Dra. Pilar Nos Mateu
Hospital Universitari i Politècnic La Fe. Valencia
FOLLOW-UP ON PATIENTS WHO HAVE UNDERWENT SURGERY DUE TO CROHN’S DISEASE
Crohn’s disease (CD) is a chronic bowel disease of unknown cause that affects an ever increasing number of patients. Despite the currently availability of potent drugs that have proven their efficacy in controlling inflammatory activity, a high percentage of patients with CD, up to 80%, require at least a resective surgery during the course of their disease, primarily in order to treat associated complications, especially symptomatic stenosis and untreatability1. The disease tends to reappear even after resection of the entire macroscopically affected intestinal tract, which is why postoperative recurrence is virtually the norm in these patients and controlling recurrence presents a real problem. The term “recurrence” is used to define the appearance of new CD lesions after a theoretically curative surgical bowel resection. This is in contrast to the term “relapse”, which refers to the reappearance of clinical symptoms within the context of an outbreak of inflammatory activity2.
Post-surgical recurrence is often located in the area of the anastomosis and/or proximally to it, reproducing the same initial disease pattern3 (Video 1 and Video 2). The tendency of recurrence is higher in CD with ileocolonic localisation (L1 and L3 of the Montreal Classification), compared to other localisations. Its incidence varies based on the published series and the type of recurrence considered (endoscopic, clinical, radiologic or surgical), but it always tends to be high. It is estimated that, in absence of treatment, more than 60% of patients who undergo operation experience endoscopic lesions in the neo-terminal ileum one year after surgery3-5 and clinical recurrence without treatment occurs in up to 20–30% of the patients one year after ileal or ileocolonic resection, with a 10% increase each subsequent year6-7. It has been proven that the severity of endoscopic lesions shows a good correlation with the probability of experiencing disease symptoms. In fact, symptoms usually appear when the patient already has severe endoscopic lesions and it is not uncommon to observe patients with advanced, recurrent lesions that still remain asymptomatic8. Therefore, clinical indices such as the Crohn’s disease activity index (CDAI) present a low sensitivity when discriminating patients that may experience a recurrence.
Several studies have tried to establish the potential risk factors for the development of recurrent CD. Among those that have proven, in most of studies, to predict an early recurrence after the surgery are the following7-8:
• Active smoking.
• Previous history of bowel resection.
• Penetrating or fistulising pattern of the disease.
• Extensive small bowel resection.
The absence of prophylactic treatment has also been associated with a higher risk of recurrence, although the recommendation of generally administering prophylaxis to all patients after surgery continues to be disputed. Since recurrence rates are very high, and since there is currently no marker or validated predictive index available to distinguish patients who can remain asymptomatic for a long time, practically all patients tend to be treated universally after surgery. Not treating can be a valid option in patients considered to be at a “very low risk” for recurrence, such as patients operated on after having a long-standing short symptomatic fibrotic stenosis that has slowly progressed. In these cases, it is important and more necessary to emphasize morphological control.
Clinical monitoring does not constitute a reliable method for evaluating recurrence, since certain symptoms within the context of post-operation (such as diarrhoea resulting from the malabsorption of bile salts, bacterial overgrowth, or short bowel syndrome after extensive bowel resection) can be erroneously interpreted as a reappearance of the disease. Furthermore, as previously mentioned, there are currently no clinical indices available that have been validated in this specific subgroup of patients. Preventive treatment for recurrence is not universally established and the suggestion has recently been made that this be performed in a tailored fashion9-11. It is recommended to endoscopically review the ascending colon of the anastomosis to ensure maintenance of the mucosal healing or to detect states of early morphologic recurrence that require a therapeutic escalation or intensified treatment12 (Fig. 1).
ILEOCOLONOSCOPY IN THE POSTOPERATIVE FOLLOW-UP OF CROHN’S DISEASE
Currently, ileocolonoscopy continues to be the technique most utilised for diagnosing morphologic recurrence and is considered the gold standard for assessment, allowing to determine the presence and severity of the recurrence, as well as predict the postoperative clinical course of the disease. Recurrent lesions invariably appear in the ascending colon of the anastomosis. Aphtha is the initial lesion, and it is preceded by inflammatory changes in the submucosa and tends to progress to ulcers. These ulcers later converge, become deeper and can lead to fistulisation, fibrosis and stenosis. In short, its progression mimics and reproduces the natural history of CD. The more advanced stages of morphologic lesions are usually symptomatic.
