ANCAfor Crohns Diseaseand Ulcerative Colitis

National Medical Policy
Subject:
ANCA for Crohns Disease and Ulcerative

Colitis
Policy Number:
NMP187
Effective Date*:
November 2004
Updated:
April 2016
This National Medical Policy is subject to the terms in the

IMPORTANT NOTICE
at the end of this document
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Crohn's Disease and Ulcerative Colitis Serum Antibodies Apr 16
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Current Policy Statement

Health Net, Inc. considers any of the following medically necessary:
1. The serologic markers anti-neutrophil cytoplasmic antibodies (ANCA), antisaccharomyces cerevisiae (ASCA) and perinuclear staining pattern antineutrophil cytoplasmic antibodies (pANCA), anti-glycan-associated
Saccharomyces cerevisiae antibodies [gASCA combined with anti-outer
membrane porin protein C of Escherichia coli antibodies [anti-OmpC], antichitobioside carbohydrate antibodies [ACCA], anti-laminaribioside
carbohydrate antibodies [ALCA], anti-mannobioside carbohydrate antibodies
[AMCA], anti-chitin antibodies [anti-C], and/or anti-laminarin antibodies [antiL]) in patients for any of the following:
Subsequent to colonoscopy in adult patients with indeterminate colitis;
In adult patients who present acutely with significant symptoms of

probable inflammatory bowel disease (IBD), but for whom colonoscopy
is contraindicated due to any of the following:
Pregnancy; or
Recent abdominal surgery; or
Post-transplant; or
Bleeding disorder.
In the initial work up of pediatric patients with inflammatory bowel

disease, when the results will be used to determine the need for more
invasive testing.
2. Genotyping for thiopurine methyltransferase (TPMT) deficiency (e.g., PROPredict TPMT) for the management of inflammatory bowel disease (IBD) prior
to initiation of azathioprine (AZA) or 6-mercaptopurine (6-MP) therapy or if
standard dosing of AZA/6-MP fails to produce a therapeutic response.
3. Monitoring thiopurine methyltransferase metabolite levels in inflammatory
bowel disease (e.g., PRO-Predict EnzAct) to guide dose changes in those who
have not responded to therapy or for those suspected of having toxic
responses to azathioprine (AZA) and/or 6-mercaptopurine (6-MP)
Investigational
Health Net, Inc. considers any of the following antibody tests investigational.
Although they may be helpful is some situations, there is a paucity of evidence in the
peer reviewed literature that altered treatment as a result of antibody tests, results
in better outcomes, for the majority of individuals. They also have not been shown to
improve health outcomes by reducing the need for other testing. Future studies may
provide additional evidence regarding the use of various antibody testing for the
management of IBD:
1. ANCA, ASCA and pANCA as the sole method to diagnose inflammatory bowel
disease in adults, to monitor disease activity, or to distinguish ulcerative colitis
from Crohn's disease. The ANCA assay has reasonable sensitivity but low
specificity for ulcerative colitis, while the ASCA assay has high specificity but very
low sensitivity for Crohn's disease;
2. 6-thioguanine nucleotide (6-TGN) and 6-methylmercaptopurine nucleotide (6MMPN) (e.g., PRO-Predict 6MP/azathioprine, PRO-Predict Metabolites);
3. PRO-Predict TNF (serology panel for pANCA, ASCA (IgG and IgA) and SAPPA
antibody markers);
4. Antibody to Escherichia coli outer membrane porin C (Omp C);
5. I-2 antibody;
6. Flagellin;
7. Fecal measurements of calprotectin for the management of inflammatory bowel
diseases
8. The Prometheus Anser IFX test measures serum infliximab (IFX) or [Remicade]
levels and antibodies to infliximab (ATI). The Prometheus Anser ADA test
measures serum adalimumab (ADA) or [Humira] levels and antibodies to
adalimumab (ATA)*
9. NOD2/CARD15 genotyping for Crohn's Disease, as the analytical validity of NOD2
genotyping has not been identified. In addition, no data regarding the impact of
NOD2 gene status on the health outcome of patients were identified.
*NOTE: Anser IFX and Anser ADA are proposed to allow for the detection of both
drug-free and drug-bound antidrug antibodies in a patient's serum. These tests are
also proposed to detect immunoglobulin subtypes, in addition to antibodies with
weak binding affinity, both of which may be missed in ELISA/ECLIA testing. However
conflicting evidence is available on the association of antibodies to infliximab (ATIs)
and of antibodies to adalimumab (ATAs) and with clinical response to these
medications in patients with IBD. Overall quality is low and does not conclusively
establish the utility of assaying antibodies to infliximab (ATIs) or adalimumab (ATA)
for management of patients with IBD with regard to long-term health outcomes.
Optimal management of patients who have lost response to these medications is
unknown; detection of ATIs or ATAs may be helpful for physicians who must decide
among these treatment alternatives, however, more research is necessary.
Investigational
Health Net, Inc. considers antibody tests investigational for any other indications
because although there are ongoing studies, there is no conclusive scientific evidence
that they serve any of the following purposes:
1. Increase the accuracy of diagnosis in patients with inflammatory bowel
disease; or
2. Distinguish ulcerative colitis from Crohn's disease; or
3. Reduce the need for other testing; or
4. Monitor response to therapy in patients with ulcerative colitis or Crohns
disease; or
5. Improve health outcomes.
Codes Related To This Policy

NOTE:
The codes listed in this policy are for reference purposes only. Listing of a code in
this policy does not imply that the service described by this code is a covered or noncovered health service. Coverage is determined by the benefit documents and
medical necessity criteria. This list of codes may not be all inclusive.
On October 1, 2015, the ICD-9 code sets used to report medical diagnoses and
inpatient procedures have been replaced by ICD-10 code sets.
ICD-9 Code
555.0-555.9
556.0-556.9
Regional enteritis (i.e., Crohns disease)

Ulcerative colitis
ICD-10 Codes
K50.001-K50.919
K51.001-K51.919
Crohns disease (regional enteritis)

