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Serum Antibodies for Diagnosis of Inflammatory Bowel Disease | |
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Description: |
Inflammatory bowel disease (IBD) can be subdivided into ulcerative colitis and Crohn's disease, both of which present with symptoms of diarrhea and abdominal pain. The definitive diagnosis can usually be established by a combination of radiographic, endoscopic and histologic criteria, although in 10-15% the distinction between the two cannot be made with certainty. Two serum antibodies, anti-neutrophilic cytoplasmic antibody (ANCA) and anti-Saccharomyces cerevisiae antibody (ASCA), have been investigated as a technique to improve the efficiency and accuracy of diagnosing IBD in order to potentially decrease the extent of the diagnostic work-up or to avoid invasive diagnostic testing. Testing of ANCA is available in most clinical laboratories, while ASCA is more recently described and may not be widely available.
The Prometheus System (Prometheus Inc.) is a commercially available diagnostic system that uses combinations of tests for ANCA and/or ASCA to aid in the diagnosis of IBD. This system initially uses an enzyme linked immunoadsorbent assay (ELISA) test to screen for ANCA or ASCA. Positive ANCA results are further analyzed by indirect immunofluorescence to determine the specific staining pattern. When a perinuclear pattern is obtained, specific enzyme reagents proprietary to the company are then used to distinguish between true positives and artifacts of fixation. In this way, the Prometheus system is intended to increase the specificity of the test compared to other laboratories. For ASCA, after a positive screen, the serum specimens are further analyzed by an ELISA microplate assay. Positive specimens are identified when the antibody level exceeds a predetermined cut-off point.
When ANCA and ASCA are used as a first screen in patients with clinical signs and symptoms suggestive of IBD, but who have not undergone confirmatory tests such as contrast radiographic studies or colonoscopy with biopsy, the average sensitivity is 38% with an average specificity of 94%. The low sensitivity indicates that a negative result will not be clinically helpful.
The average specificity of ANCA as a confirmatory test for ulcerative colitis and ASCA as a confirmatory test for Crohn's disease is 90% and 94% respectively. It is doubtful that this is high enough to confirm the diagnosis such that additional testing could be foregone.
In studies using ANCA and/or ASCA to distinguish between ulcerative colitis and Crohn's disease in patients who had already completed a conventional work-up the average specificity was 84%, still resulting in a significant number of patients being misclassified. There are no reported studies using these tests in a patient population with "indeterminate colitis".
Because of the low sensitivity and specificity, serum antibodies for diagnosis of inflammatory bowel disease are not covered.
There are no specific CPT codes for these tests.
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Policy/ Coverage: |
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Determination of anti-neutrophil cytoplasmic antibody (ANCA) and anti-saccharomyces cerevisiae antibody (ASCA) in the work-up and monitoring of patients with inflammatory bowel disease does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
For members with contracts without primary coverage criteria, determination of anti-neutrophil cytoplasmic antibody (ANCA) and anti-saccharomyces cerevisiae antibody (ASCA) in the work-up and monitoring of patients with inflammatory bowel disease is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
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Rationale: |
This policy references a 1999 Blue Cross Blue Shield Association Technology Evaluation Center Assessment that evaluated ANCA and ASCA in the 3 following clinical situations.
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.
In this setting, the average specificity of ANCA and ASCA is 90% and 94%, respectively, but the Blue Cross Blue Shield Association Technology Evaluation Center Assessment concluded that this specificity is not likely to be high enough to confirm the diagnosis such that additional testing could be foregone.
Since 1999, there have been numerous publications evaluating the diagnostic accuracy of these tests for the previous two indications, with results generally indicating performance characteristics in a similar range. The largest of these studies evaluating ANCA, reported sensitivities of 50% and 30%, respectively, and specificities of 95% and 99%. The largest studies evaluating ASCA reported sensitivities of 60% and 52%, respectively, and specificities of 91% and 96%, respectively. These studies employed normal healthy subjects as the control population, so that the reported specificity may not reflect the specificity in actual clinical practice.
