Abstract
Background
Relapse of ulcerative colitis is difficult to predict by routine colonoscopy. A high‐resolution video‐magnifying colonoscope with chromoscopy enables the observation of colorectal mucosal pit patterns.
Aims
To investigate the association of pit patterns as assessed by magnifying colonoscopy (MCS) with histological inflammation and mucosal chemokine activity in patients with quiescent ulcerative colitis, and to prospectively analyse the prognostic factors that may predict exacerbations.
Methods
MCS was performed in 113 patients with ulcerative colitis in remission. Pit patterns in the rectal mucosa were classified into four MCS grades on the basis of size, shape and arrangement. Mucosal interleukin (IL) 8 activity was measured in biopsy specimens of rectal mucosa and the specimens were assessed for histological disease activity. The patients were then followed until relapse or for a maximum of 12 months. Multivariate survival analysis was carried out to determine the independent predictors of clinical relapse.
Results
A positive correlation was identified between MCS grade, histological grade (p = 0.001) and mucosal IL8 activity (p<0.001). Multivariate proportional hazard model analysis showed that MCS grade was a significant predictor of relapse (relative risk 2.06, p = 0.001). Kaplan–Meier estimate of relapse during 12 months of follow‐up was found to increase with increasing MCS grade, with values of 0% for grade 1, 21% for grade 2, 43% for grade 3 and 60% for grade 4.
Conclusion
MCS grading is associated with the degree of histological inflammation and mucosal IL8 activity in patients with quiescent ulcerative colitis, and may predict the probability of subsequent disease relapse in patients with ulcerative colitis in remission.
Ulcerative colitis is a chronic inflammatory bowel disorder characterised by exacerbations and remissions. Endoscopic study is an important means of assessing the severity of ulcerative colitis and predicting the efficacy of treatment.1 Although the degree of inflammation as assessed by routine colonoscopy is a reliable parameter of disease activity, discrepancies between colonoscopic appearance and histopathological abnormalities are sometimes seen in patients with clinically inactive disease. Even when routine colonoscopy suggests remission and a normal mucosal appearance, microscopic abnormalities may persist2,3 and relapse may occur later.4
A recently developed high‐resolution video‐magnifying colonoscope has enabled the observation of pit patterns on the surface of the colorectal mucosa. This in turn allows an understanding of the morphological relationship between the pit patterns detected colonoscopically and the crypts observed histopathologically.5,6,7,8,9 The purpose of this technology is to provide an in vivo optical biopsy that can be used at the time of colonoscopy to enhance diagnostic precision and guide subsequent therapeutic strategies. In particular, a magnified view of the diseased colon and rectum may be useful in predicting exacerbations of the disease and in deciding whether medical treatment should be maintained. As far back as 1980, Poulsen et al10 examined biopsy specimens from the rectal mucosa of patients with ulcerative colitis under a stereomicroscope and found microstructural abnormalities in the mucosal surface in almost every patient, as well as a close correlation between stereomicroscopic features and clinical disease activity, sigmoidoscopic findings and histological activity of the disease.
Among other activities, cytokines have a role in modulating the immunopathogenesis of inflammatory bowel disease (IBD), such as ulcerative colitis and Crohn's disease, and are rapidly synthesised and secreted by inflammatory cells.11,12 Interleukin (IL) 1, IL6, IL8, tumour necrosis factor α and growth‐related gene product α have all been described as major factors increasing the inflammatory response in intestinal tissue in patients with IBD.11,12,13,14 Recent studies15,16,17,18,19 have shown that cytokine measurement can detect subtle but ongoing escalation of the inflammatory process in the mucosa of patients with IBD before clinical symptoms and endoscopic inflammation are apparent.
To help more accurately identify disease activity in patients with ulcerative colitis with clinically inactive disease, we examined pit patterns in the rectal mucosa with a high‐resolution video‐magnifying colonoscope after spraying with methylene blue and compared the findings with laboratory test results for inflammation, histopathological findings and mucosal IL8 activity. We also prospectively analysed prognostic factors that might predict exacerbations in patients with ulcerative colitis, including the pit patterns observed with high‐resolution video‐magnifying colonoscopy.
