lowers postoperative recurrence in patients CD, although the prophylactic efficacy is marginal.1 Nitroimidazole antibiotics are useful for prevention of recurrence after surgery for CD.2, 3 Recent randomized controlled trials (RCTs) suggest that azathioprine and 6-mercaptopurine may be effective for maintenance of surgically induced remission.4, 5 However, the efficacy of these medications for prevention of postoperative recurrence is suboptimal.
Infliximab is a recombinant antitumor necrosis factor (TNF)-α antibody, and it reduces intestinal inflammation in patients with CD by binding to and neutralizing TNF-α on the cell membrane and in the blood and by destroying TNF-α-producing cells. Infliximab is indicated for treatment of moderate to severely active CD for the reduction of the signs and symptoms in patients who have an inadequate response to conventional medications. At the present time, treatment with infliximab and other anti-TNF-α agents such as adalimumab and certolizumab pegol is most effective in the medical management of CD.6 Several RCTs7–9 have demonstrated that infliximab rapidly reduced clinical symptoms in patients with active CD, and the clinical improvement was associated with healing and reduction of inflammation in the intestinal mucosal tissue. In maintenance studies,10–12 a retreatment regimen of infliximab can provide long-term suppression of disease activity in patients with CD.
A recent RCT13 evaluated whether infliximab reduces postoperative recurrence in CD, and reported that infliximab therapy (started within 4 weeks of surgery and continued for 1 year) was effective in preventing endoscopic and histologic recurrence at 1 year after surgery. However, we believe that infliximab cannot be recommended for all patients after surgery because of multiple adverse effects or high medical costs. This medication should be used for patients at high risk of postoperative recurrence or short bowel syndrome. In clinical practice, several patients with CD have frequent relapses while others have prolonged periods of remission. Although smoking and perforating disease are risk factors for postoperative recurrence,14 these parameters are not so practical and of limited use.
Rutgeerts et al15 reported that in their endoscopic cohort study, endoscopic features in the early postoperative period were useful to predict future clinical relapse after resection for CD. Patients with severe endoscopic lesions in the neoterminal ileum within 1 year of resection will get early clinical relapse. In contrast, patients with no or very mild lesions have an uneventful postoperative clinical course. The severity of the endoscopic inflammation in the neoterminal ileum during the first year after resection is a reliable predictive risk factor for clinical relapse. If endoscopic inflammation in the early postoperative period can be diminished with medications, symptomatic recurrence will likely be delayed. This prospective study was designed to investigate impacts of infliximab treatment on early endoscopic lesions after resection for CD. The clinical and endoscopic disease activity and mucosal cytokine production were assessed, and the results were compared among 3 treatment groups; infliximab, azathioprine, and mesalamine.
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- Materials and Methods
The majority of patients develop early endoscopic recurrence in the neoterminal ileum after ileocolonic resection for CD before clinical symptoms become apparent. The early postoperative lesions in the neoterminal ileum is a suitable model to study the pathogenesis of CD, and also to evaluate new therapeutic modalities for prevention and treatment of progressive recurrence.15 If early endoscopic lesions are improved or cured with infliximab rapidly, the incidence of future clinical recurrence must be reduced. In this study we investigated impact of infliximab therapy on early endoscopic lesions after resection for CD. The outcomes were compared with those in patients treated with mesalamine or azathioprine.
For the treatment of patients with moderate to severely active disease or fistulizing disease, the recommended dose of infliximab is 5 mg/kg given as an induction regimen at 0, 2, and 6 weeks followed by a maintenance regimen of 5 mg/kg every 8 weeks thereafter.17, 18 However, there are no data on an optimal regimen for endoscopic recurrence in patients maintaining clinical remission after resection. In this study we used the maintenance regimen of 5 mg/kg every 8 weeks without the induction regimen because patients were maintaining clinical remission for 6 months after resection, and confirmed that our regimen was effective in suppressing disease activity. However, maintenance therapy with the standard induction regimen may be more effective, and be useful for decreasing immunogenicity. Further clinical studies are necessary to define an optimal regimen for endoscopic lesions in patients maintaining clinical remission during the postoperative period.
Pentasa is a form of 5-aminosalicylic acid (5-ASA) that contains the active ingredient in coated microgranules. The special plastic coating delays release of the active 5-ASA substance until the tablets reach the end of the ileum. This allows delivery of most of the medicine to the ileum. Current evidence shows that mesalamine (≥2 g/day) lowers postoperative recurrence in small bowel disease, although the efficacy is marginal.17 In this study, Pentasa at a dose of 3 g/day was used as mesalamine maintenance therapy after resection.
