This is a non-coverage policy for the Prometheus IBD sgi Diagnostic test. The
intended use of this test is to aid healthcare providers in differentiating
inflammatory bowel disease (IBD) vs non-IBD, and Crohn's disease (CD) vs
ulcerative colitis (UC) in a comprehensive blood test. The test includes 9
serological markers: ASCA IgA, ASCA IgG, anti-OmpC IgA, anti-CBir1 IgG,
anti-A4 Fla2 IgG, anti-FlaX IgG, IBD-specific pANCA autoantibody, IBD-specific
pANCA IFA (perinuclear pattern), IBD-specific pANCA IFA DNAse Sensitivity; 4
genetic immune response markers (SNPs): ATG16L1, STAT3, NKX2-3, and ECM1; and
5 inflammatory biomarkers: ICAM-1, VCAM-1, VEGF, CRP, and SSA. A proprietary
Smart Diagnostic Algorithm interprets patterns among the multiple assay values
to produce an IBD score. The test results are reported as "consistent with
IBD" (consistent with UC; consistent with CD, or inconclusive for UC vs CD) or
"not consistent with IBD". In addition to the algorithmic test interpretation,
the results of the 17 biomarkers are also individually reported.

CD and UC represent the 2 main forms of idiopathic chronic IBD. While the
etiology remains idiopathic, evidence suggests that the ongoing inflammation
in IBD results from persistent, overly aggressive inflammatory responses to a
subset of commensal microorganisms in a genetically susceptible host with
exposure to environmental triggers. CD is characterized by discontinuous,
transmural regions of intestinal inflammation most frequently involving the
terminal ileum and colon, but can affect any part of the gastrointestinal
tract, with symptoms of abdominal pain, weight loss, and variable degrees of
diarrhea, and complications of intestinal fibrosis, strictures, and fistula
formation. In contrast, UC is limited to the mucosa and submucosa of the
colon, with particular involvement of the rectum. Classic symptoms of active
UC include diarrhea, hematochezia, tenesmus, and defecatory urgency. Extra
intestinal manifestations of IBD occur in up to 25% of patients. Joints, skin,
and eyes may be affected. In both CD and UC, disease activity is typically
relapsing and remitting, although the disease course of CD is typically
progressive. Although UC and CD can usually be differentiated on the basis of
clinical, radiographic, endoscopic, and histologic findings, these conditions
can be difficult to distinguish in about 10% to 15% of IBD patients.

**Evolution of IBD Testing**  
In the mid-2000s, 2 serologic markers - anti-Saccharomyces cerevisiae
antibodies (ASCA) and perinuclear anti-neutrophil cytoplasmic antibodies
(pANCA) - were used to diagnose IBD and distinguish between UC and CD. Studies
had shown that patients with CD had significantly higher ASCA antibodies than
did controls or patients with UC. The reason CD patients have both IgA and
IgG-ASCA is unclear. Overall, the sensitivity for either IgA or IgG-ASCA is in
the range of 55% with specificity of about 90%. On the other hand, pANCA, a
true autoantibody, was observed to be associated with colonic forms of IBD,
particularly UC, with a sensitivity of approximately 60-70%. However, these
pANCA-positive CD patients typically have a clinical phenotype resembling
left-sided UC, so pANCA detection alone is of little value in distinguishing
between UC and Crohn's colitis.

A second generation IBD panel (IBD First Step ) was marketed by Prometheus
Laboratories (2000) consisting of more sensitive ASCA and pANCA assays and the
addition of a second microbial antigen, OmpC. Anti-OmpC was added to increase
the sensitivity for CD. Subsequently, a third-generation serology panel (IBD
Serology 7) was offered by Prometheus Laboratories in 2006. The panel is
composed of the following markers: ASCA-IgA, ASCA-IgG, anti-OmpC-IgA, anti-
CBir1-IgA, and 3 ANCA tests: pANCA, ANCA-IgG and DNAse sensitive pANCA. The
Smart Diagnostic Algorithm analyzes and correlates test results with patterns
known to the database to be associated with IBD. It supposedly can predict an
IBD diagnosis, even when all 7 of the parameters of the IBD Serology 7 panel
would be considered normal on the basis of the reference ranges provided.1 It
was reported to identify another 20% or more of otherwise seronegative CD
patients.2 The IBD Serology 7 panel has a sensitivity of 93%, specificity of
95%, and positive predictive value of 96% in population prevalence of 59%
according to Prometheus. A positive anti-CBir1 can additionally help
distinguish between UC  
and CD in pANCA positive patients. However, in a comparison study evaluating
the predictive IBD Serology 7 with routine blood test (IgA-ASCA, IgGASCA) in a
pediatric population referred for initial evaluation of suspected IBD, the
sensitivity, specificity, positive predictive value, negative predictive
value, and k value for the serologic panel was 67%, 76%, 63%,79%, and 47%. The
antiflagellin antibody assay had sensitivity of 50% and specificity of 53%.
Despite the inclusion of antiflagellin in the IBD7 panel, the IBD7 panel had
lower predictive values compared with routine laboratory tests in pediatric
screening for IBD3.