This entire sequence of events that develops in the neoileum has been known since Dr Paul Rutgeerts’ Lovaina group studies. In 1984, the initial study was published in Gut, in which endoscopic control of the disease was systematised with serial observation following resection of the neoileum13. It is the presence of aphthous ulcers that is considered as recurrence, not hyperaemia or a fragile mucosa. In this study, it was observed that significant endoscopic lesions can appear with no symptoms, particularly in the initial stages of the disease. In 1990, the famous Rutgeerts score (RS) was considered the gold standard for the quantification of recurrent lesions3.
In patients with severe lesions (RS 3 and 4), the affected length of the intestine was an average of 22 cm (10–55 cm) and an average of 8 cm (2–15 cm) in patients with milder lesions (RS 1 and 2).
Therefore, it is our opinion that, if the first 10–15 cm of the neoileum are normal, lesions observed beyond that point must not be considered a recurrence and must only be understood as something that developed in clear relative proximity to the surgical anastomosis (Fig. 2). The RS has been used in controlled clinical trials that have assessed different drugs: aminosalicylates, budesonide, azathioprine, metronidazole or infliximab in the prevention of postoperative recurrence, and an RS ≥2 is usually considered a morphologic recurrence14 (Video 3 and Video 4).
In recent years, it has been suggested that a clear differentiation in RS 2 be established between lesions extended throughout the neoileum and those confined to anastomosis15. This is due to possible ischemic mechanisms involved in the appearance of these ulcers, which are not unique to CD16. With this argument, anastomosis-confined lesions have been considered RS 2a (Fig. 3) and continuous aphthae grouped within proximity of the anastomosis, but throughout the neoileum are considered RS 2b (Fig. 4), likely authentic recurrences.
The cumulative probability of remaining free of endoscopic recurrence under azathioprine treatment is higher for patients with these lesions when comparing them to patients with more severe lesions RS 2b, 3 and 415. The most recent clinical trial that assessed azathioprine versus mesalazine in preventing postoperative recurrence has already used this variation of the Rutgeerts classification and considers a RS ≥2b a significant morphologic recurrence17.
RS quantification is not as simple as it seems. Stenoses with an inflammatory component are sometimes detected that are difficult to differentiate from authentic postoperative stenoses, and quantification of the lesion can only occur by visualising the ileal mucosa after dilation, which must be performed under safe conditions (Fig. 5).
CAPSULE ENDOSCOPY IN THE POSTOPERATIVE FOLLOW-UP OF CROHN’S DISEASE
Capsule endoscopy is a simple to use, minimally invasive diagnostic instrument that enables the morphological analysis of the gastrointestinal tract, and particularly of areas that cannot be reached via conventional endoscopy (almost the entire small intestine). Inside it contains a lamp, a colour camera, batteries and a radiofrequency transmitter. The camera captures two photographic images per second that are transmitted to a recorder (Holter system) where they are stored. Ultimately, the capsule is eliminated through defecation. The images taken (around 55,000) are visualised at a workstation (personal computer with the right software).
In CD patients in which stenosis is suspected, it is best to perform an exploration beforehand with an instrument identical to the appearance and volume of the capsule and that minimises the risks of ingesting the capsule: Patency system. This system evaluates the functional permeability of the small intestine; the Patency capsule is composed of a barium polymer with a 2 x 12 mm radiopaque rod in the centre that transmits a radiofrequency and can be detected by a detector or viewed in a plain x-ray. The capsule disintegrates through one of the heads of the device in the presence of intestinal fluids after 24–48 hours, so it is not retained in a stenosis. Sub-occlusive crises cases have been published in a fifth of the patients who have undergone this procedure18; therefore, a new capsule (Agile®), has been designed, which disintegrates from the ends of the device to ensure disintegration even when one of the heads remains embedded in a stenosis19.
