Prediction of Postoperative Recurrence in Crohn’s Disease: Where Do We Go From Here?

Postoperative recurrence (POR) of Crohn’s disease (CD) represents a major challenge in inflammatory bowel disease care. Despite significant improvements in disease management and medical treatment, a significant proportion of patients require surgery because of CD complications or refractory disease, and most of these patients need further surgical interventions.1Aniwan S. Park S.H. Loftus Jr., E.V. Epidemiology, natural history, and risk stratification of Crohn's disease.Gastroenterol Clin North Am. 2017; 46: 463-480Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar,2Gionchetti P. Dignass A. Danese S. et al.European Evidence-based consensus on the diagnosis and management of Crohn's disease 2016: Part 2: surgical management and special situations.J Crohns Colitis. 2017; 11: 135-149Crossref PubMed Scopus (516) Google Scholar Although remission is commonly achieved after resection, surgery is not curative and disease relapse is inevitable in most patients.3Rutgeerts P. Geboes K. Vantrappen G. et al.Predictability of the postoperative course of Crohn's disease.Gastroenterology. 1990; 99: 956-963Abstract Full Text PDF PubMed Google Scholar Because of a high relapse rate within the first year,3Rutgeerts P. Geboes K. Vantrappen G. et al.Predictability of the postoperative course of Crohn's disease.Gastroenterology. 1990; 99: 956-963Abstract Full Text PDF PubMed Google Scholar,4Rutgeerts P. Geboes K. Vantrappen G. et al.Natural history of recurrent Crohn's disease at the ileocolonic anastomosis after curative surgery.Gut. 1984; 25: 665-672Crossref PubMed Scopus (670) Google Scholar postsurgical patients should be monitored closely and assessed for prompt initiation of treatment.2Gionchetti P. Dignass A. Danese S. et al.European Evidence-based consensus on the diagnosis and management of Crohn's disease 2016: Part 2: surgical management and special situations.J Crohns Colitis. 2017; 11: 135-149Crossref PubMed Scopus (516) Google Scholar,5De Cruz P. Kamm M.A. Hamilton A.L. et al.Crohn's disease management after intestinal resection: a randomised trial.Lancet. 2015; 385: 1406-1417Abstract Full Text Full Text PDF PubMed Scopus (424) Google Scholar Ileocolonoscopy is the reference standard for detecting POR, and current guidelines recommend that it is performed within the first year after surgery.2Gionchetti P. Dignass A. Danese S. et al.European Evidence-based consensus on the diagnosis and management of Crohn's disease 2016: Part 2: surgical management and special situations.J Crohns Colitis. 2017; 11: 135-149Crossref PubMed Scopus (516) Google Scholar,6Maaser C. Sturm A. Vavricka S.R. et al.ECCO-ESGAR Guideline for Diagnostic Assessment in IBD Part 1: initial diagnosis, monitoring of known IBD, detection of complications.J Crohns Colitis. 2019; 13: 144-164Crossref PubMed Scopus (800) Google Scholar The severity of POR should be stratified according to the endoscopic Rutgeerts score, which also provides prognostic information on further disease course.3Rutgeerts P. Geboes K. Vantrappen G. et al.Predictability of the postoperative course of Crohn's disease.Gastroenterology. 1990; 99: 956-963Abstract Full Text PDF PubMed Google Scholar On the downside, ileocolonoscopy is invasive and resource-intensive, and patients may be reluctant to undergo frequent examinations. Thus, noninvasive markers are warranted. Previous studies nominate ultrasound and fecal calprotectin as candidate noninvasive methods to monitor disease activity in CD, well suited for repeated examinations, well-tolerated by patients, and even correlating with endoscopic activity.7Schoepfer A.M. Beglinger C. Straumann A. et al.Fecal calprotectin correlates more closely with the Simple Endoscopic Score for Crohn's disease (SES-CD) than CRP, blood leukocytes, and the CDAI.Am J Gastroenterol. 2010; 105: 162-169Crossref PubMed Scopus (464) Google Scholar,8Calabrese E. Maaser C. Zorzi F. et al.Bowel ultrasonography in the management of Crohn's disease. A review with recommendations of an international panel of experts.Inflamm Bowel Dis. 2016; 22: 1168-1183Crossref PubMed Scopus (122) Google Scholar In the current issue of Clinical Gastroenterology and Hepatology, Furfaro et al9Furfaro F. D’Amico F. Zilli A. et al.Noninvasive Assessment of Postoperative Disease Recurrence in Crohn’ Disease: A Multicenter, Prospective Cohort Study on Behalf of the Italian Group for Inflammatory Bowel Disease.Clin Gastroenterol Hepatol. 