BlueCross and BlueShield of Montana Medical Policy/Codes
Serological Markers for Diagnosis and Management of Inflammatory Bowel Disease (IBD)
Chapter: Medicine: Tests
Current Effective Date: March 15, 2014
Original Effective Date: December 27, 2013
Publish Date: January 14, 2014
Description

Inflammatory bowel disease (IBD) is a general term used to describe diseases that cause inflammation of the intestines. Crohn’s disease (CD) and ulcerative colitis (UC) are the two major IBDs. In Crohn’s disease, inflammation usually occurs in the lower part of the small intestine (distal ileum), but may affect any part of the digestive tract. The inflammation in Crohn’s disease extends deep into the affected tissue, in contrast to UC, which causes inflammation and ulcers in the top layers of the lining of the colon and rectum. Inflammation in CD is asymmetrical and segmental, with areas of both healthy and diseased tissue, in contrast to UD where inflammation is symmetrical and uninterrupted from the rectum proximally.

Both CD and UC are chronic, and affect men and women on an approximately equal basis. These diseases are seen most commonly in northern Europe and North America. Approximately 20 percent of individuals with CD have a blood relative with some form of IBD. The onset of CD is usually between ages 15 and 30 with a second smaller peak of incidence between 50 and 70. Over the past decade, several reports have noted an increase in the prevalence of CD in various geographic regions. Although there are many theories concerning the cause of CD and UC, none have been proven. Since many of the symptoms of CD and UC are similar, diagnosis is often difficult, time consuming, and invasive. Approximately 10-12 percent of cases is not initially classifiable and is referred to as "indeterminate colitis."  Over time, about half of these patients are eventually classified as CD or UC.

Anti-Neutrophil Cytoplasmic Antibody (ANCA) and Anti-Saccharomyces Cerevisiae Antibody (ASCA) have been investigated as techniques 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 imaging. Testing for ANCA is available in most clinical laboratories. ASCA is more recently developed and may not be 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. 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 (see medical policy MED207.153).

Clinical management of Crohn’s disease and ulcerative colitis requires repeated assessments; endoscopy with histological examination remains the gold standard for detecting and quantifying intestinal inflammation. Several laboratory tests have been studied but to date, a disease marker is not yet available. In recent years, research has drawn attention to fecal markers owing to their specificity for intestinal inflammation, ease of sample collection, availability of commercial immunoassays and convenience. These biologic markers have been used to assess inflammatory bowel disease patients for the purposes of their clinical management and response to treatment.

Prometheus® Laboratories Inc. (San Diego, CA) offers a variety of proprietary diagnostic tests for a variety of disorders, including one for the diagnosis of inflammatory bowel disease (IBD). The IBD First Step™ and IBD Diagnostic System tests are frequently requested by providers as "Prometheus Testing."  Prometheus® IBD sgi Diagnostic™ includes the serological markers ASCA immunoglobulin A (IgA), ASCA immunoglobulin G (IgG), ANCA IgG, perinuclear anti-neutropholic cytoplasmic antibody (pANCA), DNAse pANCA, anti-outer membrane porin C (anti-OmpC), anti-CBir1 flagellin (anti-CBir1), Fla-X flagellin, and A4-Fla2 flagellin.

Policy

Each benefit plan, summary plan description or contract defines which services are covered, which services are excluded, and which services are subject to dollar caps or other limitations, conditions or exclusions.  Members and their providers have the responsibility for consulting the member's benefit plan, summary plan description or contract to determine if there is any exclusion or other benefit limitations applicable to this service or supply.  If there is a discrepancy between a Medical Policy and a member's benefit plan, summary plan description or contract, the benefit plan, summary plan description or contract will govern.

Coverage

Serological markers for diagnosis and/or management of inflammatory bowel disease (IBD) are considered experimental, investigational and/or unproven for all the following tests; including but not limited to:

  • Anti-neutrophilic cytoplasmic antibody (ANCA), perinuclear anti-neutrophilic cytoplasmic antibody (pANCA);
  • Anti-saccharomyces cerevisiae antibody (ASCA);
  • Anti-outer membrane porin C (anti-OmpC) antibody;
  • Anti-CBir1 flagellin (anti-CBir1) antibody.

