|Year : 2014 | Volume
| Issue : 4 | Page : 151-156
Evaluation of false remission in ulcerative colitis and the need for a revised disease activity index
Alaa Elgamal1, Hanan Maklouf2
1 Assistant professor of Internal Medicine, Mansoura Faculty of Medicine, Mansoura University, Egypt
2 Assistant professor of Clinical Pathology, Fayoum Faculty of Medicine, Fayoum University, Egypt
|Date of Submission||13-Jul-2014|
|Date of Acceptance||11-Aug-2014|
|Date of Web Publication||30-Dec-2014|
Head of Internal Med. Department, Al Rashid Hospital, Po Box 8999., Salmyia 22060 Kuwait
Source of Support: None, Conflict of Interest: None
Aim of the work
To highlight some criteria of remission in ulcerative colitis, to address the issue of false remission, and settle a standard index for its detection.
Patients and methods
Patients with ulcerative colitis in clinical remission were enrolled prospectively and followed for 1 year for evaluation of clinical manifestations, C-reactive protein, fecal calprotectin, and tumor necrosis factor-α, and colonoscopic and microscopic examination for the detection of actual remission, with the exclusion of those who developed clinical relapse during the study.
Out of 36 patients, we had 11 patients (30.5%) with true remission and 25 patients (69.5%) with false remission: 19 patients (52.7%) in false remission group A with abnormal mucosal healing and six patients (16%) in false remission group B with high inflammatory markers.
There was a significant positive correlation of inflammatory markers with the ulcerative colitis disease activity index in patients with true remission. There was a significant correlation of the ulcerative colitis disease activity index and histological grades in false remission A and a significant correlation of inflammatory markers with histological grades in false remission B.
About 70% of our patients with ulcerative colitis in clinical remission had an active disease. Clinical remission in ulcerative colitis can be best expressed as true and false remission depending on histological grading in a revised ulcerative colitis disease activity index. Some inflammatory markers can be useful for the detection of true remission.
Keywords: False remission, revised ulcerative colitis disease activity index, true remission, ulcerative colitis
|How to cite this article:|
Elgamal A, Maklouf H. Evaluation of false remission in ulcerative colitis and the need for a revised disease activity index. Egypt J Intern Med 2014;26:151-6
|How to cite this URL:|
Elgamal A, Maklouf H. Evaluation of false remission in ulcerative colitis and the need for a revised disease activity index. Egypt J Intern Med [serial online] 2014 [cited 2019 Sep 18];26:151-6. Available from: http://www.esim.eg.net/text.asp?2014/26/4/151/148129
| Introduction|| |
The natural history of inflammatory bowel disease (IBD) is characterized by repeated episodes of inflammation and ulceration of the intestine, resulting in complications requiring hospitalization, surgery, and escalation of therapy ,. In fact, some patients request dose reduction or treatment withdrawal soon after the resolution of symptoms. A considerable number of patients thus do not take medication as directed. Not only patients but also some physicians instruct patients to decrease or stop drug therapy soon after the resolution of symptoms, often leading to relapse. Frequent divergence between clinical remission and the remission of intestinal lesions in ulcerative colitis (UC) has also been confirmed in previous prospective studies ,.
Research has shown that tumor necrosis factor-α (TNF-α) is overexpressed in patients with moderate to severe UC . Biomarkers such as fecal calprotectin (FCP), fecal lactoferrin, serum C-reactive protein (CRP), and fecal S1 00A12 have been shown to correlate with disease activity in UC and Crohn's disease; these biomarkers might be used as surrogate markers for mucosal healing . In a study carried out by Sipponen et al. , 11 patients achieved a partial or a complete endoscopic response, and showed a significant decrease in FCP and lactoferrin levels. No significant decrease in FCP and lactoferrin concentrations was observed in the three nonresponders.
