mp-285 - mp-285 - Medical Policies
Serum Antibodies for the Diagnosis of Inflammatory Bowel Disease
Policy Number: MP-285
Latest Review Date: December 2020
Category: Medical Policy
The use of serologic markers is considered not medically necessary and investigational for all indications, including but not limited to:
- antibodies of outer membrane porin C of the bacteria Eschericia coli (anti-OmpC)
- anti-chitobioside antibodies (ACCA IgA)
- anti-laminaribioside antibodies (ALCA IgG)
- anti-mannobioside antibodies (AMCA IgG)
- anti-neutrophil cytoplasmic antibodies (ANCA)
- anti-Saccharomyces cerevisiae (ASCA)
- flagellin CBir1 (anti-cBir1)
- Pseudomonas fluorescens-associated sequence 12 (anti-12)
DESCRIPTION OF PROCEDURE OR SERVICE:
Inflammatory bowel disease (IBD) can be subdivided into ulcerative colitis (UC) and Crohn’s disease (CD), 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 ulcerative colitis and Crohn’s disease cannot be made with certainty. Two serum antibodies, anti-neutrophilic cytoplasmic antibodies (ANCA) and anti- Saccharomyces cerevisiae (ASCA) have been associated with IBD; however, they have low sensitivities and are not completely specific to the disease. A number of subtypes of these markers have also been identified based on the specific antigen that is targeted. Testing for ANCA is currently available in most clinical laboratories. ASCA is a more recent assay that is becoming more widely available, but the reliability of testing for ASCA among different labs may be more variable as compared to ANCA.
These serum antibodies have several potential uses. They can be used as diagnostic tests to improve the efficiency and accuracy of diagnosing IBD to decrease the extent of the diagnostic workup or to avoid invasive tests. As a diagnostic test, they might also be useful in differentiating between UC and CD in cases of indeterminate colitis. A second potential use is to classify subtypes of IBD by location of disease (i.e., proximal versus distal bowel involvement) or by disease severity, thereby providing prognostic information. It has also been proposed that these markers may predict response to anti-tumor necrosis factor (TNF) therapy or identify susceptibility to IBD among family members of an affected individual.
The Prometheus© IBD Serology 7 (Prometheus Inc., San Diego, CA) is a quantitative analysis of biomarkers for IBD prediction and differentiation. Prometheus IBD Serology 7 is only offered at Prometheus. This system uses a 2-step process to diagnose IBD and to differentiate between UC and CD. The first step is a panel of four markers intended to maximize the sensitivity and negative predictive value of the test. Patients who test positive on the initial screen are further analyzed by a set of proprietary markers and enzyme reagents to distinguish between true positive results and artifacts of fixation. In this way, the Prometheus system is intended to increase the specificity of the test compared to other laboratories. The company also markets a testing strategy for predicting response to anti-TNF therapy and to monitor therapy.
Two serum antibodies, ANCA and ASCA have been associated with IBD. These antibodies may have potential use in the diagnosis of IBD, differentiating types of IBD, and predicting response to treatment.
This policy is based on an evidence review that was recently performed on December 31, 2020.
Summary of Evidence
At present, no single marker with qualities that are satisfactory for the diagnosis and treatment of IBD has been identified, although panels of some antibodies are being evaluated with keen interest. The discovery of novel IBD-specific and sensitive markers is anticipated. Such markers could minimize the use of endoscopic and radiologic examinations and could enable clinicians to implement individualized treatment plans designed to improve the long-term prognosis of patients with IBD.
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. Because of the suboptimal sensitivity levels of these serological tests, routine use of this screening is not supported. 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. Although the specificity of these tests are relatively high (82-100%), the sensitivity is low (32 -50%), which indicates that a negative result will not be clinically helpful. There is insufficient evidence in the peer-reviewed published medical literature to establish the effectiveness of this test on health outcomes when compared to established tests or technologies.
Practice Guidelines and Position Statements
American Gastroenterological Association
No guideline or position statement was found on The American Gastroenterological Association website regarding the use of serum antibodies for the diagnosis of inflammatory bowel disease.
American College of Gastroenterology
The American College of Gastroenterology practice guidelines for management of CD in adults stated that serological studies evaluating ASCA, ANCA, anti-CBir1, anti-OmpC are evolving to provide adjunctive support for the diagnosis of CD; however, they are not sensitive or specific enough to be recommended for use as a screening tools.
North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition
In 2012, the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition stated that commercially available serologic assays mail fail to detect CD in at least 30% of children with this disorder and may wrongly suggest a diagnosis of IBD that is not supported by subsequent and definitive (endoscopic study) testing. They further stated that it may be most prudent for primary care providers to avoid ordering these tests and instead pursue referral and more conclusive specialty testing.
