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Making sense of serologies: are they useful in indeterminate colitis?

Twenty-five years ago, the discovery of antibodies to bakers’ yeast (Saccharomyces cerevisiae; ASCA) in the serum of patients with Crohn’s disease (CD) sparked great interest in the concept that this and other circulating antibodies, otherwise known as serologies, reflected the underlying pathogenesis of inflammatory bowel disease (IBD).1 Indeed, an increase in intestinal permeability and loss of tolerance leading to a humoral response to translocating microbes are hallmarks of these conditions, and over subsequent years numerous other antibodies have been found to be associated with IBD. Interestingly, the earliest antibodies described, ASCA along with pANCA,2 have proved to be of greatest value, in that their presence as well as their titer patterns in combination may serve as markers of IBD, with ASCA positivity being associated with CD and pANCA positivity being associated with UC.3 Another potential use of serologies has been in discriminating between the 2 IBD phenotypes, ulcerative colitis (UC) and CD, in cases of diagnostic uncertainty, which still remains a challenge in clinical practice. Typically, antibody testing is performed in a patient who clearly has a chronic colitis, consistent with IBD, but whose features do not allow for separation into either UC or Crohn’s colitis. Such patients have been variably described as having IBD unclassified, undetermined, or indeterminate colitis (IC). Despite the common practice of using serologies for this purpose, very little research has, in fact, been published demonstrating the ability of serologies to accurately distinguish UC versus CD starting with a cohort of IC patients. Instead, prior serology research has focused on diagnostics and phenotypic differentiation by comparing a well-defined IBD cohort with control populations of healthy adults, as well with those with diarrhea or irritable bowel syndrome.4 With this in mind, in this issue of JCG, Sura et al5 have reported on the utility of serologic testing when applied specifically to an IC cohort. This was a real-world, single-center, retrospective review of 117 patients with IC who had at least 1 year of follow-up and had undergone ASCA, pANCA, and anti-OmpC serology testing at inception. The purpose of the follow-up was to allow time for the true diagnosis of either UC or CD to reveal itself on clinical grounds. The authors then looked back at the initial serology testing to determine how well these results predicted the ultimate diagnosis. The data were derived beginning with patients who presented in 2001; thus, more contemporary serologies such as anti-CBir1 did not factor significantly into the analysis. Furthermore, genetic testing (eg, NOD2 status) and the diagnostic algorithm offered by Prometheus Laboratories Inc. were also not incorporated into this study. The authors first calculated the sensitivity and specificity of each of the 3 serology tests for diagnosing UC or CD as determined after 1 year of follow-up. Then, for each individual serology, they calculated likelihood ratios (LR) expressing the probability that a serology test could identify UC (or CD) when positive or rule out UC (or CD) when negative. After 1 year, half (58) of the patients had been reclassified from IC to UC, 42% (49) were reclassified as CD, whereas the remaining 9% (10) did not develop any distinguishing characteristics and therefore retained their original IC diagnosis. How did serologic testing fare in predicting these subsequent diagnoses? A positive pANCA test had a sensitivity of 78% and a specificity of 44% for a diagnosis of UC. ASCA and anti-OmpC revealed low sensitivity (B20%) but better specificity (B80%) for CD. With regard to LRs, the results showed that only pANCA had any diagnostic value. The LR of a positive pANCA test for a diagnosis of UC was a modest 1.4, which corresponds to an increased probability of disease of about 10%. The LR for a negative pANCA test excluding CD was 2.0 (or an approximately 15% decrease in the probability of disease). Neither ASCA nor anti-OmpC demonstrated a significant likelihood ratio (positive or negative) for either diagnosis.