Three-quarters of all patients with Crohn's disease (CD) will require surgery in the course of their disease. The commonest indications for surgery include luminal fistulizing disease, abscess formation, symptomatic strictures, and failed medical therapy. Ileocolonic and small bowel disease pose the greatest risk for surgical intervention.1, 2 The commonest operation for CD therefore involves resection of the terminal ileum and proximal colon, with a primary anastomosis. Despite the removal of all macroscopically diseased intestine, disease commonly recurs in the neoterminal ileum proximal to the anastomosis.3 Early lesions can be detected within weeks of resection by endoscopy, and the severity of endoscopic recurrence predicts clinical recurrence.4 The rates of endoscopic and clinical recurrence, at 1 year after an intestinal resection, are 73% and 30%, respectively.5
Preventing recurrence is the ideal postoperative outcome, which depends on identifying factors that predispose to early postoperative clinical recurrence. Established risk factors include restoration of the luminal stream,6 ileocolonic anastomosis (as opposed to a terminal stoma),7 smoking,8, 9 and perforating disease.10, 11 The almost inevitable recurrence of CD in the neoterminal ileum provides a model to study the earliest pathophysiological changes of the disease, and to identify histological risk factors that may predict disease recurrence.
Data on the effect of medical therapy on the postoperative clinical recurrence rate have been inconsistent. The timing of postoperative therapy, the type and duration of preoperative therapy, and the number of risk factors per patient may have been confounders affecting study results. An earlier meta-analysis showed that 5-aminosalicylate acid (5-ASA) decreases the risk of postoperative recurrence by ≈13%,12 but in the largest study, conducted as part of the European Cooperative Crohn's Disease Study to examine 5-ASA for postoperative Crohn's prophylaxis, 318 patients were randomized to placebo or 5-ASA (Pentasa) 4 g daily over 18 months. Clinical recurrence rates were not significantly different between the 5-ASA group (24.5%) and placebo group (31.4%), but post-hoc analysis revealed a significant effect in the subgroup of patients with isolated small bowel disease.13 Imidazole antibiotics are effective in reducing endoscopic and clinical recurrence but at the expense of adverse events and high withdrawal rates.14, 15 Azathioprine (AZA)16 and 6-mercaptopurine (6-MP)17 have moderate effects but need to be evaluated in further trials. Recently the combination of metronidazole and AZA has been shown to be effective in reducing severe endoscopic recurrence.18
Earlier studies investigating the significance of granulomas and pathologically involved resection margins in predicting postoperative recurrence have provided conflicting results.19–21 Histological changes within the enteric nervous system, such as neural fiber hypertrophy and hyperplasia, have been observed in the mucosa, submucosa and plexus of the colon and ileum affected by CD.22–24 Until recently, no studies had investigated the role of these histological features in predicting disease recurrence. However Ferrante et al25 recently demonstrated that inflammatory activity within the enteric nervous system (myenteric plexitis) was a factor associated with postoperative CD recurrence. In that retrospective study the severity of myenteric plexitis in the proximal resection margin correlated with postoperative endoscopic recurrence at 3 months and 1 year after resection.
Current clinical practice is to divide patients into high-risk and low-risk groups, where high-risk patients are offered more intense immunosuppressive therapy.26 The impact of drug therapy on factors that may be associated with relapse, such as myenteric plexitis, has not been explored. It is possible that residual myenteric inflammation within macroscopically normal intestine may be a hallmark of a more active inflammatory process that is more likely to lead to disease recurrence.
The main aim of this study was to assess the frequency of myenteric plexitis, and to identify clinical or demographic factors associated with the presence of myenteric plexitis in the proximal margin of CD resection specimens. The secondary aims were 1) to assess the relationship between neuronal lesions in the proximal margin of CD resection specimens and subsequent postoperative clinical recurrence, and 2) to examine the relationship between the presence and the severity of neuronal lesions in both the proximal resection margins, distal resection margins, and affected segments of CD surgical specimens and preoperative medical therapy.
