Determination of anti-neutrophil cytoplasmic antibody (ANCA) and anti-Saccharomyces cerevisiae antibody (ASCA) is considered investigational in the workup and monitoring of patients with inflammatory bowel disease. 

This policy was originally based on a 1999 TEC Assessment(1) that evaluated anti-neutrophilic cytoplasmic antibody (ANCA) and anti-Saccharomyces cerevisiae antibody (ASCA) in the following three clinical situations:

        •       The use of both tests as a first screen in patients with clinical signs and symptoms suggestive of inflammatory bowel disease (IBD) but who have not undergone                        confirmatory tests such as contrast radiographic studies of colonoscopy with biopsy.

      In this setting, the sensitivity of the test, as averaged among studies, is 38% with an average specificity of 94%. The low sensitivity of the test indicates that a negative result will not be clinically helpful. A positive result indicates that IBD is likely, but it is difficult from the available data to reliably estimate the positive predictive value in a population presenting with signs and symptoms of IBD. 

       •       ANCA as a confirmatory test for ulcerative colitis, and ASCA as a confirmatory test for Crohn’s disease.

 Archived policies are inactive. Since archived policies are not updated, Plans should not use them as the sole source of information when reviewing requests for coverage unless the Plan determines that there is no new evidence that effects the conclusions of the archived policy. FEP may provide specific administrative guidance regarding the use of archived policies.

In this setting, the average specificity of ANCA and ASCA is 90% and 94%, respectively, but the TEC Assessment concluded that this specificity is not likely to be high enough to confirm the diagnosis such that additional testing would not be necessary. 

      •       The use of both tests to distinguish between Crohn’s disease and ulcerative colitis in patients who have completed the standard workup, including pathologic                              evaluation of gastrointestinal biopsies.

In this setting, the pooled sensitivity of the test is 84%. This sensitivity, although relatively high, would still result in a significant number of patient misclassifications. In addition, in the studies the patients had either established ulcerative colitis or Crohn’s disease, and this is not the population of clinical interest. 

The policy was updated regularly with searches of the MEDLINE database. The most recent literature search was performed for the period April 2009 through April 2010. Following is a summary of the key updated literature: 

In 2006, a meta-analysis of studies that evaluated the diagnostic accuracy of ASCA and ANCA in inflammatory bowel disease was published.(2) It included studies that compared ASCA or ANCA sensitivity and specificity to a “gold standard” (clinical, radiologic, endoscopic and/or histologic diagnosis). Studies included patients who ultimately had a diagnosis of ulcerative colitis and/or Crohn’s disease. A total of 60 eligible studies were identified; there were 3841 ulcerative colitis patients, 4019 patients with Crohn’s disease, and 3748 controls. Fifteen studies had a control group of healthy controls, 14 had a control group of individuals with non-IBD conditions, 14 had both types of control groups, and 15 studies had no control group (characteristics of 2 studies were not reported). For the diagnosis of ulcerative colitis, the authors examined the sensitivity and specificity of ANCA in different combinations with ASCA, and for Crohn’s disease, they looked at ASCA in different combinations with ANCA. For ulcerative colitis, the most sensitive test combination was an ANCA-positive test without information regarding ASCA status; the pooled sensitivity was 55.3% and specificity was 88.5%. The most sensitive test for Crohn’s disease was ASCA immunoglobulin (IgG)-positive or IgA-positive in sera that were ANCA-negative. The pooled sensitivity was 55% with a specificity of 93%. The tests were also examined for their ability to distinguish between Crohn’s disease and ulcerative colitis. The most sensitive test for differentiating between the two conditions was the presence of either ANCA or ASCA antibodies of any class. The combined sensitivity and specificity in this situation were 62.6% and 92.6%, respectively. The authors did a sensitivity analysis and found that including only high-quality studies (n=18) did not significantly change the findings. They did not stratify their findings by prospective versus retrospective studies or by type of control group (ie, healthy controls vs patients with conditions other than IBD). 

