None of the patients was receiving topical treatment, 34 (49%) were under stable doses of oral mesalamine (<3 g/d), and 19 (27%) were under immunosuppressant or anti-tumor necrosis factor maintenance treatment. Although it was not a prospectively established selection criteria, for the purpose of interpreting the results of the study, it should be noted that all included patients had previous evidence of endoscopic involvement of the rectal area.
High-resolution Rectosigmoidoscopy and Histology
As shown in Table 2, a minority of patients displayed irregular pit pattern with HRE-CE and HRE-NBI. The proportion of patients with large and somewhat irregular pits (grade 2) was higher with HRE-CE than with HRE-NBI. Regarding vascular pattern, most patients showed a normal vascular pattern with HRE-NBI. Globally, there were no differences in the Nishio classification determined by HRE-CE or HRE-NBI between relapsers and nonrelapsers, and vascular pattern assessed by HRE-NBI was not significantly associated with relapse. Interobserver agreement for the endoscopic features was mild (Kappa = 0.3).
Regarding histology, 57 of 64 patients (82% of relapsers and 92% of nonrelapsers) showed Matts grade 3 cellular infiltration in basal rectal biopsies. Results for the Riley classification are shown in Table 3. Overall, baseline histology features were not different between relapsers and nonrelapsers. Basal plasmacytosis was found in 38 (59%) patients but only 7 of these (18%) relapsed, whereas 10 of the 24 (38%) patients without basal plasmacytosis relapsed, so basal plasmacytosis did not appear as a predictor of relapse (P = 0.07). Finally, presence of eosinophils in rectal mucosa was observed in 32 (50%) patients but only 9 (28%) of these relapsed, similarly to the group without eosinophils where 8 of the 32 (25%) relapsed (P = 0.78). Presence of an eosinophil infiltrate was significantly associated with the presence of chronic inflammatory activity (P = 0.03).
Baseline serum and fecal biomarkers in relapsers and nonrelapsers over the 1 year follow-up are shown in Table 4. Among serum biomarkers, only platelet count was significantly associated with relapse at 1 year (P = 0.04) with low specificity (0.7) and sensitivity (0.65). Baseline FC levels were numerically higher in relapsers than in nonrelapsers, although differences were not significant (200 [20–329] µg/g versus 75 [53–191] µg/g, respectively; P = 0.75). However, the proportion of patients who relapsed was significantly higher in the group of patients with FC ≥250 µg/g (7/14 [50%]) compared with patients with FC <250 µg/g (10/49 [20%]), odds ratio = 3.9 (95% confidence interval [CI]: 1.1–13.7). The overall accuracy of this cutoff was 0.73, with a sensitivity, specificity, and negative predictive value of 0.41, 0.85, and 0.80, respectively. When a cutoff level of 100 µg/g was chosen, sensitivity was 0.5 and specificity was 0.7. Using a cutoff level of 150 µg/g, similar results were obtained.
When occurrence of relapse over the 3 months after each calprotectin measurement was assessed, FC levels were significantly higher in relapsers than in nonrelapsers (204 µg/g [44–486] versus 65 µg/g [40–123]; P = 0.02). A cutoff level of 100 µg/g (odds ratio = 2.2 [95% CI: 1.1–4.5]) or 250 µg/g (odds ratio = 4.5 [95% CI: 2.1–9.5]) significantly predicted relapse. Global accuracy, sensitivity, specificity, and negative predictive values were 0.64, 0.53, 0.67, and 0.88 respectively, for a cutoff 100 µg/g and 0.78, 0.45, 0.85, and 0.88 for a cutoff 250 µg/g.
FC levels were not correlated with endoscopic lesion severity (P = 0.88 for pit pattern by CE, P = 0.32 for pit pattern by NBI, and P = 0.06 for vascular pattern by NBI) or histologic activity assessed according to Riley or Matts scores (P = 0.4 and P = 0.09, respectively).
