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Keywords:

  • myenteric plexitis;
  • enteric nervous system;
  • Crohn's disease;
  • azathioprine;
  • postoperative recurrence

Abstract

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

Background:

Recurrence of Crohn's disease (CD) after ileal or colonic resection is common. Myenteric plexitis in the proximal resection margin of an ileocolonic CD resection specimen may indicate ongoing pathology that relates to disease recurrence. We assessed risk factors for myenteric plexitis, the effect of plexitis on clinical recurrence, and whether preoperative medical therapies affect the intensity of plexitis.

Methods:

Ileocolonic resection specimens from 99 patients with CD were histologically scored for the presence and severity of plexitis. Myenteric plexitis was correlated with immunosuppressive therapy before index surgery. Univariate and multivariate analyses were performed to identify predictive factors for plexitis.

Results:

Myenteric plexitis was present in 43% and 85% of cases in the proximal resection margin and the affected resected segments of CD, respectively. Patients with a previous resection were more likely to have plexitis than those with no previous resection (odds ratio [OR] 3.5, 95% confidence interval [CI] 1.21–10.15, P = 0.02), and those with a greater duration of disease were less likely to have plexitis in the proximal resection margin (OR 0.68, 95% CI 0.48–0.96, P = 0.03). Preoperative immunosuppressive therapy was not associated with a lesser incidence of plexitis. Twelve of 40 (30%) patients with plexitis and 9 of 54 (16%) patients without plexitis in the proximal resection margin subsequently developed clinical recurrence (median 10 months; P = 0.17).

Conclusions:

Previous resections and shorter disease duration are associated with plexitis in proximal resection margin of CD. The prognostic value of plexitis in postoperative disease recurrence and risk stratification remain to be prospectively established. (Inflamm Bowel Dis 2009)

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.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

Patients

In this retrospective cross-sectional study, all patients who underwent an ileocolonic resection between 2002 and 2005 were identified from pathology records. Surgery included ileocecal resection/right hemicolectomy, ileocolonic resection if the patient had had a previous ileocecal resection, and segmental colonic resection. Patients who had other types of operation without resection such as abscess drainage, stricturoplasty, fistula repair, and stoma closure were excluded.

The following information was recorded: age, duration of disease, date of resection (index case), smoking status, disease behavior, number of previous resections, postoperative clinical recurrence, time interval between resection and clinical recurrence, and therapy 3 months before resection. The Montreal Classification was used to describe disease location: L1, terminal ileum; L2, colon; L3, ileocolon, and disease behavior: B1, nonstricturing nonpenetrating; B2, stricturing; B3, luminal (not perianal) penetrating; and p, perianal disease.

Ethical approval was obtained from the Harrow Research Ethical Committee.

Histology

Ninety-nine ileocolonic Crohn's resection specimens were analyzed by 2 pathologists (F.S. and T.G.) blinded to the patients' clinical history, preoperative therapy, and postoperative evolution. For each case hematoxylin and eosin (H&E) slides from both resection margins (ileal and colonic margins) and the inflamed segment were reviewed. From the affected bowel segment only those sections where no transmural inflammation was present were selected. Three slides from each patient, from the relevant areas, were reviewed.

The myenteric plexus was examined and plexitis was defined as the presence of 1 or more chronic inflammatory cells (eosinophils, lymphocytes, mast cells, plasma cells) appositioned to or within ganglion cells or nerve bundles. In each segment, plexitis was graded based on the appearance of the most severely inflamed area. In cases where several sections of the proximal or distal margins were available, all were examined, but only the section with the most severe plexitis was used for analysis. The severity of plexitis was graded according to classification proposed by Ferrante et al25 as mild (G1) if the plexus contained <4 inflammatory cells per high-power field (×400), moderate (G2) if it contained between 4–9 inflammatory cells, and severe (G3) if it contained ≥10 inflammatory cells. Some examples are demonstrated in Figure 1. In cases where lymph nodes had been retrieved, the presence of epithelioid Crohn's granulomas was recorded.

thumbnail image

Figure 1. Normal and inflamed enteric nervous system in CD resection specimen. (A) Two normal myenteric ganglia with no plexitis, G0 (arrows) (H&E original magnification ×100). (B) Mild myenteric plexitis, G1 (H&E original magnification ×100). (C) Severe myenteric plexitis with lymphocytes surrounding a ganglion cell, G3 (arrow) (H&E original magnification ×100). (D) Severe myenteric plexitis (H&E original magnification ×200). [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.]

