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Keywords:

  • inflammatory bowel disease;
  • mucosal inflammation;
  • clinical remission

Abstract

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

Background:

Management of inflammatory bowel disease (IBD) is increasingly focused on mucosal remission. We assessed the prevalence of mucosal inflammation during clinical remission, the clinical consequences, and the impact on disease course.

Methods:

IBD patients from two referral centers who underwent a surveillance colonoscopy while clinically in remission between January 2001 and December 2003 were included. Follow-up ended May 1, 2009. Clinical data were collected from patient charts. Statistical analysis was performed using independent t-tests and nonparametric tests.

Results:

In total, 152 IBD patients were included (98 [65%] ulcerative colitis, 46 [30%] Crohn's disease; 85 [56%] males). Median follow-up was 6.8 years (interquartile range [IQR] 6–8). Forty-seven (31%) patients had no signs of inflammation during endoscopy (group A). Of the remaining 105 (68%) patients, 51 (49%) had both endoscopic and histological inflammation (group B), 51 (49%) histological inflammation only (group C), two (2%) endoscopic lesions only (group D). Two years later, 29% of all patients had endoscopic inflammation and another 27% had only microscopic inflammation. In 39% the inflammation had resolved spontaneously. Inflammation was more often found in group B+C (n = 62/102; 61%) than in group A (n = 17/47; 36%; P = 0.21). Inflammation was not associated with more frequent clinical relapses nor with stricture formation, nor with the need for surgery.

Conclusions:

A large proportion of IBD patients have mucosal inflammation without clinical symptoms. Although one-third recover spontaneously, mucosal inflammation in patients who are clinically in remission is associated with more severe mucosal disease activity, but not with more complications or symptomatic flares during follow-up. (Inflamm Bowel Dis 2012)

In patients with inflammatory bowel disease (IBD) clinical symptoms are not an accurate measurement for mucosal disease activity.1, 2 Recently, it was demonstrated that the clinical Crohn's Disease Activity Index (CDAI) correlates poorly (40%) with the findings of disease activity during endoscopy.2

Mucosal remission has been observed after treatment with traditional immunosuppressive agents and with antitumor necrosis factor (TNF) agents.3, 4 It is considered an important parameter in the individual follow-up of patients to guide treatment and to prevent long-term complications.4, 5 In patients with early stage CD mucosal remission has been associated with significantly higher steroid-free remission rates 4 years after start of therapy and with the development of fewer fistulas.6 Moreover, in ulcerative colitis (UC) patients it has been found to be a strong predictor of less surgery and subsequent complications after 1 year of surgery.7

However, data are lacking on the prevalence of mucosal inflammation in patients in clinical remission, the implications for clinical practice, and the associated disease course. We therefore aimed to assess the prevalence and severity of endoscopic and histological inflammation in IBD patients in clinical remission, the therapeutic decisions following this finding, and the consequences of these decisions on the disease course.

MATERIALS AND METHODS

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

Study Population

All IBD patients who underwent a surveillance colonoscopy in the Erasmus Medical Center, Rotterdam and the University Medical Center Utrecht, The Netherlands between January 2001 and December 2003, were identified. Surveillance colonoscopies were defined as colonoscopies in which two to four random biopsy specimens every 10 cm from the entire colon with additional samples of suspicious areas were taken.8, 9 Patients were followed up until May 1, 2009. Inclusion criteria were: a diagnosis of IBD, as verified by endoscopy, histology, or radiology.10, 11 Patients had to be in clinical remission for at least a month before endoscopy. No clinical remission (clinical activity) was defined as having one of the following symptoms: abdominal pain, diarrhea, blood loss, fever, weight loss, and/or a physician global assessment of clinical disease activity.

Outcome Parameters

The primary outcome was the prevalence and severity of mucosal inflammation in IBD patients in clinical remission. Secondary outcomes were the therapeutic strategies following a colonoscopy and the impact of endoscopic and histological disease activity on the course of disease during follow-up. We distinguished between endoscopic and histological inflammation to assess any disparities with regard to treatment strategy and course of disease.