The results of this prospective cohort study do not confirm the usefulness of advanced endoscopy or histology for prediction of relapse in patients with UC in remission, by contrast thrombocytosis, and increased FC were significantly associated with higher relapse rates, although accuracy of these predictors is low and the usefulness of the biomarkers in clinical practice has limitations.
The capability of advanced endoscopy for the identification of histologic persistence of inflammation and prediction of relapse could be a valuable, simple, and practical tool that could potentially improve management of patients with UC, and a landmark for mucosal healing assessment in the context of clinical trials. Nishio et al22 evaluated pit pattern in rectal mucosa of 113 clinically quiescent patients with UC, using high-resolution video-magnifying methylene blue CE for prediction of relapse. A positive correlation was found between magnifying CE grades and histologic inflammation, and the endoscopic classification was a predictor of relapse. Other studies had demonstrated that CE with and without magnification was more accurate than white light conventional endoscopy for the assessment of extent and degree of mucosal alterations in UC.27
Our prospective study in a homogeneous population of patients with UC in clinical and endoscopic remission, defined as a Mayo endoscopy subscore of 0, shows that HRE-CE findings are not associated with the risk of relapse. Also, HRE-NBI could not detect differences in pit pattern or in vascular pattern intensity between relapsers and nonrelapsers. The discrepancy with the results of Nishio et al22 can be explained by several factors. Probably the most important factor is that the study by Nishio et al includes not only patients in endoscopic remission (Mayo endoscopy subscore of 0) but also those with granularity or erythema at endoscopic examination (Mayo endoscopic subscore of 1). By contrast, very strict inclusion criteria were followed in our study, accepting exclusively patients with Mayo endoscopic subscore of 0, who are those really in endoscopic remission. Indeed, the objective of this study was to determine if mucosal alterations only detectable by advanced endoscopic techniques such as CE or NBI had a predictive value. Actually, previous evidence has demonstrated that minimal endoscopic activity detected by conventional endoscopy, such as a Mayo endoscopic subscore of 1, is associated with higher risk of relapse in comparison with a score of 0.8 Second, patients under immunosuppressant therapy were not included in the study by Nishio et al; these patients may have a lower risk of relapse, despite the presence of endoscopic activity. Finally, Japanese authors used a magnification endoscope that could be technically superior to the one we used, and this could represent a potential drawback to our study. However, magnification endoscopes are expensive and not widely available in western countries, whereas the newly commercialized high-resolution endoscopes represent a reasonable alternative. Additionally, they are supplemented by electronic chromoscopy technology such as NBI that provides the capacity of enhancing mucosal superficial vascular network and as a consequence could be very useful to detect subtle inflammatory changes.
Regarding the pathology, results from our study showed that, despite complete absence of endoscopic activity, most of patients had persistent histologic inflammatory lesions (89% according to Matts classification). In this study, histologic changes did not appear as a predictor of relapse. In 1991, Riley et al6 evidenced a high prevalence of histologic abnormalities in quiescent patients with UC, but association between inflammatory infiltrate severity and frequency of UC relapse was only observed for acute inflammatory infiltrates and not for chronic changes. More recently, Bitton et al25 reported that basal plasmacytosis was a predictive of relapse in patients with UC in clinical remission. However, in our series, only 18% of patients with basal plasmacytosis relapsed, in contrast with the 38% of patients without basal plasmacytosis. Once again, we consider that the strict selection criteria of our study could be determinant to explain this disagreement. In fact, the above-mentioned studies included patients with mild endoscopic activity, which could account for their positive results. In addition, we only included patients in stable remission and required at least a 3-month period after induction treatment or dose adjustment, whereas in previous studies, patients with shorter periods of remission were included.25 It is remarkable that, among serum biomarkers, high platelet count was a significant predictor of relapse in 1-year period. This is a finding that needs to be confirmed because previous studies did not show an ability of serum biomarkers to predict relapse in UC.28–30