Newer clinical trials are incorporating mucosal healing as an end point for the evaluation of efficacy. However, before mucosal healing becomes sufficient to guide therapy, clinicians need a standard definition of mucosal healing. Achievement of long-term mucosal healing has been associated with a decreased risk of colectomy and colorectal cancer in patients with UC. Numerous endoscopic indices have been used to assess disease activity in clinical trials of UC. A European Crohn's and Colitis Organization consensus conference on mucosal healing in IBD concluded that mucosal healing is important, but this conference highlighted the need for large, prospective studies assessing the impact of mucosal healing and histological healing on the natural course of this disease . Further, researchers still face the problems associated with the use of different endoscopic assessment scales .
| Aim of the work|| |
To date, there is no universal agreement on a validated scale to define remission in UC, and because frequent divergence occurs between clinical and histological intestinal lesions, we attempted to highlight some criteria that may differentiate true and false remission in patients with UC, to address the issue of false remission, and to establish a standard index for its detection.
| Patients and methods|| |
Patients with a confirmed diagnosis of UC in clinical remission were prospectively enrolled in this study. Patients were followed every 4 months up to 1 year for the evaluation of clinical, laboratory, and colonoscopy examination with histological examination for the detection of true and false remission, with the exclusion of those who developed clinical relapse at any time during the study. Only 36 patients completed the study. Clinical remission is recognized by the absence of diarrhea and bloody stools. All patients were followed by clinical, laboratory, endoscopic, and histological criteria. Clinical and endoscopic criteria of remission were evaluated according to the ulcerative colitis disease activity index (UCDAI),  including stool frequency, rectal bleeding, endoscopic findings, and global assessment, considering the disease in remission to be in the range of 0-2 and active disease in the range of 3-12, with grade 3-6 indicating mild disease, grade 7-10 indicating moderate disease, and more than 10 indicating severe disease.
We assessed patients clinically using UCDAI. Colonoscopy and histological biopsies were performed for all patients by the same colonoscopist at the time of enrollment and every 4 months for 1 year. All patients were provided with a detailed explanation of the objectives of the examination. Total colonoscopy was performed after standard preparation procedures. The macroscopic endoscopic features of mucosa were evaluated and multiple biopsies were taken from both diseased and healthy areas for histopathological examination. The results of endoscopic mucosal appearance according to UCDAI were classified as follows: grade 0 indicated a normal bowel, grade 1 indicated mild friability, grade 2 indicated moderate friability, and grade 3 indicated exudation, and spontaneous bleeding.
Stool samples for FCP analysis and serum samples for TNF-α and CRP analysis were collected at baseline and every 4 months of the study. FCP was measured using a commercial enzyme-linked immunoassay method (Calprest; Dynex Elisa Eurospital, Trieste, Italy). The FCP results are expressed in mg of calprotectin per kilogram of wet feces with a reference range of less than 50 mg/kg . CRP and TNF-α concentrations were determined using the commercially available enzyme-linked immuno-sorbent assay supplied by Biosource International (Camarillo, California, USA). The assays use the quantitative sandwich enzyme immunoassay technique with a cut-off value of 1.9 pg/ml for TNF-α and 6 mg/l for CRP. All assays were performed according to the manufacturers' instructions.
Multiple biopsies were taken from different sites, embedded in formalin containers, sectioned, and stained with hematoxylin and eosin for conventional histopathological examination. We used Truelove's histological activity index modified by Geboes et al. , which has six grades ranging from normal mucosa (grade 0) to surface epithelial erosions and ulceration (grade 6).
We divided patients according to the gold standard of activity, that is, histologic findings, into two main groups: true remission group with UCDAI between 0 and 2, plus the normal reference level of inflammatory markers with normal colonic mucosa by both endoscopy and microscopy, and false remission group with UCDAI between 0 and 2, but with abnormal histological findings, further divided as follows: group A with mild to moderate friability of endoscopic mucosal appearance and normal laboratory markers and group B with abnormally high inflammatory markers and a normal mucosal appearance.
Exclusion criteria include: UC patients in clinical relapse, patients with disease complications, those with significant side effects of therapy, those who did not respond to treatment, those who were receiving treatment for other significant conditions, or pregnant patients were excluded. Patients with incomplete colonoscopy, a history of any malignant condition, a history of major gastrointestinal surgical procedures, liver cell failure, coagulopathy, chronic renal failure, smokers, those with drug or alcohol abuse, and NSAID use were also excluded from the study.