Data Extraction

Detailed clinical data were collected from patient charts, endoscopy reports, and pathology reports. The clinical data included: type of IBD, age, gender, date of IBD diagnosis, date of onset symptoms attributable to IBD, extent and severity of disease, history of colonic surgery, presence of concomitant primary sclerosing cholangitis (PSC), time of diagnosis of PSC, use of medication, and surveillance details. The complete medical history was assessed, including prior colonoscopies and pathology reports. Symptoms and relapses at 1 month and 1 year prior to surveillance colonoscopy were noted as well as any change in treatment policy after surveillance colonoscopy. In addition, clinical details during follow-up including comorbidity and concomitant dysplasia or colorectal carcinoma (CRC) were recorded. Extent of disease was subdivided into six categories based on type and extent of inflammation: left-sided UC, extensive UC, limited CD, extensive CD, limited unclassified colitis, or extensive unclassified colitis. Extensive UC was defined as colitis beyond the splenic flexure. Limited CD was defined as <50% segmental colonic disease activity including those with terminal ileitis or ileocecal inflammation. Extensive CD was defined as involvement of >50% of the colonic surface. Severity of disease was graded as absent, mild, moderate, or severe colitis or ileitis based on both histological and endoscopic features. Endoscopic severity of disease was scored according to the four-point Mayo score as recommended by the most recent guideline for surveillance colonoscopies12: 0, normal; 1, mild disease (erythema, decreased vascular pattern, mild friability, no contact bleeding); 2, moderate disease (marked erythema, absent vascular pattern, friability, erosions, contact bleeding); 3, severe disease (spontaneous bleeding, ulceration). Histological severity of disease was scored accordingly on a four-point scale: 0, no active histological disease activity; 1, mild active inflammation (cryptitis, but no crypt abscesses); 2, moderate active inflammation (few crypt abscesses); 3, severe active inflammation (numerous crypt abscesses).

Duration of medication use during follow-up was divided into four categories (0%–25%, 25%–50%, 50%–75%, >75% of duration of follow-up). A relapse was defined as: recurrence of inflammation confirmed by endoscopy or by any other imaging tool, or an increase of complaints that required hospitalization, surgery, or adjustment of medication. The latter was defined as increasing or initiating steroids (including budesonide, systemic, or topical), mesalazine (systemic or topical), methotrexate (MTX), or antitumor necrosis factor agents (anti-TNF). The increase of purine antagonist dosage in case of a registered increase of symptoms was also scored as a relapse. Mucosal healing was defined as the absence of mucosal ulcerations on endoscopy.4

Statistical Analysis

Statistical analyses were performed using descriptive statistics, independent t-tests, and nonparametric tests. Nonparametric tests (χ2) were used to assess correlations between mucosal inflammation and clinical characteristics. Two-sided P-values <0.05 were considered significant. Mann–Whitney U-tests were used to compare two independent samples, and Kruskal–Wallis tests were used to compare more than two groups. Independent samples t-tests were used to compare the average time intervals for those with inflammation compared with those without inflammation, including duration of disease, age at onset of IBD, and time between colonoscopies. To compare characteristics of inflammation between UC and CD patients, the group unclassified colitis was combined with UC for statistical purposes. Statistical analyses were performed with SPSS for Windows software (v. 15.0, Chicago, IL).

RESULTS

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

Patient Characteristics

In total, 159 patients underwent a surveillance colonoscopy between January 2001 and December 2003. Seven patients were not in clinical remission and were therefore excluded. The remaining 152 patients were included for further analysis; 98 (65%) patients had UC, 46 (30%) had CD, and eight (5%) patients were diagnosed with unclassified colitis. The median age at diagnosis of IBD was 26 years (interquartile range [IQR] 20–34), and 85 patients (56%) were male. Median duration of disease at time of the index surveillance colonoscopy was 17.3 years (IQR 12–23). All CD patients had documented disease activity in the colon.

Details of Surveillance Program

For 90 patients (59%), the index colonoscopy was their first surveillance colonoscopy. The other patients had on average had one surveillance colonoscopy prior to this index endoscopy (IQR 1–2). Patients were included in a surveillance program after a median of 16 years of disease (IQR 10–22), with a median time interval of 2 years between each surveillance colonoscopy (IQR 2–3).

Primary Outcome Parameter

Mucosal Inflammation While in Clinical Remission

Table 1 depicts the disease characteristics found during index surveillance colonoscopy. In total, 105 patients (69%) had active mucosal inflammation. Twenty (13%) patients relapsed in the 12 months prior to the surveillance colonoscopy. Eighteen (90%) of these patients had active mucosal inflammation during colonoscopy. Excluding these patients did not influence the results: of the 127 patients who had been in remission for >1 year, 83 (65%) had active inflammation during colonoscopy (data missing in five patients). The percentage of UC patients and CD patients with active disease, subdivided into histological and endoscopic inflammation, is shown in Table 2. There was no significant difference in the prevalence of inflammation among CD patients compared with UC patients (P = 0.5).