Materials and methods
Participants
The study was conducted according to a prospective design in patients with clinically inactive ulcerative colitis, who underwent high‐resolution video‐magnifying colonoscopy (EC‐410CM; Fujinon, Saitama, Japan) at the Department of Gastroenterology, Nagoya University Graduate School of Medicine, Nagoya, Japan, between March 1995 and April 2000. Clinical disease activity was assessed in each patient by the ulcerative colitis disease activity index (DAI) score covering four items, each scored from 0 to 3—namely, stool frequency, stool blood, endoscopic severity and overall well‐being.20 In accordance with the definition of Oren et al,21 DAI scores of ⩽3 were judged to represent clinical remission. Only patients with an inactive mucosal appearance, obscure vascular patterns, granularity of the mucosa or erythema on routine high‐resolution video‐colonoscopic examination (EC‐410HM; Fujinon) were included, whereas those with contact bleeding, spontaneous bleeding, erosions or ulceration were excluded. Moreover, patients who were on immunosuppressant treatment or had a higher degree of inflammation at the proximal colon were excluded. Ulcerative colitis was diagnosed in all patients on the basis of previous colonoscopic and histopathological examinations with unequivocal features of active ulcerative colitis including the rectum. Informed consent was obtained from all patients in accordance with the Helsinki Declaration.
High‐resolution video‐magnifying colonoscopy
Each patient was pretreated with an oral agent for bowel cleansing—ie, 2 l of polyethylene glycol. After examination of the entire bowel by conventional colonoscopy, mucus was completely removed from the rectum by sufficient irrigation with water, and 20–30 ml of 0.1% methylene blue was sprayed over the mucosa. The colonoscope was removed, and the patient's posture was altered repeatedly between prone and supine for 5 min. A high‐resolution video‐magnifying colonoscope with a fixed focus (Fujinon EC410CM) was then inserted, and the pit pattern of the rectal mucosa and methylene blue staining were recorded. The patterns were classified into the following four magnifying colonoscopy (MCS) grades on the basis of the size, shape and arrangement of the pits (fig 1).
Figure 1 Grading of pit structures in the colorectal mucosa of patients with inactive ulcerative colitis. (A) Magnifying colonoscopy (MCS) grade 1: pits small, round and regularly arranged. (B) MCS grade 2: pits rather large, oval and somewhat irregular in arrangement. (C) MCS grade 3: pits of various shapes and sizes and irregularly arranged. (D) MCS grade 4: dispersed pits varying in morphology associated with the presence of small erosions.
Grade 1: pits small, round and regularly arranged (fig 1A).
Grade 2: pits rather large, oval and somewhat irregular in arrangement (fig 1B).
Grade 3: pits of various shapes and sizes and irregularly arranged (fig 1C).
Grade 4: dispersed pits varying in morphology, associated with the presence of small erosions (fig 1D).
When the characteristics of more than one grade were present in the same patient, the higher grade was recorded.
When κ coefficients were calculated to examine the degree of agreement between readers on MCS grade, preliminary study confirmed that the intraobserver and interobserver coefficients for MCS grade were 0.89 and 0.79, respectively. There was no discordance of ⩾2 MCS grades in either intraobserver or interobserver agreement.
Laboratory test and histological disease activity
Blood samples were obtained immediately before colonoscopy; white cell count (WBC), C reactive protein (CRP) and erythrocyte sedimentation rate (ESR) were examined as laboratory test parameters of disease activity.
Under colonoscopic guidance, the biopsy specimens used for organ culture and microscopic examination were obtained by targeted biopsy of the rectal area where MCS grade was recorded to investigate the precise correlation among MCS grade, the degree of histological inflammation and mucosal IL8 activity. A pathologist who was blinded to the patient's clinical data and the results of pit patterns assessed histological disease activity by classifying haematoxylin–eosin preparations of specimens into five grades by Riley's method.22 The scores included grade 0, normal; grade 1, mild increase in chronic inflammatory cell infiltrate and no tissue destruction; grade 2, moderate increase in chronic inflammatory cell infiltrate and no tissue destruction; grade 3, marked increase in chronic inflammatory cell infiltrate and mild tissue destruction; and grade 4, marked increase in chronic inflammatory cell infiltrate and obvious tissue destruction. In a preliminary study, in a subgroup of 12 patients, we carried out detailed high‐magnification chromoendoscopy and localised the spot with highest MCS grade. This spot was then biopsied in duplicate for assessment of histological grade. We found that the histological grades in the paired biopsies in 11 of the 12 patients (92%) were identical, whereas in the remaining patient the histological grades were discordant by only one grade. This result indicated that a single biopsy was a good representative of the state of mucosal inflammation in patients with quiescent ulcerative colitis, certainly when localised by MCS.
