In order to evaluate the activity of ulcerative colitis (UC) in a given patient, physicians rely on a combination of parameters, such as symptoms, levels of laboratory biomarkers, as well as clinical and endoscopic findings.1–3 The correlation between endoscopic severity and patient symptoms is often limited, and colonoscopy has the drawbacks of being invasive, time-consuming, and expensive.4–8 Thus, several laboratory biomarkers have been evaluated for the purpose of monitoring endoscopic UC activity.9 In UC, active inflammation is associated with an acute phase reaction and migration of leukocytes to the bowel lumen. As such, elevated levels of several proteins can be measured in serum and feces.10 Increased levels of C-reactive protein (CRP) were found to be associated with clinical and endoscopic activity in UC.5,11,12 Fecal calprotectin (FC) is a biomarker that is frequently used for monitoring inflammatory bowel disease (IBD) activity.5,13 FC represents 60% of cytosolic proteins in granulocytes.13 Increased fecal concentrations of this protein are proportional to the neutrophil migration to the gastrointestinal mucosa.13 FC is stable for up to 1 week at room temperature.13 Assessment of levels of this biomarker allows accurately distinguishing IBD from noninflammatory bowel diseases, such as irritable bowel syndrome (IBS). Furthermore, increased concentrations of FC have been reported to be indicative of clinical relapse in IBD patients.14–16 Several studies in pediatric and adult cohorts have demonstrated that FC levels are reflective of the severity of mucosal inflammation17,18 and, thus, can help to distinguish between active and inactive IBD.4,13,19 Furthermore, activity in UC is also associated with hematologic alterations such as thrombocytosis and anemia.20
The utility of different biomarkers in assessing endoscopic disease activity can be crucial for early detection of relapse and for tailoring individual therapy. Current scientific evidence indicates that it is important to strive not only for clinical remission, but also for mucosal healing (MH), which is associated with a reduced need for hospitalization and UC-related surgery, as a therapeutic target.16,21 As such, assessment of suitable biomarkers plays an increasingly vital role in UC patient management in clinical practice.5
A number of scoring systems for the assessment of endoscopic activity in UC patients have been developed over the past decades. The Lichtiger Index, also known as the modified Truelove and Witts Severity Index, has been used in several adult clinical trials.22–24 Eight clinical variables determine the Lichtiger Index (Table 1). The calculation of the index does not require any laboratory data. The index ranges from 0–21 points, and a score of ≤3 points has been defined as clinical remission.25 The Lichtiger Index has not yet been extensively validated. Furthermore, the correlation of the Lichtiger Index with the endoscopic severity and levels of various biomarkers reflective of inflammation has not yet been evaluated in clinical studies. In this study, we have chosen to focus on the Lichtiger Index, as it is based on clear clinical item definitions and as it is easy to use.
Endoscopic disease severity was judged using the Modified Baron Score (Table 2).26 This scoring system ranks the endoscopic activity on a 5-point scale (0–4) and was first used by Feagan et al26 in a placebo-controlled trial in which patients with active UC were treated with an anti-α4β7 integrin antibody (Table 2). The modified Baron Score has not yet been validated.
Until now, there have been no prospective studies that have evaluated how endoscopic activity, assessed using the modified Baron Score, correlates with either clinical activity (evaluated using the Lichtiger Index), or with levels of various biomarkers (CRP, hemoglobin, platelets, blood leukocytes, and FC) in UC patients.
In this study we aimed to answer the following questions: Is there any noninvasive marker (clinical activity, CRP, hemoglobin, platelets, blood leukocytes, FC) able to discriminate between the five severity degrees of the modified Baron Score? And second, what is the correlation of the Lichtiger Index with the endoscopic disease activity?