The study was carried out after obtaining written informed consent from all the patients, and the protocol was approved by the Ethical Review Board of the hospital.
Data were analyzed using the SPSS software (version 17.0, Sofinic International, SA. USA). Quantitative data were expressed as mean ± SD, whereas qualitative data were expressed as number and percentage. Comparisons between the groups were performed using Student's t-test whenever applicable. A value of P less than 0.05 was considered statistically significant. Correlations between different variables were evaluated using the Spearman rank correlation coefficient test.
| Results|| |
Thirty-six patients in clinical remission, who completed the study, were followed for 1 year. There were 11 patients (30.5%) in the true remission group, five with pancolitis and six with left-sided colitis, versus 25 patients (69.44%) in the false remission group, 10 with pancolitis and 15 with left-sided colitis. There were no significant differences between the two main groups of remission in terms of age, disease duration, and levels of inflammatory markers, including CRP, FCP, and TNF-α. A significantly higher level of UCDAI was found in the false remission group versus the true remission groups [Table 1]. We further divided the false remission group into two groups: 19 patients (52.7%) in the false remission group A with an abnormal mucosal appearance and six patients (16%) in the false remission group B with abnormally high levels of inflammatory markers, as shown in [Figure 1].
There was a significant increase in UCDAI in the false remission group A versus those in the false remission group B, and a significant increase in inflammatory markers including CRP, FCP, and TNF-α in the false remission group B versus those in the false remission group A [Table 2].
|Table 2: Comparison of clinical, laboratory, and endoscopic parameters in false remission groups|
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There was a significant positive correlation of inflammatory markers with UCDAI grade in patients with true remission, and a nonsignificant correlation of both groups of false remission [Table 3] and [Figure 2].
|Figure 2: Correlation of inflammatory markers with UCDAI. CRP, C-reactive protein; FCP, fecal calprotectin; FR, false remission; TNF-, tumor necrosis factor-α; TR, true remission; UCDAI, ulcerative colitis disease activity index.|
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In the false remission group A, there was a significant correlation of UCDAI with histological grade and a nonsignificant correlation of inflammatory markers with histological grade. In the false remission group B, there was a significant correlation of inflammatory markers with histological grades and a nonsignificant correlation of UCDAI with histological grade [Table 4].
|Table 4: Correlation of UCDAI and inflammatory markers with histological grades|
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| Discussion|| |
Assessment of disease activity in IBD is a challenging aspect; however, there is no consensus on a validated scale to define disease activity, and combinations of endoscopy and clinical disease activity indices have been used .
There is no validated definition of what constitutes mucosal healing in IBD. An International Organization of IBD task force proposed defining mucosal healing in UC as the absence of friability, blood, erosions, and ulcers in all visualized segments of gut mucosa . Nevertheless, endoscopy may not show mucosal damage when microscopic inflammation is present and it has been reported that endoscopy contributes little additional information toward scoring clinical activity .
In some patients who achieved mucosal healing with biological treatment, endoscopy on relapse showed exactly the same pattern and location of the disease as before mucosal healing . Microscopic (histological) healing may be a better predictor for relapse than the macroscopic appearance (or clinical criteria). Histological assessment showed that indicators of acute mucosal inflammation, including crypt abscesses, mucin depletion, or an acute inflammatory cell infiltrate, were associated with a two- to three-fold increase in the risk of UC relapse during 12 months' follow-up . The presence of basal plasmacytosis (i.e. dense infiltration of plasma cells in the lower third of the mucosa) in patients with quiescent UC has also been associated with a 4.5-fold increased risk of relapse . Using a novel six-point histological scoring system, Rubin et al.  reported that an increased level of histological inflammation can predict both colectomy and hospitalization in patients with UC. A prospective study has shown only modest agreement between clinical, endoscopic, and histological measures of remission, with complete agreement in just 58 and 89% agreement between endoscopy and histopathology, although a third, 36% of those with histological remission, had clinical symptoms of activity .
