Journal of Crohn's and Colitis Advance Access published February 29, 2016 Journal of Crohn's and Colitis, 2016, 1–8 doi:10.1093/ecco-jcc/jjw025 Original Article
Original Article
Consecutive Measurements by Faecal Immunochemical Test in Quiescent Ulcerative Colitis Patients Can Detect Clinical Relapse
Downloaded from http://ecco-jcc.oxfordjournals.org/ by guest on March 22, 2016
Sakiko Hiraokaa, Jun Katob, Asuka Nakaraia, Shiho Takashimaa, Toshihiro Inokuchia, Daisuke Takeia, Yuusaku Sugiharaa, Masahiro Takaharaa, Keita Haradac, Hiroyuki Okadaa Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan bSecond Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan cDepartment of Endoscopy, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan a
Corresponding author: Sakiko Hiraoka, MD, Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan. Tel: (+81)-86-235-7219; Fax: (+81)-86-225-5991; Email: [email protected]
Abstract Background: We have reported that results of the quantitative faecal immunochemical test (FIT; haemoglobin concentrations in faeces measured using an antibody for human haemoglobin) effectively reflect the mucosal status of ulcerative colitis (UC). The aim of this study was to evaluate the predictability of flare-up in quiescent UC patients by consecutive FIT evaluation. Methods: Patients with UC who fulfilled the following criteria by index colonoscopy were enrolled: clinical remission; mucosal healing (Mayo endoscopic subscore 0); and negative FIT (less than 100 ng/mL). These patients were followed up prospectively every 1–3 months by monitoring patient symptoms and FIT results between index and subsequent colonoscopies. Results: The intervals between 2 colonoscopies (median 2.51 years) of 83 patients (49 males, median age at onset 34 years, median disease duration 9.74 years) were analysed. None of the 43 (52%) patients who maintained negative FIT throughout the observation period exhibited clinical relapse. On the other hand, 25/40 (63%) patients who showed positive conversion of FIT during the period experienced relapse. The cutoff FIT value of 450 ng/mL could predict relapse with 73% positive predictive value and 96% negative predictive value. Moreover, positive conversion of FIT preceded occurrence of symptoms by 1 month or more in nearly one-third of patients with relapse. Conclusions: Consecutive measurements of FIT in quiescent UC patients who achieved mucosal healing with negative FIT would help identify patients with clinical relapse whose symptoms had not yet presented. Further investigations are required for more precise prediction of relapse with this modality. Key Words: Ulcerative colitis; subclinical relapse; quantitative faecal immunochemical test
1. Introduction Ulcerative colitis (UC) is an idiopathic chronic inflammatory disorder characterized by manifestations such as diarrhoea, rectal bleeding, abdominal pain, fever, anaemia and body weight loss.1 Recently, not only clinical remission but also endoscopic mucosal healing has
been being pursued as the treatment goal for UC. Patients with UC who achieve mucosal healing have been shown to have a lower rate of relapse and a reduced risk of hospitalization and colectomy.2,3 However, relapse cannot be completely prevented even in patients who achieve mucosal healing, and continuous follow-up is required
Copyright © 2016 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: [email protected]
1
S. Hiraoka et al.
2
2. Methods 2.1. Patients This was a prospective observational study for UC patients who were followed with colonoscopies and FITs. We enrolled UC patients who paid periodic visits to Okayama University Hospital between January 2008 and December 2013 and fulfilled the following inclusion criteria by index colonoscopy: clinical remission; complete mucosal healing (MES 0); and negative FIT (less than 100 ng/mL). All of the patients had an established diagnosis of UC according to endoscopic and histologic assessments and had received medical therapy. Exclusion criteria were observation periods shorter than 6 months and the interval between hospital visits of more than 3 months. If a patient had 2 or more colonoscopies with inclusion criteria during the study period, only the data of the first colonoscopy were included. In this study, we focused on the period between the index colonoscopy and the subsequent colonoscopy. This period was designated
as the ‘observation period’, and the associations between presence or absence of relapse, changes in FIT results and findings of the subsequent colonoscopy during the observation period were investigated. This study was approved by the institutional review board of Okayama University Graduate School of Medicine. Informed consent was obtained from each patient.