The North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the Crohn’s and Colitis Foundation of America's consensus conference report on differentiating UC from CD in children and young adults stated that the clinical value of serology in patients with indeterminate colitis (IC) remains a topic of research, and further investigation should ascertain, among other areas, the role of surrogate laboratory markers (e.g., genetics, microbiology, and serology) in distinguishing these entities. A proposed algorithm to aid clinicians in differentiating UC from CD does not include serological testing.
U.S. Preventive Services Task Force
ANCA, Antibodies for the Diagnosis of Ulcerative Colitis and Crohn’s Disease, ASCA, Crohn’s Disease, (ANCA, ASCA), Prometheus System, Diagnosis of Inflammatory Bowel Disease, Ulcerative Colitis, Prometheus Labs, anti-neutrophil cytoplasmic antibody, anti-Saccharomyces cerevisiae antibody, DNA testing for Crohn’s disease, inflammatory bowel disease, Prometheus, Prometheus Crohn’s prognostic test for DNA testing, Prometheus NOD2/CARD15, Prometheus IBD sgi diagnostic, IBSchek, Biomarker, Serological antibody, antibodies of outer membrane porin C of the bacteria Eschericia coli, anti-OmpC, Pseudomonas fluorescens-associated sequence I2, anti-I2, flagellin CBir1, anti-cBir1, antichitobioside antibodies, ACCA IgA, antilaminaribioside antibodies, ALCA IgG, antimannobioside antibodies, AMCA IgG
APPROVED BY GOVERNING BODIES:
Prometheus is located in San Diego, CA and licensed in several states including New York and California. It has not been cleared or approved by the U.S. Food and Drug Administration. Prometheus Laboratories Inc. is a CAP accredited CLIA laboratory.
Coverage is subject to member’s specific benefits. Group specific policy will supersede this policy when applicable.
ITS: Home Policy provisions apply
FEP contracts: Special benefit consideration may apply. FEP does not consider investigational if FDA approved and will be reviewed for medical necessity.
There is no specific CPT code for detection of ANCA or ASCA. Providers may be using the following nonspecific CPT codes:
Immunoassay for analyte other than infectious agent antibody or infectious agent antigen; qualitative or semiquantitative, multiple step method
Immunoassay for analyte other than infectious agent antibody or infectious agent antigen; quantitative, not otherwise specified.
Immunofluorescence, per specimen; initial single antibody stain procedure
each additional single antibody stain procedure (List separately in addition to code for primary procedure)
Gastroenterology (irritable bowel syndrome [IBS]), immunoassay for anti-CdtB and anti-vinculin antibodies, utilizing plasma, algorithm for elevated or not elevated qualitative results
Cytolethal distending toxin B (CdtB) and vinculin IgG antibodies by immunoassay (i.e., ELISA) (Effective 07/01/2020) (For IBSchek)
According to information on the Prometheus Laboratories Inc. website, the Prometheus® IBD sgi Diagnostic™ test is billed using 83520 (x8), 82397 (x3), 86140 (x1), 88346, 88350, 81479 (x4).
According to information on Prometheus Laboratories Inc. website, the Prometheus® Crohn’s Prognostic test is billed using 83520 (x5), 88346, 88350, and 81401.
Cytolethal distending toxin B (CdtB) and vinculin IgG antibodies by immunoassay (i.e. ELISA) (Deleted 12/31/2020) (For IBSchek)
- American College of Gastroenterology. (2018, March). ACG Practice Guidelines. Management of Crohn’s disease in adults. Retrieved November 29, 2018 from http://gi.org/guideline.
- Anand V, Russell AS, Tsuyuki R, Fedorak R. Perinuclear antineutrophil cytoplasmic autoantibodies and anti-Saccharomyces cerevisiae antibodies as serological markers are not specific in the identification of Crohn's disease and ulcerative colitis. Can J Gastroenterol. 2008 Jan; 22(1):33-6.
- Annese V, Andreoli A, Andriulli A, et al. Familial expression of anti- Saccharomyces cerevisiae Mannan antibodies in Crohn’s disease and ulcerative colitis: A GISC study. Am J Gastroenterol 2001; 96(8): 2407-1
- Blue Cross Blue Shield Association. Technology Evaluation Center Assessment 1999, Tab 12.
- Blue Cross Blue Shield Association. Serum antibodies for the diagnosis of inflammatory bowel disease. Medical Policy Reference Manual, June 2010.