Download figure to PowerPoint

For each patient the presence of plexitis in the proximal resection margin was correlated with drug therapy in the 3 months preceding surgery.

Postoperative Recurrence

Clinical recurrence was defined as the presence of symptoms related to CD, associated with radiologic, endoscopic, or laboratory findings, considered severe enough to require steroid treatment, or an increase of existing treatment. Surgical recurrence was defined as a further operation, because of recurrent symptoms refractory to medical treatment or a new complication.

Statistical Methods

Stata (v. 9.2) by StataCorp (College Station, TX) software was used for all statistical analysis. The association of each clinical variable/risk factor with the presence of myenteric plexitis was examined in a series of univariate analyses. A subsequent multivariate analysis was performed to examine the joint effect of the clinical variables on plexitis. An advantage of the multivariate analysis is that the effect of each variable on the outcome is adjusted for the effect of the other explanatory variables, and so should give a better view of the underlying factors influencing the outcome. A backward logistic regression selection procedure was used to determine the final model. This method involves removing nonsignificant variables from the analyses, 1 at a time, until all remaining variables are statistically significant. P < 0.05 was considered statistically significant.

RESULTS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

Patient Characteristics

Ninety-nine patients with CD were included. The baseline characteristics of patients are shown in Table 1. The mean age of the patients was 39 years old (range 17 to 77). Two-thirds of the patients were younger than 40 years old. Approximately half of the patients had had CD for longer than 10 years. The majority of patients were on some form of medical therapy before the index resection; these included mesalazine, corticosteroids, AZA, 6-MP, or infliximab (Table 2).

Table 1. Patient Characteristics
Baseline CharacteristicsN=99 (%)
Sex 
 Female55 (56%)
 Male44 (44%)
Age at indicator resection (yr) 
 Younger than 4065 (66%)
 40 and older34 (34%)
Smoking status at index surgery 
 Current43 (43%)
 Never51 (52%)
 Ex5 (5%)
Duration of disease at indicator resection (yr) 
 <1043 (43%)
 10 or more56 (57%)
Location (Montreal Classification) 
 L1: Terminal ileal36 (36%)
 L2: Colonic13 (13%)
 L3: Ileocolonic50 (51%)
Behavior (Montreal Classification) 
 B1: nonstricturing nonpenetrating54 (55%)
 B2: stricturing23 (23%)
 B3: penetrating22 (22%)
 p: perianal25 (25%)
Number of previous resection before index surgery 
 0 resection42 (42%)
 1 resection29 (29%)
 2 resections9 (9%)
 3 resections4 (4%)
Single vs. multiple29 vs 13
Type of indicator resection 
Single type of resection93 (94%)
Multiple (combination) resections6 (6%)
 Ileocolonic resection72 (73%)
 Small bowel resection14 (14%)
 Colectomy12 (12%)
 Other types of surgery6 (6%)
Table 2. Patients' Preoperative Therapy
TreatmentNumber (N=94)
  1. AZA + azathioprine ± corticosteroids, 5-ASA + 5-ASA ± corticosteroids.

No preoperative therapy17 (18%)
Preoperative therapy (total)77 (82%)
AZA+28 (36%)
5-ASA+30 (39%)
Corticosteroids alone16 (21%)
Infliximab3 (4%)

Histological Features

All patients had typical Crohn's lesions in the affected bowel segment such as inflammatory cells infiltration, architectural alterations, crypt abscess, granulomas, erosions, and ulcers. The pathologic features of patients with CD are summarized in Table 3. Forty-three percent (40/94) of patients had myenteric plexitis in the proximal resection margin; 5 patients were excluded due to the lack of muscularis propria (n = 3), the absence of myenteric plexus in the histological section (n = 1), and the presence of transmural inflammation in the entire affected segment (n = 1). Granulomas were present in 6% of the proximal resection margin. Epithelioid granulomas in regional lymph node were seen in 30% of cases.

Table 3. Histological Features
Site of PlexitisNumber (%)
  • a

    Five patients were excluded (n=3 no muscularis propria, n=1 no myenteric plexus in the slide, n=1 transmural inflammation in the entire affected segment).

  • b

    Distal resection margin was inflamed anal area in 1 patient.