Organ culture and IL8 assay
Colonic biopsy tissues were cultured on a culture insert as described previously.23 IL8 content in the culture supernatant was measured in duplicate by an ELISA (TFB, Tokyo, Japan) in accordance with the manufacturer's instructions.24 The amount of IL8 secreted in the organ cultures was expressed relative to protein content in the biopsy tissue homogenate (pg/mg biopsy protein).
Follow‐up
Patients were followed up at 4‐week intervals until relapse or for a maximum of 12 months after the start of the study, whichever came first. DAI score was assessed at each visit. Following the definition of Oren et al,21 relapse was diagnosed if the score increased by ⩾3 points compared with that at the time of magnifying colonoscopic examination.
Statistical analysis
Correlations of MCS grade with clinical profiles, laboratory test parameters, histological disease activity and mucosal chemokine activity were analysed by Spearman's rank correlation test. The Kruskal–Wallis test was used for comparisons of patients with and without relapse in regard to discrete variables such as disease extent. Prognostic factors affecting relapse were initially examined using a univariate proportional hazards model, after which multivariate analysis was carried out to adjust for potential confounders. Time‐to‐relapse curves after the magnifying colonoscopic examination were estimated by the Kaplan–Meier method, and statistical significance was determined using the log rank test. Two‐sided p values are reported, and significance was set at a value of p⩽0.05.
Results
Patients
A total of 113 patients comprising 64 men and 49 women with age at entry ranging from 18 to 82 years, fulfilled the inclusion criteria. A total of 48 patients had total colitis, 39 had left‐sided colitis and 26 had proctitis. Mean duration of disease was 7.0 years (range 0.3–26.7 years). At the start of the study, 48 patients were receiving sulfasalazine alone (1.0–3.0 g/day), 14 were receiving 5‐amino salicylic acid alone (1.0–2.25 g/day), 10 were receiving prednisolone alone (5–15 mg/day), 18 were being treated with prednisolone (2.5–20 mg/day) and sulfasalazine (1.0–4.0 g/day), and 12 with 5‐amino salicylic acid (1.5–2.25 g/day) and 11 were not receiving any specific drugs. Change in treatment such as a decrease in the dosage of prednisolone, was permitted for any patient, at the discretion of the attending doctor who knew the MCS grade after the start of the study.
MCS grade
The duration of examination for magnifying endoscopy and pit scoring was generally <5 min/case. Of the 113 patients, 19 were MCS grade 1, 44 were grade 2, 35 were grade 3 and 15 were grade 4. No differences in grade were seen by sex, age, total duration of disease or disease extent (table 1). Moreover, there was no relationship between MCS grade and drug treatment (data not shown). The mucosa in the grade 1 and 2 cases had a greater dye affinity for methylene blue than in the grade 3 and 4 cases, suggesting that dye endoscopy using methylene blue allows estimation of the degree of repair of the colonic epithelium. No significant differences were found in WBC, CRP or ESR values by MCS grade (table 2).
Table 1 Patient characteristics and clinical profile by magnifying colonoscopy profile.
| MCS grade | Sex (M/F) | Age* (years) | Disease duration* (years) | Disease extent total/left‐sided/proctitis |
|---|---|---|---|---|
| 1, n = 19 | 14/5 | 34.4 (20–61) | 5.3 (0.6–13.2) | 8/5/6 |
| 2, n = 44 | 26/18 | 38.1 (18–82) | 6.3 (3.4–26.7) | 22/14/8 |
| 3, n = 35 | 19/16 | 39.9 (22–69) | 8.8 (0.3–22.2) | 13/14/8 |
| 4, n = 15 | 5/10 | 38.2 (18–68) | 6.4 (1.2–15.2) | 5/6/4 |
F, female; M, male; MCS, magnifying colonoscopy.
*Values are means (ranges).
Table 2 Haematological parameters by magnifying colonoscopy grade.
| MCS grade | WBC (×103/μl) | CRP (mg/dl) | ESR (mm/h) |
|---|---|---|---|
| 1, n = 19 | 5.80 (4.00–9.60) | 0 (0–2.8) | 5 (0–53) |
| 2, n = 44 | 5.35 (5.90–10.40) | 0.1 (0–2.8) | 4 (1–80) |
| 3, n = 35 | 6.50 (2.80–16.00) | 0.1 (0–2.2) | 6 (1–71) |
| 4, n = 15 | 6.70 (1.40–13.60) | 0.1 (0–1.4) | 9 (1–14) |
CRP, C reactive protein; ESR, erythrocyte sedimentation rate; MCS, magnifying colonoscopy; WBC, white cell count.