- Desplat-Jego S, Johanet C, Escande A, Goetz J, Fabien N, Olsson N, et al. Update on Anti-Saccharomyces cerevisiae antibodies, anti-nuclear associated anti-neutrophil antibodies and antibodies to exocrine pancreas detected by indirect immunofluorescence as biomarkers in chronic inflammatory bowel diseases: results of a multicenter study. World J Gastroenterol. 2007 Apr 28; 13(16):2312-8.
- Dotan I. New serologic markers for inflammatory bowel disease diagnosis. Dig Dis. 2010; 28(3):418-423.
- Dubinsky M, Ofman J, Urman M, Targan S, Seidman E. Clinical utility of serodiagnostic testing in suspected pediatric inflammatory bowel disease. Am J Gastroenterol. 2001 Mar; 96(3):758-65.
- Dubinsky MC, Lin YC, Dutridge D, Picornell Y, Landers CJ, Farrior S, et al., for the Western Regional Pediatric IBD Research Alliance. Serum immune responses predict rapid disease progression among children with Crohn's disease: immune responses predict disease progression. Am J Gastroenterol. 2006 Feb; 101(2):360-7.
- Gupta A, Derbes C, Sellin J. Clinical indications of the use of antineutrophil cytoplasmic antibodies and anti-Saccharomyces cerevisiae antibodies in the evaluation of inflammatory bowel disease at an academic medical center. Inflamm Bowel Dis. Oct 2005; 11(10):898-902.
- Gupta SK, Fitzgerald JF, Croffie JM, et al. Comparison of serological markers of inflammatory bowel disease with clinical diagnosis in children. Inflamm Bowel Dis 2004; 10(3): 240-4.
- Hanauer SB, Sandborn W and the Practice Parameters Committee of the American College of Gastroenterology. Management of Crohn’s disease in adults. American Journal of Gastroenterology 2001, Vol. 96, No. 3.
- Hayes, Inc. Hayes Genetic Testing Evaluation (Report). Lansdale, PA: Hayes, Inc. Use of Anti-Infliximab Antibody Levels to Monitor Infliximab Treatment in Patients with Inflammatory Bowel Disease (IBD) Dec. 2017
- Hayes, Inc. Medical Technology Directory. (2013, March; last update search January 2017). Serological assays for the diagnosis and management of inflammatory bowel disease: Crohn’s Disease
- Israeli E, Grotto I, Gilburd B, et al. Anti-Saccharomyces cerevisiae and antineutrophil cytoplasmic antibodies as predictors of inflammatory bowel disease. Gut. Sept 2005; 54(9):1232-6.
- Joossens S, Reinisch W, Vermeire S, et al. The value of serologic markers in indeterminate colitis: a prospective follow-up study. Gastroenterology 2002; 122(5): 1242-7.
- Kaul A, et al. Serum anti-glycan antibody biomarkers for inflammatory bowel disease diagnosis and progression: a systematic review and meta-analysis. Inflamm Bowel Dis 2012 Oct; 28(10):1872-84.
- Kornbluth A, Sachar DB; Practice Parameters Committee of the American College of Gastroenterology. Ulcerative colitis practice guidelines in adults (update): American College of Gastroenterology, Practice Parameters Committee. Am J Gastroenterol. 2004 Jul; 99(7):1371-85. Accessed August 12, 2008. Available at URL address: http://www.gi.org/physicians/clinicalupdates.asp#guidelines
- Lichtenstein GR, Hanauer SB, Sandborn WJ, and the Practice Parameters Committee of the American College of Gastroenterology. Management of Crohn’s disease in adults. Am J Gastroenterol. 2009; 104(2):465-483.
- Linskens RK, Mallant-Hent RC, Groothuismink A, Bakker-Jonges LE, van de Merwe JP, Hooijkaas H, et al. Evaluation of serological markers to differentiate between ulcerative colitis and Crohn’s disease: pANCA, ASCA and agglutinating antibodies to anaerobic coccoid rods. Eur J Gastroenterol Hepatol. 2002 Sep 01; 14(9):1013-18.
- Lombardi G, Annese V, Piepoli A, et al. Antineutrophil cytoplasmic antibodies in inflammatory bowel disease: Clinical role and review of the literature. Dis Colon Rectum 2000; 43(7): 999-1007.
- Mitsuyama K, et al. Antibody markers in the diagnosis of inflammatory bowel disease. World J Gastroenterol. 2016 Jan 21; 22(3): 1304–1310. Published online 2016 Jan 21. Accessed October 18, 2019. Available at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4716040/
- Mokhtarifar A, Ganji A, Sadrneshin M. et al. Diagnostic value of ASCA and atypical p-ANCA in differential diagnosis of inflammatory bowel disease. Middle East J Dig Dis 2014 Apr; 5(2); 93-97.