PATIENTS AND METHODS
Of 305 adult outpatients and inpatients with UC referred for colonoscopy at the Departments of Gastroenterology of the University Hospitals of Lausanne, Bern, Basel, Zurich, and Jena, between January 2008 and October 2010, 228 patients (75%) were enrolled in the study. Enrolled patients were diagnosed with UC on the basis of standard clinical, endoscopic, and histologic criteria.27 The study was conducted as a nested project of the Swiss IBD Cohort Study with approval by each local Ethics Committee.28 Following instructions given by the local investigator, patients were provided with a fecal specimen collection set consisting of two fecal collection tubes (one tube for FC testing, catalog number 55478, Sarstedt, Nümbrecht Germany, and one tube for stool culture and Clostridium difficile toxin assay). Collection of the fecal specimens was performed by the patients themselves. The fecal specimens from outpatients were shipped to the laboratory by mail. As for the fecal samples from the inpatients, the fecal collection set was processed by a trained nurse and then sent to the laboratory. Fecal samples for bacterial analysis were processed immediately upon arrival, whereas fecal samples for measurement of calprotectin levels were stored at −40°C until further analysis (within 72 hours after fecal collection). Blood samples for a complete blood count and measurement of CRP levels were drawn within 3 days prior to endoscopy.
UC for a duration of >3 months, complete colonoscopy with intubation of the cecum (intubation of terminal ileum was not mandatory), biopsies (at least six biopsies from the areas of the colon and rectum affected by UC), completion of a written informed consent form, age 18–85 years, and fecal samples delivered 1–3 days prior to colonoscopy were inclusion criteria. UC patients with left-sided colitis, extensive colitis, and pancolitis were included. Left-sided colitis was defined as proctocolitis up to the splenic flexure, extensive colitis was defined as proctocolitis going beyond the splenic flexure but not reaching the cecum, and pancolitis was defined as proctocolitis that also involved the cecal pole.
Patients suffering only from ulcerative proctitis, incomplete colonoscopy (cecum not reached), infectious enterocolitis (positive stool culture for Salmonella, Shigella, or Campylobacter species, and/or positive C. difficile Toxin A & B assay, cytomegalovirus-positive histology or immunohistochemistry), colorectal cancer, Crohn's disease (CD), indeterminate colitis, urinary incontinence (due to the risk of contamination of fecal samples), inability to collect fecal samples, pregnancy, history of colorectal surgery (hemicolectomies, colectomies, proctocolectomies), regular intake of aspirin and/or other nonsteroidal antiinflammatory drugs (NSAID, ≥2 tablets/week) were exclusion criteria.
In total, 166 UC patients (73%) had a small bowel imaging (computed tomography [CT] scan or magnetic resonance imaging [MRI]) at the time of diagnosis. Systematic small bowel imaging was not requested as inclusion criterion.
If patients required several colonoscopies during the inclusion period, only the first endoscopic assessment was used for study purposes.
Patients included in the study underwent endoscopic examination for one or more reasons: clinically active disease (flare) (n = 99, 43%), assessment of endoscopic activity after medical treatment (n = 64, 28%), and dysplasia surveillance for long-standing disease (n = 65, 29%). The Lichtiger Index for a given patient was calculated by a physician not performing the colonoscopy. Five experienced board-certified gastroenterologists (A.M.S., C.B., A.S., C.S., S.R.V.), with at least 5 years of experience in conducting colonoscopic examinations, performed the endoscopies and graded the findings according to the modified Baron Score. To avoid potential bias, none of the gastroenterologists performing the endoscopies had access to the information regarding the Lichtiger Index, FC concentration, levels of CRP, hemoglobin, platelets, and blood leukocytes of individual patients.
The control group was comprised of 52 healthy individuals from the clinical and laboratory staff willing to provide blood and fecal samples. Healthy control individuals had no history of abdominal afflictions. The control group did not undergo endoscopy. Except for oral contraceptives, the individuals in the control group were not on any regular medication at the time of the study.
Lichtiger Index and Modified Baron Score
The items evaluated as a part of the Lichtiger Index are shown in Table 1. Disease activity is evaluated based on eight variables: number of stool passages per day, number of nocturnal stool passages, presence of visible blood in stool, fecal incontinence, abdominal pain/cramping, general well-being, abdominal tenderness, and need for antidiarrheal medication. Scores range from 0 to 21 points. Clinical response was defined as a reduction of a score by 3 points or more, whereas remission was defined as a Lichtiger Index of 3 points or less.24,29 We defined the different degrees of clinical activity of UC as follows: inactive (remission) disease: 0–3 points; mild activity: 4–8 points; moderate activity: 9–14 points; and high activity of the disease: ≥15 points.
The modified Baron Score assesses endoscopic activity on a 5-point scale (Table 2). The modified Baron Score has not yet been validated.25 We rated endoscopically active disease as a score of ≥2 points.