This series of evidence proves the benefits of capsule endoscopy in diagnosing CD in patients with high clinical suspicion, although without radiological or colonoscopic signs that confirm it. There is not much evidence regarding the use of the capsule in monitoring the progress of patients. There are only two studies that have compared its use versus colonoscopy in the assessment of postoperative recurrence, with mixed results (Case 4)20, 21.
The first of them20 described that capsule endoscopy had less sensitivity than ileocolonoscopy in detecting postoperative recurrence. In the second study, the results were better for the capsule21, especially because it labelled as RS 2a a lot of patients that had been labelled as RS 1 via ileocolonoscopy. Furthermore, it allows the information to be completed, since it visualises the entire intestine and lesions were detected in the upper tracts in more than half of the patients. The latter study was previously conducted with Patency in order to minimise the possibility of impaction, and it also included a subjective assessment of the technique by the patient; all patients preferred capsule endoscopy versus colonoscopy. The therapeutic impact was high, since the treatment was modified in 16 of the 22 patients assessed, with the result that capsule endoscopy provided more comprehensive information, not only for the neoileum, but also the rest of the small intestine. These discordant results are like to be due to the length of the tract explored with ileoscopy. The type of anastomosis performed oftentimes complicates the possibility of intubation and progression in the neoileum and the finding of an aphtha can classify the patient as RS1 or RS 2, depending on the visualised extension reached.
CORRELATION TO CLINICAL INDICES AND OTHER IMAGING TESTS
CDAI is the clinical index most often used in quantifying the inflammatory activity of CD22. It has used numerous controlled clinical trials to classify the patient as “active” and to define the remission. CDAI includes eight variables, seven of which are clinical (number of stools, abdominal pain, general condition, the presence of extraintestinal manifestations, the intake of anti-diarrhoea medicines, abdominal mass and weight) and only one analytical parameter (haematocrit). Therefore, it is an index more for clinical severity than inflammatory activity. The final score obtained establishes a numerical grading of the disease that allows for discerning small changes within the same category, something that qualitative indices lack.
Among the many criticisms CDAI has received is its high subjectivity, and therefore its high interobserver variability; thus, the score assigned to the same case by different physician can experience significant variations. In addition, the quantification of CD via CDAI requires 7 days and is impractical when applied to the admitted patient. Its objective variables do not include the erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) or albumin, which could be important in quantifying inflammatory activity. Abdominal pain and general condition, signs that are too subjective and therefore unquantifiable, have a weight of 39% of the equation value. It is even more difficult to apply if the patient has undergone an operation, since the number of stools in the operated subject may not express inflammatory activity and may be a result of, as previously mentioned, diarrhoea episodes due to bile salts or bacterial overgrowth, or this may even be a result of the bowel resection itself. This is likewise true when taking anti-diarrhoea medicine, which many operated patients take in the absence of activity. Usually, a CDAI ≥220 is considered a person with moderate activity and a CDAI <150 is calculated as remission. A 70-point decrease is considered a response (partial remission). Pharmacological studies for recurrence prevention have at times used CDAI values >250 as way of determining clinical recurrence23,24.
Thus, the need to reproduce and validate CDAI in the clinical recurrence situation has been insisted upon14 and recently, this concept has been prospectively assessed25. The Canadian and American Surgical Crohn’s Disease Trial (CAST) assessed recurrence rates based on the type of surgical anastomosis performed, without observing any differences among those groups26; it performed a prospective follow-up that included a calculation of the RS, the CDAI and the IBDQ quality of life questionnaire at 12 months following the surgery26; 93 patients completed the follow-up, in which they could document through a statistical analysis with ROC curves that a CDAI >148 has a sensitivity of 70% and a specificity of 81% in detecting postoperative recurrence. The study concludes that, although the traditional CDAI value of >150 seems reasonable in order to define clinical postoperative recurrence, in clinical trials it is desirable to add the combination of endoscopic evidence of the reappearance of lesions as well as clinical symptoms, which can be quantified with the traditional clinical index. This data has been subsequently refuted although, in a short series of patients (n = 4), the correlation between CDAI and RS was very poor, with a k coefficient of 0.1227.
Historically, CD patients have been assessed via barium radiology techniques, either with simple contrast or via enteroclysis. Initially, traditional barium studies were considered supplemental to capsule endoscopy in the recurrence assessment in cases in which there are stenoses or technical difficulties that would prevent passage28. With visualisation of the entire small intestine via capsule endoscopy and, especially, with the generalisation of resonance to assess lesions and their activity, barium studies have fallen into disuse.
