Postsurgical recurrence of Crohn disease is a very frequent event, and none of the drugs used for the purpose has really shown a clear-cut efficacy.1 Infliximab, a monoclonal antibody anti–tumor necrosis factor α (antiTNF-α), is very effective in the treatment of active Crohn disease, but its benefit in preventing postoperative recurrence is still unknown. Yet, its impact, both medical and economic, could be major.2 Local injection of infliximab for early mucosal postoperative recurrence of Crohn disease seems feasible and safe; however, preliminary results have been disappointing.3 By contrast, a patient treated with intravenous infliximab immediately after surgery to prevent the recurrence of colonic Crohn disease has been disease free for 48 months after surgery.4
In the present prospective pilot study, infliximab was administered 2 weeks after surgery, along with low-dose methotrexate, whereas controls were treated with mesalamine alone. There is no evidence for a role of methotrexate in preventing recurrence5; however, we elected to use this drug because it is known to reduce long-term immunogenicity of infliximab.6 This is not a randomized study: the decision to include a patient in one group or the other, given the experimental nature of the infliximab-based preventive strategy, was solely based on the full understanding and approval (with written informed consent) of each patient. Before surgery, patients to be treated with infliximab were screened (purified protein derivative skin test, chest radiography, and careful history taking) and were found negative for latent tuberculosis. They were also evaluated (and found negative) for past and present cardiac, neurologic, lymphoproliferative, and other neoplastic diseases. After surgery, patients were subjected to endoscopy at 12 and 24 months; small-bowel enteroclysis or magnetic resonance imaging at 12 and 24 months; and physical examination with interviews, together with an extensive battery of blood tests (complete blood cell count; erythrocyte sedimentation rate; C-reactive protein, albumin, electrolyte, autoantibody, and thyroid hormone levels; and liver and renal function tests) every 3 months. Infliximab was given as a slow intravenous infusion at the dosage of 5 mg/1 kg of body weight, with an intravenous 100-mg bolus hydrocortisone starting from 2 weeks after surgery, followed by standard maintenance treatment (2, 6, and then every 8 weeks) and therapy with low-dose methotrexate (10 mg/wk by mouth).
Patients in the control group were also subjected to endoscopy and small-bowel enteroclysis or magnetic resonance imaging once a year and physical examinations with interviews and blood tests every 3 months. Controls were given mesalamine-coated tablets, 800 mg 3 times daily, starting from 2 weeks after surgery.
In both groups, the use of all medications was discontinued at least a month before surgery. No other medications were allowed except for occasional tablets of paracetamol or nonsteroidal anti-inflammatory drugs. Recurrence was defined as any evidence of disease at 2 years according to simplified endoscopic or clinical criteria. In particular, clinical relapse was defined as a score of 2 or greater on the clinical recurrence grading scale (where 1 indicates absent; 2, mild; 3, moderate; and 4, severe symptoms) recently proposed by Hanauer et al,7 while endoscopic relapse was defined as a score of 2 or greater on the scale of Rutgeerts et al.8 The study protocol was approved by the institution ethics committee.
The Table illustrates the patients included in the study and their clinical features. Seven patients in total (3 women and 4 men) were treated postoperatively with infliximab and low-dose methotrexate. Ages ranged from 23 to 64 years (median, 36 years). Of these patients, 4 had an ileocecal resection, 1 a segmental ileal resection (he had been previously subjected to ileocecal resection), and 2 a segmental sigmoid resection (1 of these patients previously underwent ileocecal resection). Indications for resection included disease activity (2 patients) and stricture (5 patients). The disease had been present for a minimum of 3 to a maximum of 14 years (median, 7 years). Two patients currently smoke, while 1 is taking oral contraceptives.
The clinical features of the control group are also illustrated in the Table. Sixteen patients (5 women and 11 men) in total were operated on and treated postoperatively with mesalamine. Ages ranged from 23 to 70 years (median, 40.5 years). Nine patients underwent ileocecal resection (1 of whom had previously undergone segmental sigmoid resection); 1, proctocolectomy; 2, right hemicolectomy plus ileal resection; 1, left hemicolectomy; 1, cecal resection; 1, ileal resection; and 1, segmental sigmoid resection. The reason for surgery was a stricture in 8 patients, disease activity in 7, and combined stricture and disease activity in 1. The disease had been present for a minimum of 1 to a maximum of 23 years (median, 5.5 years). Four patients currently smoke, while none was taking oral contraceptives.
