Complete endoscopic remission was observed in 111 colonoscopies (63%), whereas mild inflammation was present in 40 (23%), moderate inflammation in 15 (8%), and severe inflammation in 10 colonoscopies (6%) (Table 2). Therefore, 151 procedures (86%) were categorized as effective surveillance and 25 procedures (14%) as ineffective surveillance.
The median simple clinical colitis activity index and Harvey Bradshaw score was 0 (range, 0–15). Increased Harvey Bradshaw (>4) and simple clinical colitis activity index (>3) scores were observed in 12 patients with CD and 12 patients with UC or IBD-U.18,19 Of the 24 patients with increased Harvey Bradshaw or simple clinical colitis activity index scores, only 7 (29%) were classified as ineffective surveillance during endoscopy.
Median calprotectin levels for the effective and ineffective surveillance group were 84 mg/kg (range, 20–4609) and 1605 mg/kg (range, 66–26,336), respectively (P < 0.01; Fig. 2).
ROC curve analysis showed that a cutoff level of 539 mg/kg optimally distinguished patients with effective surveillance from patients with ineffective surveillance with 84% sensitivity, 89% specificity, a positive predictive value of 55%, and a negative predictive value of 97% (Fig. 3). Overall, the diagnostic accuracy of calprotectin as reflected by the area under the ROC curve was 0.89. These results were similar for patients with UC as compared with CD (area under the ROC curves 0.86 versus 0.92, respectively, P = 0.42).
If the calprotectin cutoff level of 539 mg/kg would be applied to the study population, 38 patients (22%) had levels above the cutoff of which 21 (55%) were classified as ineffective surveillance and 17 (45%) as effective surveillance. Of the 138 patients with levels below the cutoff, only 4 patients (3%) were classified as ineffective surveillance. Therefore, calprotectin testing before a scheduled surveillance colonoscopy could potentially reduce the incidence of ineffective surveillance because of inflammation from 25 procedures to 4 procedures (14%–3%, P < 0.01) with a number needed to test to identify 1 patient with ineffective surveillance of 8.4.
During a total of 176 surveillance colonoscopies, 30 dysplastic lesions were detected in 23 colonoscopies (13%). Two patients were diagnosed with LGD detected in a random biopsy. The remaining 28 dysplastic lesions were diagnosed in endoscopically visible lesions, which were classified by the endoscopists as adenoma-like in 24 lesions and as non-adenoma-like in the remaining 4 lesions (Table 2). The adenoma-like lesions were histologically classified as tubular adenomas (n = 21) serrated adenomas (n = 2), and tubulovillous adenoma (n = 1) all containing LGD. The 4 non-adenoma-like lesions contained LGD in all 4 cases.
Among the 111 surveillance colonoscopies with no inflammation, the neoplasia yield was 24 dysplastic lesions in 18 colonoscopies (16%). In 4 of 40 colonoscopies with mild inflammation, 5 dysplastic lesions were detected (10%). Only 1 dysplastic lesion in 15 colonoscopies with moderate inflammation (7%) and no dysplastic lesions in 10 colonoscopies with severe inflammation (0%) was found (P = 0.34; Fig. 4). The dysplasia yield among the 151 patients with effective surveillance was 15% compared with 4% among the 25 patients with ineffective surveillance (P = 0.15).
Endoscopic surveillance in patients with longstanding colonic IBD is challenging because IBD-associated dysplasia is more difficult to detect than sporadic adenomas in patients without IBD. Good bowel preparation, optimal visualization with chromoendoscopy, and an absence of mucosal disease activity are therefore of utmost importance to optimize the effectiveness of this procedure and increase dysplasia detection rates. This study shows that fecal calprotectin testing before a scheduled surveillance colonoscopy can significantly reduce the number of ineffective procedures, defined as colonoscopies showing persistent moderate or severe inflammation from 14% to 3%.
The large proportion of active inflammation encountered among patients undergoing surveillance in our study (37% including patients with mild inflammation) is in line with previous studies, which reported endoscopic inflammation in 34% to 50% of cases, despite the fact that these patients were in clinical remission.14,20 This is most likely because clinical symptoms do not accurately predict mucosal inflammation in both CD and UC patients.12,13
Although our results show that a cutoff of 539 mg/kg of calprotectin can predict ineffective surveillance, we did not investigate what the best management is when calprotectin is above this threshold. Baars et al21 showed that a short course of corticosteroids before a surveillance colonoscopy might decrease histological disease severity, although the decrease in endoscopic disease severity was not statistically significant. Postponing the procedure and initiating a step-up in maintenance therapy to achieve mucosal healing seems to be a logical approach, although this was not the scope of this study.