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- PATIENTS AND METHODS
We have demonstrated that myenteric plexitis can be present in otherwise uninvolved proximal resection margins and, less frequently, in the distal resection margins of CD specimens. Immunosuppressive therapy before surgery did not influence the presence of myenteric plexitis in the proximal resection margin—a potentially important finding, and one which needs to be further assessed prospectively in treatment studies. Further novel findings were that patients with CD who had had at least 1 previous resection were more likely to have plexitis in the proximal resection margin than de novo patients. In addition, longer disease duration before index surgery was associated with a reduced likelihood of showing plexitis in the proximal resection margin.
Our findings are consistent with that of Ferrante et al25 in that approximately half of the patients in our cohort had features of myenteric plexitis at the proximal resection margins in the absence of transmural inflammation, whereas plexitis was seen in only 12% of cases at the distal resection margin. This may partly explain the preferable location of CD recurrence at the ileal site of the ileocolonic anastomosis, and support the hypothesis that inflammation almost invariably spread proximally.
Although clinical recurrence was not significantly associated with plexitis, our study may have been underpowered to detect this and it was not the primary aim of our study. Ferrante et al25 found that in a small cohort of 16 patients who required a reintervention during follow-up, those with myenteric plexitis had this reintervention earlier (mean, 5.30 versus 7.00 years; P = 0.174).
Ferrante et al25 examined the number of myenteric ganglia/plexi and reported a median of 14 myenteric ganglia (range, 6–32) and 9 submucosal ganglia (range, 5–18) in the proximal resection margin of patients with CD. It is possible that there is drop out of ganglia in the proximal resection margin of patients with Crohn's disease as a result of inflammation, but in order to determine this the inflamed plexi will need to be compared with a normal plexi. As Ferrante et al's article had not shown any significant relevance in the number of ganglia in CD, we did not examine this specifically in our study.
In contrast to Ferrante et al's article, our study was primarily designed to examine the relationship between clinical risk factors and plexitis, The relationship between plexitis and other histological features was not part of this study, although in future studies this would be interesting to examine.
One consistent predictor of disease recurrence is the behavior of CD.27, 28 We found that disease behavior had no impact on the histological changes of the myenteric plexus, a finding consistent with those of Ferrante et al.25 Other clinical features such as age at surgery and smoking status also had no relationship with the presence of myenteric plexitis. A recent meta-analysis demonstrated that the indication for reoperation in CD tends to be the same as the primary operation, and perforating disease appears to be associated with higher recurrence rates than nonperforating disease.29
We have made 2 novel observations: there was a trend for worse endoscopic findings in patients with plexitis, and more patients with plexitis had penetrating disease (Table 4), suggesting that myenteric plexitis may be associated with a more severe phenotype.
It is plausible that plexitis is indicative of an acute inflammatory process. This might also explain why there was less plexitis in those with a long history of CD and why previous resection was associated with myenteric plexitis. This is concordant with previous clinical studies showing that the number of previous resections is a predictor for Crohn's recurrence. Multiple resections most likely reflect more severe disease activity.4 This, however, is speculative and larger numbers of cases will be required to confirm this.
In our study, and previously unreported, a shorter disease duration before index surgery was associated with plexitis, suggesting that neuronal inflammation may be a more acute event.
What does the presence of plexitis represent? Most likely this inflammatory neural process is reflective of, and secondary to, an ongoing antigenic drive and inflammatory process. It may result directly from a luminal antigenic stimulus, or may be a neural response to the lack of epithelial integrity that characterizes the ulceration of CD. Alternatively, it may be a part of the primary disease process. Ferrante et al25 have shown that plexitis did not appear to be associated with a higher epithelial inflammatory activity. Given the lack of association between plexitis and the inflammatory cell infiltrate in their study, we did not specifically examine the inflammation scores in our study.