Table 1. Disease Characteristics During Index Surveillance Colonoscopy
 N (%)N No Inflammation (%)N Asymptomatic Inflammation (%)
No. of patients15247105
Disease   
 Ulcerative colitis98 (65)32 (68)66 (63)
 Crohn's disease46 (30)14 (30)32 (31)
 Unclassified colitis8 (5)1 (2)7 (7)
Gender   
 Male85 (56)24 (51)61 (58)
 Female67 (44)23 (49)44 (42)
Median age at diagnosis IBD (IQR)25.8 (20-34)24.9 (20-31)26.6 (21-36)
Median duration of IBD (IQR)17.3 (IQR 12-23)20.3 (14-28)16.4 (12-22)
Concomitant PSC28 (18)6 (13)22 (21)
Maximum disease extent   
 Left-sided colitis (UC)25 (19)8 (20)17 (18)
 Pan-colitis (UC)68 (51)22 (55)46 (49)
 < 50% segmental colitis (limited CD)6 (4)2 (5)4 (4)
 > 50% segmental colitis (extensive CD)27(20)7 (18)20 (21)
 Limited unclassified colitis1(1)1 (3)
 Extensive unclassified colitis7(5)7 (7)
 Unknown18 11
Ileitis terminalis?   
 Yes: - backwash ileitis (UC)4 (3)4 (4)
 - Crohn's lesions5 (3)5 (5)
 No84 (55)29 (62)55 (52)
 Terminal ileum not seen59 (39)18 (38)41 (39)
Pseudopolyps in history44 (35)12 (34)32 (36)
 Unknown281216
Relapse during the last year20 (13)2 (4)18 (18)
 Unknown5 (3)
Relapse during last month
 Colon surgery in history15 (10)6 (13)9 (9)
Abnormalities during surveillance   
 Inflammation105 (69)0105 (100)
 Dysplasia14 (9)7 (15)7 (7)
 Colorectal cancer1 (1)1 (2)
 Pseudopolyps30 (20)8 (17)22 (21)
Treatment schedule   
 None/expectative139 (91)47 (100)92 (88)
 Increasing dose2 (1)2(2)
 Changed to another drug6 (4)6 (6)
 Endoscopy schedule altered1 (1)1 (1)
 Another drug added to current regimen4 (3)4 (4)
Median time to next colonoscopy (IQR)2.1 (1.5-2.9)2.2 (1.8-3.2)2.0 (1.2-2.8)
Effect treatment (next colonoscopy)   
 None25 (17)5 (12)20 (20)
 Less inflammation31 (22)1 (2)30 (30)
 Mucosal healing42 (29)19 (46)23 (23)
 More inflammation39 (27)16 (39)23 (23)
 Dysplasia3 (2)3 (3)
 Unknown1266
Table 2. Frequency of Endoscopic and Histological Inflammation Without Clinical Symptoms
 Total (%)*UC Patients (%)CD Patients (%)*
  • *

    Accurate data on endoscopic inflammation was missing in one patient.

No. of patients15210646
No inflammation47 (31)33 (31)14 (31)
Endoscopic + histological activity (group A)51 (34)39 (37)12 (27)
Only histological activity (group B)51 (34)33 (31)18 (40)
Only endoscopic activity2 (1)1 (1)1 (2)
Severity of Disease

Table 3 shows the histological scoring of disease activity by endoscopy and histology. In 97 out of 152 patients (64%), no visible inflammation was seen during surveillance colonoscopy. However, histological examination revealed that only 47 patients (31%) had no mucosal activity. In 51 patients (34%), both endoscopic and histological inflammation was found (group B), and in 51 patients (34%) only histological inflammation could be demonstrated (group C).

Table 3. Endoscopic and Histological Disease Activity During Surveillance Colonoscopy
 Histological Severity of Disease 
  No ActivityMildModerateSevereDysplasiaCancerTotal
Endoscopic severity of diseaseNo activity40 (26%)39 (26%)10 (7%)7 (5%)1 (1%)97 (64%)
Mild2 (1%)26 (17%)11 (7%)3 (2%)4 (3%)46 (30%)
Moderate1 (1%)2 (1%)2 (1%)5 (3%)
Severe1 (1%)1 (1%)2 (1%)
Missing2 (1%)2 (1%)
Total42 (28%)68 (45%)23 (15%)6 (4%)12 (8%)1 (1%)152

Use of medication in the year prior to surveillance or in the month prior to surveillance was not associated with inflammation in groups B and C, nor was the duration of medication use (all P > 0.05).