Values are medians (ranges).
Histopathology
When MCS grades were compared according to the histological grade, histological disease activity was found to increase with increasing MCS grade (p = 0.001; table 3). The severity of monocyte and neutrophil infiltration into the lamina propria also increased with MCS grade (data not shown). MCS grade in patients with ulcerative colitis in remission thus reflected histological ulcerative colitis activity well, indicating that it provides greater accuracy in the determination of ulcerative colitis remission status than conventional colonoscopy.
Table 3 Histological activity according to Riley's histological grade by magnifying colonoscopy grade.
| MCS grade | Histological grade | ||||
|---|---|---|---|---|---|
| 0 | 1 | 2 | 3 | 4 | |
| 1, n = 19 | 2 | 9 | 7 | 1 | 0 |
| 2, n = 44 | 1 | 16 | 22 | 5 | 0 |
| 3, n = 35 | 0 | 8 | 19 | 8 | 0 |
| 4, n = 15 | 0 | 2 | 7 | 4 | 2 |
MCS, magnifying colonoscopy.
p = 0.001 (Spearman's rank test).
IL8 activity
MCS grade showed a positive correlation with mucosal IL8 activity in organ cultures of colonoscopic biopsy specimens from patients with ulcerative colitis with quiescent disease (table 4), and thus reflected activity of chemokines such as IL8 in the rectal mucosa of patients with ulcerative colitis in remission. Mucosal IL8 activity also showed a positive correlation with the histological grade (p = 0.014).
Table 4 Comparison of mucosal interleukin 8 activity with magnifying colonoscopy grades.
| MCS grade | Mucosal IL8 activity (pg/mg protein) |
|---|---|
| 1, n = 19 | 25 (5–86) |
| 2, n = 44 | 33 (2–165) |
| 3, n = 35 | 54 (9–277) |
| 4, n = 15 | 85 (1–197) |
IL8, interleukin 8; MCS, magnifying colonoscopy
Values are median (range).
p<0.001 (Spearman's rank test).
Ulcerative colitis relapse rate
Follow‐up for at least 12 months after the start of the study was possible in all patients. During the study, 33 (29.2%) patients relapsed, with a mean time to relapse of 6.8 months (range 1–12 months). When hazard ratios (HR), 95% confidence intervals (CI), and p values for clinical profile, MCS grade, haematological parameters, mucosal IL8 activity and histological grade were calculated, WBC (relative risk (RR) 1.14, 95% CI 1.00 to 1.29, p = 0.047), the HR of MCS grades (RR 2.31, 95% CI 1.56 to 3.41, p<0.001) and mucosal IL8 activity (RR 1.01, 95% CI 1.00 to 1.01, p = 0.004) were found to show a significant association with relapse. In contrast, no influence on relapse was seen for clinical profile, ESR, CRP or histological grade (table 5). Multivariate analysis showed a significant relationship between MCS grade and relapse (RR 2.06, 95% CI 1.34 to 3.17, p = 0.001), but not between relapse and WBC or mucosal IL8 activity (table 6). In addition, when the relationship between MCS grade and relapse rate at 12 months after MCS was assessed by the Kaplan–Meier method, the relapse rate was found to increase with increasing grade, with rates of 0% (0/19) for grade 1, 21% (9/44) for grade 2, 43% (15/35) for grade 3 and 60% (9/15) for grade 4 (fig 2). On the other hand, the relapse rate showed no significant difference between those receiving prednisolone and other patients, with rates of 0% (0/4) and 0% (0/15) for grade 1, 36% (4/11) and 15% (5/33) for grade 2, 53% (9/17) and 33% (6/18) for grade 3 and 63% (5/8) and 57% (4/7) for grade 4, respectively. Moreover, relapse was significantly more frequent in the MCF grade 3 and 4 patients (24/50, 48.0%) than in those with grades 1 and 2 (9/63, 14.3%, p<0.001), and was also significantly more frequent in the MCF grade 3 and 4 patients (6/27, 54.2%) than in those with grades 1 and 2 (13/24, 22.2%, p = 0.02) when analysis was limited to patients with a reduction in therapeutic drugs such as prednisolone after the start of the study.