Concern has been raised about serologic testing for IBD because the data
evaluating the role of serologic testing were obtained in individuals with a
known diagnosis of either CD or UC. In many of these studies, the controls
were normal healthy individuals. The use of the Smart Diagnostic Algorithm
based on pattern recognition has not been published in a peer-reviewed
journal. Similarly, the characteristics of the validation cohort (age, gender,
race, etc.) are not known or whether any of these patient characteristics
affect serologic markers. However, the greatest uncertainty pertains to the
precise role for serologic testing in the diagnosis of IBD patients. Austin,
et al1 state that "while there are no prospectively validated data on the
accuracy of IBD serologic testing in patients with suspected IBD, the presence
of positive serologic markers likely does increase the probability that the
person has IBD compared with the general population". However, they note that
when a physician has a reasonable index of suspicion for IBD, more definitive
imaging and endoscopic studies are required to confirm or refute the diagnosis
and plan treatment, regardless of the serologic results. When the physician
has a low index of suspicion for IBD, a positive serologic test is likely to
result in unnecessary evaluation, and a negative serologic test only adds
additional expense without benefit. These authors specify that further
research is required to develop the evidence that is necessary for rational
use of serologic testing.

The American College of Gastroenterology, in its guideline on the clinical
management of Crohn's Disease in adults, states that serologic tests are not
routinely recommended to establish a diagnosis of CD.4 The American College of
Gastroenterology, in its "Ulcerative Colitis Practice Guidelines in Adults,"5
specifies that serologic testing (ANCA/ASCA) may be useful in the occasional
patient in whom no other clinical or pathologic features allow a differential
diagnosis between UC and CD. Additionally, serological studies evaluating
anti-glycan antibodies and antibodies to microbial antigens are being studied
to support the diagnosis of inflammatory bowel disease, but the reliability of
these tests in helping establish a diagnosis is still not sufficient.5



The fourth iteration of Prometheus' IBD testing, IBD sgi Diagnostic test,
combines serologic (n=8), genetic (n=4) and inflammatory biomarkers (n=5). In
addition to the 7 serologic tests in the IBD Serology 7, 2 additional
serologic markers: anti-Fla-X and anti-A4- FL2; 4 genetic markers: ATG16L1,
ECM1, NKX2.3 and STAT3; and 4 inflammatory markers: VEGF, ICAM and VCAM, CRP
and SAA are marked to increase the discriminatory ability of the assay to be
an adjunct in the diagnosis of UC vs CD. The IBD sgi Diagnostic product
monograph6 includes an extensive bibliography that documents associations of
the 17 component markers, individually and in combination, with UC and/or CD.
Development and performance characteristics of the 17-marker panel are
described without citation, and it is unclear what standard criterion was used
for diagnosis. Overall sensitivity for IBD, UC, and CD is reported as 74%,
98%, and 89%, respectively; specificity is reported as 90%, 84%, and 81%,
respectively; receiver operating characteristic (ROC) analysis showed greater
discrimination with the 17-marker panel (area under the curve [AUC], 0.871)
compared with any individual marker (greatest AUC=0.690 for IgA anti-
Saccharomyces cerevisiae antibodies [ASCA]). Test performance characteristics
for distinguishing UC from CD were not provided.

In a 2012 review of the monograph, Shirts et al,7 observed that serologic
tests for ASCA-IgA, ASCA-IgG, and atypical perinuclear anti-neutrophil
cytoplasmic antibody are standard of care in the diagnostic workup of IBD,
although not all investigators include these tests in recommended diagnostic
strategies. These 3 markers are included in the 17-marker panel. Based on a
meta-analysis of 60 studies (total N=11,608), pooled sensitivity and
specificity of the 3-test panel were 63% and 93%, respectively, for diagnosing
IBD. Because the product monograph does not include a comparison of the
17-marker panel with the 3- marker panel, incremental improvement in diagnosis
with the 17-marker panel is unknown. Shirts et al, calculated an AUC for the
3-marker panel of 0.899.

Level of Evidence  
Quality: Poor  
Strength: Moderate  
Weight: Moderate

Although manufacturer data supports clinical validity of the test for
diagnosing IBD, this evidence is insufficient to support an indirect chain of
evidence for clinical utility due to lack of details about study methodology
and lack of replication of the findings. For distinguishing UC from CD,
clinical validity has not been established. No studies examining the clinical
utility of IBD sgi Diagnostic have been identified. Furthermore, there are no
US Preventive Services Task Force (USPSTF) recommendations for genetic or
molecular testing for IBDs, and no recommendations for multi-marker panels
that include genetic tests to facilitate diagnosis or prognosis of CD or UC.4,
5 Consequently, this assay does not meet Medicare's reasonable and necessary
criteria for coverage. Additionally, each of the individual components that
comprise this assay, except ASCA-IgA, ASCA-IgG, and atypical perinuclear anti-
neutrophil cytoplasmic antibody, are additionally non-covered for the
diagnosis of IBD.