- Mow WS, Vasiliauskas EA, Lin YC, et al. Association of antibody responses to microbial antigens and complications of small bowel Crohn’s disease. Gastroenterology 2004; 126(2): 414-24.
- North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition. Rufo, PA, Denson LA, Sylvester FA et al. Health supervision in the management of children and adolescents with IBD: NASPGHAN recommendations. JPGN 2012; 55: 93-108.
- North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition; Colitis Foundation of America, Bousvaros A, Antonioli DA, Colletti RB, et al. Differentiating ulcerative colitis from Crohn disease in children and young adults: Report of a working group of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the Crohn’s and Colitis Foundation of America. J Pediatr Gastroenterol Nutr. 2007; 44(5):653-674.
- Papp M, et al. Serological studies in inflammatory bowel disease: how important are they? Curr Opin Gastroenterol 2014 Jul; 30(4):359-64.
- Papp M, Norman GL, et al. Utility of serological markers in inflammatory bowel diseases: Gadget or magic? World J Gastroenterol, April 2007; 13(14): 2028-2036.
- Peeters M, Joossens S, Vermeire S, et al. Diagnostic value of anti- Saccharomyces cerevisiae and antineutrophil cytoplasmic autoantibodies in inflammatory bowel disease. Am J Gastroenterol 2001; 96(3): 730-4.
- Reese GE, Constantinides VA, Simillis C, et al. Diagnostic precision of anti-Saccharomyces cerevisiae antibodies and perinuclear antineutrophil cytoplasmic antibodies in inflammatory bowel disease. Am J Gastroenterol, October 2006; 101(10): 2410-2422.
- Reumaux D, Colombel JF, Masy E, et al. 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. Titres of anti-neutrophil cytoplasmic antibodies in inflammatory bowel disease are not related to disease activity. QJM 1999; 92(11): 651-8.
- Russell RK, Ip B, Aldhous MC, et al. Anti-Saccharomyces cerevisiae antibodies status is associated with oral involvement and disease severity in Crohn Disease. Journal of Pediatric Gastroenterology and Nutrition, February 2009, Vol. 48, No. 2, pp. 161-167.
- Rutgeerts P, Vermeire S. Clinical value of the detection of antibodies in the serum for diagnosis and treatment of inflammatory bowel disease. Gastroenterology. 1998; 115(4):1006-1009.
- Sabery N, Bass, D. Use of Serologic Markers as a Screening Tool in Inflammatory Bowel Disease Compared With Elevated Erythrocyte Sedimentation Rate and Anemia Pediatrics 2007 119: e193-e199.
- Saito H, Fukuda Y, Katsuragi K, et al. Isolation of peptides useful for differential diagnosis of Crohn’s disease and ulcerative colitis. Gut. 2003 Apr; 52(4):535-40.
- Schoepfer AM, Trummler M, Seeholzer P, et al. Discriminating IBD from IBS: Comparison of the test performance of fecal markers, blood leukocytes, CRP, and IBD antibodies. Inflamm Bowel Dis, January 2008; 14(1): 32-39.
- Shaw M, Gebhard R, Loftus E, Pieper-Bigelow C. Institute for Clinical Systems Improvement Technology Assessment Report #65. Serum antibodies for the diagnosis of inflammatory bowel disease (IBD): pANCA for ulcerative colitis (UC) and ASCA for Crohn’s Disease (CD). ICSI; 2002. Accessed August 12, 2008. Available at URL address: http://www.icsi.org/index
- Sura SP, Ahmed A, Cheifetz A, et al. Characteristics of inflammatory bowel disease serology in patients with indeterminate colitis. J Clin Gastroenterol. 2014 Apr; 48(4): 351-355.
- Sutton CL, Yang H, Li Z, et al. 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. Alpha1-antitrypsin phenotypes and anti-neutrophil cytoplasmic auto-antibodies in inflammatory bowel disease. Eur J Gastroenterol Hepatol 1999; 11(11): 1293-8.
- Teml A, Kratzer V, Schneider B, et al. Anti-Saccharomyces cerevisiae antibodies: a stable marker for Crohn’s disease during steroid and 5-aminosalicylic acid treatment. Am J Gastroenterol 2003; 98(10): 2226-31.
- Vermeire S, Joossens S, Peeters M, et al. Comparative study of ASCA assays in inflammatory bowel disease. Gastroenterology. 2001; 120(4)827-833.