In a study carried out by Yokoyama et al. , active intestinal lesions were found in 29 patients in clinical remission (76%), despite the absence of diarrhea or bloody stools. In our group of patients, we found intestinal lesions in 19 patients in clinical remission (53%), despite the absence of clinical symptoms of activity, 11 patients (30.5%) with true remission, where there was complete agreement between clinical, endoscopic findings and histopathology, and six patients (17%) in the false remission group with agreement between clinical and endoscopic findings, but with high inflammatory markers. These data probably indicate that UCDAI as well as most of the UC evaluation criteria, which lack the gold standard criteria of true remission, that is histological normalization cannot define actual remission in UC accurately, and it classified 70% of our patients with active disease as showing remission. Thus, we recommend a revised UCDAI classification system with the addition of histological grades to include five categories:
- stool frequency,
- rectal bleeding,
- mucosal appearance,
- physician's rating of disease activity, and
- histological findings.
The use of surrogate markers for periodic monitoring of inflammation could be valuable as a sensitive, noninvasive screening tool to identify asymptomatic patients who could benefit from endoscopy. A combination of stool markers, CRP, and activity index may increase the accuracy of measuring endoscopic inflammation and may be an important avenue for improving noninvasive monitoring of intestinal inflammation. Such an assessment may also indicate the risk of relapse after achieving clinical remission if CRP and or FCP are elevated . However, several other internal and external factors affecting the serum level of inflammatory markers minimize their detection ability and their use in UC patients. In this study, only 16% of our patient group were detected to be in false remission depending on inflammatory markers as an initial test with a normal UCDAI grade and were proven to have abnormal histological findings.
We found a significant correlation of histological grade with UCDAI in patients under false remission with abnormal mucosal appearance and this correlation was actually present between abnormal mucosal appearance and histological grades because the patient was in clinical remission. Also, histological grades are correlated to inflammatory markers in the false remission group with abnormal inflammatory markers; thus, we conclude that patients with clinical remission either have an abnormal mucosal appearance, which is correlated to histological grade, or they have abnormal inflammatory markers, which are correlated to histological grades.
This study highlighted the need for large studies assessing a novel UC evaluation scale with the impact of mucosal and histological healing and its effects on the course of the disease. Furthermore, researchers still face the problems associated with the use of different endoscopic assessment scales.
| Conclusion|| |
About 70% of our patients with UC in clinical remission have an active disease. Clinical remission in UC can be best expressed as true and false remission depending on histological grading in a new revised UCDAI. This improved its ability to detect cases with false remission and may be a sufficient guide to therapy. Even if the UCDAI grade is 0 and the mucosa appears healthy, it is better to include both microscopic and macroscopic criteria of remission as factors of mucosal healing. Thus, we need a new clinical scale for evaluation of UC including both endoscopic mucosal healing parameters and standardized histological findings. Inflammatory markers such as CRP, FCP, and TNF-α are somewhat useful in the detection of true remission.
| Acknowledgements|| |
Conflicts of interest
There are no conflicts of interest.
| References|| |
Peyrin-Biroulet L, Loftus EV Jr, Colombel JF, Sandborn WJ. The natural history of adult Crohn′s disease in population-based cohorts. Am J Gastroenterol 2010; 105:289-297.
Langholz E. Ulcerative colitis. An epidemiological study based on a regional inception cohort, with special reference to disease course and prognosis. Dan Med Bull 1999; 46:400-415.
Meucci G, Fasoli R, Saibeni S, Valpiani D, Gullotta R, Colombo E, et al
. IG-IBD Prognostic significance of endoscopic remission in patients with active ulcerative colitis treated with oral and topical mesalazine: a prospective, multicenter study. Inflamm Bowel Dis 2012; 18:1006-1010.
Colombel JF, Rutgeerts P, Reinisch W, Esser D, Wang Y, Lang Y, et al
. Early mucosal healing with infliximab is associated with improved long-term clinical outcomes in ulcerative colitis. Gastroenterology 2011; 141:1194-1201.