Ulcerative Colitis
CPT Codes
83516
86849
88346
88347
Immunoassay for analyte other than infectious agent antibody

or infectious agent antigen, qualitative or semiquantitative;
multiple step method
Unlisted immunology procedure
Immunofluorescence, per specimen; initial single antibody stain
procedure
Immunofluorescent study, each antibody; indirect method
(code deleted 12/2015)
2016 CPT Codes

88350
Immunofluorescence, per specimen; each additional single

antibody stain procedure
HCPCS Codes
N/A
Scientific Rationale Update April 2016

El-Matary et al (2015) reported the role of noninvasive biologic markers for disease
activity is very important in children with Crohn's disease. The authors sought to
assess an association between disease activity and quantitative serum antiSaccharomyces cerevisiae antibody (ASCA) titres. Anti-Saccharomyces cerevisiae
antibody immunoglobulin (Ig) A and immunoglobulin G titres, paediatric Crohn's
disease activity index (PCDAI), serum albumin and C-reactive protein (CRP) were
repeatedly measured simultaneously in children with Crohn's disease. A possible
association between ASCA IgA and IgG titres and changes in PCDAI was examined.
Serial 136 measurements of ASCA IgA and IgG titres were documented in 57
children with Crohn's disease over a mean duration of 3.1 2.1 years. In a
univariate linear regression model, there were significant correlations between ASCA
IgA titres and PCDAI (p < 0.001), CRP (p <0.01) and low serum albumin (p <
0.001), respectively. Similarly, ASCA IgG titres significantly correlated with PCDAI,
CRP and low serum albumin. The authors concluded both ASCA IgA and IgG titres
seemed to correlate well with clinical Crohn's disease activity in children. Measuring
these antibodies may be considered during routine clinical care for those patients.
Paul et al (2015) reported the usefulness of anti-glycan antibodies alone or combined

with anti-saccharomyces cerevisiae [ASCA] or perinuclear antineutrophil cytoplasmic
[pANCA] antibodies for diagnosis of inflammatory bowel disease [IBD],
differentiation between Crohn's disease [CD] and ulcerative colitis [UC], disease
stratification including IBD phenotype, and also for determination of the course of
the disease, remain unclear. A large panel of serological anti-glycan carbohydrate
antibodies, including anti-mannobioside IgG antibodies [AMCA], anti-chitobioside IgA
[ACCA], anti-laminaribioside IgG antibodies [ALCA], anti-laminarin [anti-L] and antichitine [anti-C] were measured in the serum from a cohort of 195 patients with IBD]
[107 CD and 88 UC]. The respective accuracy of isolated or combined markers for
diagnosis, disease differentiation, stratification disease phenotype, and severity of
the disease course, defined by a wide panel of criteria obtained from the past
medical history, was assessed. The positivity of at least one anti-glycan antibody
was detected in a significant higher proportion of CD and UC compared with healthy
controls [p < 0.0001 and p < 0.0007, respectively]. Whereas ASCA and ANCA
antibody status had the highest efficacy to be associated with CD in comparison with
UC (area under receiver operating characteristic curve [AUROC] = 0.70 for each],
the adjunction of anti-laminarin antibody substantially improved the differentiation
between CD and UC [AUROC = 0.77]. Titres of ACCA [> 51U/ml] and anti-laminarin
[> 31U/ml] were significantly linked with a higher association with steroid
dependency (odds ratio [OR] =2.0 [1.0-4.0], p = 0.03 and OR = 2.4 [1.1-5.2], p =
0.02, respectively]. The authors further defined the respective performance of antiglycan antibodies to discriminate between patients with severe or not severe CD and
UC course and determined the associated optimal cut-off values: severe CD course
was significantly more likely in case of AMCA > 77U/ml [OR = 4.3; p = 0.002], ASCA
> 63U/ml [OR = 3.5; p < 0.009] and at a lesser degree ACCA > 50U/ml [OR = 2.8;
p < 0.02] and severe UC course was significantly associated with AMCA > 52U/ml
[OR = 3.4; p = 0.04] and ACCA > 25U/ml [OR = 3.0; p < 0.04]. The authors
concluded anti-glycan antibodies are valuable serological markers, especially AMCA
antibodies that may help clinicians to promptly classify patients into high risk for
severe disease.
Scientific Rationale Update April 2015