2023; 21: 3143-3151Abstract Full Text Full Text PDF Scopus (2) Google Scholar demonstrate that ultrasound examination combined with fecal calprotectin may be sufficient to detect POR with a high positive predictive value (PPV). In a prospective, multicenter study on 91 patients with CD, the authors selected ultrasonographic variables and biochemical markers for predicting POR using the endoscopic Rutgeerts score as a validated reference standard. By using a multivariable model with backward elimination, bowel wall thickness (BWT) exceeding 3 mm, the presence of lymph nodes, and fecal calprotectin were retained and combined showed high specificity for detecting POR. The clinical utility of fecal calprotectin in monitoring CD activity is increasingly being recognized, and the normalization of calprotectin is now regarded a short-term treatment target.10Turner D. Ricciuto A. Lewis A. et al.STRIDE-II: an update on the Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) Initiative of the International Organization for the Study of IBD (IOIBD): determining therapeutic goals for treat-to-target strategies in IBD.Gastroenterology. 2021; 160: 1570-1583Abstract Full Text Full Text PDF PubMed Scopus (786) Google Scholar Growing evidence points to calprotectin as a useful tool for activity monitoring in patients with CD after surgery,11Wright E.K. Kamm M.A. De Cruz P. et al.Measurement of fecal calprotectin improves monitoring and detection of recurrence of Crohn's disease after surgery.Gastroenterology. 2015; 148: 938-947Abstract Full Text Full Text PDF PubMed Scopus (224) Google Scholar,12Qiu Y. Mao R. Chen B.L. et al.Fecal calprotectin for evaluating postoperative recurrence of Crohn's disease: a meta-analysis of prospective studies.Inflamm Bowel Dis. 2015; 21: 315-322Crossref PubMed Scopus (56) Google Scholar further supported by the present study. Despite clear benefits of calprotectin, it is inferior to ileocolonoscopy in detecting relapse in POR, leaving invasive investigations unavoidable. By adding ultrasound measurements to the equation, however, Furfaro et al9Furfaro F. D’Amico F. Zilli A. et al.Noninvasive Assessment of Postoperative Disease Recurrence in Crohn’ Disease: A Multicenter, Prospective Cohort Study on Behalf of the Italian Group for Inflammatory Bowel Disease.Clin Gastroenterol Hepatol. 2023; 21: 3143-3151Abstract Full Text Full Text PDF Scopus (2) Google Scholar show that the PPV significantly improves to the point that disease recurrence can be ruled in. Consistent with previous studies,13Maconi G. Nylund K. Ripolles T. et al.EFSUMB Recommendations and Clinical Guidelines for Intestinal Ultrasound (GIUS) in inflammatory bowel diseases.Ultraschall Med. 2018; 39: 304-317Crossref PubMed Scopus (123) Google Scholar,14Rispo A. Imperatore N. Testa A. et al.Diagnostic accuracy of ultrasonography in the detection of postsurgical recurrence in Crohn's disease: a systematic review with meta-analysis.Inflamm Bowel Dis. 2018; 24: 977-988Crossref PubMed Scopus (44) Google Scholar BWT was found to be the most important ultrasound variable. However, as calprotectin, BWT alone does not have sufficient accuracy to discriminate between surgical remission and POR. Of note, increased BWT is not solely a marker of inflammation, but can also signify fibrosis, anastomosis, or other structural changes following surgery.15Bettenworth D. Bokemeyer A. Baker M. et al.Assessment of Crohn's disease-associated small bowel strictures and fibrosis on cross-sectional imaging: a systematic review.Gut. 2019; 68: 1115-1126Crossref PubMed Scopus (164) Google Scholar,16Coelho R. Ribeiro H. Maconi G. Bowel thickening in Crohn's disease: fibrosis or inflammation? Diagnostic ultrasound imaging tools.Inflamm Bowel Dis. 2017; 23: 23-34Crossref PubMed Scopus (40) Google Scholar Thus, additional sonographic findings should complement BWT measurements to aid differentiation between these entities. On ultrasound, inflammatory segments could be depicted as loss of stratification, prominent submucosal layer, and increased Doppler signals, whereas preserved stratification and thickened muscularis propria layer suggests fibrosis.17Ellrichmann M. Wietzke-Braun P. Dhar S. et al.Endoscopic ultrasound of the colon for the differentiation of Crohn's disease and ulcerative colitis in comparison with healthy controls.Aliment Pharmacol Ther. 2014; 39: 823-833Crossref PubMed Scopus (50) Google Scholar, 18Maconi G. Carsana L. Fociani P. et al.Small bowel stenosis in Crohn's disease: clinical, biochemical and ultrasonographic evaluation of histological features.Aliment Pharmacol Ther. 2003; 18: 749-756Crossref PubMed Scopus (115) Google Scholar, 19Ripolles T. Martinez-Perez M.J. Paredes J.M. et al.The role of intravenous contrast agent in the sonographic assessment of Crohn's disease activity: is contrast agent injection necessary?.J Crohns Colitis. 