Currently, enteric magnetic resonance is a non-invasive technique that has been adopted for the exploration of the small intestine, enables visualisation of the small intestine and, with enhanced visualisation of the intestinal wall, it gives a very adequate approximation of the intensity of the inflammatory process29. Resonance has been compared to ileocolonoscopy in a study conducted on 30 patients with suspected postoperative recurrence30 (Video 5). This study also developed an index (MR score) to quantify the severity of the recurrence. Compared to ileocolonoscopy (RS), resonance had a sensitivity of 100% with a specificity of 89% for detecting morphologic recurrence, and the MR score was adequately correlated to the RS with adequate interobserver variability (78%) and a k coefficient of 0.673. In a subsequent independent study, the same authors confirm these results in 29 patients whose average recurrence after undergoing surgery was 35 months, and in which the ileocolonscopy and resonance were performed within a period of three days31. The correlation is higher for RS 3 and 4 (Fig. 6) and MR enterography did not provide sufficient information to differentiate between RS 1 and RS 2, upon which both are included within the same MR score category, MR1. This is significant because it marks the difference in clinical trials between what is considered a significant and a non-significant recurrence, and it dovetails with what was discussed earlier in regards to different morphological and endoscopic situations that are included within RS 2.
BIOLOGICAL MARKERS. VALUE IN DETECTING POSTOPERATIVE RECURRENCE
The first study, in which new faecal calprotectin and lactoferrin markers were assessed in operated patients, was a transversal study that detected that these could remain high even in the absence of clinical recurrence32. The authors deemed that this could be due to the presence of active, non-resected, persistent microscopic inflammatory disease and that the value of this finding would not have any special transcendence.
Subsequent studies have prospectively assessed this situation in 50 operated patients, of which 39 had an endoscopic recurrence after one year (RS >1)33. A calprotectin value >200 three months following the operation showed high sensitivity (63%) and specificity (75%) for predicting morphologic recurrence after one year and, in this study, calprotectin was better than ultrasound, whose sensitivity and specificity for predicting this recurrence was 26% and 90%, respectively. These results are similar to those of a prospective study conducted on 35 patients, in which the calprotectin values at 3 and 6 months, with a cut-off point of 200 and 350 respectively, were predictors of morphologic recurrence (quantified by endoscopy with RS >1 or MR enterography >1)34.
These faecal markers could have a higher predictive value than more traditional serological markers. Likewise, in another study, a postoperative cohort of 13 patients participated in a prospective follow-up for a year with faecal calprotectin and faecal lactoferrin35. Moreover, only one stool sample was analysed in a second group of 104 operated patients (with an average of 24 months after resection). The faecal tests were compared to the Harvey Bradshaw clinical index, the endoscopic examination of the neoileum (RS), the CRP values and the platelet quantification. In patients with a course with no complications, both faecal markers returned to normal within 2 months. Both calprotectin and lactoferrin correlated significantly to the Harvey Bradshaw index (p <0.001). Patients with severe active disease had high average calprotectin levels of 661.1 µg/g and lactoferrin levels of 116.6 µg/g, and inactive patients had low levels of 70.2 and 5.9 respectively. In patients with mild or moderate active disease, these markers identified individuals with and without recurrent inflammatory disease. Faecal markers were more accurate in predicting disease activity than CRP, platelet count and even endoscopic appearance. The number of patients who underwent an endoscopy was limited, but the study opens the debate on the relation between these markers, underlying inflammation, which may not cause mucosal changes, endoscopic changes, and, which is most important, its prognostic significance.
1. Caprilli R, Gassull MA, Escher JC, Moser G, Munkholm P, Forbes A, et al. European evidence based consensus on the diagnosis and management of Crohn’s disease: special situations. Gut. 2006; 55(Suppl 1): i36-i58.
2. Van Assche G, Dignass A, Panes J, Beaugerie L, Karagiannis J, Allez M, et al. The second European evidence based consensus on the diagnosis and management of Crohn’s disease: definitions and diagnosis. J Crohns Colitis. 2010; 4(1): 7-27.