Table 5 Prognostic factors for relapse by a univariate proportional hazard model.
| Non‐relapse | Relapse | HR (95% CI) | p Value | |
|---|---|---|---|---|
| n | 80 | 33 | ||
| Sex (M:F) | 64:49 | 14:19 | 1.96 (0.98 to 3.92) | 0.06 |
| Mean age (years) | 38.4 | 37.2 | 1.00 (0.97 to 1.02) | 0.70 |
| Disease duration (years) | 7.0 | 6.8 | 1.00 (0.99 to 1.00) | 0.78 |
| Disease extent | NS* | |||
| Proctitis | 19 | 7 | 1 | |
| Left‐sided colitis | 39 | 48 | 1.10 (0.43 to 2.80) | 0.84 |
| Total colitis | 34 | 14 | 1.09 (0.44 to 2.71) | 0.84 |
| WBC (×103/μl) | 6.10 | 7.13 | 1.14 (1.00 to 1.29) | 0.047 |
| CRP (mg/dl) | 0.20 | 0.16 | 0.73 (0.25 to 2.17) | 0.57 |
| ESR (mm/h) | 9 | 10 | 1.00 (0.98 to 1.03) | 0.74 |
| MCS grade | 2.31 (1.56 to 3.41) | <0.001 | ||
| Grade 1 | 19 | 0 | ||
| Grade 2 | 35 | 9 | ||
| Grade 3 | 20 | 15 | ||
| Grade 4 | 6 | 9 | ||
| Histological grade | 1.49 (0.99 to 2.26) | 0.058 | ||
| 0 | 3 | 0 | ||
| 1 | 30 | 5 | ||
| 2 | 33 | 22 | ||
| 3 | 13 | 5 | ||
| 4 | 1 | 1 | ||
| Mucosal IL8 activity (ng/mg protein) | 46.9 | 74.2 | 1.01 (1.00 to 1.01) | 0.004 |
CRP, C reactive protein; ESR, erythrocyte sedimentation rate; F, female; IL, interleukin; M, male; MCS, magnifying colonoscopy; WBC, white cell count.
*Calculated by Kruskal–Wallis test for censored data (p = 0.95).
Table 6 Prognostic factors for relapse by a multivariate proportional hazard model.
| HR (95% CI) | p Value | |
|---|---|---|
| WBC (×103/μl) | 1.07 (0.94 to 1.20) | 0.31 |
| MCS grade | 2.06 (1.534 to 3.17) | 0.001 |
| Mucosal IL8 activity (ng/mg protein) | 1.00 (0.94 to 1.20) | 0.24 |
MCS, magnifying colonoscopy; WBC, white cell count.
Figure 2 Kaplan–Meier survival analysis showing the cumulative proportion of patients who had a relapse according to magnifying colonoscopy (MCS) grade group.
Discussion
We performed magnifying colonoscopy using methylene blue spray in patients with ulcerative colitis in remission, and classified pit patterns in the rectal mucosa into four grades on the basis of the size, shape and arrangement of the pits. The term “pit” refers to the orifices of the colorectal crypts, and the “pit pattern” is the specific arrangement of the opening of the crypt. In patients with ulcerative colitis, pit pattern may be influenced by the process of destruction and regeneration of glandular ducts. Dye endoscopy with methylene blue has the advantage that the dye is absorbed by the colonic epithelial cells, making the pit pattern more distinct, and staining intensity reflects the absorption ability of the mucosal epithelium.25 Kiesslich et al7 showed that chromoendoscopy using methylene blue permits more accurate diagnosis of the extent and severity of inflammatory activity in ulcerative colitis than conventional colonoscopy. This method thus seemed to offer promise in evaluation of the degree of epithelial cell injury. Given that ulcerative colitis is a chronic inflammatory disease which mainly involves the colonic mucosal surface in continuous areas from the rectum, assessment of ulcerative colitis activity by observation of pit pattern was considered a rational means of judging the disease stage.
