Antineutrophil Cytoplasmic Antibodies and Anti‐<i>Saccharomyces cerevisiae</i> Antibody: Clinical Tools or Clues for Research?

The diagnosis of inflammatory bowel disease has been established based on a compatible history, radiologic, endoscopic and histologic findings. Recently, antineutrophil cytoplasmic antibodies (ANCA) and anti-Saccharomyces cerevisiae antibody (ASCA) serologic tests have been recommended as tools to facilitate screening for inflammatory bowel disease in children with suggestive symptoms (Gastroenterology 1998;115: 822–829) and to differentiate ulcerative colitis from Crohn's disease (Gut 1998;42:788–791). ANCAs are immunoglobulin (Ig) G antibodies directed against cytoplasmic components of neutrophils. The subtype of ANCA with a perinuclear staining pattern on immunofluorescence (p-ANCA) is associated with ulcerative colitis. The specificity of perinuclear staining for ulcerative colitis can be confirmed by its disappearance after deoxyribonuclease (DNase) digestion of neutrophils. The precise identity of the target antigen in IBD continues to be disputed. In contrast to pANCA, ASCAs are not autoantibodies. Rather, they are IgG and IgA antibodies which react against mannose sequences in the cell wall of S. cerevisiae, stain Su1. Laboratory tests useful in screening for suspected disease should have few false negatives and few false positives. Otherwise stated, serologic tests should be sensitive, i.e. able to detect disease when it is present, and specific, i.e. able to recognize when disease is not present. Studies in both adult and pediatric patients have consistently supported the specificity of pANCA for inflammatory bowel disease versus infectious colitides and other gastrointestinal disorders. However, sensitivity is poor since pANCA is positive in only 50–65% of pediatric patients. Less data are available concerning the prevalence of ASCA positivity in Crohn's disease. In the few reported studies ASCA is detected in 55–60% of children and adults with Crohn's disease, and in 5–10% of controls with other gastrointestinal disorders, findings indicating good specificity but relatively poor sensitivity. The relatively low sensitivities of serology for Crohn's disease and ulcerative colitis argues against there being any additional value for ASCA/pANCA as routine or first-line screening tests for inflammatory bowel disease compared to clinical acumen and the equally sensitive (albeit less specific) measurement of acute phase reactants. For instance, erythrocyte sedimentation rate was elevated in 88% of over 600 children at the time of diagnosis of Crohn's disease at the Hospital for Sick Children in Toronto, Canada. Moreover, the need to perform definitive radiological and endoscopic studies to guide therapy by defining the extent and nature of inflammatory bowel disease will not be averted by positive serologic tests. Combined pANCA/ASCA testing has recently been recommended to help differentiate Crohn's disease from ulcerative colitis. Differentiation of Crohn's disease from ulcerative colitis is clinically problematic only when inflammation is confined to the colon. Hence, the clinically important question concerns the sensitivity and specificity of ASCA/pANCA testing for isolated colonic Crohn's disease versus ulcerative colitis. Findings to date suggest that CD patients with colonic inflammation are more likely to be pANCA positive than those with disease apparently confined to the small bowel (Scand J Gastroenterol 1995;30:693–698). Similarly, ASCA is less often detected in patients with CD limited to the colon than in those with small intestinal inflammation (Gut 1998;42:788–791). Hence, the utility of serology is less in the setting where it is needed most. In the one published study clearly reporting sensitivity, specificity and predictive values of combined serologic testing, the sensitivity of ASCA+ pANCA− serology for Crohn's colitis versus ulcerative colitis was only 32% (Gut 1998;42:788–791). However, the specificities of positive ASCA and pANCA negative serology for Crohn's colitis and pANCA+ ASCA− serology for ulcerative colitis are high, so that the predictive values are also high in the presence of a positive test. Clearly there is an urgent need for more data concerning combined pANCA and ASCA testing among patients with IBD involving the colon only. Published information concerning patients with both pANCA and ASCA positivity is completely lacking. Whether or not ASCA and pANCA measurements will prove helpful in classifying otherwise “indeterminant” colitis cannot as yet be ascertained. Only a few patients have been studied, and follow-up is too limited. Beyond labels, the clinically important questions are whether serology can be used to predict disease patterns and the likelihood of response to specific therapies. Preliminary data suggest that pANCA positive Crohn's disease may be relatively refractory to anti-TNFα therapy (Gastroenterology 1997;112:A1062). Such associations should continue to be explored in the research setting. The significance of ANCA in the pathogenesis of inflammatory bowel disease is unknown. ANCAs are produced by B cells in the lamina propria of the colonic mucosa, but do not appear to contribute directly to tissue injury in inflammatory bowel disease. Rather, pANCA is considered a marker of the immunologic disturbance that underlies the development of chronic intestinal inflammation. Some, but not all, studies report an increased prevalence of pANCA in healthy relatives of patients with ulcerative colitis. Further, there is evidence that HLA class II genes influence ANCA status (Inflammatory Bowel Dis 1998;4:18–26). Hence, ANCA may prove to be a marker of heterogeneity of genetic susceptibility to inflammatory bowel disease. The pathogenetic significance of ASCA in Crohn's disease is even less clear. The specificity of the antibody response makes it unlikely that the elevated titers result merely from increased intestinal permeability. The single study measuring ASCA in relatives reported an increased prevalence of 20% (Am J Gastroenterol 1998;93:1306–1310). Whether such clustering is due to genetic or environmental factors is unknown. It is possible that S. cerevisiae shares antigenic determinants with another organism of true pathogenetic significance in Crohn's disease. Even though many factors limit the present clinical utility of serologic tests, the specificities of pANCA and ASCA for chronic inflammatory bowel diseases are intriguing. pANCA and ASCA provide potentially important clues which may well help to unravel the etiology and pathogenesis of ulcerative colitis and Crohn's disease.

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