We also reported a lower dysplasia yield as the severity of inflammation found during surveillance increased. Although not statistically significant, the dysplasia yield decreased from 16% in patients with complete mucosal healing to 0% in patients with severe inflammation. This seems in contrast to the commonly accepted concept that persistent inflammation in IBD is a risk factor for the development of colitis-associated carcinoma.22–24 We believe that this can be attributed to the difficulty of detecting dysplasia in inflamed mucosa. Missed lesions and the carcinogenic effect of ongoing inflammation most likely explain the increased risk of neoplasia in these cases over time as reported by previous studies.
Analysis of 1 calprotectin sample costs around 30 euros (40 dollars) as compared with 459 euros (623 dollars) for colonoscopy. Based on our study cohort, calprotectin testing would have cost 5280 euros (7161 dollars) and saved 9639 euros (13,074 dollars) in colonoscopy costs. Therefore, the costs of calprotectin testing before a surveillance colonoscopy seem to be balanced out by the cost savings of reducing the number of ineffective surveillance procedures.
Our study has several limitations that need to be addressed. The low positive predictive value of 55% implies that the surveillance procedure would be incorrectly postponed in 45% of cases with calprotectin levels above the cutoff of 539 mg/kg. Therefore, postponing the procedure and initiating a step-up in therapy cannot be based solely on an elevated calprotectin level, which limits its usefulness in clinical practice.
Because of the low incidence of dysplasia, we were only able to identify trends regarding differences in dysplasia yield between patients with effective and ineffective surveillance. Although the strategy of fecal calprotectin testing was able to significantly reduce the number of ineffective surveillance procedures, the strategy of postponing all surveillance colonoscopies when calprotectin is above the cutoff level would have resulted in a nonsignificant increase in dysplasia yield from 13% to 15% in our study population (P = 0.64).
Therefore, we cannot definitively conclude that calprotectin testing before a surveillance colonoscopy increases the dysplasia yield and therefore the effectiveness of the procedure.
There is no well-defined cutoff to determine when a surveillance procedure is ineffective because of inflammation. Current surveillance guidelines simply state that surveillance colonoscopies, whenever possible, should be performed when the disease is in remission.4 We chose to classify patients with moderate and severe inflammation as ineffective procedures and mild or no inflammation as effective. The gradually decreasing neoplasia yield as the severity of inflammation increases would suggest that the neoplasia yield might be even better when patients with mild inflammation were also classified as ineffective surveillance. If patients with mild inflammation had classified as ineffective surveillance as well, 65 procedures (37%) would have been ineffective. Using a lower cutoff of 140-mg/kg calprotectin would have identified 56 of these patients (86%). Regarding the dysplasia yield, postponing all these procedures would increase the dysplasia yield only marginally to 16% as compared with 15% when only patients with moderate or severe inflammation were classified as ineffective. Because 40 patients were diagnosed with mild inflammation leading to a considerable rise in the number of procedures that need to be postponed, we feel that a cutoff at moderate or severe inflammation offers the best compromise between the number of procedures that need to be postponed and the increase in neoplasia yield.
The decision to abort the surveillance colonoscopy and repeat the procedure after induction therapy was left at the discretion of the endoscopists in this study population, rather than the aforementioned cutoff of patients with moderate or severe inflammation. Therefore, the procedure was repeated in only 7 patients of the 25 classified as ineffective surveillance. Because the endoscopists knew that the procedure would be repeated, their effort to detect neoplasia was probably lower, which could explain the lower yield in neoplasia in patients with inflammation. If these 7 patients were excluded, neoplasia yield changed from 8% to 7% for the patients with moderate inflammation and remained 0% for the patients with severe inflammation.
In conclusion, low fecal calprotectin can accurately identify patients with IBD without active inflammation in which CRC surveillance is most effective. Future studies should focus on whether the routine use of this tool and postponing surveillance procedures based on the calprotectin level is cost effective.
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Keywords:© Crohn's & Colitis Foundation of America, Inc.
calprotectin; inflammatory bowel disease; colorectal cancer; surveillance; inflammation