the value of serologic markers in indeterminate colitis: a prospective follow-up study

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DOUGLAS O. FAIGEL, M.D. M. BRIAN FENNERTY, M.D. Oregon Health and Science University Portland, Oregon 1. Faigel DO, Fennerty MB. “Cutting the Cord” for capsule endoscopy. Gastroenterology 2002;123:1385–1397. 2. Katz LB. The role of surgery in occult gastrointestinal bleeding. Gastrointest Dis 1999;10:78 – 81. 3. Zaman A, Sheppard B, Katon RM. Total peroroal intraoperative enteroscopy for obscure GI bleeding using a dedicating push en- teroscope: diagnostic yield and patient outcome. Gastrointest En- dosc 1999;50:506 –510. doi:10.1016/S0016-5085(03)01155-7 The Value of Serologic Markers in Indeterminate Colitis: A Prospective Follow-up Study Dear Sir: Joossens et al. 1 concluded in their prospective study that ASCA()/p-ANCA(-) predicts Crohn’s disease (CD) in 80% of pa- tients with indeterminate colitis and ASCA(-)/p-ANCA() predicts ulcerative colitis (UC) in 64% of patients. This study is very interesting in that it showed that the majority of patients with indeterminate colitis tend to be ASCA(-)/p-ANCA(-). These patients were also found to more likely remain indeterminate compared with the ones who have a positive serology at the time of diagnosis. This raises the possibility of another subgroup of IBD. From previous studies in patients with classified IBD, we know that the combination of ASCA()/p-ANCA(-) and ASCA(-)/p- ANCA() are strongly associated with CD and UC, respectively, and that these tests can help us make the correct diagnosis. 2 The objective of this study was to determine the usefulness of these serologic markers in categorizing patients with indeterminate colitis. The conclusion of the study states that ASCA()/ p-ANCA(-) have an 80% positive predictive value for Crohn’s disease in patients with indeterminate colitis and 64% for UC. These calculations, however, only apply to the group of patients who eventually reach a definitive diagnosis; and the majority of the patients in this study did not reach a definitive diagnosis (68%). Taking the definition of positive pre- dictive value as the probability of being affected with a disease in a patient with a positive test result, including the patients who re- mained indeterminate, the positive predictive value of this test will be only 30% for CD and 35% for UC. We think this clarification is necessary because the interpretation of these results may be misleading. After all, upon encountering a patient with indeterminate colitis for the first time, there is no way of telling whether they will eventually have a diagnosis of CD, UC, or, as in the majority of patients in this study, remain indeterminate. SILVIA CASTILLO, M.D. BHARATI RAMAIAH, M.D. STEVE BLUM, Ph.D. PROSPERE REMY, M.D. Gastroenterology Division Bronx Lebanon Hospital Bronx, New York 1. Joossens S, Reinisch W, Vermiere S, et al. The value of serologic markers in indeterminate colitis: a prospective study. Gastroenter- ology 2002;122:1242–1247. 2. Peeters M, Joossens S, Vermiere S, et al. Diagnostic value of ASCA and p-ANCA in IBD. Gastroenterology 1998;115:1006 – 1022. doi:10.1016/S0016-5085(03)01141-7 Reply. We would like to thank Castillo et al. for their interest in our paper. We partially agree with their comments. We investigated the positive predictive value (PPV) in those patients who eventually reached a diagnosis of Crohn’s disease (CD) or ulcerative colitis (UC). These phenotypes of IBD have been found to be associated with ASCA/pANCA- and ASCA-/pANCA, respectively and therefore the analysis was focused on these marker combinations. 1 However, as pointed out by Castillo et al., the results are different if all serologic results are considered. Accounting for all possible test combinations and analyzing all patients, PPV indeed becomes 31% for CD and 35% for UC. Although we were able to include 97 IC patients for this study, which is a relative large cohort of this disease phenotype, taking their prevalence into account, 2 subgroups remain rather small for analysis and the study may lack power to detect any interaction effect between the serologic markers on disease status. We therefore reanalyzed our data, using a univariate (logistic regression) (SAS Software release 8.2) and multivariate (bivariate Dale model, 3 Gauss for Windows NT/95 version 3.2.32) approach. Logis- tic regression analysis suggests that CD is significantly associated to ASCA (odds ratio: 5.675, 95% CI: 1.718 –18.744, P 0.004) and UC to pANCA (odds ratio: 5.355, 95% CI: 1.593–18.000, P 0.007). This is in line with earlier work. 1 Despite this confirmation, a substantial amount of statistical uncertainty was observed, due to the limited number of patients in the study. In addition, when combining the serologic markers in a multivariate analysis, the asso- ciation structure between ASCA and pANCA showed no significant relationship with CD nor UC. In summary, the conclusion of our paper that the contribution of ASCA and pANCA is useful in the diagnosis of indeterminate colitis stands. The authors believe that the way to further investigate the value of the serologic tests is to expand on the study population of the IC patients, to carry out a further follow up on the present cohort and finally to investigate new markers in patients who are ASCA-/ pANCA-. SOFIE JOOSSENS, M.Sc. Gastroenterology Unit University Hospital Gasthuisberg Leuven, Belgium KRISTEL VAN STEEN, Ph.D. SE ´ VERINE VERMEIRE, MD, Ph.D. Center for Statistics Limburgs Universitair Centrum Diepenbeek, Belgium WALTER REINISCH, M.D. Division of Gastroenterology and Hepathology University of Vienna Vienna, Austria JEAN-FRE ´ DE ´ RIC COLOMBEL, M.D., Ph.D. PAUL RUTGEERTS, M.D., Ph.D. Gastroenterology Unit CHRU Lille Lille, France September 2003 CORRESPONDENCE 999