Prometheus Laboratories Inc. offers nonradiolabled, fluid phase homogenous mobility
shift assay (HMSA) tests called Anser IFX (July 2012) and Anser adalimumab (ADA)
(August 13, 2013). The Anser IFX test measures serum infliximab (IFX), [Remicade]
levels and antibodies to infliximab (ATI). The Anser ADA test measures serum
adalimumab (ADA) [Humira] levels and antibodies to adalimumab (ATA). Per the
Prometheus website: These two tests help determine personalized solutions for
managing loss of response to infliximab or adalimumab, for individuals with
inflammatory bowel disease. Neither test is ELISA based, but each can measure
antidrug antibodies in the presence of detectable drug levels, improving upon a
limitation of the ELISA method. These tests are regulated under the Clinical
Laboratory Improvement Amendments (CLIA) of 1988. Premarket approval from the
Food and Drug Administration (FDA) is not required for this laboratory test.
With both the Anser IFX and the Anser ADA test, the drug is tagged with a
fluorescent label and incubated with serum. If antibodies are present, the resulting
drug antibody complex has a significantly higher molecular weight than free drug,
thus allowing the separation of free drug from antibody-bound drug for
quantification.
Unlike solid-phase detection methods (eg., ELISA/ECLIA), that can only detect
antidrug antibodies that are not bound to circulating drug, the methodology used by
Anser IFX and Anser ADA allows for the detection of both drug-free and drug-bound
antidrug antibodies in a patient's serum. These new tests also detect all
immunoglobulin subtypes, in addition to antibodies with weak binding affinity, both
of which may be missed in ELISA/ECLIA testing.
The technology of PROMETHEUS Anser IFX lowers infliximab limit of detection to
0.0074 g/mL. It also provides a testing range for antibodies to infliximab in serum
(0.56 g/mL-27 g/mL). The technology of PROMETHEUS Anser ADA lowers
adalimumab limit of detection to 0.018 g/mL. It also provides a testing range for
antibodies to adalimumab in serum (0.063 g/mL-25 g/mL).
Both tests are proposed by Prometheus to overcome many of the limitations
associated with solid-phase assays, resulting in fewer false positives due to less
background interference and fewer false negatives due to greater assay sensitivity.
The detection and quantitative measurement of antidrug antibodies has had various
issues. First generation assays (i.e. enzyme-linked immunosorbent assays (ELISA)
can only measure antidrug antibodies in the absence of detectable drug levels due to
interference of the drug with the assay, limiting clinical utility. Other techniques
available for measuring antibodies include radioimmunoassay (RIA) method, and
more recently, the homogenous mobility shift assay (HMSA) using high performance
liquid chromatography.
Disadvantages of the RIA method are associated with complexity of the test and
prolonged incubation time, and safety concerns related to the handling of radioactive
material. The HMSA has the advantage of being able to measure antidrug antibodies
when infliximab is present in the serum. Studies evaluating the validation of the
results between different assays are lacking, making inter-study comparisons
difficult. It is also difficult to interpret drug levels in the absence of antibody levels,
and to interpret antibody levels in the absence of serum drug levels. Measuring one
without the other may result in an incorrect interpretation of a clinical situation.
Studies
O'Meara et al. (2014) Antibodies to infliximab (ATIs) have been associated with a
risk of infusion reactions in some studies of patients with inflammatory bowel
disease. However, many factors, such as immunomodulators and dosing schedule,
may influence this association. The aim of this study was to provide a pooled
estimate of the risk of infusion reactions according to patients' ATI status and
analyze the relationship of immunomodulators to this risk. Public databases were
searched for eligible studies. Quality assessment was undertaken for all studies using
Grading of Recommendations Assessment, Development and Evaluation criteria. Raw
data from studies meeting inclusion criteria were pooled for meta-analysis of effect
estimates. Sensitivity analysis was performed for all outcomes. Funnel plot was
performed to assess for publication bias. Eight studies met the inclusion criteria, with
a pooled total of 1351 subjects. Seven of the 8 studies had a high risk of bias in at
least 1 quality domain. The cumulative data indicated that there was a higher risk
ratio (RR) of any acute infusion reaction (RR 2.4; 95% confidence interval [CI] 1.53.8, P < 0.001) and severe infusion reactions (RR 5.8, 95% CI 1.7-19, P = 0.004) in
patients with ATIs when compared with patients without ATIs. The RR of delayed
hypersensitivity reactions was not significantly different between ATI+ and ATIpatients (RR 2.8, 95% CI 0.2-33, P = 0.4). Patients prescribed immunomodulators
during maintenance infliximab therapy had a reduction in their risk for ATI
development (RR 0.6, 95% CI 0.4-0.9, P = 0.02) and infusion reactions (RR 0.6,
95% CI 0.4-0.8, P < 0.001). The presence of ATIs is associated with a significantly
higher risk of acute infusion reactions, but not delayed hypersensitivity reactions, in
patients with inflammatory bowel disease. Concomitant immunomodulators may
reduce this risk.
McTigue et al. (2013) completed a retrospective study of electronic medical records
of all IBD patients who underwent IFX/ ATI testing between 1/1/2010 and
12/31/2012. 148 tests were done using the ELISA assay and 57 tests were done with
the Anser IFX assay. 52% (77/148) of the ELISA tests and 47% (27/57) of the Anser
IFX tests were done to evaluate inadequate/ LOR to IFX. Overall, 48% (49/103) of
patients experiencing LOR had therapeutic IFX levels. Using the ELISA assay, 11/31
patients (35%) with undetectable IFX levels were ATI-positive as compared with
10/11 patients (91%) tested using the Anser IFX assay. 2/13 (15%) of patients with
subtherapeutic IFX concentrations found using the Anser IFX assay were ATI-positive
(ATIs could not be measured in the 41 patients with subtherapeutic IFX
concentrations tested using the ELISA assay). In total, 11/72 patients (15%) with
undetectable or subtherapeutic IFX concentrations as measured by ELISA, as
compared with 12/24 of patients (50%) with undetectable or subtherapeutic IFX
concentrations as measured by Anser IFX, had detectable ATI. Use of the Anser IFX
assay is associated with an increase in the proportion of patients with undetectable
or subtherapeutic IFX concentrations who are found to be ATI-positive. These
preliminary findings should be confirmed prospectively in a study with paired ELISA
and Anser IFX assays in the same patients. If confirmed these findings suggest that
the Anser assay may explain the underlying reason for undetectable or
subtherapeutic IFX concentrations in a larger proportion of patients.
Casteele et al. (2013) retrospectively investigated the pharmacokinetics (PK) of
antibodies to infliximab (ATI) formation and infliximab levels in 90 patients with IBD.
The study tested ATI levels and infliximab trough levels in 1232 blood samples from
64 patients with CD and 26 patients with UC using Anser IFX, a new homogeneous
mobility shift assay (HMSA) that allows quantification of ATI antibodies in the
presence of infliximab. Patients were treated with infliximab at weeks 0, 2, and 6.
Patients had previously been evaluated for ATIs using an ELISA method. Treating
clinicians had no knowledge of the results of assays. More than half of the patients
(59%) were ATI-positive at 1 or more time points using the new assay. In 15 (28%)
ATI-positive patients, 3 of whom were using immunosuppressive therapy, ATIs were
transient. Patients with sustained ATIs were more likely to discontinue treatment
with infliximab (RR = 5.1; 95% CI 1.4 to 19.0; P=0.0005). The ELISA and HMSA
results demonstrated good correlation for both ATIs (Pearson R = 0.83; P<0.0001)
and trough levels of infliximab (R = 0.88; P<0.0001). Four of the patients who were
ATI-negative on ELISA were classified as having transient ATIs by HMSA. One patient
with sustained ATI by ELISA had transient ATI by HMSA. One patient who was ATI
negative by ELISA had transient ATIs by HMSA. Trough levels of infliximab were
negatively correlated with ATI levels (R = 0.373; P=0.01). Low trough levels of
infliximab at week 14 predicted discontinuation of infliximab due to loss of response
or hypersensitivity reaction with 82% sensitivity and 74% specificity (likelihood ratio
[LR] = 3.1; P=0.0026). In patients who lost response to infliximab, interventions
(defined as a decrease of infusion interval or increasing dose) were less effective in
patients with sustained ATIs than in those with negative ATIs (P<0.0001) and those
with transient ATIs (P=0.0028). Successful interventions were associated with lower
ATI levels than unsuccessful interventions (0 units per milliliter [U/mL] versus 13.1
U/mL; 95% CI 0 to 23.7 U/mL; P<0.001). Receiver operating characteristic (ROC)