The concentration of FC was measured using a quantitative enzyme-linked immunosorbent assay (ELISA; PhiCal Test, ordered from Medical Instrument, Solothurn, Switzerland, Cat. No. 006; the test is produced by Calpro, Oslo, Norway). Fecal specimens were diluted at 1:2500. All the samples were coded, such that the scientist (M.T.) performing the analyses was blinded to the identity of the patients and their clinical and endoscopic findings. All fecal samples were processed within 72 hours after collection. The assays were performed according to the instructions supplied by the manufacturer. ELISA plates were read using a Spectra minireader (TECAN, OD at 450 nm). According to the manufacturer's instructions, samples containing 50 or more μg of calprotectin per 1 g of feces (≥50 μg/g of feces) were considered calprotectin-positive.
Hemoglobin, Platelets, Blood Leukocytes, and CRP
Hemoglobin (normal range for women 120–160 g/L, for men 140–180 g/L), platelets (normal range 150–350 G/L), blood leukocytes (normal range 2.6–7.8 G/L), and CRP levels (upper limit of normal <5 mg/L) were determined by routine laboratory analysis within 3 days prior to endoscopy.
Data were stored in an Excel sheet (Microsoft Office Excel 2003, Microsoft Switzerland). The statistical analysis was performed using Stata (v. 9, College Station, TX). Normal distribution of data was tested using a Normal-QQ-Plot. Results of parametric numerical data are presented as mean ± standard deviation (SD) and as median and interquartile range (IQR) for nonparametric data. The t-test was used to explore associations between parametric numerical data, whereas the Wilcoxon rank sum test was used to explore associations between nonparametric numerical data. P < 0.05 was considered statistically significant. A Bonferroni adjustment was performed in case of multiple testing. The association between endoscopic disease activity and either clinical activity, FC concentration, CRP, blood leukocytes, thrombocytes, and hemoglobin levels was assessed by determination of Spearman's rank correlation coefficient (r). A receiver operating characteristic (ROC) analysis was performed to evaluate the test characteristics of the noninvasive items to predict endoscopically active disease.
An a priori power analysis revealed that a sample size of 22 in each of the five subgroups of endoscopic disease activity (total n = 110) would have 90% power to detect a difference in the mean calprotectin level between the subgroups using a Mann–Whitney rank-sum test with a 0.05 two-sided significance level.
Characteristics of Patients and Controls
Table 3 provides an overview of the clinical characteristics of the patients included in the study. Disease location was categorized using the Montréal Classification system.30 Baseline clinical and laboratory characteristics of cases and controls are listed in Table 4. Of the 77 excluded UC patients, 45 did not have a complete colonoscopy, 21 were unwilling to participate in the study, five were taking NSAID(s), four were nonadherent with fecal collection, and two had C. difficile colitis (positive cytotoxin A & B assay). The control group was comprised of 52 healthy individuals from the clinical and laboratory staff willing to provide blood and fecal samples. Of those, 39 were females (75%), mean age was 37 ± 9 years (range 21–59 years).
Correlation of the Modified Baron Score with the Lichtiger Index, FC, CRP, Hemoglobin, Platelets, and Blood Leukocytes
The modified Baron Score significantly correlated with levels of FC (Spearman's rank correlation coefficient r = 0.821), the Lichtiger Clinical Activity Index (r = 0.682), CRP levels (r = 0.556), platelets (r = 0.488), hemoglobin levels (r = −0.3882 for both genders together, r = −0.4615 for females, and r = −0.4489 for males), and blood leukocyte levels (r = 0.401). For all items, P < 0.001 was found. Figure 1 demonstrates the relationship between the modified Baron Index score and FC concentration using boxplots.
In Table 5 we present the relationship between the different degrees of endoscopic severity based on the modified Baron Score with their corresponding clinical activity (Lichtiger Index), FC concentration, levels of CRP, hemoglobin (stratified according to gender), platelets, or blood leukocytes.