Secondary Outcome Parameter

Therapeutic Strategies After Surveillance Colonoscopy

In 13 (12%) patients with endoscopic and/or histological inflammation the therapeutic strategy was adjusted after endoscopy. Thus, in 92 of the 105 (88%) cases with endoscopic or histological inflammatory activity, treatment was not changed (Table 1). The decision to change treatment strategy was significantly associated with the endoscopic (P < 0.001) and histological (P = 0.001) severity of disease. In 2/97 (2%) patients without endoscopic disease activity the strategy was altered, against 7/39 (15%) patients with mild endoscopic inflammation, 2/3 (40%) with moderate, and 2/2 (100%) of patients with severe endoscopic inflammation.

Follow-up

In total, from 119 patients (78%) data were available until the end of the study period. Twenty-seven patients (18%) were lost to follow-up. Six patients (4%) died of causes unrelated to IBD: one died because of metastasized duodenum carcinoma (age 58), another because of acute leukemia (age 57), one because of toxic epidermiolysis (age 57), and in three patients the cause of death was unknown (ages 61, 51, and 88). Overall time of follow-up was 6.8 years (IQR 6–8). Of the 33 patients who died or were lost to follow-up, median time of follow-up was 3 years (IQR 1.7–4.9). The median time interval between the index surveillance colonoscopy and the next colonoscopy was 2.1 years (IQR 1.5–2.9). Inflammation at index colonoscopy did not influence the time to the next endoscopy.

Two-year Prognosis of Mucosal Inflammation at Index Endoscopy

During the two years follow-up endoscopy, overall 55% of patients had active mucosal inflammation; 27% both endoscopic and histological inflammation, 2% only endoscopic, and 26% only histological inflammation.

Of the patients in group A, 38% (15/40) had mucosal inflammation at the second endoscopy compared with 61% (59/96) of patients in group B+C (Fig. 1). In group B, 29% (n = 15) regressed to histological inflammation only, and 33% (n = 16) remained to have both endoscopic and histological inflammation. Of the patients in group C, 27% (n = 12) still had only histological inflammation during the second colonoscopy but 29% (n = 13) progressed to both endoscopic and histological inflammation. The proportion of patients with mucosal inflammation during the next colonoscopy was not significantly different between groups B and C, P = 0.14.

thumbnail image

Figure 1. The frequency of mucosal inflammation during follow-up colonoscopy (2 years later). Group A includes patients with both endoscopic and histological inflammation. Group B includes patients with histological inflammation only. *Data on the next colonoscopy missing in seven patients. **Data on the next colonoscopy missing in four patients. ***Data on the next colonoscopy missing in six patients.

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In 37/96 (39%) of patients in groups B and C no disease activity was found during the 2-year follow-up endoscopy, compared with 25/40 (63%) in group A, P = 0.02. Patients with inflammation (group B+C) did not have more pseudopolyps during the next colonoscopy than patients without inflammation (Group A), P = 0.34.

Effect of Changing Treatment Strategy (2 Years Later)

The choice of treatment strategy did not influence the maximum severity of inflammation or the maximum extent of disease, both endoscopic and histological, or the presence of pseudopolyps (all P > 0.05).

Influence of Mucosal Inflammation at First Endoscopy on Disease Course (Total Follow-up Period)

Inflammation at baseline was not associated with an ongoing active inflammatory disease (P = 0.65) nor with more relapses during follow-up (P = 0.18): 21/105 patients (21%, data missing in four cases) with inflammation had a relapse during follow-up compared with 5/47 patients (12%, data missing in four cases) without inflammation. Inflammation did not lead to a higher mortality rate (P = 0.35). In 15 patients the maximum extent of disease during follow-up was unknown. None of the remaining 144 patients developed a new stricture or fistulizing disease during follow-up. There was no significant difference in the number of surgeries performed between the groups with and without inflammation (P = 0.1): 2/47 (4%) patients in group A versus 14/102 (14%) patients in group B+C had colon surgery during follow-up

Influence of Microscopic Mucosal Inflammation Only (Group C) on Long-term Prognosis

Patients in group C did not have a different course of disease than those in group B. All the outcome measurements for course of disease during follow-up as discussed above were not significant (P > 0.05).