3. Rutgeerts P, Geboes K, Vantrappen G, Beyls J, Kerremans R, Hiele M. Predictability of the postoperative course of Crohn’s disease. Gastroenterology. 1990 Oct;99(4):956-63.
4. Olaison G, Smedh K, Sjödahl R. Natural course of Crohn’s disease after ileocolic resection: endoscopically visualised ileal ulcers preceding symptoms. Gut. 1992; 33: 331-5.
5. Rutgeerts P. Protagonist: Crohn’s disease recurrence can be prevented after ileal resection. Gut. 2002; 51: 152-3.
6. Terdiman JP. Prevention of postoperative recurrence in Crohn’s disease. Clin Gastroenterol Hepatol. 2008; 6: 616-20.
7. Nos P, Domenech E. Postoperative Crohn’s disease recurrence: a practical approach. World J Gastroenterol. 2008; 14: 5540-8.
8. Onali S, Petruzziello C, Calabrese E, Condino G, Zorzi F, Sica GS, et al. Frequency, pattern, and risk factors of postoperative recurrence of Crohn’s disease after resection different from ileo-colonic. J Gastrointest Surg. 2009; 13: 246-52.
9. Bordeianou L, Stein SL, Ho VP, Dursun A, Sands BE, Korzenik JR, et al. Immediate versus tailored prophylaxis to prevent symptomatic recurrences after surgery for ileocecal Crohn’s disease? Surgery. 2011; 149: 72-8.
10. Ng SC, Kamm MA. Management of postoperative Crohn’s disease. Am J Gastroenterol 2008; 103: 1029-35.
11. Sorrentino D. State-of-the-art medical prevention of postoperative recurrence of Crohn’s disease. Nat Rev Gastroenterol Hepatol. 2013; 10(7): 413-22.
12. Rutgeerts P. Review article: recurrence of Crohn’s disease after surgery – the need for treatment of new lesions. Aliment Pharmacol Ther. 2006; 24(Suppl. 3): 29-32.
13. Rutgeerts P, Geboes K, Vantrappen G, Kerremans R, Coenegrachts JL, Coremans G. Natural history of recurrent Crohn’s disease at the ileocolonic anastomosis after curative surgery. Gut. 1984; 25: 665-72.
14. Sandborn WJ, Feagan BG, Hanauer SB, Lochs H, Löfberg R, Modigliani R, et al. A review of activity indices and efficacy endpoints for clinical trials of medical therapy in adults with Crohn’s disease. Gastroenterology. 2002; 122: 512-30.
15. Domènech E, Mañosa M, Bernal I, Garcia-Planella E, Cabré E, Piñol M, et al. Impact of azathioprine on the prevention of postoperative Crohn’s diseaserecurrence: results of a prospective, observational, long-term follow-up study. Inflamm Bowel Dis. 2008; 14: 508-13.
16. Chari ST, Keate RF. Ileocolonic anastomotic ulcers: a case series and review of the literature. Am J Gastroenterol. 2000; 95: 1239-43.
17. Reinisch W, Angelberger S, Petritsch W, Shonova O, Lukas M, Bar-Meir S, et al. Azathioprine versus mesalazine for prevention of postoperative clinical recurrence in patients with Crohn’s disease with endoscopic recurrence: efficacy and safety results of a randomised, double-blind, double-dummy, multicentre trial. Gut. 2010; 59: 752-9.
18. Rondonotti E, Herrerias JM, Pennazio M, Caunedo A, Mascarenhas-Saraiva M, de Franchis R. Complications, limitations, and failures of capsule endoscopy: a review of 733 cases. Gastrointest Endosc. 2005; 62: 712-6.
19. Herrerias JM, Leighton JA, Costamagna G, Infantolino A, Eliakim R, Fischer D, et al. Agile patency system eliminates risk of capsule retention in patients with known intestinal strictures who undergo capsule endoscopy. Gastrointest Endosc. 2008; 67: 902-9.
20. Bourreille A, Jarry M, D’Halluin PN, Ben-Soussan E, Maunoury V, Bulois P, et al. Wireless capsule endoscopy versus ileocolonoscopy for the diagnosis of postoperative recurrence of Crohn’s disease: a prospective study. Gut. 2006; 55(7): 978-83.
