Postoperative Surveillance and Management of Crohn’s Disease

Fig. 43.1

The natural course of postoperative Crohn’s disease

Postoperative Crohn’s disease recurrence is often clinically silent. Rutgeerts and colleagues found in their initial seminal study of the natural history of postoperative recurrent CD that 72% of examined patients (21 out of 29) had recurrent endoscopic CD within 1 year of curative resection and that a remarkable number of these patients were asymptomatic [11]. In a subsequent prospective cohort of 8-year follow-up study of 89 patients after resection, Rutgeerts et al. found that only 20 and 34% of patients were symptomatic 1 and 3 years after surgery, respectively, despite endoscopic disease found in 73 and 85% of these patients [7]. Regueiro and colleagues observed similar findings in their postoperative randomized placebo-controlled infliximab (IFX) trial, as they determined the kappa coefficient of agreement between the patients’ endoscopic scores, and their clinical Crohn’s Disease Activity Index (CDAI) scores was only 0.12 [12].

The degree of endoscopic disease severity at 1 year, as judged by the now classified Rutgeerts score (Table 43.1), directly correlated with the progression to symptomatic recurrence and was the most statistically significant variable in predicting outcome [7]. For example, only 8.6% of patients with no or only mild endoscopic disease at 1 year, as defined by Rutgeerts score i0 or i1, had clinical symptoms at 8 years, while 100% of patients with severe endoscopic disease, as defined by Rutgeerts score i4, had symptomatic recurrence by 4 years. Although the Rutgeerts score has not been validated as a measure of treatment response, most studies now define endoscopic postoperative remission as i0 or i1, and recurrence as i2, i3, or i4.

Table 43.1

Rutgeerts postoperative Crohn’s disease endoscopic scoring system

Endoscopic score	Endoscopic findings
i0	No lesions
i1	≤5 aphthous lesions
i2	>5 aphthous lesions with normal mucosa between the lesions, or skip areas of larger lesions or lesions confined to the ileocolonic anastomosis (i.e., <1 cm in length)
i3	Diffuse aphthous ileitis with diffusely inflamed mucosa
i4	Diffuse inflammation with already larger ulcers, nodules, and/or narrowing

Since symptom assessment is an unreliable and delayed measure of POR, ileocolonoscopy utilizing the Rutgeerts scoring system is the current gold standard test for POR assessment and is recommended to be performed 6 months to 1 year after surgery. The Rutgeerts scoring system defines severity of disease on a 0–4 scale based on the extent of aphthous ulcerations in the neoterminal ileum (Table 43.1) [7]. Complete endoscopic remission with no lesions is classified as i0, while mild disease consisting of five or fewer aphthous ulcers is classified as i1. Moderate disease defined by more than five aphthous lesions with normal mucosa between the lesions, or skip areas of larger lesions or lesions confined to the ileocolonic anastomosis is classified as i2. Diffuse aphthous ileitis with diffusely inflamed mucosa is classified as i3, and the most severe disease characterized by diffuse inflammation with already larger ulcers, nodules, and/or narrowing is classified as i4 disease.

Though ileocolonoscopy is sensitive at detecting POR, the invasive nature of the test is associated with patient discomfort, high cost, and procedural risk. Fecal calprotectin (fCal), produced by gut leukocytes and epithelial cells at sites of mucosal injury including in Crohn’s disease, is being investigated as a potential noninvasive marker of POR. Lasson et al. reported that there was no significant difference in fCal levels between POCD patients with endoscopic recurrence versus patients in endoscopic remission at 1 year after surgery, in a small study of 30 patients [13]. In contrast, Boschetti and colleagues recently published the results of their larger study of 86 asymptomatic POCD patients within 18 months after surgery in which they found that patients with endoscopic recurrence (i2-4) have significantly higher levels of fecal calprotectin than patients in endoscopic remission (i0-1) (mean ± s.e.m.: 473 ± 78 μg/g vs. 115 ± 18 μg/g; P < 0.0001), and that fCal levels strongly correlate with Rutgeerts scores (r = 0.65, P < 0.0001) [14]. The authors also found that high-sensitivity C-reactive protein was elevated in patients with POR, but to a lesser degree than fCal, and concluded that fCal was a superior noninvasive marker of POR. Given the limited studies to date and their discordant findings, further research is required to determine whether the measurement of fCal is a valid assessment for POR.

Noninvasive radiographic studies such as small intestine contrast ultrasonography (SICUS) have also been investigated to evaluate POR. Calabrese et al. reported that SICUS utilizing oral contrast detected POR, defined by increased bowel wall thickness (BWT) ((>3 mm) for at least 4 cm at the perianastomotic area), in 62 out of 67 patients with endoscopic recurrent disease (i1-4) (92.5% sensitivity), and that BWT strongly correlated with the Rutgeerts score (r = 0.67, P < 0.0001) [15]. Paredes and colleagues had similar findings in their study of contrast-enhanced US utilizing IV contrast in which they found that BWT > 5 mm or contrast enhancement >46% on US had a sensitivity, specificity, and accuracy of 98, 100, and 98.3% for the diagnosis of endoscopic recurrence (i1-4) [16]. Despite these positive findings, the use of SICUS in clinical practice in the United States is currently limited as it requires experienced radiologists with advanced training.