  • c

    In 20 patients, myenteric plexitis were not evaluated due to transmural inflammation in affected bowel segment.

  • d

    In 16 patients, lymph node was not retrieved.

Proximal resection margin
 Myenteric plexitisa40/94 (43%)
 Granuloma6/94 (6%)
Distal resection margin
 Myenteric plexitisb12/98 (12%)
 Granuloma8/98 (8%)
Affected bowel segment
 Myenteric plexitisc67/79 (85%)
 Granuloma27/79 (34%)
Lymphnode
 Granulomad25/83 (30%)

The frequency of plexitis and granulomas in the distal resection margin and affected bowel segment is also demonstrated in Table 3.

The proximal cut end, demonstrating myenteric plexitis, was small bowel in 35 patients of a total of 86 small bowel proximal margin, and colon in 5 cases of a total of 12 proximal colonic margin.

In 25/40 (67%) of the cases with myenteric plexitis the inflammation was graded mild (G1), in 12 (28%) moderate (G2), and in 3 (5%) severe (G3). Fifty-four CD cases were graded as G0 (no plexitis in the proximal resection margin).

There was no difference between myenteric plexitis at the proximal resection margins and granulomas. Of the 40 patients with plexitis in the proximal resection margin, 5 had granulomas and 35 had no granulomas. Of the 54 patients without plexitis in the proximal resection margins, 1 had granulomas and 53 had no granulomas.

Associations with Myenteric Plexitis

We evaluated whether sex, age at index resection, smoking status, duration of disease, disease location, disease behavior (stricturing or perforating), previous resection for CD, and drug therapy 3 months before index resection were associated with the presence of myenteric plexitis.

Forty-three percent of patients were active smokers at the time of resection. One-third of patients had had 1 previous Crohn's resection and 13 percent had had 2 or more resections.

The disease duration before index surgery was ≤5 years in 21%, 6–10 years in 23%, 11–20 years in 39%, and 21 years or more in 16%.

Approximately half of the patients had stricturing or penetrating disease, while one-quarter had perianal disease. The number of patients with and without plexitis based on the Montreal Classification is shown in Table 4. There were no significant differences in the plexitis and nonplexitis group based on disease behavior. However, of the 3 patients with severe myenteric plexitis (G3), 2 patients had penetrating disease and 1 patient had perianal disease, suggesting a more severe disease phenotype. One of the 3 patients had endoscopic and clinical recurrence.

Table 4. Disease Behavior and Plexitis of the Proximal Resection Margin
Disease BehaviorPlexitisNo PlexitisTotal
  • *

    Six patients excluded due to lack of muscularis propria, no myenteric plexus in the slide, or transmural inflammation in the entire affected segment.

B1 (nonstricturing, Nonpenetrating)22 (41%)32 (59%)54
B2 (stricturing)6 (35%)11 (65%)17*
B3 (penetrating)12 (55%)10 (45%)22
Perianal10 (40%)15 (60%)25

Most patients were on a combination of preoperative therapy. Seventy-eight patients were on some form of therapy (AZA, steroids, or 5-ASA), while 16 patients were not on any medication. Forty patients were on an immunosuppressant (AZA or 6-MP) preoperatively.

Thirteen of 40 patients (33%) with plexitis and 16 of 54 patients (30%; NS) without plexitis in the proximal resection margin were on AZA or 6-MP before their index resection (P = NS). Twenty-one of 67 patients (31%) with plexitis and 4 of 12 patients (33%) without plexitis in the affected Crohn's segment were on AZA or 6-MP before resection (P = NS). There were no significant differences in the severity of myenteric plexitis in the proximal resection margins between the immunosuppressant and no immunosuppressant group (data not shown).

Univariate Analyses

Univariate analysis showed that smoking status, history of previous resection, disease behavior, and preoperative therapy were not predictive of the presence of myenteric plexitis in the proximal resection margin. Treatment with AZA, corticosteroids, or mesalazine for at least 3 months before index surgery was not associated with a different incidence of plexitis in the proximal resection margin (Table 5A).

Table 5A. Univariate Analysis of Risk Factors and Plexitis in the Proximal Resection Margin
VariablePlexitis Present N (%)Odds Ratio (95% CI)P-value
  1. B1: nonstricturing non-penetrating; B2: stricturing; B3: penetrating; AZA: azathioprine; other medication: 5-ASA ± corticosteroids.