21. Pons Beltrán V, Nos P, Bastida G, Beltrán B, Argüello L, Aguas M, et al. Evaluation of postsurgical recurrence in Crohn’s disease: a new indication for capsule endoscopy? Gastrointest Endosc. 2007; 66: 533-40.
22. Best WR, Becktel JM, Singleton JW, Kern F. Development of a Crohn’s disease activity index. National cooperative Crohn’s disease study. Gastroenterology. 1976; 70: 439-44.
23. Lochs H, Mayer M, Fleig WE, Mortensen PB, Bauer P, Genser D, et al. Prophylaxis of postoperative relapse in Crohn’s disease with mesalamine: European Cooperative Crohn’s Disease Study VI. Gastroenterology. 2000; 118: 264-73.
24. Rutgeerts P, Van Assche G, Vermeire S, D’Haens G, Baert F, Noman M, et al. Ornidazole for prophylaxis of postoperative Crohn’s disease recurrence: a randomized, double-blind, placebo-controlled trial. Gastroenterology. 2005; 128: 856-61.
25. Walters TD, Steinhart AH, Bernstein CN, Tremaine W, McKenzie M, Wolff BG, et al. Validating Crohn’s disease activity indices for use in assessing postoperative recurrence. Inflamm Bowel Dis. 2011; 17: 1547-56.
26. McLeod RS, Wolff BG, Ross S, Parkes R, McKenzie M; Investigators of the CAST Trial. Recurrence of Crohn’s disease after ileocolic resection is not affected by anastomotic type: results of a multicenter, randomized, controled trial. Dis Colon Rectum. 2009; 52: 919-27.
27. Regueiro M, Kip KE, Schraut W, Baidoo L, Sepulveda AR, Pesci M, et al. Crohn’s disease activity index does not correlate with endoscopic recurrence one year after ileocolonic resection. Inflamm Bowel Dis. 2011; 17: 118-25.
28. Buchman AL, Miller FH, Wallin A, Chowdhry AA, Ahn C. Videocapsule endoscopy versus barium contrast studies for the diagnosis of Crohn’s disease recurrence involving the small intestine. Am J Gastroenterol. 2004; 99: 2171-7.
29. Allen PB, De Cruz P, Lee WK, Taylor S, Desmond PV, Kamm MA. Noninvasive imaging of the small bowel in Crohn’s disease: the final frontier. Inflamm Bowel Dis. 2011; 17: 1987-99.
30. Sailer J, Peloschek P, Reinisch W, Vogelsang H, Turetschek K, Schima W. Anastomotic recurrence of Crohn’s disease after ileocolic resection: comparison of MR enteroclysis with endoscopy. Eur Radiol. 2008; 18: 2512-21.
31. Koilakou S, Sailer J, Peloschek P, Ferlitsch A, Vogelsang H, Miehsler W, et al. Endoscopy and MR enteroclysis: equivalent tools in predicting clinical recurrence in patients with Crohn’s disease after ileocolic resection. Inflamm Bowel Dis. 2010; 16: 198-203.
32. Scarpa M, D’Incà R, Basso D, Ruffolo C, Polese L, Bertin E, et al. Fecal lactoferrin and calprotectin after ileocolonic resection for Crohn’s disease. Dis Colon Rectum. 2007; 50: 861-9.
33. Orlando A, Modesto I, Castiglione F, Scala L, Scimeca D, Rispo A, et al. The role of calprotectin in predicting endoscopic post-surgical recurrence in asymptomatic Crohn’s disease: a comparison with ultrasound. Eur Rev Med Pharmacol Sci. 2006; 10: 17-22.
34. Moret I, Cerrillo E, Iborra M, Rausell F, Tortosa L Bastida G, et al. Perfil evolutivo de biomarcadores en pacientes con enfermedad de Crohn tras la cirugía: identificación de predictores de recurrencia. Gastroenterol Hepatol. 2013; 36: 157-8.
35. Lamb CA, Mohiuddin MK, Gicquel J, Neely D, Bergin FG, Hanson JM, et al. Faecal calprotectin or lactoferrin can identify postoperative recurrence in Crohn’s disease. Br J Surg. 2009; 96: 663-74.