IBD diagnostic testing combining serologic, genetic, and inflammatory markers (eg, Prometheus® IBD sgi Diagnostic™) is considered experimental investigational and/or unproven.

Rationale

A serology panel including anti-neutrophil cytoplasmic antibodies (ANCA), anti-Saccharomyces cerevisae IgG and IgA antibodies (ASCA), and anti-OmpC antibodies (outer membrane porin from E. coli) are marketed by Prometheus Laboratories as the IBD First Step. This panel has not been shown to have levels of specificity sufficient to distinguish ulcerative colitis from CD in indeterminate cases.

Research into the pathogenesis of inflammatory bowel disease in the areas of mucosal immunology, genetics, the role of bacterial products, and mediators of tissue damage has identified new sets of “subclinical” serological markers known as ANCA. ANCA have also been found to be associated with Wegener's granulomatosis and other forms of systemic vasculitides, and more recently with sclerosing cholangitis and other autoimmune liver diseases.

“Atypical” ANCA yielding a perinuclear staining pattern (pANCA) with alcohol-fixed neutrophils is primarily found in patients with ulcerative colitis; pANCA has been found to be detectable in 50-80% of patients with ulcerative colitis, and 10-40% of patients with Crohn's disease. Anti-Saccharomyces cerevisae antibody (ASCA) is primarily detected in patients with Crohn's disease; ASCA has been found to be detectable in 46% to 70% of patients with Crohn's disease and 6-12% of patients with ulcerative colitis.

These tests, however, have insufficient sensitivity to diagnose ulcerative colitis or Crohn's disease. In a paper for the North American Society for Pediatric Gastroenterology and Nutrition, Griffith's concluded that “the relatively low sensitivities of serology for Crohn's disease and ulcerative colitis as documented in all studies argue against there being any greater value of ASCA/ANCA as routine or first-line screening tests for inflammatory bowel disease in comparison to clinical acumen and the equally sensitive measurement of acute phase reactants. Moreover, the need for performance of definitive radiologic and endoscopic studies to guide therapy by defining the extent and nature of IBD will not be averted by positive serologic tests.” Gupta, et al. examined the concordance of serologic testing for inflammatory bowel disease with clinical diagnosis established by traditional testing in children. The investigators found that the sensitivity of serologic testing is insufficient to replace traditional studies when evaluating children for inflammatory bowel disease. The investigators evaluated the results of ANCA and ASCA testing in 107 children who had serologic testing for inflammatory bowel disease at their center, and compared these results with their clinical diagnosis. The investigators calculated that the sensitivity, specificity, positive and negative predictive values of serologic testing for UC were 69.2%, 95.1%, 90.0% and 87.1%, respectively, and for CD were 54.1%, 96.8%, 90.9% and 80.8% respectively. The investigators concluded, “The low sensitivity, especially for CD, precludes the possibility that the IBD Diagnostic System can replace traditional studies when evaluating for inflammatory bowel disease.”

Some investigators have proposed using these serologic tests to differentiate Crohn's disease from ulcerative colitis (Kornbluth & Sachar, 2004). Differentiation of Crohn's disease from ulcerative colitis is clinically problematic only when inflammation is confined to the colon. A number of studies have reported that IgA and IgG ASCA titers are significantly greater and highly specific for CD, and that pANCA positivity is highly specific for ulcerative colitis. However, there is much less published information concerning the subgroup of IBD patients with colitis only, where differentiation of ulcerative colitis from Crohn's disease is clinically problematic. One investigator reported ASCA positivity in only 47% of 17 patients with Crohn's colitis. Another investigator found only 32% of 37 patients with Crohn's colitis were ASCA positive and pANCA negative. Conversely, studies have found that the majority of Crohn's patients positive for pANCA have ulcerative colitis-like presentations. Griffiths explained, “hence, the usefulness of serology is less (where it is needed most), given the higher prevalence of pANCA positivity and the lower prevalence of ASCA positivity in CD confined to the colon.”