- Winifred S. Hayes, Inc. Medical Technology Directory. (2013, April; last update search March 2017). Serological assays for the diagnosis and management of inflammatory bowel disease: Ulcerative colitis
- Zholudev A, Zurakowski D, Young W, et al. Serologic testing with ANCA, ASCA and anti-OmpC in children and young adults with Crohn’s disease and ulcerative colitis: Diagnostic value and correlation with disease phenotype. Am J Gastroenterol 2004; 99(11): 2235-41.
Medical Policy Group, July 2006 (2)
Medical Policy Administration Committee, August 2006
Available for comment August 15-September 28, 2006
Medical Policy Group, July 2008 (1)
Medical Policy Group, July 2010 (1)
Medical Policy Group, June 2012 (1) Update to Description, Key Points and References; no change in policy statement
Medical Policy Group, October 2015 (3): Updates to Description, Key Points, Key Words, Approved Governing Bodies, Coding and References. Policy statement clarified by adding additional serologic markers. No change in policy intent.
Medical Policy Group, November 2015: 2016 Annual Coding Update. Added CPT code 88346 and new CPT code 88350 to current coding section and moved CPT code 88347 from current coding to previous coding.
Medical Policy Group, June 2019: July 2019 quarterly coding update. Added new CPT code 0085U under Current Coding section.
Medical Policy Group, October 2019 (9): 2019 Updates to Description, Key Points, References. Removed previous coding section: 83516, 83520, 88346, 88347, and 88350. Added key words: Biomarker, Serological antibody, antibodies of outer membrane porin C of the bacteria Eschericia coli, anti-OmpC, Pseudomonas fluorescens-associated sequence I2, anti-I2, flagellin CBir1, anti-cBir1, antichitobioside antibodies, ACCA IgA, antilaminaribioside antibodies, ALCA IgG, antimannobioside antibodies, AMCA IgG. No changes to policy statement.
Medical Policy Group, November 2019: 2020 Annual Coding Update. Created Previous Coding Section to include code 0085U.
Medical Policy Group, February 2020 (9): Removed codes 81401 and 81479 from policy.
Medical Policy Group, March 2020: Quarterly coding update. Added new CPT code 0164U to Current Coding.
Medical Policy Group, June 2020: Quarterly coding update. Added new CPT code 0176U to Current Coding.
Medical Policy Group, October 2020: 2021 Annual Coding Update. Code 0085U was already listed in Previous Coding Section. Added deleted effective date of 12/31/2020.
Medical Policy Group, December 2020 (9): 2020 Updates to Description, Key Points, References. No change to policy statement.
This medical policy is not an authorization, certification, explanation of benefits, or a contract. Eligibility and benefits are determined on a case-by-case basis according to the terms of the member’s plan in effect as of the date services are rendered. All medical policies are based on (i) research of current medical literature and (ii) review of common medical practices in the treatment and diagnosis of disease as of the date hereof. Physicians and other providers are solely responsible for all aspects of medical care and treatment, including the type, quality, and levels of care and treatment.
This policy is intended to be used for adjudication of claims (including pre-admission certification, pre-determinations, and pre-procedure review) in Blue Cross and Blue Shield’s administration of plan contracts.
The plan does not approve or deny procedures, services, testing, or equipment for our members. Our decisions concern coverage only. The decision of whether or not to have a certain test, treatment or procedure is one made between the physician and his/her patient. The plan administers benefits based on the member’s contract and corporate medical policies. Physicians should always exercise their best medical judgment in providing the care they feel is most appropriate for their patients. Needed care should not be delayed or refused because of a coverage determination.
As a general rule, benefits are payable under health plans only in cases of medical necessity and only if services or supplies are not investigational, provided the customer group contracts have such coverage. The following Association Technology Evaluation Criteria must be met for a service/supply to be considered for coverage:
1. The technology must have final approval from the appropriate government regulatory bodies;
2. The scientific evidence must permit conclusions concerning the effect of the technology on health outcomes;
3. The technology must improve the net health outcome;
4. The technology must be as beneficial as any established alternatives;
5. The improvement must be attainable outside the investigational setting.
Medical Necessity means that health care services (e.g., procedures, treatments, supplies, devices, equipment, facilities or drugs) that a physician, exercising prudent clinical judgment, would provide to a patient for the purpose of preventing, evaluating, diagnosing or treating an illness, injury or disease or its symptoms, and that are:
1. In accordance with generally accepted standards of medical practice; and
2. Clinically appropriate in terms of type, frequency, extent, site and duration and considered effective for the patient’s illness, injury or disease; and
3. Not primarily for the convenience of the patient, physician or other health care provider; and
4. Not more costly than an alternative service or sequence of services at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of that patient’s illness, injury or disease.