analyses showed that low trough levels of infliximab < 13 g/mL were 72% sensitive
and 81% specific for formation of ATIs. Trough levels < 2.2 g/mL were 79%
sensitive and 94% specific for formation of ATIs. ATI formation at time of loss of
response was 65% sensitive and 82% specific for unsuccessful intervention (LR =
3.6; P=0.003). Patients who ever had trough levels < 0.91 grams per milliliter
(g/mL) were at risk for failure of infliximab (OR 6.5; 95% CI 2.4 to 17.8; P=0.0003),
as were patients who ever had ATI levels > 7.95 U/mL (OR 5.1; 95% CI 2.0 to 13;
P=0.0007). The authors concluded that ATIs may be transient, are not necessarily
related to worse clinical outcomes, and that retesting of ATIs in patients with positive
ATIs is reasonable. They proposed a treatment algorithm in which trough levels are
assayed first, followed by ATIs only if trough levels are low or undetectable. (NOTE:
Prometheus Laboratories Inc. provided support funding for the study. Several study
authors disclosed relationships with industry).
Unger et al. (2013) to characterize the temporal evolution of antibodies to infliximab
(ATI), the authors completed this prospective observational study of infliximabtreated patients with inflammatory bowel disease between 2009 and 2012. Trough
levels of infliximab and ATI were measured before each infusion by anti- ELISA.
Patients were monitored for disease activity by clinical activity indexes and for doseintensification or infliximab cessation. The occurrence of transient ATI disappearing
spontaneously without intervention was recorded separately. 125 patients were
included (98 Crohn's disease, 27 ulcerative colitis, median follow-up 11.522
months) and 1119 sera were analysed for infliximab and ATI levels. Kaplan-Meier
analysis showed that 42% of patients remained ATI-free by 4 years of treatment.
Most (90%) of the patients who developed ATI did so within the first 12 months of
therapy, whereas transient ATI were detected throughout the duration of infliximab
therapy (p<0.001). ATI incidence was similar between patients who received
infliximab previously (episodic/interrupted therapy patients, n=14) and scheduledtherapy patients (n=111). In the scheduled group, combination
immunomodulator+infliximab resulted in longer ATI-free survival compared with
monotherapy (p=0.003, logrank test). Survival free of clinical loss of response was
noted by 51% of patients, and serial measurements showed that ATI development
often preceded the onset of clinical flare. When followed prospectively, most
patients who develop ATI do so within the first 12 months of therapy. This incidence
is reduced by concomitant immunomodulator even in scheduled-therapy patients. In
contrast, transient ATI, which are of little clinical significance, can appear
haphazardly at any time during treatment. The onset of clinical loss of response may
lag behind the appearance of anti-infliximab antibodies.
Summary
Antibodies to infliximab (ATI) or to adalimumab (ATA) are present in a substantial
number of patients treated with infliximab or adalimumab, and there may be a
correlation between the level of these antibodies and clinical response. However, the
clinical utility of measuring antidrug antibody concentrations has not been
established, as it is not known how patient management would change based on test
results. Limited evidence describes changes in the management after measurement
of ATI, but does not compare these management changes to those made in the
absence of ATI measurement. In addition, there are technical factors relating to the
use of different assay methods across studies, it has not yet been established
whether the use of threshold levels aids in the discrimination of treatment response,
nor has the optimal timing of when to measure antibody levels been established.
There is insufficient evidence in the peer reviewed published medical literature to

determine the role of the measurement of antibodies to infliximab or adalimumab,
whether performed separately or combined with testing blood levels. There is
insufficient evidence to demonstrate the use of these tests (i.e., Anser IFX or Anser
ADA) results in improved health outcomes compared to usual clinical management.
These tests are regulated under the Clinical Laboratory Improvement Amendments
(CLIA) of 1988. Premarket approval from the Food and Drug Administration (FDA) is
not required for this laboratory test.
Scientific Rationale Update September 2014