Most studies have included populations of patients with established ulcerative colitis and Crohn’s disease. An exception is Joossens et al, which identified 97 patients with indeterminate colitis followed up prospectively.(3) A definitive diagnosis of ulcerative colitis was made in 11 patients; 7 of 11 were ANCA positive and ASCA negative. A diagnosis of Crohn’s disease was made in 10 patients; 8 of 10 were ANCA negative and ASCA positive. Approximately half of the patients with indeterminate colitis did not have positivity for either serum marker.

Archived policies are inactive. Since archived policies are not updated, Plans should not use them as the sole source of information when reviewing requests for coverage unless the Plan determines that there is no new evidence that effects the conclusions of the archived policy. FEP may provide specific administrative guidance regarding the use of archived policies. 

Several articles attempted to correlate titers of ANCA and/or ASCA with disease activity. Mow et al investigated whether serologic antibodies were associated with disease complications.(4) In this case series of 303 patients with Crohn’s disease, certain antibodies were associated with fibrostenosis or perforating disease. In a study conducted in Scotland, Russell et al evaluated the association between ASCA status and disease phenotype.(5) The study included a total of 301 patients (197 with Crohn’s disease, 76 with ulcerative colitis, and 28 with indeterminate colitis). In multivariate analysis, they found a significant association between ASCA positivity and a higher likelihood of oral Crohn’s disease (adjusted odds ratio [OR], 22.2; 95% confidence interval [CI], 3.4 to 142.9) and the presence of hypoalbuminemia (adjusted OR=4.78; 95% CI, 1.40 to 16.4). Confidence intervals were wide, indicating a high degree of uncertainty. In both the Mow and Russell studies, it is unclear how this information would be used in the management of the patient. 

Other studies evaluated the presence of serum markers in unaffected relatives of patients with IBD,(6,7) reporting positive results in approximately 25% to 50% of family members. However, these studies did not report on the incidence of IBD in relatives with positive antibodies. Two additional antibodies have been also been studied, Escherichia coli outer membrane porin C (anti-OmpC) and I2 antibody.(8) However, the same limitations in the published literature apply to these antibodies. 

A study by Schoepfer et al studied the results of various testing in 64 patients to compare the accuracy of fecal markers (ie, PhiCal Test, IBD-SCAN) , C-reactive protein, blood leukocytes, and antibody panels (ASCA and pANCA) for discriminating IBD from irritable bowel syndrome and to define a "best test."(9) The authors concluded PhiCal Test and IBD-SCAN are highly accurate for discriminating IBD from irritable bowel syndrome. Additional diagnostic accuracy is only marginal when the PhiCal Test and IBDSCAN are combined with ASCA and pANCA. ASCA and pANCA have a high specificity for IBD; however, they should not be primarily measured for discriminating IBD from irritable bowel syndrome, as their additional value to fecal leukocyte markers in this issue is only marginal. 

A review article published in 2007 discussed the expansion of the panel of serologic markers for IBD. (10)

An increasing amount of data are available on newly discovered antibodies (ie, Anti-OmpC, Anti-12, Anti-

CBir1, and antiglycan antibodies) directed against various microbial antigens. However, ASCA and PANCA remain the most widely investigated. The authors noted that the role of the assessment of various antibodies in the current IBD diagnostic algorithm is often questionable due to limited sensitivity. They concluded that further prospective clinical studies are needed to establish the clinical role of serologic tests in IBD.

Summary 

A number of studies have examined the association between the serologic markers ASCA and ANCA and inflammatory bowel disease. Systematic reviews have found relatively low sensitivity and moderately high specificity. Moreover, the clinical utility of these assays has not been demonstrated. No studies demonstrated the use of these markers in lieu of a standard workup for IBD. A number of authors claim that these markers can be used to avoid invasive testing, but no studies demonstrated an actual decrease in the number of invasive tests through use of serum markers. These technologies are investigational for the diagnosis and monitoring of inflammatory bowel disease given the insufficient evidence to evaluate the impact on net health outcome.