Rutgeerts P, Vermeire S, Van Assche G. Mucosal healing in inflammatory bowel disease: impossible ideal or therapeutic target? Gut 2007; 56:453-455.
Dave M, Loftus EV Jr. Mucosal healing in inflammatory bowel disease-a true paradigm of success? Gastroenterol Hepatol (N Y) 2012; 8:29-38.
Sipponen T, Savilahti E, Kärkkäinen P, Kolho KL, Nuutinen H, Turunen U, Färkkilä M Fecal calprotectin, lactoferrin, and endoscopic disease activity in monitoring anti-TNF-alpha therapy for Crohn′s disease. Inflamm Bowel Dis2008; 14:1392-1398.
Peyrin-Biroulet L, Ferrante M, Magro F, Campbell S, Franchimont D, Fidder H, et al
. Scientific Committee of the European Crohn′s and Colitis Organization Results from the 2nd Scientific Workshop of the ECCO. I: impact of mucosal healing on the course of inflammatory bowel disease. J Crohns Colitis 2011; 5:477-483.
Sutherland LR, Martin F, Greer S, Robinson M, Greenberger N, Saibil F, et al
. 5-Aminosalicylic acid enema in the treatment of distal ulcerative colitis, proctosigmoiditis, and proctitis. Gastroenterology. 1987; 92:1894-1898.
Erbayrak M, Turkay C, Eraslan E, Cetinkaya H, Kasapoglu B, Bektas M. The role of fecal calprotectin in investigating inflammatory bowel diseases. Clinics (Sao Paulo) 2009; 64:421-425.
Geboes K, Riddell R, Ost A, Jensfelt B, Persson T, Löfberg R. A reproducible grading scale for histological assessment of inflammation in ulcerative colitis. Gut 2000; 47:404-409.
Stange EF, Travis SP, Vermeire S, Reinisch W, Geboes K, Barakauskiene A, et al
. European Crohn′s and Colitis Organisation (ECCO) European evidence-based Consensus on the diagnosis and management of ulcerative colitis: definitions and diagnosis. J Crohns Colitis 2008; 2:1-23.
D′Haens G, Sandborn WJ, Feagan BG, Geboes K, Hanauer SB, Irvine EJ, et al
. A review of activity indices and efficacy end points for clinical trials of medical therapy in adults with ulcerative colitis. Gastroenterology 2007; 132:763-786.
Burger D, Thomas SJ, Walsh AJ, et al.
Depth of remission may not predict outcome of ulcerative colitis over 2 years. J Crohn′s Colitis 2011; 5:S4-S5.
Riley SA, Mani V, Goodman MJ, Dutt S, Herd ME. Microscopic activity in ulcerative colitis: what does it mean? Gut 1991; 32:174-178.
Bitton A, Peppercorn MA, Antonioli DA, Niles JL, Shah S, Bousvaros A, et al
. Clinical, biological, and histologic parameters as predictors of relapse in ulcerative colitis. Gastroenterology 2001; 120:13-20.
Rubin DT, Huo D, Hetzel JT, et al.
Increased degree of histological inflammation predicts colectomy and hospitalization in patients with ulcerative colitis [abstract]. Gastroenterology 2007; 132:A-19.
Thomas SJ, Walsh AJ, Von Herbay A, et al.
How much agreement is there between histological, endoscopic and clinical assessments of remission in ulcerative colitis. Gut 2009; 58:A101.
Yokoyama K, Kobayashi K, Mukae M, Sada M, Koizumi W. Clinical study of the relation between mucosal healing and long-term outcomes in ulcerative colitis. Gastroenterol Res Pract 2013; 2013:192794.
Solem CA, Loftus EV Jr, Tremaine WJ, Harmsen WS, Zinsmeister AR, Sandborn WJ. Correlation of C-reactive protein with clinical, endoscopic, histologic, and radiographic activity in inflammatory bowel disease. Inflamm Bowel Dis 2005; 11:707-712.
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4]