Mokhtarifar et al (2013) sought to evaluate the diagnostic value of two serological
markers, atypical perinuclear anti-neutrophil cytoplasmic antibodies (atypical-PANCA) and anti-Saccharomyces cerevisiae antibodies (ASCA), with the intent to
determinetheir relationship to ulcerative colitis (UC) and Crohn's disease (CD), in
addition to the location and extent of bowel involvement. There were 97 patients
enrolled in this study, 72 diagnosed with UC and 25 with CD. The control group
consisted of 40 healthy individuals. ASCA was determined by enzyme-linked
immunosorbent assay (ELISA) and atypical-P-ANCA by indirect immunofluorescence
assay (IIF). For data analyses, we used the chi-square and independent t-tests.
Significance was considered to be p<0.05. For CD, the sensitivityof ASCA was 16%
and its specificity was 97%.ASCA had a specifity of 90% in UC patients. The atypical
P-ANCA test had a sensitivity of 44% and specificity of 86% for UC. The positive
predictive value (PPV) for atypical P-ANCA in UC patients was 78% and for the
negative predictive value (NPV), it was 58%.There was no correlation between ASCA
and atypical P-ANCA results and the location of gastrointestinal (GI) involvement in
CD (p=0.61) and UC (p=0.28) patients. Investigators concluded the results, ASCA
and atypical P-ANCA markers are not useful for IBD screening. The study suggests
that atypical P-ANCA is a useful parameter to differentiate UC from CD. However,
ASCA is of limited value for screening and differentiating UC from CD
Elkadri et al (2013) evaluated the prevalence of pANCA, IgA and IgG antiSaccharomyces cerevisiae antibodies, anti-OmpC, and anti-flagellin in a large welldefined population of patients with CD and UC and analyzed for various clinical
outcomes. Samples were collected from 391 patients with CD, 207 patients with UC,
and 62 healthy controls. Patients were phenotyped using the Montreal classification.
Blinded serological analyses were performed for pANCA, IgA and IgG antiSaccharomyces cerevisiae antibodies, anti-OmpC, and anti-flagellin. In CD,
increasing quantitative levels for antibodies were associated with a younger age of
diagnosis, longer disease duration, increased surgeries, ileocolonic and perianal
disease, and internal perforating behavior. In UC, they were associated with
colectomy. An increasing number of seropositive antibodies in CD was associated
with a younger age at diagnosis, increased disease duration, ileocolonic and perianal
disease, internal penetrating and stricturing behavior, and increased surgeries.
Multivariate analysis confirmed the association of antimicrobial antibodies with
features of complicated CD and UC. Investigators concluded increased serological
markers are associated with a more aggressive CD phenotype and an increased need
for colectomy in UC. This raises the possibility for use of these markers in patients at
risk of complex disease.

Initial research focused on two markers that may be useful for diagnosing IBD and
better classifying the two diseases. These initial markers consisted of two
autoantibodies, anti-Saccharomyces cerevisiae antibody(ies) (ASCA) and perinuclear
antineutrophil cytoplasmic antibody (pANCA). Subsequent research has identified a

number of other serum biomarkers in addition to ASCA and pANCA that may also
be useful for the diagnosis and differentiation of CD and UC, as a means to
understand the pathogenesis of disease and predict disease course in patients with
these disorders, and to identify different disease phenotypes and predict treatment
response. The presence and level of these antibodies is determined by testing blood
samples using serological assays, particularly enzyme-linked immunosorbent assays
(ELISAs) and indirect immunofluorescence assays (IFAs).
Anti-Outer Membrane Porin C Antibodies (Anti-OmpC):
Escherichia coli (E. coli) refers to bacteria often found in the gastrointestinal tract.
Porin C is a major outer membrane protein of E. coli. Excessive secretion of
antibodies directed against this protein (anti-OmpC) reportedly has been
identified in patients with CD, UC, or indeterminate colitis (IC), and in unaffected
family members of patients with CD.
Anti-glycan Antibodies: Glycans, also known as oligosaccharides, are predominant
surface components found on microorganisms, immune cells, erythrocytes, and
tissue matrices. The most commonly studied anti-glycan antibodies include
antibodies directed against mannan (anti-glycan-associated S. cerevisiae antibodies
[gASCA]), mannobiosides (anti-mannobioside carbohydrate IgG antibodies [AMCA]),
laminaribioside (anti-laminaribioside carbohydrate IgG antibodies [ALCA]), or
chitobioside (antichitobioside carbohydrate IgA antibodies [ACCA ]) Recently, two
additional anti-glycan antibodies, anti-laminarin IgA (anti-L) and anti-chitin IgA
(anti-C), also have been studied. Anti-glycan antibodies, also called nticarbohydrate
antibodies, are usually identified with ELISA kits.
ASCA and pANCA can be measured alone and combined, and also in combinations
with other antibodies (anti-outer membrane porin protein C of Escherichia coli
antibodies [anti-OmpC], or anti-glycan antibodies). Combinations of antibodies are
generally assessed using serological assay panels, which determine the presence and
level of multiple antibodies within a serum sample.
Guidelines from the American College of Gastroenteroloy (ACG) on Management of
Crohns disease (2009) reported,
The diagnosis of CD is based on a composite of endoscopic, radiographic, and
pathological findings documenting focal, asymmetric, transmural, or
granulomatous features. The sequence of diagnostic maneuvers is based on
presenting symptoms, physical findings, and basic laboratory abnormalities
(grade C). Currently, the measurement of genetic mutations in patients with
CD remains a research tool that is not yet proven to be of clinical benefit for
the general assessment of diagnosis, guidance of patient care, or prediction of
response to specific medical therapies. The use of genetic testing is currently
not recommended in the caring of patients with CD (level C). Additionally,
serological studies evaluating antibodies against Saccharomyces cerevisiae,
antineutrophil cytoplasmic antibodies, antibodies directed against CBir1, OmpC
are evolving to provide adjunctive support for the diagnosis of CD but are not
sufficiently sensitive or specific to be recommended for use as a screening
tools.
Another guideline from the ACG on Ulcerative Colitis (UC) (2010) reported,
Perinuclear antineutrophil cytoplasmic antibodies (pANCA) have been identified
10
in 60 70 % of UC patients, but are also found in up to 40% of patients with