DISCUSSION

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

We demonstrate a high prevalence of endoscopic and/or histological disease activity in IBD patients who are in clinical remission. Additionally, we show that in a large proportion of patients histological inflammation is diagnosed without any signs of active disease during endoscopy. The incentive to treat patients in clinical remission but with inflammation found during endoscopy appears to be low in clinical practice. Although 39% of the patients with inflammation spontaneously recovered, endoscopic and/or histological inflammation without any symptoms is associated with more severe mucosal inflammation at 2 years follow-up. However, we could not demonstrate that this affected the disease course during follow-up.

Our results are in contrast with a previously published study, which reported that endoscopy had little additional value compared to noninvasive disease indices such as patient-reported stool frequency or bloody stools.13 The authors concluded that clinical symptoms in UC are predictive of mucosal inflammation and can be used as surrogate makers. In the present study we demonstrate that two-third of IBD patients have mucosal inflammation despite the lack of clinical symptoms. This underscores the limited reliability of clinical symptoms in UC patients as surrogate markers for mucosal inflammation.

We confirm that inflammatory activity can be present in endoscopic normal mucosa.14, 15 Earlier studies demonstrated that endoscopic appearance alone tends to underestimate the extent of disease relative to histological evaluation.16–19 This could be important information for clinical practice, as it has been demonstrated that in patients with quiescent UC histological evidence of an acute inflammatory cell infiltrate, crypt abscesses, or mucin depletion is correlated with a 2–3-fold increase in the relapse rate.18 However, in our study population we could not confirm the latter.

In our cohort mucosal inflammation did not result in a worse outcome with respect to the disease course during 7 years of follow-up. Mucosal healing has been linked with a lower risk of relapse, a reduced risk of colorectal cancer, a decreased need for surgery, and improved quality of life.20 This would highlight the need to abolish disease activity and aim for mucosal healing in clinical practice. However, in contrast to well-cited randomized controlled trials that stress the importance of mucosal healing,5, 7 we could not confirm that mucosal inflammation leads to a worse course of disease in patients without clinical symptoms.

These conflicting data could be explained by a difference in study population. In contrast to previous studies that included IBD patients with a CDAI score of 220 to 400, the present study only included patients who were in clinical remission.4, 5 It could be hypothesized that inflammation without clinical activity represents a different disease entity with other consequences for follow-up than symptomatic mucosal inflammation. Moreover, in our study a large proportion of patients with PSC (18%) were included, while in literature the prevalence of PSC is only 5% of IBD patients.21 Disease activity of IBD in PSC patients is often mild and occasionally completely asymptomatic and associated with a low colectomy rate.22 In our cohort only 20% of CD patients had stricturing and/or fistulizing disease, while it had been previously demonstrated that 60% of CD patients develop stricturing or penetrating disease. This low rate of strictures and fistulas could be explained by the relatively small number of patients with terminal ileitis in our cohort. Moreover, all the patients in our cohort, both UC and CD patients, had colitis. This was also the sole indication for their colonoscopy, as we only included patients who received a surveillance colonoscopy. All in all, our cohort could therefore consist of a subset of IBD patients with an uncomplicated disease, who all seemed to have responded well to treatment. Caution is therefore needed in extrapolating our results to patients with an early complicated disease course.

Patients with histological inflammation, but endoscopically free of inflammation, had a similar prognosis as those who also had endoscopic signs of inflammation. Therefore, biopsies may represent a better indicator for the severity and extent of disease.

It seems that physicians do not consistently treat mucosal inflammation when patients are in clinical remission. The decision to interfere appears to be mostly guided on endoscopic findings, as treatment was more often changed when endoscopic inflammation was found than when only histological inflammation was found. Nonetheless, changing therapy seemed no more successful than the wait-and-see policy, since in both groups 60%–70% of patients still had inflammation 2 years later. However, only in a small number of patients therapy was changed, and more often in patients with more severe disease activity. Nonetheless, 39% had a spontaneous recovery. This suggests that if we aim to assess mucosal healing, a substantial proportion of patients could be unnecessarily exposed to drugs.

In conclusion, we present a high prevalence of endoscopic and/or mucosal disease activity in a cohort of IBD patients in clinical remission. Furthermore, we could not confirm that mucosal healing results in a more favorable course of disease during 7 years of follow-up. We could not show a beneficial effect of therapeutic intervention, and moreover found spontaneous recovery of inflammation in one-third of the patients. We therefore conclude that the clinical benefit of unconditionally treating all patients with mucosal inflammation in order to improve long-term prognosis needs to be further investigated.

REFERENCES

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