In this setting, the pooled sensitivity of the test is 84%. This specificity, although still 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.
2005 Update
Since 1999, several publications have addressed this issue. Similar to previous research, these studies all used populations of patients with established UC and CD, with one exception. Joossens et al. identified 97 patients with indeterminate colitis (IC) followed prospectively. A definitive diagnosis of UC was made in 11 patients; 7 of 11 were ANCA positive and ASCA negative. A diagnosis of CD was made in 10 patients; 8 of 10 were ANCA negative and ASCA positive. Approximately half of the patients with IC did not have positivity for either serum marker.
Several studies evaluated the use of these markers for indications not covered in the original assessment. Several articles attempted to correlate titers of ANCA and/or ASCA with disease activity, but did not generally find such a correlation. Other studies evaluated the presence of serum markers in unaffected relatives of patients with IBD, reporting positive results in approximately 25%–50% of family members. However, these studies did not report on the incidence of IBD in these relatives with positive antibodies.
No studies demonstrated the use of these markers in lieu of a standard work-up 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.
2006 Update
A literature review was conducted for the period of April 2005 through August 2006. The results of that literature review did not result in a change to the policy statement. No clinical studies were identified that addressed the open issues identified above. Additional references to descriptive studies were added to the policy.
2007–2008 Update
A literature review was conducted using MEDLINE in January 2008. The results of that literature review did not result in a change to the policy statement. No clinical studies were identified that addressed the open issues identified above. One additional reference is added to the policy.
2012 Update
A literature review was conducted through May 2012. There were no articles identified that would prompt a change in the coverage statement. Andreoli and Carpenter’s Cecil Essentials of Medicine textbook has the following information, ““Perinuclear antineutrophil cytoplasmic antibody (p-ANCA) is positive in up to 70% of patients with ulcerative colitis but rarely positive in patients with Crohn’s disease, whereas anti-Saccharomyces cerevisiae antibodies (ASCA) are common in Crohn’s disease and are rarely found in ulcerative colitis. However, these serologic tests are not sensitive or specific enough to use in routine clinical practice.”
There is a lack of scientific evidence to demonstrate that the use of these markers in place of the standard work-up for IBD improve health outcomes. The policy statement is unchanged.
2013 Update
A literature search was conducted using the MEDLINE database through May 2013. There was no new literature identified that would prompt a change in the coverage statement.
2014 Update
A literature search conducted through May 2014 did not reveal any new information that would prompt a change in the coverage statement.
2017 Update
A literature search conducted using the MEDLINE database through November 2017 did not reveal any new information that would prompt a change in the coverage statement.
2018 Update
A literature search was conducted through November 2018. There was no new information identified that would prompt a change in the coverage statement.
2021 Update
Annual policy review completed with a literature search using the MEDLINE database through November 2021. No new literature was identified that would prompt a change in the coverage statement.
2022 Update
Annual policy review completed with a literature search using the MEDLINE database through November 2022. No new literature was identified that would prompt a change in the coverage statement.
2023 Update
Annual policy review completed with a literature search using the MEDLINE database through November 2023. No new literature was identified that would prompt a change in the coverage statement.