“Similarly, whether or not ASCA/ANCA measurement may be helpful in classifying otherwise 'indeterminate' colitis cannot as yet be ascertained. Only a few patients have been studied, and follow-up is too limited.” In the only prospective study of serologic testing in indeterminate colitis, Joossens et al. examined the results of serologic testing for ASCA or ANCA and final diagnosis of Crohn's disease or ulcerative colitis after a six-year follow-up of 97 patients with indeterminate colitis. The largest group of 47 subjects was negative for both ANCA and ASCA; three of these patients had a final diagnosis of Crohn's disease, four patients had a final diagnosis of ulcerative colitis and 40 patients had a final diagnosis of indeterminate colitis. Of 26 subjects who were ASCA positive and ANCA negative, eight had a final diagnosis of Crohn's disease after six years follow up, two had a final diagnosis of ulcerative colitis, and 16 remained with a diagnosis of indeterminate colitis. Of 20 subjects who were ASCA negative and ASCA positive, four had a final diagnosis of Crohn's disease, seven had a final diagnosis of ulcerative colitis, and nine had a final diagnosis of indeterminate colitis. Only four of the 97 subjects were positive for both ANCA and ASCA; two of these had a final diagnosis of Crohn's disease, one had a final diagnosis of ulcerative colitis, and one remained with a final diagnosis of indeterminate colitis. Thus, about one-third (31%) of subjects who were ASCA positive and ANCA negative progressed to Crohn's disease during the six-year follow-up period, and about one third (35%) of subjects who were ASCA negative and ANCA positive progressed to ulcerative colitis during the six-year follow-up period. Joossens, et al. (2002) calculated that, thus far, the sensitivity of ASCA+/ANCA- for Crohn's disease was 66.7% and the specificity is 77.8%, and the sensitivity of ASCA-/ASCA+ for ulcerative colitis is 77.8% and the specificity is 66.7%. Noting that these calculations exclude subjects who remained with the diagnosis of indeterminate colitis, a technology assessment of serologic testing for inflammatory bowel disease by the Institute for Clinical Systems Improvement noted that only a “small number” (21) of subjects were included in this analysis of sensitivity and specificity. Based on their analysis of this prospective study and other published studies of serologic testing in indeterminate colitis, the Institute for Clinical Systems Improvement (ICSI) concluded that the clinical utility of serologic testing in indeterminate colitis has not been established. It has also been noted that this study does not provide direct evidence of improvement in clinical outcomes by basing the management of persons with indeterminate colitis on serologic testing.

ANCA and ASCA testing has not been proven to be useful in selecting therapeutic interventions. “Although this would be desirable, there is no evidence as yet that serological test results can be used to predict the likelihood of therapeutic response to specific interventions,” Griffiths explained. In a prospective clinical study of Crohn's disease patients, Esters, et al. (2002) found no significant relationship between these serologic markers and response to anti-tumor necrosis factor (TNF) therapy.

In addition, studies have not demonstrated correlation of ANCA or ASCA with disease activity, duration of illness, extent of disease, extra-intestinal complications, or surgical or medical treatment in patients with IBD. The Institute for Clinical Systems Improvement (ICSI) technology assessment of serologic testing for IBD concluded “the clinical utility of serological testing is not yet established for the diagnosis of inflammatory bowel disease in patients presenting with symptoms suggestive of IBD” and “the clinical utility of serological testing is not yet established for differentiating between UC and CD in patients with inflammatory bowel disease”.

Additional assays have been developed to use in conjunction with ANCA and ASCA in an effort to improve the diagnostic capabilities of serologic testing. OmpC IgA is an autoantibody to outer membrane porin to Escherichia coli (E. coli) included in the Prometheus serology panel to enhance detection of Crohn's disease (Landers et al). I2 is an IgA antibody that has been detected in patients with Crohn's disease. The I2 serologic response recognizes a novel homologue of the bacterial transcription-factor families from a Pseudomonas fluoresceins associated sequence (Sandborn 2004). However, there are no studies of the clinical utility of anti-OmpC and I2 IgA antibodies in distinguishing CD from UC colitis in persons with inflammatory bowel disease whose diagnosis cannot be established by standard methods.