2.2. Follow-up of patients Patients were followed up prospectively once every 1–3 months and symptoms were monitored. Submission of faecal samples for FIT was requested at every visit during the observation period. The subsequent colonoscopy was performed for evaluation of endoscopic inflammation or for the purpose of cancer surveillance. Patients for whom flare-up was suspected during the observation period immediately underwent colonoscopy. Colonoscopy was also recommended for patients who had an elevated FIT value without recurrence of clinical symptoms, but most of these patients did not receive colonoscopy in such a situation with elevated FIT without symptoms. For the patients who skipped colonoscopy, the decision on this matter was put off until the next hospital visit. In contrast, the indication of colonoscopy for most patients with clinical remission was cancer surveillance. The policy for surveillance colonoscopy was once every 3–4 years for patients with disease duration 8 years.19,20,21 Therefore, more than 1 index colonoscopy was performed in some cases, and 2 or more observation periods were evaluated in some patients who remained in clinical remission and mucosal healing for a long time. Clinical disease activity was scored using the Mayo score, which is based on the following four criteria: stool frequency; rectal bleeding; endoscopic findings; and physician’s global assessment (0, normal; 1, mild disease; 2, moderate disease; 3, severe disease).22 Clinical remission was defined as a Mayo stool frequency subscore of 0 or 1 and a Mayo rectal bleeding subscore of 0. Relapse was defined as requiring additional therapy, or increase in dose or modification of concomitant medications due to mucosal inflammation. Findings of the index and subsequent colonoscopies were also evaluated using the MES: those of the index colonoscopy must be MES 0 throughout the colorectum, and assessments of the subsequent colonoscopy were determined according to the most severe area in the colorectum.
2.3. Faecal sampling and instrument for FIT analysis Details of the method used for the FIT were described previously.17 Briefly, patients prepared faecal samples within 2 days before hospital visit using an OC-Hemodia sampling probe (Eiken Chemical, Tokyo, Japan) provided by the manufacturer. The patient inserts the probe into several different areas of stool and then firmly places it back into the tube to seal it. The probe tip with the faecal sample is suspended in a standard volume of haemoglobin-stabilizing buffer. Submitted stool samples were immediately processed and examined using OC-SENSOR neo or DIANA (Eiken Chemical), which can accurately measure faecal haemoglobin concentrations from 50 to 1000 ng/mL. Faecal specimens with a haemoglobin concentration over 1000 ng/mL were measured following dilution. Because FIT results are inaccurate at haemoglobin concentrations below 50 ng/ mL, specimens with a haemoglobin concentration in this range were categorized as one category (less than 50 ng/mL). Based on our previous reports,17,18 a negative FIT result was defined as faecal haemoglobin concentration
Original Article
Consecutive Measurements by Faecal Immunochemical Test in Quiescent Ulcerative Colitis Patients Can Detect Clinical Relapse
Downloaded from http://ecco-jcc.oxfordjournals.org/ by guest on March 22, 2016
Sakiko Hiraokaa, Jun Katob, Asuka Nakaraia, Shiho Takashimaa, Toshihiro Inokuchia, Daisuke Takeia, Yuusaku Sugiharaa, Masahiro Takaharaa, Keita Haradac, Hiroyuki Okadaa Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan bSecond Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan cDepartment of Endoscopy, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan a
Corresponding author: Sakiko Hiraoka, MD, Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan. Tel: (+81)-86-235-7219; Fax: (+81)-86-225-5991; Email: [email protected]
Abstract Background: We have reported that results of the quantitative faecal immunochemical test (FIT; haemoglobin concentrations in faeces measured using an antibody for human haemoglobin) effectively reflect the mucosal status of ulcerative colitis (UC). The aim of this study was to evaluate the predictability of flare-up in quiescent UC patients by consecutive FIT evaluation. Methods: Patients with UC who fulfilled the following criteria by index colonoscopy were enrolled: clinical remission; mucosal healing (Mayo endoscopic subscore 0); and negative FIT (less than 100 ng/mL). These patients were followed up prospectively every 1–3 months by monitoring patient symptoms and FIT results between index and subsequent colonoscopies. Results: The intervals between 2 colonoscopies (median 2.51 years) of 83 patients (49 males, median age at onset 34 years, median disease duration 9.74 years) were analysed. None of the 43 (52%) patients who maintained negative FIT throughout the observation period exhibited clinical relapse. On the other hand, 25/40 (63%) patients who showed positive conversion of FIT during the period experienced relapse. The cutoff FIT value of 450 ng/mL could predict relapse with 73% positive predictive value and 96% negative predictive value. Moreover, positive conversion of FIT preceded occurrence of symptoms by 1 month or more in nearly one-third of patients with relapse. Conclusions: Consecutive measurements of FIT in quiescent UC patients who achieved mucosal healing with negative FIT would help identify patients with clinical relapse whose symptoms had not yet presented. Further investigations are required for more precise prediction of relapse with this modality. Key Words: Ulcerative colitis; subclinical relapse; quantitative faecal immunochemical test
1. Introduction Ulcerative colitis (UC) is an idiopathic chronic inflammatory disorder characterized by manifestations such as diarrhoea, rectal bleeding, abdominal pain, fever, anaemia and body weight loss.1 Recently, not only clinical remission but also endoscopic mucosal healing has
been being pursued as the treatment goal for UC. Patients with UC who achieve mucosal healing have been shown to have a lower rate of relapse and a reduced risk of hospitalization and colectomy.2,3 However, relapse cannot be completely prevented even in patients who achieve mucosal healing, and continuous follow-up is required
Copyright © 2016 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: [email protected]