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CPT/HCPCS: | |
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References: |
1999 Blue Cross Blue Shield Association Technology Evaluation Center Assessment; Tab 12. Abad E, Tural C, Mirapeix E, et al.(1997) Relationship between ANCA and clinical activity in inflammatory bowel disease: variation in prevalence of ANCA and evidence of heterogeneity. J Autoimmunity 1997; 10:175-80. Accelerated Partial Breast Irradiation as Sole Source Radiotherapy After Breast-Conserving Surgery For Early Stage Breast Cancer. Blue Cross Blue Shield Association Technology Evaluation Center. August 2007. Annese V, Andreoli A, Andriulli A, et al.(2001) Familial expression of anti-Saccharomyces cerevisiae Mannan antibodies in Crohn’s disease and ulcerative colitis: a GISC study. Am J Gastro 2001; 96(8):2407-12. Bansi DS, Chapman RW, Fleming KA.(1996) Prevalence and diagnostic role of antineutrophil cytoplasmic antibodies in inflammatory bowel disease. Eur J Gastroenterol Hepatol 1996; 8:881-5. Claise C, Johanet C, Bouhnik Y, et al.(1996) Antineutrophil cytoplasmic autoantibodies in autoimmune liver and inflammatory bowel disease. Liver 1996; 16:28-34. Forde AM, Freighery Jackson J.(1996) Anti-monocyte cytoplasmic antibodies in granulomatous disease. Clin Immunol Immunopathol 1996; 81:88-95. Freeman H, Roeck B, Devine D, et al.(1997) Prospective evaluation of neutrophil autoantibodies in 500 consecutive patients with inflammatory bowel disease. Can J Gastro 1997; 11:203-7. Gigase P, De Clerck LS, Van Cotthem KA, et al.(1997) Anti-neutrophil cytoplasmic antibodies in inflammatory bowel disease with special attention for IgA-class antibodies. Digest Dis Sci 1997; 42:2171-4. Hardarson S, LaBrecque DR, Mitros FA, et al.(1993) Antineutrophil cytoplasmic antibody in inflammatory bowel and hepatobiliary diseases. High prevalence in ulcerative colitis, primary sclerosing cholangitis, and autoimmune hepatitis. Am J Clin Pathol 1993; 99:277-81. Hertervig E, Wieslander J, Johansson C, et al.(1995) Anti-neutrophil cytoplasmic antibodies in chronic inflammatory bowel disease. Prevalence and diagnostic role. Scan J Gastroenterol 1995; 30:693-8. Huang C.S., Saubermann L.J., & Farraye F.A.(2007) Inflammatory Bowel Disease. In T.E. Andreoli, Carpenter C.J., Griggs R.C., & Benjamin I.J. (Eds.), Andreoli and Carpenter’s Cecil Essentials of Medicine (p.408 ). Philadelphia, PA: Saunders, Elsevier. Jennette JC, Falk RJ.(1993) Antineutrophil cytoplasmic autoantibodies in inflammatory bowel disease. Am J Clin Pathol 1993; 99:221-3. Joossens S, Reinisch W, Vermeire S et al.(2002) The value of serologic markers in indeterminate colitis: a prospective follow-up study. Gastroenterology 2002; 122(5):1242-7. Joossens S, Reinisch W, Vermeire S, et al.(2002) The value of serologic markers in indeterminate colitis: a prospective follow-up study. Gastro 2002; 122(5):1242-7. Kaneko K, Suzuki T, et al.(1995) Antineutrophil cytoplasmic antibodies in Japanese children with ulcerative colitis. J Paediatr Child Health 1995; 31:336-8. Lombardi G, Annese V, Piepoli A, et al.(2000) Antineutrophil cytoplasmic antibodies in inflammatory bowel disease: clinical role and review of the literature. Dis Colon Rectum 2000; 43(7):999-1007. MacDermott RP.(1999) Lack of current clinical value of serological testing in the evaluation of patients with IBD. Inflamm Bowel Dis 1999; 5:64-5. Materials from company's website. http://www.prometheus-labs.com; 1999. Mow WS, Vasiliauskas EA, Lin YC, et al.(2004) Association of antibody responses to microbial antigens and complications of small bowel Crohn’s disease. 