Landers et al. (2002) reported on serologic test results of a referral center population of 151 patients with Crohn's disease. This study found that immune responses to specific antigens (ASCA, pANCA, OmpC, and I2) are not uniform among Crohn's disease patients. ASCA was detected in 56% of patients, OmpC in 55% of patients, I2 in 50% of patients, and ANCA in 23% of patients. The investigators reported that 85% of patients responded to at least one antigen and that only 4% responded to all four. This study did not demonstrate, however, how these serologic test results relate to clinical behavior and response to therapy. The authors stated, “The relationship of these different patterns of immune responses to clinical behavior is not yet clear.” The authors concluded, “Defining how these antibody re-activities relate to clinical behavior and response to therapeutic modalities will require larger numbers of phenotypically well-characterized patients.”

Mow et al. (2004) reported on the results of a hypothesis generating study, the aim of which was to determine whether Crohn's patients with predominant serum antibody reactivity toward bacterial antigens OmpC and/or I2 were more likely to achieve remission with antibiotics. Study subjects were patients with moderately active right-sided colonic and/or small bowel Crohn's disease who were participating in an 8-week randomized clinical trial comparing the steroid budesonide with or without the antibiotics metronidazole and ciprofloxacin. Subject's serum was analyzed for ASCA, pANCA, anti-OmpC, and anti-I2 antibodies, and subjects were put into one of four “profile groups” (ASCA, pANCA, anti-OmpC/I2, and no or little antibody) depending upon the subjects' levels of antibody response. Twenty-five of 121 subjects were excluded from the analysis because their level of antibody response did not fit the four predominant profile groups. Only two subjects had an ANCA predominant profile, and these subjects were excluded from the analysis. In the steroid plus antibiotic group, 5 of 11 subjects (45.5%) with predominant OmpC and I2 antibodies achieved remission, 5 of 16 subjects with predominantly ASCA antibody (31.3%) achieved remission (similar to the overall remission rate), and 5 of 21 subjects (23.8%) with little or no antibodies achieved remission. In the steroid only group, 7 of 16 subjects (43.8%) with little or no antibodies achieved remission, 8 of 20 (40%) with predominantly ASCA antibody achieved remission, and 3 of 10 (30%) subjects with predominant OmpC and I2 antibodies achieved remission. Although there was a trend toward greater responsiveness to therapy that includes antibiotics in subjects with predominant OmpC and I2 antibodies, and a trend toward less responsiveness in subjects with little or no antibodies, these trends did not achieve statistical significance. The authors concluded that this hypothesis-generating study provides preliminary evidence to suggest that serologic information about Crohn's disease patients may be helpful in defining patients who would best respond to therapy. The authors noted, however, that, “although these trends are provocative, they lack statistical significance.”  The authors concluded that “prospective randomized placebo controlled trials that do not limit patient selection by disease location and do not have concomitant therapy are warranted to test this hypothesis.”

Mow et al. (2004) evaluated the sera of 303 patients with Crohn's disease to determine whether expression of certain antibodies is associated with phenotypic manifestations. The investigators found that patients expressing I2 were significantly more likely to have fibrostenosing Crohn's disease (64.4% versus 40.7%), and to require small bowel surgery (62.2% versus 37.4%). Patients with anti-OmpC were more likely to have internal perforating disease (50% versus 30.7%) and to require small bowel surgery (61.4% versus 44.2%). The investigators stated that these findings suggest an association between these immune responses and Crohn's disease complications. The investigators concluded, “in the future, knowledge of serological response may help the clinician determine the risk for more severe disease characteristics and predict disease behaviors. As a result, it may be possible to tailor therapy more effectively on the basis of specific serological responses. However, these findings must be confirmed by prospective studies that evaluate the presence of these antibody responses and the development of complicated small bowel disease phenotypes.”  An editorial accompanying this study explained that this study is limited by its retrospective nature (Vermeire & Rutgeerts, 2004): “Therefore, it is important that these findings first be confirmed in independent series and more importantly, that prospective studies with these markers be conducted to assess the risk of microbial responses on the development of strictures and perforations and subsequent need for surgery.”