CD. 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 Crohns colitis. However, reactivity to CBir 1, an
anti-fl agellin antibody, is preferentially present in pANCA-positive CD patients
as compared with pANCA-positive UC patients, 44% vs. 4%, respectively. The
low sensitivity of pANCA for the diagnosis of UC prevents it from serving as a
useful diagnostic tool. However, their specificities may make these assays
useful in the occasional patient in whom no other clinical or pathologic features
allow a differential diagnosis between UC and Crohns colitis. Although this
distinction is not always crucial, it may have important consequences in terms
of counseling, prognosis, and the choice of medical and surgical therapies.
ACG grade A recommendations imply that there is consistent level 1 evidence
(randomized controlled trials), grade B indicates that the evidence would be level 2
or 3, which are cohort studies or casecontrol studies. Grade C recommendations are
based on level 4 studies, meaning case series or poor-quality cohort studies, and
grade D recommendations are based on level 5 evidence, meaning expert opinion.
Reider et al (2012) tested a panel of serological anti-glycan antibodies including the
novel anti-laminarin (Anti-L) and anti-chitin (Anti-C) antibodies in pediatric Crohn's
disease (CD) patients for diagnosis of CD and association with complicated CD
behavior. In addition, they compared this panel in pediatric CD with adult CD
patients for possible changes in accuracy over time. Anti-L, Anti-C, anti-chitobioside
(ACCA), anti-laminaribioside (ALCA), anti-mannobioside (AMCA), and antiSaccaromyces cervisiae (gASCA) antibodies were tested in serum samples of 131
pediatric participants (59 CD, 27 ulcerative colitis [UC], and 45 noninflammatory
bowel disease [IBD] controls) with enzyme-linked immunosorbent assay (ELISA).
The results were compared to an adult cohort of 728 participants (355 CD, 129 UC,
and 244 non-IBD controls). In all, 78% of the pediatric CD patients were positive for
at least one of the anti-glycan antibodies. gASCA was most accurate for the
diagnosis of CD, but combined use of the antibodies improved differentiation of CD
from UC. gASCA, AMCA, ALCA, or Anti-L and an increasing antibody level were
independently linked to complicated CD behavior, CD-related surgery, and ileal
disease location (odds ratio 3.9-8.7). Considering the age at sample procurement the
accuracy of the markers compared to an adult cohort remained stable for the
differentiation of CD versus UC as well as for the association with complications, CDrelated surgery, and ileal disease involvement. Investigators concluded a panel of
anti-glycan antibodies including the novel Anti-L and Anti-C may aid in the
differentiation of pediatric CD from UC and is associated with complicated CD
behavior. The marker accuracy remained constant over time.
Zhang et al (2012) reported that recent studies suggested that anti-Saccharomyces
cerevisiae antibody (ASCA) status was associated with diagnostic findings, stratified
classification phenotypes, disease activity and clinical course of Crohn's disease (CD).
However, the relationship between ASCA status and phenotypes of CD remains
controversial in these studies. The authors evaluated whether ASCA status is
associated with the phenotypes and the risk of surgery in diverse populations in CD.
The authors conducted a meta-analysis of studies assessing the association of ASCA
status with phenotypes and risk of surgery in CD. Three independent reviewers
undertook data extraction. They pooled odds ratios separately for the cohort and
case-control studies. They identified ten cohort studies (n = 2,365) and 14 casecontrol studies (n = 1,887) that investigated the association of ASCA status with
11
phenotypes and risk of surgery in CD. The meta-analysis of the cohort studies
showed significant association between the ASCA-positive status and higher risk of
early-onset age (OR 2.25, 95 % CI 1.41-3.57, P < 0.001), ileal involvement disease
(1.70, 1.05-2.77, P = 0.03), complicated disease behavior (2.09, 1.71-2.57, P <
0.001), perianal disease (1.49, 1.14-1.94, P = 0.004), and risk for surgery (1.61,
1.29-2.01, P < 0.001). Meta-analysis of the case-control studies also showed a
significantly higher risk in ileal involvement disease (1.77, 1.25-2.49, P = 0.001),
complicated disease behavior (2.13, 1.70-2.68, P < 0.001), perianal disease (1.96,
1.38-2.78, P < 0.001), and risk for surgery (1.71, 1.17-2.49, P = 0.005), except for
the early-onset age (1.16, 0.80-1.69, P = 0.44). Authors concluded the metaanalysis indicated that positive ASCA status is a risk factor for early-onset age, ileal
involvement, complicated behavior, perianal disease and requirement for surgery in
CD.

NOD2 genotyping is being proposed in patients with a clinical diagnosis of CD, for
diagnostic confirmation, prognostication, and medical management. In addition, the
test is also proposed to establish a diagnosis in patients with indeterminate colitis. It
may also be offered to at-risk, asymptomatic individuals (such as family members of
affected individuals) for risk assessment purposes. The Prometheus NOD2/CARD15
assay is available in the United States through Prometheus Inc. (San Diego, CA). It
is performed using allele-specific polymerase chain reaction (PCR) amplification.
At the present time, data supporting the clinical utility of NOD2 genotyping for CD
are lacking. Additional studies are needed to assess the impact of NOD2 testing on
the health outcomes of both patients and at-risk individuals. No studies examining
the analytical validity of NOD2 genotyping were identified.
The majority of studies are designed to investigate the molecular mechanisms
underlying Crohns disease.
There is a Clinical Trial from 2011 currently being done at Johns Hopkins University
titled: Identifying Disease Variants for Familial Crohns Disease (5RO1DK08355302) The data will be analyzed to identify the markers that are highly transmitted with
Crohns disease There is no primary completion date noted within this study.
There is a Clinical Trial on Immunological Consequences of CARD15/NOD2 Mutations
in Crohn's Disease (PLAC). This project is based on adult and paediatric cohorts
among the largest ones in Paris and located at Saint Louis and Robert Debr
hospitals. The ClinicalTrials.gov Identifier is NCT00780949. Although the estimated
primary completion date is September 2012, the recruitment status of this study is
unknown because the information has not been verified recently.