2004. Oudkerk Pool M, Ellerbroek PM, Ridwan BU, et al.(1993) Serum antineutrophil cytoplasmic autoantibodies in inflammatory bowel disease are mainly associated with ulcerative colitis. A correlation study between perinuclear antineutrophil cytoplasmic autoantibodies and clinical parameters, medical, and surgical. Gut 1993; 34:46-50. Peen E, Almer S, Bodemar G, et al.(1993) Anti-lactoferrin antibodies and other types of ANCA in ulcerative colitis, primary sclerosing cholangitis, and Crohn's disease. Gut 1993; 34:56-62. Peeters M, Joossens S, Vermeire S, et al.(2001) Diagnostic value of anti-Saccharomyces cerevisiae and antineutrophil cytoplasmic autoantibodies in inflammatory bowel disease. Am J Gastro 2001; 96(3):730-4. Present DH, Banks PA.(1999) The role of pANCA and ASCA in differentiating ulcerative colitis, Crohn's disease and indeterminate colitis. Inflamm Bowel Dis 1999; 5:66-7. Proujansky R, Fawcett PT, Gibney KM, et al.(1993) Examination of anti-neutrophil cytoplasmic antibodies in childhood inflammatory bowel disease. J Pediatr Gastroenterol Nutr 1993; 17;193-7. Quinton JF, Sendid B, Reumaux D, et al.(1998) Anti-Saccharomyces cerevisiae mannan antibodies combined with antineutrophil cytoplasmic autoantibodies in inflammatory bowel disease: prevalence and diagnostic role. Gut 1998; 42:788-91. Reumaux D, Colombel JF, Masy E et al.(2000) Anti-neutrophil cytoplasmic auto-antibodies (ANCA) in ulcerative colitis (UC): no relationship with disease activity. Inflamm Bowel Dis 2000; 6(4):270-4. Reumaux D, Colombel JF, Masy E, et al.(2000) Anti-neutrophil cytoplasmic auto-antibodies (ANCA) in ulcerative colitis (UC): no relationship with disease activity. Inflamm Bowel Dis 2000; 6(4):270-4. Roozendaal C, Pogany K, Hummel EJ, et al.(1999) Titres of anti-neutrophil cytoplasmic antibodies in inflammatory bowel disease are not related to disease activity. QJM 1999; 92(11):651-8. Ruemmele FM, Targan SR, Levy G, et al.(1998) Diagnostic accuracy of serological assays in pediatric inflammatory bowel disease. Gastroenterolgy 1998; 115:822-9. Satsangi J, Landers CJ, Welsh KI, et al.(1998) The presence of antineutrophil antibodies reflects clinical and genetic heterogeneity within inflammatory bowel disease. Inflamm Bowel Dis 1998; 4:18-26. Sendid B, Colombel JF, Jacquinot PM, et al.(1996) Specific antibody response to oligomannosidic epitopes in Crohn's disease. Clin Diagn Lab Immunol 1996; 3:219-26. Sutton CL, Yang H, Li Z, et al.(2000) Familial expression of anti-Saccharomyces cerevisiae mannan antibodies in affected and unaffected relatives of patients with Crohn’s disease. Gut 2000; 46(1): 58-63. Taddei C, Audrain MA, Reumaux D, et al.(1999) Alpha1-antitrypsin phenotypes and anti-neutrophil cytoplasmic auto-antibodies in inflammatory bowel disease. Eur J Gastroenterol Hepatol 1999; 11(11):1293-8. Targan SR.(1999) The utility of ANCA and ASCA in inflammatory bowel disease. Inflamm Bowel Dis 1999; 5:61-3. Vecchi M, Bianchi MB, Sinico RA, et al.(1994) Antibodies to neutrophil cytoplasm in Italian patients with ulcerative colitis: sensitivity, specificity, and recognition of putative antigens. Digestion 1994; 55:34-9. Winter HS, Landers CJ, Winkelstein A, et al.(1994) Antineutrophil cytoplasmic antibodies in children with ulcerative colitis. J Pediatr 1994; 125:707-11;. |
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Group specific policy will supersede this policy when applicable. This policy does not apply to the Wal-Mart Associates Group Health Plan participants or to the Tyson Group Health Plan participants.
CPT Codes Copyright © 2024 American Medical Association. |