2019; 13: 585-592Crossref PubMed Scopus (25) Google Scholar, 20Nylund K. Jirik R. Mezl M. et al.Quantitative contrast-enhanced ultrasound comparison between inflammatory and fibrotic lesions in patients with Crohn's disease.Ultrasound Med Biol. 2013; 39: 1197-1206Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar Here, Furfaro et al9Furfaro F. D’Amico F. Zilli A. et al.Noninvasive Assessment of Postoperative Disease Recurrence in Crohn’ Disease: A Multicenter, Prospective Cohort Study on Behalf of the Italian Group for Inflammatory Bowel Disease.Clin Gastroenterol Hepatol. 2023; 21: 3143-3151Abstract Full Text Full Text PDF Scopus (2) Google Scholar find that the presence of lymph nodes is highly specific of POR, indicating that it is an underappreciated tool in the sonographer’s armamentarium. Still, it is mandatory that future research confirm these findings, especially because lymph nodes have generally been considered as an nonspecific finding in CD.13Maconi G. Nylund K. Ripolles T. et al.EFSUMB Recommendations and Clinical Guidelines for Intestinal Ultrasound (GIUS) in inflammatory bowel diseases.Ultraschall Med. 2018; 39: 304-317Crossref PubMed Scopus (123) Google Scholar Not included in the final predictive test, color Doppler could still play an important role in evaluating disease recurrence, evident with an odds ratio of 18.6 for POR in the univariable analysis. In cases where neither calprotectin nor lymph nodes are available, color Doppler could therefore be useful to evaluate the presence of POR. In contrast to ileocolonic surveillance, noninvasive tests as proposed by Furfaro et al9Furfaro F. D’Amico F. Zilli A. et al.Noninvasive Assessment of Postoperative Disease Recurrence in Crohn’ Disease: A Multicenter, Prospective Cohort Study on Behalf of the Italian Group for Inflammatory Bowel Disease.Clin Gastroenterol Hepatol. 2023; 21: 3143-3151Abstract Full Text Full Text PDF Scopus (2) Google Scholar could be repeated more frequently enabling close monitoring of patients. Serial examinations with ultrasound and calprotectin could potentially make up for the relatively lower accuracy compared with endoscopy. The optimal frequency for these examinations should be investigated in future work. As pointed out by the authors, the presence of risk factors for POR was not investigated because this was a methodologic study aiming to select noninvasive markers. The PPV and negative predictive value of a test vary according to the prevalence of the disease in the population, thus the PPV might be higher in the high-risk group than in those without risk factors. Still, the noninvasive test seems applicable to this relatively heterogenous postoperative CD population. An alternative strategy to ease interpretation of increased BWT after surgery could be to compare a baseline examination (eg, short time after the ileocecal resection) with ultrasound examinations during follow-up (eg, 6–12 months) to detect changes over time, similar to a recently suggested algorithm for activity monitoring.21Maaser C. Maconi G. Kucharzik T. et al.Ultrasonography in inflammatory bowel disease: so far we are?.United European Gastroenterol J. 2022; 10: 225-232Crossref PubMed Scopus (10) Google Scholar Any benefit of such an approach remains to be explored. If the combination of ultrasound and fecal calprotectin can reliably determine relapse in CD and is sufficient to initiate treatment escalation, the diagnostic algorithm should be changed. Although some questions remain, we may now have a cost-effective and easy-to-use tool that might reduce the need for invasive endoscopies in routine surveillance for POR in the near future. Noninvasive Assessment of Postoperative Disease Recurrence in Crohn’s Disease: A Multicenter, Prospective Cohort Study on Behalf of the Italian Group for Inflammatory Bowel DiseaseClinical Gastroenterology and HepatologyVol. 21Issue 12PreviewColonoscopy (CS) is the gold standard to assess postoperative recurrence (POR) in Crohn’s disease (CD). However, CS is invasive and may be poorly tolerated by patients. The aim of this study was to prospectively assess the diagnostic accuracy of a noninvasive approach in detecting POR, using the endoscopic Rutgeerts’ score (RS) as the reference standard. Full-Text PDF