FC levels allowed discriminating between all the subclasses of endoscopic activity. The Lichtiger Index could distinguish between all the subclasses of endoscopic severity, except between a modified Baron Score of 0 and 1. CRP levels could discriminate between grade 3 and 4 of endoscopic severity. Hemoglobin levels in female patients did not allow discriminating between different grades of endoscopic activity, whereas in males the hemoglobin levels discriminated grade 3 and 4 of endoscopic severity. Platelets could discriminate between grade 3 and 4 of endoscopic activity, whereas blood leukocyte levels allowed discriminating between grades 2 and 3 of the modified Baron Score.
Correlation of the Lichtiger Index Subgroups with FC and Endoscopic Disease Activity
In Table 6 the FC concentrations and endoscopic activity corresponding to the different subgroups of the Lichtiger Index are shown.
According to the scores of the Lichtiger Index, patients were classified into four groups: 1) clinical remission (63 patients, 28%); 2) mild disease (61 patients, 27%); 3) moderate disease (71 patients, 31%); and 4) severe disease (33 patients, 14%).
The median calprotectin concentrations differed significantly between the different subgroups of the Lichtiger Index (P = 0.004 for remission vs. mild disease activity, P < 0.001 for mild vs. moderate disease activity, and P < 0.001 for moderate vs. severe disease activity).
Also, the endoscopic activity was significantly different between the various clinical activity subgroups (P < 0.001 for discrimination between all the subgroups).
Test Characteristics of the Lichtiger Index, FC, CRP, and Blood Leukocytes in Predicting Endoscopically Active Disease
The test performance characteristics of the Lichtiger Index, FC, CRP, platelets, hemoglobin (stratified according to gender), and blood leukocytes in predicting endoscopically active disease (modified Baron Index ≥2) are presented in Table 7.
FC testing with a cutoff of ≥57 μg/g of feces had the best sensitivity and specificity (91% and 90%, respectively) for the detection of endoscopically active disease. A calprotectin cutoff of ≥50 μg/g (as recommended by the manufacturer) had a sensitivity of 92% and a specificity of 86% for the detection of endoscopically active disease. The Lichtiger Index with a cutoff ≥4 points (sensitivity 82%, specificity 74% for the detection of endoscopically active disease) was superior to the test performance of CRP (cutoff ≥6 mg/L, 68% sensitivity, 72% specificity), platelets (cutoff ≥298 G/L, sensitivity 69%, specificity 66%), hemoglobin values (cutoff females ≤117 g/L, sensitivity 67%, specificity 64%; cutoff males ≤136 g/L, sensitivity 65%, specificity 64%), and blood leukocytes (cutoff ≥7.2 G/L, sensitivity 61%, specificity 62%). The corresponding ROC curves are illustrated in Figures 2 and 3.
Our prospective study in a considerably large cohort of UC patients lends further evidence to the appraisal that FC represents a useful biomarker for noninvasive monitoring of UC disease activity. Although inferior to the degree of correlation exhibited by FC, the Lichtiger Index also correlated well with endoscopic activity. In contrast, levels of CRP, hemoglobin, platelets, and blood leukocytes only weakly correlated with the endoscopic activity.
There is accumulating evidence that FC testing is not only useful for the accurate discrimination between IBD and IBS, but also for differentiation between inactive and active forms of IBD.5,14,17,19,31 Furthermore, several studies have demonstrated that increases in FC concentration are indicative of clinical relapse in UC patients.32,33 Thus far, only a few studies have evaluated the relationship between the categorically ordered endoscopic disease activity index (inactive disease, mild disease activity, moderate disease activity, and high disease activity) and FC levels.
Evaluating the correlation between different subclasses of endoscopic disease activity and levels of noninvasive biomarkers in UC is of major clinical interest, given the potential of these markers to serve as simple disease monitoring tools. We recently evaluated the relationship between endoscopic disease activity according to the categorically ordered Rachmilewitz Index, clinical activity, FC concentration, levels of CRP, and blood leukocyte levels.6 Similar to the current study, we found that endoscopic disease activity according to the Rachmilewitz Index correlated stronger with FC levels than clinical activity, levels of CRP, or blood leukocytes. Langhorst et al4 examined the relationships between endoscopic activity and concentration of FC, lactoferrin, polymorphonuclear (PMN)-elastase, CRP, as well as different clinical indices in 41 adult UC patients. A significant correlation between FC levels and the binary-ordered (active vs. nonactive) endoscopic disease activity was demonstrated. In a recently published study, Ricanek et al34 reported a significant correlation between FC levels and degrees of endoscopic severity assigned using the Mayo score (P = 0.048 for discriminating mild vs. moderate, and P = 0.007 for discriminating mild vs. severe disease) in an adult cohort of 61 UC patients. However, the authors found no difference in FC levels between endoscopically moderate and severe inflammation, which may be related to the cohort selection (33% with proctitis, 17% with left-sided colitis, and 50% with extensive colitis). As expected, FC levels were higher in UC patients with left-sided and extensive colitis when compared to patients suffering from proctitis.