In all cases, surgery was considered radical (ie, it completely removed the involved intestine). Preoperatory assessment (endoscopy and radiology) had excluded disease outside the operated location. Of the 23 patients, none had operative or postoperative complications and none was lost to follow-up.
The results, summarized in the last column of the Table, show that in the group treated postoperatively with infliximab and low-dose methotrexate, none has had, after 2 years, endoscopic or clinical recurrence as defined in the “Methods” section. No abnormalities were detected in blood test results during the study period and at the 2-year follow-up examination. We did not record any potential adverse effect that could be attributed to these medications. However, 2 patients showed transient and borderline positivity for lupus anticoagulant but none of the typical features of frank systemic lupus erythematosus, a very rare complication of infliximab treatment.9 All the patients in this group reported an excellent quality of life and still receive maintenance treatment.
The group treated with mesalamine also tolerated the drug well, and no adverse effects were recorded during the study period. However, in contrast to the group treated with infliximab and low-dose methotrexate, only 4 of the 16 patients (25%) were disease free 2 years after surgery. In particular, of the 12 patients with recurrent disease, 7 had endoscopic relapse, while 5 fulfilled both the endoscopic and the clinical criteria of recurrence. Of the latter patients, 1 developed a perianal fistula. Of the 12 patients with endoscopic recurrence, 9 had a score of 3 or greater on the clinical recurrence grading scale. Of the 5 patients with a clinical (as well as endoscopic) recurrence, 4 had a score of 3 or greater. Most patients with any type of recurrence had elevation of the inflammatory indexes and/or a modest to moderate decrease in hemoglobin level. These data are consistent with well-known recurrence rates recently published in the literature7,10 and further indicate that mesalamine is not an effective therapy to prevent recurrence.11
The Figure shows the endoscopic appearance of the mucosal anastomosis in 2 patients 2 years after ileocecal resection and maintenance treatment with intravenous infliximab with low-dose methotrexate (A) or mesalamine (B).
Endoscopic appearance of the mucosal anastomosis of 2 patients with Crohn disease 2 years after ileocecal resection and maintenance treatment with infliximab and low-dose methotrexate (A) or mesalamine (B). Note the complete absence of macroscopic signs of inflammation in the patient treated with infliximab and methotrexate as opposed to the extensive and large ulcerations—in a clear setting of postsurgical recurrence of Crohn disease—in the mesalamine-treated patient. The latter patient also had moderate clinical symptoms (score of 3 on the clinical recurrence grading scale [see the “Methods” section]).
Although we are well aware of the many limitations of our study (eg, lack of randomization, small sample size, and single-center experience), in our series of patients, infliximab with low-dose methotrexate was extremely effective in preventing postsurgical recurrence of Crohn disease. Although we cannot exclude a priori an effect of methotrexate in preventing recurrence, the lack of previous evidence5 and the very small dose used in this study argue against it.
The results of this study reinforce the hypothesis that infliximab may actually be capable, if given early, to change the natural history of Crohn disease. We believe that a multicenter, randomized, controlled study to firmly establish the impact of this medication on the inevitability of disease recurrence12 is warranted.
Correspondence: Prof Sorrentino, Chair of Gastroenterology, University Hospital, Pad.Scrosoppi, Via Colugna, 33100 Udine, Italy (Sorrentino@uniud.it).
Author Contributions:Study concept and design: Sorrentino and Terrosu. Acquisition of data: Sorrentino, Terrosu, Avellini, and Maiero. Analysis and interpretation of data: Sorrentino, Terrosu, Avellini, and Maiero. Drafting of the manuscript: Sorrentino. Critical revision of the manuscript for important intellectual content: Sorrentino, Terrosu, and Avellini. Administrative, technical, and material support: Maiero. Study supervision: Sorrentino, Terrosu, and Avellini.
Financial Disclosure: Prof Sorrentino has acted as a consultant for Schering Plough. This study was not sponsored by the pharmaceutical industry.
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