The dose (50 mg/day) of azathioprine in this study is smaller than that in Western countries. The recommended dose of azathioprine for maintenance of remission in patients with inflammatory bowel disease is different between Japan and Western countries. In Western countries a dose of 2.0–3.0 mg/kg/day is recommended.18 In contrast, in Japan many patients do not tolerate azathioprine at a dose of ≥2.0 mg/kg/day or ≥100 mg/day because of low thiopurine S-methyltransferase (TPMT) activity. A dose of 50 mg/day is effective and safe for maintenance of remission in the Japanese population.19 The 6-thioguanine nucleotide (6-TGN) concentrations in Japanese patients on low-dose azathioprine (50 mg/day) therapy are comparable to those reported from Western countries.20 Therefore, in Japan azathioprine at a dose of 50 mg/day is recommended for maintenance of remission in patients with inflammatory bowel disease.19, 20
Several clinical parameters such as smoking, perforating disease (abscess or fistula), and preoperative use of immunosuppressant or infliximab may affect the outcomes. In this trial the proportion of patients with these parameters was small, and was not significantly different among the 3 treatment groups (Table 1). Therefore, it is not likely that these parameters significantly affected our results. Methods for follow-up and assessment of disease activity were the same during the study. We found that infliximab significantly reduced clinical disease activity in patients with early endoscopic lesions. All patients treated with infliximab maintained clinical remission during the 6-month observation. In contrast, clinical recurrence occurred in 70% of patients treated with mesalamine, and 38% of those treated with azathioprine. The CDAI score significantly decreased at 2 months after the start of infliximab therapy, and then maintained at a low level. In patients treated with mesalamine and azathioprine, the CDAI score increased during 4 months after the start of treatment, and then it decreased in patients with azathioprine therapy. Thus, infliximab induces a more rapid therapeutic response in patients with early endoscopic lesions than azathioprine.
In this study, azathioprine and infliximab therapy was started for patients with endoscopic recurrence at 6 months after resection, and the treatment duration was 6 months. Since azathioprine acts slowly, if azathioprine therapy is started in the perioperative period of resection, and is continued for longer periods, it may be more useful for prevention of clinical and endoscopic recurrence. In this study, mesalamine showed no benefit in prevention of clinical recurrence in patients with early endoscopic recurrence. Our results suggest that patients who developed endoscopic recurrence despite mesalamine maintenance therapy after resection should be treated with more powerful medications.
At 6 months the rate of endoscopic improvement was 75% in patients treated with infliximab compared with 38% in those with azathioprine and 0% in those with mesalamine (P = 0.006). Complete mucosal healing achieved in 38% of patients in the infliximab group, 13% in the azathioprine group, and 0% in the mesalamine group. Clinical improvement after infliximab therapy in patients with early postoperative lesions was accompanied by significant improvement of endoscopic lesions. Similar results have been reported in the infliximab study for patients with active CD with clinical symptoms.21
A previous study22 found that downregulation of mucosal inflammatory mediators including cytokines occurred after infliximab therapy for patients with CD. In this study we found similar results. At baseline, mucosal levels of inflammatory cytokines were significantly elevated compared with the control group (patients without ileal inflammation). During the 6-month observation, the mucosal cytokine levels significantly decreased in patients treated with infliximab, but not in those with azathioprine or mesalamine. Thus, infliximab significantly inhibited inflammatory cytokine production in the intestinal mucosa of patients with CD. Changes in the mucosal cytokine levels significantly correlated with endoscopic efficacies; in patients with endoscopic improvement, the cytokine levels significantly decreased.
Regueiro et al13 reported that infliximab therapy for the first year after operation reduced the risk of CD recurrence. In their study, 24 patients who underwent ileocolonic resection were randomly assigned to receive infliximab (n = 11) or placebo (n = 13) for 1 year. The endoscopic and histologic recurrence rates at 1 year were significantly lower in the infliximab group compared with the placebo group (endoscopic, 9.1 versus 84.6%; P = 0.0006, and histologic, 27.3 versus 84.6%; P = 0.01). There was a nonsignificant higher proportion of patients in clinical remission in the infliximab group (80.0 versus 53.8%; P = 0.38).
In the study by Regueiro et al,13 administration of infliximab (5 mg/kg) was started within 4 weeks of surgery, which was different from our protocol. We started it at 6 months after surgery for patients who developed endoscopic recurrence. However, the clinical and endoscopic efficacies of infliximab at 1 year after surgery seemed to be similar between the 2 studies. These findings may indicate that a 6-month postoperative observation period does not adversely affect the outcomes of infliximab therapy. Our protocol is more in line with current clinical practice for prevention of postoperative recurrence in CD. Because of potential adverse effects and high costs, infliximab therapy after resection should be used for selected patients at high risk of recurrence. In our proposed treatment algorithm, for patients with known adverse risk factors such as smoking, perforating disease, and previous resections, immunosuppressive therapy is started in the perioperative period. Six months later, infliximab therapy is considered when severe endoscopic lesions are detected even though clinical symptoms are not apparent. In this trial we confirmed that infliximab therapy started at 6 months after operation significantly reduced future clinical recurrence, and improved endoscopic inflammation.
In conclusion, infliximab therapy showed clear suppressive effects on clinical and endoscopic disease activity, and mucosal cytokine production in patients with early endoscopic lesions after resection for CD. These results may have been predictable, but to the best of our knowledge, this is the first study reporting the efficacies of infliximab on endoscopic recurrence developed after resection for CD. These data strongly suggest that infliximab can delay the timing of postoperative recurrence and reduce recurrence rates by improving early endoscopic lesions. Patients with early endoscopic lesions are good candidates for infliximab therapy after operation. Although the results were indeed significant, there are several limitations of the methodology in this pilot trial. There was neither randomization nor a blinding procedure. Furthermore, the number of patients was small. To confirm our conclusions, RCTs with a larger number of patients are necessary.