Enteric glial cells in the normal human intestine have membranous expression of major histocompatibility class (MHC) II antigen, suggesting that they can function as antigen-presenting cells and interact with lymphocytes.30, 31 They also have receptors for cytokines and produce interleukin-(IL) 6, which may be modulated by neurotransmitters.32, 33 The ability of enteric glial cells to interface between the neural and immune systems in the gut suggests that they may play an important role in the pathophysiology of inflammatory bowel disease (IBD). The mechanisms involved in the recurrence of inflammation and/or ulcers at the anastomosis and neoterminal ileum are unclear. It has been suggested that low ileal IL-10 concentrations may be predictive of disease recurrence in the neoterminal ileum. Changes in the enteric nervous system in IBD are likely to be immunologically mediated.34 The immunomodulatory potential of the enteric nervous system either in the form of T-cell activation via antigen-presenting cells or through cytokine production indicates they may be therapeutic targets for intestinal inflammation.
The majority of the patients in our cohort were taking medical therapy in the form of steroids, 5-ASA, or immunosuppressive drugs before their resection. Approximately one-third were on 5-ASA and a further one-third were on azathioprine. Ferrante et al25 found no association between preoperative corticosteroids and AZA and the presence of myenteric plexitis; however, only a small number of patients were on treatment before surgery. We have shown in a larger cohort of patients that the use of AZA and/or corticosteroids before surgery was not preventive for the presence or severity of plexitis. A longer time course and more patients will be required to address the relationship between immune suppression and myenteric plexitis.
The retrospective nature of this study is a limiting factor, as we were not able to accurately assess the preoperative disease severity and exact timing and duration of therapy. There have been 3 studies evaluating the role of AZA or 6-MP in the postoperative setting; the benefit of preventing postoperative recurrence is moderate.22–24 In contrast, conventional steroids have not been shown to be beneficial in postoperative prophylaxis of CD.35, 36 In addition, we were not able to control for factors during surgery including the precise location where the surgeons chose to transect the bowel (i.e., distance from ileocecal valve, distance from gross disease, density and location of adhesions, surgical techniques) but we did make a careful assessment from the operative notes. Our current prospective study will take these factors into account.
We found no relationship between the presence of granulomas and clinical recurrence at 1 year, although the number of cases examined was modest. One-third of patients in our cohort had granulomas in the resected bowel segment. Earlier studies suggested that the presence of granulomas in the resected specimen is associated with a lower recurrence rate, at least in the colon and anus,37, 38 but this correlation was not seen with granulomas of the ileocolonic anastomosis.39 Heimann et al40 showed that patients with granulomas were younger, had more extensive disease, and a shorter duration of disease. Follow-up at 5 years showed a trend toward greater recurrence rate in the patients with granulomas. It has also been reported that the need of immunosuppressive therapy and surgical interventions were significantly more frequent in the patients with granuloma.41
More patients with neuronal inflammation in the proximal resection margin developed symptomatic recurrence of their CD. At the time when this work was performed, only one-fifth of patients had an ileocolonoscopy to assess for endoscopic recurrence when they present with symptoms of clinical relapse. We were therefore unable to correlate plexitis with postoperative endoscopic recurrence. Nonetheless, clinical recurrence was based on the need for corticosteroids or a step-up in existing medical therapy supported by clinical, biochemical, and, in some cases, radiological evidence of active disease. Although Rutgeerts endoscopy score has been used in only ileocolonic anastomosis, a few patients with pure ileal disease were assessed by this classification as there are no grounds to believe that endoscopic grading would be any different for other types of anastomosis.
In conclusion, we have shown that patients with a previous resection for CD and those with shorter preoperative disease duration are more likely to have myenteric plexitis in the proximal margins of ileocolonic resection specimens. Preliminary data also suggest an early need to reintervene in patients with plexitis as more patients develop clinical recurrence. Preoperative immunosuppressive therapies, however, did not alter the presence of inflammation within the enteric nervous system. Routine assessment of plexitis postoperatively may help to identify patients with CD who are at higher risk of endoscopic and clinical recurrence, and thus may require more aggressive therapy. The value of such risk stratification, akin to pathological assessment following cancer surgery, remains to be prospectively proven.