2010 Update

Several articles attempted to correlate titers of ANCA and/or ASCA with disease activity, but did not generally find such a correlation. Mow and colleagues investigated whether serologic antibodies were associated with disease complications. In this case series of 303 patients with Crohn’s disease, certain antibodies were associated with fibrostenosis or perforating disease. However, 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, 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. Two additional antibodies have been also been studied, E.coli anti-OmpC and I2 antibody. However, the same limitations in the published literature apply to these antibodies.

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.

Schoepfer and colleagues studied the results of various testing in 64 patients to compare the accuracy of fecal markers (i.e., PhiCal Test, IBD-SCAN) , C-reactive protein, blood leukocytes, and antibody panels (ASCA and pANCA) for discriminating IBD from IBS and to define a "best test."  The authors concluded PhiCal Test and IBD-SCAN are highly accurate for discriminating IBD from IBS. Additional diagnostic accuracy is only marginal when the PhiCal Test and IBD-SCAN 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 discussed the expansion of the panel of serologic markers for IBD. An increasing amount of data are available on newly discovered antibodies (i.e., Anti-OmpC, Anti-12, Anti-CBir1, and antiglycan antibodies) directed against various microbial antigens. However, ASCA and P-ANCA 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.

2013 Update

A review conducted in 2012 (42) noted that due to their lack of sensitivity, serological markers are not advisable for use in the diagnosis of IBD but rather in differentiating CD from UC, particularly with the use of a wide panel of antibodies. The author noted that evidence points to the clinical utility of serological markers being one of stratifying patients according to risk for aggressive disease phenotype or postoperative complications. Such as a “risk score” that would integrate markers of immune response, genetic markers and clinical characteristics that might enable the application of personally-tailored therapeutic strategies and better surveillance of patients at risk. However, the author notes, “At the current time, there is insufficient evidence of usefulness of serological markers in monitoring the treatment of IBD patients.”

The American College of Gastroenterology (ACG) in a 2010 consensus statement notes that for CD, serological studies are evolving to provide adjunctive support for the diagnosis of CD but are not sufficiently sensitive or specific to be recommended for use as screening tools. Similarly, reported in published ACG practice guidelines for UC, pANCA, and ASCA currently are neither a first step nor a definitive step in differential diagnosis or clinical decision making. (43)

Coding

Disclaimer for coding information on Medical Policies

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

The presence or absence of procedure, service, supply, device or diagnosis codes in a Medical Policy document has no relevance for determination of benefit coverage for members or reimbursement for providers. Only the written coverage position in a medical policy should be used for such determinations.

Benefit coverage determinations based on written Medical Policy coverage positions must include review of the member’s benefit contract or Summary Plan Description (SPD) for defined coverage vs. non-coverage, benefit exclusions, and benefit limitations such as dollar or duration caps.

ICD-9 Codes

Experimental, investigational and/or unproven for all diagnoses.

ICD-10 Codes

Experimental, investigational and/or unproven for all diagnoses.

Procedural Codes: 83516, 88347
References
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History
September 2013  New 2013 BCBSMT medical policy.
March 2014 Document updated with literature review. Title changed from Biologic Markers for Diagnosis and Management of Inflammatory Bowel Disease (IBD). Policy no longer addresses fecal markers. The following was added to the experimental investigational and/or experimental listing of testing: anti-outer membrane porin C (anti-OmpC) antibody and anti-CBir1 flagellin (anti-CBir1) antibody. In addition, the following was also added: IBD diagnostic testing combining serologic, genetic, and inflammatory markers (eg, Prometheus® IBD sgi Diagnostic™) is considered experimental investigational and/or unproven.
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Serological Markers for Diagnosis and Management of Inflammatory Bowel Disease (IBD)