Beltro et al. (2010) have assessed various serological markers with a potential
value for the diagnosis of pathologies; in particular, the anti-Saccharomyces
cerevisiae antibodies (ASCA) and anti-neutrophil cytoplasmic antibodies (ANCA). Also
of note are the anti-goblet cells antibodies (anti-CCI) and the anti-pancreatic
exocrine autoantibodies that react with the pancreatic acinus (anti-AP). The authors
have compared the efficiency between immune enzymatic (ELISA) and indirect
immunofluorescence tests in the identification of ASCA of IgG or IgA class. A set of
81 serum samples were studied (with an initial diagnosis of IBD) and 33 control
12
samples from healthy blood donors. The laboratory tests were correlated with the
diagnosis of each patient, based on conventional methods. The agreement between
the two laboratory methods employed in the identification of the ASCA was excellent
(k = 0.63) for the IgG antibodies and good (k = 0.56) for the IgA antibodies. A weak
agreement was found (k = 0.137) between ELISA (MPO and PR3 purified antigens)
and the IFA test for ANCA. Regarding the serologic markers ANCA, anti-AP and antiCCI, only the later showed no differences in the distribution of positive results
between the studied groups. Positive ASCA IgG and IgA were significantly associated
with diagnosis of DC, with both laboratorial methods tested. The identification of
ANCA with the available solidphase tests does not seem appropriate for the
screening of the autoantibodies with the atypical p-ANCA pattern of IBD. The
combination between anti-AP and ASCA antibodies seems a good option for the
laboratorial diagnosis of CD. This study shows that these serologic markers in spite
of being non invasive laboratory tests, also have a considerable overlapping in the
different IBD. Nevertheless, further prospective studies based on larger populations
are required to clarify the relationship between these antibodies, the diagnosis and
clinical evolution of inflammatory bowel disease.
Dotan et al. (2010) reviewed inflammatory bowel diseases (IBD). Antibodies against
luminal antigens are specifically associated with Crohn's disease (CD). In addition to
the previously described antibodies antineutrophil cytoplasmic (auto)antibodies
(ANCA), anti-Saccharomyces cerevisiae antibodies (ASCA), OmpC, I2 and CBir1
Flagellin, new anti-glycan antibodies were recently added to the armamentarium of
serologic markers in IBD. Glycans are sugars associated with proteins, abundant on
many living cells. The anti-glycan antibodies are directed against laminaribioside,
chitobioside, mannobioside and mannan residues and are designated antilaminaribioside carbohydrate antibodies (ALCA), anti-chitobioside carbohydrate
antibodies (ACCA), anti-mannobioside carbohydrate antibodies (AMCA) and gASCA,
respectively. Anti-laminarin IgA (Anti-L), and anti-chitin IgA (Anti-C) are new
members of this family. Laminarin and chitobioside are capable of stimulating the
innate immune system, thus the finding of antibodies against these glycans suggests
a connection between the adaptive and innate arms of the immune response in CD
patients. The contribution of serologic markers, specifically the anti-glycan
antibodies, to IBD diagnosis may be in differentiating IBD from other gastrointestinal
diseases, and between CD and ulcerative colitis (UC), in better classifying
undetermined colitis and for decision-making prior to proctocolectmy in UC patients.
The anti-glycan antibodies are specifically important in ASCA-negative CD patients.
Correlation between serologic markers and genetic variations may contribute to
reclassifying IBD into new and more homogeneous subclasses. Their significance in
diagnosing populations at risk, such as unaffected relatives of IBD patients and CD
patients prior to diagnosis, is under current investigation.
Scientific Rationale Update December 2010

Benor et al. (2010) The goal of this study was to compare the predictive values of
the Prometheus Inflammatory Bowel Disease (IBD) Serology 7 (IBD7) panel
(Prometheus Laboratories, San Diego, CA) with the predictive values of routine blood
tests in a population of children referred for initial evaluation of suspected IBD.
Medical records of pediatric patients referred for evaluation of IBD for whom IBD7
testing was performed at Prometheus Laboratories between January 2006 and
November 2008 were reviewed. Patients underwent diagnosis by pediatric
gastroenterologists on the basis of clinical, radiologic, endoscopic, and pathologic
evaluations. A total of 394 records were identified. We excluded 90 records on the
basis of age of >21 years, previous diagnosis of IBD, or unclear diagnosis. The
13
prevalence of IBD in this cohort was 38%. The sensitivity, specificity, positive
predictive value, negative predictive value, and kappa value for the serological panel
were 67%, 76%, 63%, 79%, and 42%, respectively, compared with values for a
combination of 3 abnormal routine laboratory test results of 72%, 94%, 85%, 79%,
and 47%. The antiflagellin antibody assay, the newest assay added to the panel, had
sensitivity of 50% and specificity of 53%. Repeat serological testing failed to produce
consistent results for 4 of 10 patients. Despite its recent inclusion of the antiflagellin
assay, the IBD7 panel has lower predictive values than routine laboratory tests in
pediatric screening for IBD.
Inflammatory bowel diseases (IBD) are chronic intestinal disorders where, in
genetically susceptible hosts, an intestinal microorganism triggers an over-reactive
immune response. Antibodies against luminal antigens are specifically associated
with Crohn's disease (CD). In addition to the previously described antibodies
antineutrophil cytoplasmic (auto)antibodies (ANCA), anti-Saccharomyces cerevisiae
antibodies (ASCA), OmpC, I2 and CBir1 Flagellin, new anti-glycan antibodies were
recently added to the armamentarium of serologic markers in IBD. Glycans are
sugars associated with proteins, abundant on many living cells. The anti-glycan
antibodies are directed against laminaribioside, chitobioside, mannobioside and
mannan residues and are designated anti-laminaribioside carbohydrate antibodies
(ALCA), anti-chitobioside carbohydrate antibodies (ACCA), anti-mannobioside
carbohydrate antibodies (AMCA) and gASCA, respectively. Anti-laminarin IgA (AntiL), and anti-chitin IgA (Anti-C) are new members of this family. Laminarin and
chitobioside are capable of stimulating the innate immune system, thus the finding of
antibodies against these glycans suggests a connection between the adaptive and
innate arms of the immune response in CD patients. The contribution of serologic
markers, specifically the anti-glycan antibodies, to IBD diagnosis may be in
differentiating IBD from other gastrointestinal diseases, and between CD and
ulcerative colitis (UC), in better classifying undetermined colitis and for decisionmaking prior to proctocolectmy in UC patients. The anti-glycan antibodies are
specifically important in ASCA-negative CD patients. Correlation between serologic
markers and genetic variations may contribute to reclassifying IBD into new and
more homogeneous subclasses. Their significance in diagnosing populations at risk,
such as unaffected relatives of IBD patients and CD patients prior to diagnosis, is
under current investigation.
Scientific Rationale Update March 2007