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DOUGLAS O. FAIGEL, M.D.M. BRIAN FENNERTY, M.D.Oregon Health and Science UniversityPortland, Oregon

1. Faigel DO, Fennerty MB. “Cutting the Cord” for capsule endoscopy.Gastroenterology 2002;123:1385–1397.

2. Katz LB. The role of surgery in occult gastrointestinal bleeding.Gastrointest Dis 1999;10:78–81.

3. Zaman A, Sheppard B, Katon RM. Total peroroal intraoperativeenteroscopy for obscure GI bleeding using a dedicating push en-teroscope: diagnostic yield and patient outcome. Gastrointest En-dosc 1999;50:506–510.

doi:10.1016/S0016-5085(03)01155-7

The Value of Serologic Markers inIndeterminate Colitis: A ProspectiveFollow-up StudyDear Sir:

Joossens et al.1 concluded in their prospective study thatASCA(�)/p-ANCA(-) predicts Crohn’s disease (CD) in 80% of pa-tients with indeterminate colitis and ASCA(-)/p-ANCA(�) predictsulcerative colitis (UC) in 64% of patients.

This study is very interesting in that it showed that the majorityof patients with indeterminate colitis tend to be ASCA(-)/p-ANCA(-).These patients were also found to more likely remain indeterminatecompared with the ones who have a positive serology at the time ofdiagnosis. This raises the possibility of another subgroup of IBD.

From previous studies in patients with classified IBD, we knowthat the combination of ASCA(�)/p-ANCA(-) and ASCA(-)/p-ANCA(�) are strongly associated with CD and UC, respectively, andthat these tests can help us make the correct diagnosis.2 The objectiveof this study was to determine the usefulness of these serologicmarkers in categorizing patients with indeterminate colitis. Theconclusion of the study states that ASCA(�)/ p-ANCA(-) have an80% positive predictive value for Crohn’s disease in patients withindeterminate colitis and 64% for UC. These calculations, however,only apply to the group of patients who eventually reach a definitivediagnosis; and the majority of the patients in this study did not reacha definitive diagnosis (68%). Taking the definition of positive pre-dictive value as the probability of being affected with a disease in apatient with a positive test result, including the patients who re-mained indeterminate, the positive predictive value of this test will beonly 30% for CD and 35% for UC.

We think this clarification is necessary because the interpretationof these results may be misleading. After all, upon encountering apatient with indeterminate colitis for the first time, there is no wayof telling whether they will eventually have a diagnosis of CD, UC,or, as in the majority of patients in this study, remain indeterminate.

SILVIA CASTILLO, M.D.BHARATI RAMAIAH, M.D.STEVE BLUM, Ph.D.PROSPERE REMY, M.D.Gastroenterology DivisionBronx Lebanon HospitalBronx, New York

1. Joossens S, Reinisch W, Vermiere S, et al. The value of serologicmarkers in indeterminate colitis: a prospective study. Gastroenter-ology 2002;122:1242–1247.

2. Peeters M, Joossens S, Vermiere S, et al. Diagnostic value ofASCA and p-ANCA in IBD. Gastroenterology 1998;115:1006–1022.

doi:10.1016/S0016-5085(03)01141-7

Reply. We would like to thank Castillo et al. for their interest inour paper. We partially agree with their comments. We investigatedthe positive predictive value (PPV) in those patients who eventuallyreached a diagnosis of Crohn’s disease (CD) or ulcerative colitis (UC).These phenotypes of IBD have been found to be associated withASCA�/pANCA- and ASCA-/pANCA�, respectively and thereforethe analysis was focused on these marker combinations.1 However, aspointed out by Castillo et al., the results are different if all serologicresults are considered. Accounting for all possible test combinationsand analyzing all patients, PPV indeed becomes 31% for CD and35% for UC.

Although we were able to include 97 IC patients for this study,which is a relative large cohort of this disease phenotype, taking theirprevalence into account,2 subgroups remain rather small for analysisand the study may lack power to detect any interaction effect betweenthe serologic markers on disease status.

We therefore reanalyzed our data, using a univariate (logisticregression) (SAS Software release 8.2) and multivariate (bivariate Dalemodel,3 Gauss for Windows NT/95 version 3.2.32) approach. Logis-tic regression analysis suggests that CD is significantly associated toASCA (odds ratio: 5.675, 95% CI: 1.718–18.744, P � 0.004) andUC to pANCA (odds ratio: 5.355, 95% CI: 1.593–18.000, P �0.007). This is in line with earlier work.1 Despite this confirmation,a substantial amount of statistical uncertainty was observed, due tothe limited number of patients in the study. In addition, whencombining the serologic markers in a multivariate analysis, the asso-ciation structure between ASCA and pANCA showed no significantrelationship with CD nor UC.

In summary, the conclusion of our paper that the contribution ofASCA and pANCA is useful in the diagnosis of indeterminate colitisstands. The authors believe that the way to further investigate thevalue of the serologic tests is to expand on the study population of theIC patients, to carry out a further follow up on the present cohort andfinally to investigate new markers in patients who are ASCA-/pANCA-.

SOFIE JOOSSENS, M.Sc.Gastroenterology UnitUniversity Hospital GasthuisbergLeuven, Belgium

KRISTEL VAN STEEN, Ph.D.SEVERINE VERMEIRE, MD, Ph.D.Center for StatisticsLimburgs Universitair CentrumDiepenbeek, Belgium

WALTER REINISCH, M.D.Division of Gastroenterology and HepathologyUniversity of ViennaVienna, Austria

JEAN-FREDERIC COLOMBEL, M.D., Ph.D.PAUL RUTGEERTS, M.D., Ph.D.Gastroenterology UnitCHRU LilleLille, France

September 2003 CORRESPONDENCE 999