Various attempts have long been made to observe the magnified features of the gastrointestinal mucosa by stereomicroscopy of resected specimens. In 1980, Poulsen et al10 compared colonoscopic findings in patients with ulcerative colitis with stereomicroscopic findings in biopsy specimens and found a close correlation between the number of crypt openings and clinical disease activity. Recent advances in high‐resolution video‐magnifying colonoscopes have enabled observation of the surface microstructure of colorectal mucosa, with results approaching the diagnostic capability of the stereomicroscope.26 Moreover, magnifying colonoscopy with chromoscopy helps to detect dysplasia and colitic cancer in patients with longstanding ulcerative colitis.7,27 On the other hand, the diagnostic ability of the magnifying colonoscope in histological disease activity has been confirmed in patients with both inactive and active ulcerative colitis, and furthermore, use of the high‐resolution video colonoscope facilitates the differentiation of quiescent from inflamed mucosa.7,28,29,30 Moreover, it is not unusual for routine colonoscopy performed to assess the stage of ulcerative colitis to show quiescent colitis despite the histological persistence of inflammation,2,3,31 which later results in the relapse of colonic inflammation.4
Here, to determine the predictability of relapse in ulcerative colitis, we examined four grades of pit pattern in the rectal mucosa under a magnifying colonoscope in patients with ulcerative colitis in clinically and colonoscopically diagnosed remission. Results showed that the MCS grades used not only correlated well with histopathological activity but also reflected the mucosal chemokine activity of the rectal mucosa in these patients. In addition, whereas histopathological assessment by biopsy alone leads to diagnosis based on lesions at a single site, observation of magnified features allows diagnosis over an extensive area of mucosa.
Chemokines are deeply involved in the pathogenesis of ulcerative colitis. IL8, a member of the α‐chemokine subfamily, attracts and activates primarily neutrophils, and increase in IL8 activity is in fact a well‐known phenomenon in patients with ulcerative colitis.32,33 Given the association of mucosal IL8 activity with the degree of mucosal inflammation in ulcerative colitis,13,14 IL8 activity may be a useful factor in predicting the clinical course in patients who achieve remission. Yamamoto et al19 reported that mucosal IL8 levels could predict future exacerbations of ulcerative colitis. We examined the association of mucosal pit patterns as assessed by MCS with mucosal IL8 activity, and also evaluated whether this chemokine is able to predict disease relapse in patients with ulcerative colitis. Results showed that mucosal IL8 activity correlated positively with MCS grade, but that it is a less useful predictor of disease relapse than MCS grade.
In patients with ulcerative colitis in remission, stratification according to relapse risk seems useful in determining maintenance treatment, particularly for those identified at high risk. Although several prospective studies have investigated the risk factors for relapse using various modalities and examinations,4,19,34,35,36,37 no reliable predictor has yet been identified. Here, we assessed the degree of inflammation in the mucosa of patients with inactive ulcerative colitis by MCS with chromoscopy and prospectively identified factors predictive of relapse. Multivariate analysis showed that MCS grade was a significant independent predictor of relapse for 12 months after colonoscopy. Particularly, early relapse within 6 months was frequent in grade 3 and 4 cases, with rates at this time of 0% for grade 1, 9.1% for grade 2, 17.1% for grade 3 and 26.7% for grade 4. These findings indicate the need for care in any reduction in therapeutic drugs such as prednisolone and 5‐amino salicylic acid in patients with MCS grade 3 or 4 pits.
We classified pit patterns in the rectal mucosa into four MCS grades on the basis of size, shape and arrangement. When pit patterns were classified into two grades by combination—namely, MCS grade 1+2 and 3+4—this grading provided significant independent prediction of relapse for 12 months (RR 3.11, 95% CI 1.31 to 7.42, p = 0.01). However, when attention was restricted to patients with MCS grade 1 or 2, no relapse was seen within 12 months in the MCS grade 1 patients, although more than a few (21%) patients relapsed in the MCS grade 2 group. Moreover, the mode value of histological disease activity in the MCS grade 1 patients was in discord with that in the MCS grade 2 patients (histological grade 1 v 2). On the other hand, when attention was focused on patients in the MCS grade 3 and 4 groups, more than half (60%) of the grade 4 patients relapsed within 12 months, whereas less than half (43%) of the grade 3 patients did so. We therefore consider our four MCS grades to provide adequate classification for the inflammation of the rectal mucosa and prediction of relapse in patients with ulcerative colitis in remission.
Although MCS grade positively correlated with histological grade and mucosal IL8 activity, the mucosal IL8 activity parameters were less accurate predictors of disease relapse, possibly because they are assessed in biopsy specimens derived from a specific and limited area. On the other hand, magnifying colonoscopy allows the observation of a more extended and representative area of colorectal mucosa and hence has greater accuracy by MCS grading.
In conclusion, the results of our study indicate that MCS grading based on observation of the colonic mucosa by MCS in patients with ulcerative colitis in remission reflects histological disease activity, and that MCS is a useful tool in predicting the relapse of ulcerative colitis.