1
S. Hiraoka et al.
2
2. Methods 2.1. Patients This was a prospective observational study for UC patients who were followed with colonoscopies and FITs. We enrolled UC patients who paid periodic visits to Okayama University Hospital between January 2008 and December 2013 and fulfilled the following inclusion criteria by index colonoscopy: clinical remission; complete mucosal healing (MES 0); and negative FIT (less than 100 ng/mL). All of the patients had an established diagnosis of UC according to endoscopic and histologic assessments and had received medical therapy. Exclusion criteria were observation periods shorter than 6 months and the interval between hospital visits of more than 3 months. If a patient had 2 or more colonoscopies with inclusion criteria during the study period, only the data of the first colonoscopy were included. In this study, we focused on the period between the index colonoscopy and the subsequent colonoscopy. This period was designated
as the ‘observation period’, and the associations between presence or absence of relapse, changes in FIT results and findings of the subsequent colonoscopy during the observation period were investigated. This study was approved by the institutional review board of Okayama University Graduate School of Medicine. Informed consent was obtained from each patient.
2.2. Follow-up of patients Patients were followed up prospectively once every 1–3 months and symptoms were monitored. Submission of faecal samples for FIT was requested at every visit during the observation period. The subsequent colonoscopy was performed for evaluation of endoscopic inflammation or for the purpose of cancer surveillance. Patients for whom flare-up was suspected during the observation period immediately underwent colonoscopy. Colonoscopy was also recommended for patients who had an elevated FIT value without recurrence of clinical symptoms, but most of these patients did not receive colonoscopy in such a situation with elevated FIT without symptoms. For the patients who skipped colonoscopy, the decision on this matter was put off until the next hospital visit. In contrast, the indication of colonoscopy for most patients with clinical remission was cancer surveillance. The policy for surveillance colonoscopy was once every 3–4 years for patients with disease duration 8 years.19,20,21 Therefore, more than 1 index colonoscopy was performed in some cases, and 2 or more observation periods were evaluated in some patients who remained in clinical remission and mucosal healing for a long time. Clinical disease activity was scored using the Mayo score, which is based on the following four criteria: stool frequency; rectal bleeding; endoscopic findings; and physician’s global assessment (0, normal; 1, mild disease; 2, moderate disease; 3, severe disease).22 Clinical remission was defined as a Mayo stool frequency subscore of 0 or 1 and a Mayo rectal bleeding subscore of 0. Relapse was defined as requiring additional therapy, or increase in dose or modification of concomitant medications due to mucosal inflammation. Findings of the index and subsequent colonoscopies were also evaluated using the MES: those of the index colonoscopy must be MES 0 throughout the colorectum, and assessments of the subsequent colonoscopy were determined according to the most severe area in the colorectum.
2.3. Faecal sampling and instrument for FIT analysis Details of the method used for the FIT were described previously.17 Briefly, patients prepared faecal samples within 2 days before hospital visit using an OC-Hemodia sampling probe (Eiken Chemical, Tokyo, Japan) provided by the manufacturer. The patient inserts the probe into several different areas of stool and then firmly places it back into the tube to seal it. The probe tip with the faecal sample is suspended in a standard volume of haemoglobin-stabilizing buffer. Submitted stool samples were immediately processed and examined using OC-SENSOR neo or DIANA (Eiken Chemical), which can accurately measure faecal haemoglobin concentrations from 50 to 1000 ng/mL. Faecal specimens with a haemoglobin concentration over 1000 ng/mL were measured following dilution. Because FIT results are inaccurate at haemoglobin concentrations below 50 ng/ mL, specimens with a haemoglobin concentration in this range were categorized as one category (less than 50 ng/mL). Based on our previous reports,17,18 a negative FIT result was defined as faecal haemoglobin concentration