With regard to fecal biomarkers, several studies have shown that FC is a valid biomarker for differentiating active and inactive UC and its levels correlate with endoscopic disease severity.29,31 FC levels have also been studied as predictors of relapse: Costa et al12 found that FC was a strong predictor of clinical relapse in UC and a cutoff level of 150 mg/g had the highest sensitivity and specificity. Nevertheless, this study has some limitations that prevent its results to be reproduced in our setting. First, they included both patients with Crohn's disease and UC. Second, relapse was diagnosed based only on clinical criteria; presence of lesions was not assessed at inclusion and relapse was not corroborated by endoscopic examination. Our results showed that FC was able to identify patients who would relapse in the next 3 or 12 months with high specificity and negative predictive value. Therefore, FC can be used in clinical practice to select patients who need colonoscopy to confirm the relapse, which would limit the number of invasive procedures and would also result in savings on health resources. Given the high specificity of high FC levels for prediction of relapse, it remains to be seen if a management strategy based solely on FC measures, without endoscopic confirmation of activity, can improve disease course in the long-term and is cost-effective. Although previous studies suggest that FC is correlated with intestinal inflammation and presence of leucocytes in epithelium, we did not find a relation between histologic findings and FC levels.10
The strengths of this study lie on its prospective design, the power, the strict inclusion criteria, and an exhaustive follow-up. Moreover, it is the first study that compares 2 promising and novel strategies such as advanced endoscopy and fecal biomarkers for prediction of relapse in UC.
Assessment of endoscopic lesions in this study was limited to the rectosigmoid area. Rectal sparing occurs in some patients with UC, particularly those with associated primary sclerosing cholangitis.32 In our cohort, all included patients had evidence of involvement of the rectum in previous endoscopic examinations, including 2 patients having concomitant primary sclerosing cholangitis. Patients receiving treatments for UC could also have rectal sparing. However, this condition appears to be rare since in an ongoing study to assess correspondence between endoscopic activity in the rectosigmoid and more proximal colonic segments, more severe lesions in proximal segments were found in only 2.5% of cases, so its impact on the overall results should be minimal (Julian Panés, MD, PhD, personal communication, March 2014).
Another limitation of this study could be the use of a high-resolution endoscope without magnification. However, the evaluation of pit pattern and vascular intensity with these high-resolution endoscopes has demonstrated to be highly accurate for the diagnosis of malignancy.33 Moreover, our results suggest that these technical aspects are not a limitation because there were no microscopic architectural changes predictive of relapse. In fact, taking into account the results of this study, we hypothesize that more subtle changes in the mucosa should be studied as potential predictors of long-term outcome. Actually, preliminary results have shown that confocal endomicroscopy could be a useful tool for prediction of relapse in UC.34
In conclusion, high-resolution endoscopy with CE and NBI and histology were not useful for prediction of 1-year relapse in patients with UC in clinical and endoscopic remission. By contrast, FC could predict relapse in 3- and 12-month period with high specificity but low sensitivity. Future studies evaluating biomarkers and new endoscopic technology should be accomplished to progress in the development of a useful and simple tool for the assessment of mucosal changes in patients with UC that may guide management decisions.
Author contributions: M. Pellise designed the study; M. Aceituno, J. Panés, M. Sans, E. Ricart, and I. Ordás conducted patient recruitment; M. Lopez-Cerón, M. Aceituno, B. González, J. Llach, C. Rodriguez de Miguel, S. Pino, M. Zabalza, A. Jauregui-Amezaga, and M. Pellise worked on the acquisition of data, endoscopic examinations, and follow-up; M. Jimeno and M. Cuatrecasas conducted the pathological examinations; and A. Jauregui-Amezaga, J. Panés, and M. Pellise were in charge of the analysis and interpretation of data. All the authors helped on the critical revision of the article.
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Keywords:© Crohn's & Colitis Foundation of America, Inc.
ulcerative colitis; chromoendoscopy; narrow band imaging; fecal calprotectin; predictor; relapse