Abbreviations
CRP - C reactive protein
DAI - disease activity index
ESR - erythrocyte sedimentation rate
IBD - inflammatory bowel disease
MCS - magnifying colonoscopy
WBC - white cell count
Footnotes
Competing interests: None.
References
- 1.Ando T, Watanabe O, Furuta R.et al Predictors of a response to cyclosporine or leukocyte removal therapy in patients with refractory ulcerative colitis. Dig Endosc 200517153–158. [Google Scholar]
- 2.Matts S G. The value of rectal biopsy in the diagnosis of ulcerative colitis. QJM 196130393–407. [PubMed] [Google Scholar]
- 3.Powell‐Tuck J, Day D W, Buckell N A.et al Correlation between defined sigmoidoscopic appearances and other measures of disease activity in ulcerative colitis. Dig Dis Sci 198227533–537. [DOI] [PubMed] [Google Scholar]
- 4.Riley S A, Mani V, Goodman M J.et al Microscopic activity in ulcerative colitis: what does it mean? Gut 199132174–178. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Kudo S, Rubio C A, Teixeira C R.et al Pit pattern in colorectal neoplasia: endoscopic magnifying view. Endoscopy 200133367–373. [DOI] [PubMed] [Google Scholar]
- 6.Kato S, Fujii T, Koba I.et al Assessment of colorectal lesions using magnifying colonoscopy and mucosal dye spraying: can significant lesions be distinguished? Endoscopy 200133306–310. [DOI] [PubMed] [Google Scholar]
- 7.Kiesslich R, Fritsch J, Holtmann M.et al Methylene blue‐aided chromoendoscopy for the detection of intraepithelial neoplasia and colon cancer in ulcerative colitis. Gastroenterology 2003124880–888. [DOI] [PubMed] [Google Scholar]
- 8.Hurlstone D P, Cross S S, Adam I.et al Efficacy of high magnification chromoscopic colonoscopy for the diagnosis of neoplasia in flat and depressed lesions of the colorectum: a prospective analysis. Gut 200453284–290. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Hurlstone D P, Cross S S. Role of aberrant crypt foci detected using high‐magnification‐chromoscopic colonoscopy in human colorectal carcinogenesis. J Gastroenterol Hepatol 200520173–181. [DOI] [PubMed] [Google Scholar]
- 10.Poulsen S S, Christensen K C, Petri M.et al Stereomicroscopic examination of stained rectal biopsies in ulcerative colitis and Crohn's disease. Scand J Gastroenterol 198015535–544. [DOI] [PubMed] [Google Scholar]
- 11.MacDermott R P. Alterations of the mucosal immune system in inflammatory bowel disease. J Gastroenterol 199631907–916. [DOI] [PubMed] [Google Scholar]
- 12.Rogler G, Andus T. Cytokines in inflammatory bowel disease. World J Surg 199822382–389. [DOI] [PubMed] [Google Scholar]
- 13.Ina K, Kusugami K, Yamaguchi T.et al Mucosal interleukin‐8 is involved in neutrophil migration and binding to extracellular matrix in inflammatory bowel disease. Am J Gastroenterol 1997921342–1346. [PubMed] [Google Scholar]
- 14.Imada A, Ina K, Shimada M.et al Coordinate upregulation of interleukin‐8 and growth‐related gene product‐α is present in the colonic mucosa of inflammatory bowel disease. Scand J Gastroenterol 200136854–864. [DOI] [PubMed] [Google Scholar]
- 15.Schreiber S, Nikolaus S, Hampe J.et al Tumor necrosis factor α and interleukin 1β in relapse of Crohn's disease. Lancet 1999353459–461. [DOI] [PubMed] [Google Scholar]
- 16.Arnott I D R, Drummond H E, Ghosh S. Gut mucosal secretion of interleukin 1β and interleukin‐8 predicts relapse in clinically inactive Crohn's disease. Dig Dis Sci 200146402–409. [DOI] [PubMed] [Google Scholar]
- 17.Meresse B, Rutgeerts P, Malchow H.et al Low ileal interleukin 10 concentrations are predictive of endoscopic recurrence in patients with Crohn's disease. Gut 20025025–28. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Yamamoto T, Umegae S, Kitagawa T.et al Mucosal cytokine production during remission after resection for Crohn's disease and its relationship to future relapse. Aliment Pharmacol Ther 200419671–678. [DOI] [PubMed] [Google Scholar]