Given the natural predisposition for POR, preventive therapy has received considerable attention, particularly for high-risk patients who have had penetrating or perforating disease, and/or multiple prior CD-related bowel surgeries, and/or cigarette smoking after surgery [17]. Identified risk factors for POR in pediatric CD patients include colonic Crohn’s disease, high preoperative Pediatric Crohn Disease Activity Index (PCDAI), and immunomodulator therapy before surgery [9]. It is the authors’ opinion that patients with a short (<10 years) disease duration before needing surgery and who have a long (>10 cm) stricture with active inflammation are at moderate risk for POR. Patients with long-standing (10 years or more) CD who undergo surgery for the first time for only a short noninflammatory stricture are at low risk for POR.

Nonbiologic Treatment Options for Postoperative Crohn’s Disease

Standard medical therapies including antibiotics, aminosalicylates, and immunomodulators have been shown to moderately reduce the risk of clinical and endoscopic disease recurrence [18] (Table 43.2). Mesalamine is a safe but minimally effective drug to prevent POR. A Cochrane analysis by Doherty et al. found that mesalamine does reduce clinical recurrence (RR 0.76; 95% CI 0.62–0.94) and severe endoscopic recurrence (RR 0.50; 95% CI 0.29–0.84) compared to placebo, but with a number needed to treat (NNT) of 12 and 8, respectively [19]. A subsequent systemic review and meta-analysis by Ford et al. concluded that mesalamine is of only modest benefit in preventing POR compared to placebo and should only be considered if immunosuppressive therapy is not warranted or is contraindicated [20].

Table 43.2

Summary of postoperative Crohn’s disease randomized controlled trials

Postop prevention RCTs	Clinical recurrence (%)	Endoscopic recurrence (%)
Placebo	25–77	53–79
5-ASA	24–58	63–66
Budesonide	19–32	52–57
Nitroimidazole	7–8	52–54
AZA/6-MP	34–50	42–44

In the aforementioned Cochrane analysis, azathioprine (AZA)/6-mercaptopurine (6-MP) was found to significantly reduce clinical recurrence (RR 0.59; 95% CI 0.38–0.92, NNT = 7) and severe endoscopic recurrence (RR 0.64; 95 CI 0.44–0.92, NNT = 4) compared to placebo and was found to be superior to mesalamine [19]. Similar findings were reported by Peyrin-Biroulet et al. in a concurrent meta-analysis of four controlled trials, in which AZA/6-MP was determined to be more effective than placebo for preventing clinical recurrence at 1 year (mean difference, 95% CI: 8, 1–15%, P = 0.021, NNT = 13) and 2 years (mean difference, 95% CI: 13%, 2–24%, P = 0.018, NNT = 8) after surgery, and endoscopic recurrence (i2-4) (mean difference, 95% CI: 23%, 9–37%, P = 0.0016, NNT = 4) at 1 year after surgery [21].

Metronidazole (20 mg/kg) may significantly reduce the incidence of severe (i3-4) endoscopic recurrent disease compared to placebo-treated patients at 3 months after surgery (3 of 23; 13% vs. 12 of 28; 43%; P = 0.02), and clinical recurrence at 1 year (1 of 23; 4% vs. 7 of 28; 25%; P = 0.044) [22]. Combining metronidazole with AZA may improve outcomes further. POCD patients treated with metronidazole for 3 months and AZA (100–150 mg qd dependent on body mass) for 12 months had significantly less endoscopic recurrent disease (i2-4) at 1 year after surgery than patients treated with metronidazole alone at 1 year after surgery (14 of 32; 43.7% vs. 20 of 29; 69.0%; P = .048) [23]. The limitation of metronidazole is that patients often do not tolerate high doses, and long-term prevention of recurrence is lost when the antibiotic is stopped.

Anti-TNFs for Prevention of Postoperative Crohn’s Disease

Growing evidence demonstrates that anti-TNF therapy is the most effective treatment to prevent POR and may have the potential to change the natural course of Crohn’s disease after surgery. Since Sorrentino and colleagues first reported the successful use of prophylactic IFX in a Crohn’s colitis patient after a partial colonic resection [24], multiple small randomized and prospective open-label trials have found that IFX and adalimumab (ADA) are superior to placebo, mesalamine, and AZA at preventing POR (Table 43.3). Regueiro and colleagues performed the first randomized placebo-controlled trial examining the ability of IFX (5 mg/kg every 8 weeks) to prevent endoscopic recurrence of Crohn’s disease at 1 year after ileal resection [25]. In a relatively small study of patients with ileal or ileocolonic disease at moderate to high risk for disease recurrence, the rate of endoscopic recurrence (i2-4) was significantly lower in IFX-treated patients (9.1%, n = 11) compared to the placebo group (84.6%, n = 13) (P = 0.0006). Several other small randomized studies verified that infliximab prevents POR [26, 27]. The protective effects of IFX appear to be a class effect of TNF inhibitors, as ADA has also been found to prevent POR in several small open-label and randomized studies [28, 29, 30]. Overall, anti-TNF therapy is the most effective treatment to prevent POR as verified by recent systematic review and network meta-analysis examining the comparative efficacy of all drugs studied to prevent POR [31]. Accordingly, the authors recommend anti-TNF therapy as first-line prophylactic therapy for patients at high risk for POR or for patients who have tried and failed or are intolerant of AZA/6-MP.

Table 43.3

Postoperative Crohn’s prevention trials investigating the rates of endoscopic recurrence with anti-TNF therapy versus control

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