The clinical impact of using noninvasive markers as tools for monitoring disease activity is highlighted in studies evaluating the correlation between endoscopic activity and risk of developing tumors, undergoing UC-related surgery, and hospitalization. Rutter et al35 demonstrated that the severity of colonic inflammation (both endoscopic and histologic) was associated with colorectal neoplasia in a study in which 68 UC patients with colorectal neoplasia were compared to an age- and sex-matched cohort of 136 UC patients without colorectal neoplasia. Froslie et al21 followed incident UC cases over a period of 5 years and documented that the rate of colectomies in patients with mucosal healing was significantly decreased compared to those with persistent inflammation. This finding implies that mucosal healing may alter the natural course of UC. The good correlation between FC levels with endoscopic severity makes this biomarker a useful tool for noninvasive activity monitoring. It is noteworthy that various definitions of mucosal healing have been applied in clinical trials and that a consensus definition of MH is still missing for UC and also CD.36
This is the first study to evaluate the correlation between the Lichtiger Index and the modified Baron Score. Our results lend further support to the observation that, in contrast to patients with CD, patients with UC have only a weak CRP response.37 This finding may be related to the fact that the inflammation in UC patients is confined to the mucosa, whereas it is transmural in patients with CD. Therefore, CRP levels do not seem to represent a suitable biomarker for monitoring endoscopic activity in UC.
Our study has several potential limitations. First, we chose to include only UC patients with left-sided and extensive colitis. As such, the results of this study may not be applicable to patients with ulcerative proctitis. We decided to exclude patients with ulcerative proctitis, as FC concentrations depend on the extent of the affected mucosal surface.34 Furthermore, from an ethical point of view, it is difficult to argue that a colonoscopic examination extending to the cecum is necessary for patients with known solely ulcerative proctitis. Second, we chose not to evaluate other fecal leukocyte markers, such as lactoferrin or PMN-elastase for the following reasons: 1) the correlations between these markers and FC levels have already been evaluated in other studies; and 2) there exist extensive data on the biologic stability and practical application of FC.4,13,38 Third, the topic of mucosal healing is still controversial, and available evidence on the impact of mucosal healing in UC is not abundant.39 Nonetheless, our results provide evidence that mucosal healing may be assessed in a noninvasive manner by determining FC concentration as a surrogate marker of mucosal inflammation. Fourth, the results of this study may potentially raise the question regarding the necessity of performing a complete colonoscopy in every UC patient to assess endoscopic activity. We performed a complete colonoscopy in all patients, as 41% of the patients had topical therapies that can influence the endoscopic activity in the left colon and thereby could lead to an underestimation of endoscopic severity if only a left-sided colonoscopy were performed. Finally, we defined the disease to be endoscopically active when a score of 2 or more points was assigned according to the modified Baron Index. This is in contrast to the definition set by Feagan et al,26 who defined active disease to have a modified Baron Index score ≥1. We a priori defined endoscopically active disease as a score of ≥2 given the absence of a validated definition of mucosal healing for this particular score and to ensure the presence of robust mucosal alterations. We perceive this cutoff as clinically relevant, given that a score of 0 or 1 would not justify therapeutic changes in daily practice.
In summary, we demonstrated that FC concentration strongly correlated with endoscopic severity according to the modified Baron Score. FC was the only noninvasive marker that allowed distinguishing between the different degrees of endoscopic activity. Although inferior to the level of correlation exhibited by FC, the Lichtiger Index demonstrated a good correlation with the endoscopic disease activity. Our study provides further evidence that FC is a useful biomarker for noninvasive activity monitoring in UC.
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Keywords:© Crohn's & Colitis Foundation of America, Inc.
fecal calprotectin; ulcerative colitis; biomarkers; disease activity; Lichtiger Index; modified Baron Score