- 19.Yamamoto T, Umegae S, Kitagawa T.et al Systemic and local cytokine production in quiescent ulcerative colitis and its relationship to future relapse: a prospective, pilot study. Inflamm Bowel Dis 200511589–596. [DOI] [PubMed] [Google Scholar]
- 20.Sandborn W J, Tremaine W J, Schroeder K W.et al Cyclosporine enemas for treatment‐resistant, mildly to moderately active, left‐sided ulcerative colitis. Am J Gastroenterol 199388640–645. [PubMed] [Google Scholar]
- 21.Oren R, Arber N, Odes S.et al Methotrexate in chronic active ulcerative colitis: a double‐blind, randomized, Israeli multicenter trial. Gastroenterology 19961101416–1421. [DOI] [PubMed] [Google Scholar]
- 22.Riley S A, Mani V, Goodman M J.et al Comparison of delayed release 5‐aminosalicylic acid (mesalazine) and sulphasalazine in the treatment of mild to moderate ulcerative colitis relapse. Gut 198829669–674. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Kusugami K, Fukatsu A, Tanimoto M.et al Elevation of interleukin‐6 in inflammatory bowel disease is macrophage‐ and epithelial cell‐dependent. Dig Dis Sci 199540949–959. [DOI] [PubMed] [Google Scholar]
- 24.Ando T, Kusugami K, Ohsuga M.et al Interleukin‐8 activity correlates with histological severity in Helicobacter pylori‐associated antral gastritis. Am J Gastroenterol 1996911150–1156. [PubMed] [Google Scholar]
- 25.Tada M, Katoh S, Kohli Y.et al On the dye spraying method in colonofiberscopy. Endoscopy 1977870–74. [DOI] [PubMed] [Google Scholar]
- 26.Kudo S, Hirota S, Nakajima T.et al Colorectal tumors and pit pattern. J Clin Pathol 199447880–885. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Sada M, Igarashi M, Yoshizawa S.et al Dye spraying and magnifying endoscopy for dysplasia and cancer surveillance in ulcerative colitis. Dis Colon Rectum 2004471816–1823. [DOI] [PubMed] [Google Scholar]
- 28.Matsumoto T, Kuroki F, Mizuno M.et al Application of magnifying chromoscopy for the assessment of severity in patients with mild to moderate ulcerative colitis. Gastrointest Endosc 199746400–405. [DOI] [PubMed] [Google Scholar]
- 29.Fujiya M, Saitoh Y, Nomura M.et al Minute findings by magnifying colonoscopy are useful for the evaluation of ulcerative colitis. Gastrointest Endosc 200256535–542. [DOI] [PubMed] [Google Scholar]
- 30.Kunihiro M, Tanaka S, Sumii M.et al Magnifying colonoscopic features of ulcerative colitis reflect histologic inflammation. Inflamm Bowel Dis 200410737–744. [DOI] [PubMed] [Google Scholar]
- 31.Kleer C G, Appelman H D. Ulcerative colitis: patterns of involvement in colorectal biopsies and changes with time. Am J Surg Pathol 199822983–989. [DOI] [PubMed] [Google Scholar]
- 32.Mahida Y R, Ceska M, Effenberger F.et al Enhanced synthesis of neutrophil‐activating peptide‐1/interleukin‐8 in active ulcerative colitis. Clin Sci 199282273–275. [DOI] [PubMed] [Google Scholar]
- 33.Mazzucchelli L, Hauzer C, Zgraggen K.et al Expression of interleukin‐8 gene in inflammatory bowel disease is related to the histological grade of active inflammation. Am J Pathol 1994144997–1007. [PMC free article] [PubMed] [Google Scholar]
- 34.Ludwig D, Wiener S, Brüning A.et al Mesenteric blood flow is related to disease activity and risk of relapse in ulcerative colitis: a prospective follow up study. Gut 199945546–552. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 35.Tibble J A, Sigthorsson G, Bridger S.et al Surrogate markers of intestinal inflammation are predictive of relapse in patients with inflammatory bowel disease. Gastroenterology 200011915–22. [DOI] [PubMed] [Google Scholar]
- 36.Bitton A, Peppercorn M A, Antonioli D A.et al Clinical, biological, and histologic parameters as predictors of relapse in ulcerative colitis. Gastroenterology 200112013–20. [DOI] [PubMed] [Google Scholar]
- 37.Higaki S, Nohara H, Saitoh Y.et al Increased rectal wall thickness may predict relapse in ulcerative colitis: a pilot follow‐up study by ultrasonographic colonoscopy. Endoscopy 200234212–219. [DOI] [PubMed] [Google Scholar]