Smoking   
 Non/exsmoker23 (44%)1 
 Current smoker17 (41%)0.89 (0.39, 2.04)0.79
Previous resection   
 None20 (37%)1 
 One or more20 (51%)1.79 (0.78, 4.13)0.17
Disease behavior   
 B122 (41%)1 
 B26 (35%)0.79 (0.26, 2.46) 
 B312 (55%)1.75 (0.64, 4.74)0.43
Preoperative therapy   
 AZA13 (45%)1 
 Other medication21 (43%)0.92 (0.36, 2.33) 
 No medication6 (40%)0.82 (0.23, 2.91)0.95
Duration of disease before index surgery0.85 (0.65, 1.12)0.25
Age1.06 (0.91, 1.23)0.44
Sex   
 Female19 (37%)1 
 Male21 (51%)1.82 (0.79,4.19)0.16

Univariate analysis also showed that smoking, previous resections, disease behavior, disease duration, and preoperative therapy had no significant effect on the presence of plexitis in the distal resection margin (data not shown), but a greater duration of disease was associated with a decrease in the likelihood of plexitis in the affected Crohn's segment.

The patient's sex, age, disease location, and presence or absence of perianal disease were not associated with plexitis in either the proximal and distal resections margins, or affected Crohn's segments.

Multivariate Analyses

In a multiple regression logistic analysis, previous resection for CD and the length of disease duration before index surgery were independent predictors of plexitis. After adjusting for disease duration, patients with a previous resection were more likely to have plexitis than those with no previous resection (odds ratio [OR] 3.5, 95% confidence interval [CI] 1.21–10.15, P = 0.02). In contrast, patients with a longer disease duration were less likely to have plexitis in the proximal resection margin (OR 0.68, 95% CI 0.48–0.96, P = 0.03). An increase in disease duration of 5 years was associated with a one-third reduction in the likelihood of plexitis in the proximal resection margin (Table 5B).

Table 5B. Multivariate Analyses of Risk Factors and Plexitis in the Proximal Resection Margin
VariableOdds Ratio (95% CI)P-value
Previous resection  
 None1 
 One or more3.51 (1.21, 10.15)0.02
Duration of disease0.68 (0.48, 0.96)0.03

Multivariate analyses showed that only the duration of disease had a significant effect on plexitis in the affected Crohn's segment (data not shown).

Myenteric Plexitis and Clinical Recurrence of CD

At 1 year after the index resection, 21 of 99 patients developed postoperative clinical Crohn's recurrence and 5 patients developed surgical recurrence. Twelve of the 40 patients (30%) with plexitis at the proximal resection margin developed clinical recurrence, and 9 of 54 patients (16%) without plexitis had clinical recurrence at a median of 10 months (range, 2–36 months) (P = 0.14). Of the 21 patients with clinical recurrence, all patients had increased bowel frequency and abdominal pain requiring a step-up in existing medical therapy or steroids; in addition, 5 patients had colonoscopic evidence of inflammation at the anastomosis and neoterminal ileum, 11 patients had raised C-reactive protein, and 5 patients had an abnormal barium follow-through suggestive of inflammation in the distal ileum. Two of the 5 patients who required repeat resection at a median of 12 months had plexitis in the proximal resection margin.

Nineteen patients (19%) had an ileocolonoscopy at a median of 6 months (range, 3–36 months) after resection. Ileocolonoscopy showed a normal anastomosis in 8 patients, mild disease in 4 patients, moderate disease in 5 patients, and severe disease in 2 patients. These endoscopic findings were as reported by the individual endoscopist.

Seven of 11 patients (64%) with endoscopic recurrence and 2 of 8 patients (25%) without endoscopic recurrence had plexitis in the proximal resection margins. (P = 0.67; Fisher's exact test).

Granulomas

The presence of granulomas within the resection margins, the affected bowel segment, and/or within regional lymph nodes had no significant impact on clinical recurrence. One (9%) and 7 (64%) of 11 patients who developed endoscopic recurrence had granulomas in the proximal resection margins and affected bowel segments, respectively. There was no relationship between disease behavior and lymph node granulomas (data not shown).

DISCUSSION

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

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.

Acknowledgements

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

The authors thank Paul Bassett for help in the statistical analysis of the study.

REFERENCES

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES
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