Vergara et al (2006), acknowledging that the presence of specific serological markers
could be helpful in the characterization of patients with ulcerative colitis and its
association with clinical features, studied the prevalence of ANCA and ASCA in 64
patients with ulcerative colitis (UC) in remission. They found that 44% were positive
for ANCA, 9% for ASCA and 6% for both markers. There was a significant correlation
between the presence of ANCA and duration of the UC (<5 years 50%, 5-10 years
42.9%, 15 years 30%) and the number of crises (one crises 31%, 2-5 crises 51.9%
and >5 crises 87.5). The proportion of colectomized patients with positive ANCA was
higher (57.1%). The authors concluded that the prevalence of ANCA in the studied
population is similar to the published data. The presence of ANCA was significantly
higher in UC patients with shorter evolution, higher number of crises and in those
with a history of colectomy. There was a low prevalence of ASCA positive patients.
Reese et al (2006) assessed the diagnostic precision of anti-saccharomyces
cerevisiae (ASCA) and perinuclear antineutrophil cytoplasmic antibodies (pANCA) in
inflammatory bowel disease (IBD) and evaluate their discriminative ability between
14
ulcerative colitis (UC) and Crohn's disease (CD). A meta-analysis of studies reporting
on ASCA and pANCA in IBD was performed. Sixty studies comprising 3,841 UC and
4,019 CD patients were included. The ASCA+ with pANCA test offered the best
sensitivity for CD (54.6%) with 92.8% specificity. Sensitivity and specificity of
pANCA+ tests for UC were 55.3% and 88.5%, respectively. Sensitivity and specificity
were improved to 70.3% and 93.4% in a pediatric subgroup when combined. Metaregression analysis showed decreased diagnostic precision of ASCA for isolated
colonic CD. They came to the conclusion that ASCA and pANCA testing are specific
but not sensitive for CD and UC, however, they may be particularly useful for
differentiating between CD and UC in the pediatric population.
Canani et al (2006) evaluated the effectiveness of the combined use of fecal
calprotectin (FC), anti-Saccharomyces cerevisiae antibody (ASCA), perinuclear
staining antineutrophil antibody (pANCA), small intestinal permeability test (IP), and
bowel wall ultrasonography measurement (BWUS) in the diagnostic work-up of
children with suspected inflammatory bowel disease (IBD). Patients with symptoms
or signs (right-lower quadrant mass, perianal disease, or hematochezia) mandating a
complete work-up for IBD were excluded. All enrolled patients underwent a clinical,
laboratory, radiographic, and endoscopic evaluation including biopsy examinations.
The immunoglobulin (Ig)G and IgA ASCA, IgG pANCA, FC, IP, and BWUS were tested
in all patients at the initial assessment. A final diagnosis of IBD was made in 27
patients: 17 Crohn's disease and 10 ulcerative colitis. Eighteen children had other
gastrointestinal diagnoses (8 functional bowel disorders, 5 food allergy-mediated
diseases, 4 infectious enterocolitis, 1 familial Mediterranean fever). In patients with
simultaneous abnormal values of FC, BWUS, and ASCA/pANCA, the estimated
probability of having IBD was 99.47%. Patients with negative results on all tests had
a 0.69% of probability of IBD. They deduced that the incorporation of noninvasive
diagnostic tests into the initial diagnostic approach may avoid unnecessary invasive
procedures and facilitate clinical decision-making when the diagnosis of IBD in
children is initially uncertain.
Kaila et al (2005) determined the utility of the anti-Saccharomyces cerevisiae
antibody (ASCA) ELISA test developed in Manitoba in 2001 in a population-wide
sample referred from physicians across Manitoba in their investigation of patients
with gastrointestinal symptoms. Patients whose serum was referred for ASCA testing
in 2001 and 2002 were eligible for the present study. ELISA was performed by a
technologist, blind to patient diagnoses. A single investigator contacted physicians to
facilitate chart review. Data collected included demographics, final diagnoses and
tests used to substantiate the final diagnosis. Of 482 subjects identified, 410 charts
were available for review and 29 of those were unavailable for follow-up or had
incomplete charts. The present study population included Crohn's disease (CD,
n=114), ulcerative colitis (n=74), indeterminate colitis (n=31), celiac disease (n=9),
irritable bowel syndrome (n=75), other diagnoses (n=33) and no disease (n=45).
ASCA had a sensitivity of 37% (95% CI 27.8 to 46.8) and specificity of 97% for
diagnosing CD. The 47 ASCA-positive patients included the following diagnoses:
CD=39, ulcerative colitis=3, indeterminate colitis=1, celiac disease=3 and no
disease=1. The likelihood of having an inflammatory disease if ASCA is positive was
nearly 40-fold. The authors surmised that a positive ASCA test using this assay
nearly clinches a diagnosis of some form of inflammatory intestinal disease, which is
highly likely to be CD. In symptomatic patients, a positive ASCA test should
encourage the clinician to pursue further investigations.
15
Gupta et al (2005) determine the clinical impact of ANCA/ASCA testing by evaluating

how these tests were used in an academic referral center. Retrospective chart review
to classify the indications for testing and effect on diagnosis or management was
performed on 76 patients who had serological tests for IBD. Indications included
differentiating ulcerative colitis (UC) from Crohn's disease (CD) in established
patients with IBD (13%); establishing a diagnosis in patients with atypical signs of
inflammation as detected by endoscopy, histology, or radiology (50%); evaluation of
chronic diarrhea (22%); evaluation of a family history of IBD (4%); and
differentiating pouchitis from CD (4%). Review of the subsequent course indicated
that serologic testing had an important role in diagnosis in 28% of patients, a
supportive role in 26%, and was not helpful in 46%. Serologic testing clarified the
clinical presentation in 61% of those presenting with atypical inflammatory changes.
It proved valuable in establishing a diagnosis of UC or CD in a subset of middle-aged
patients with inflammatory changes in the sigmoid colon. For patients with chronic
diarrhea, the yield was lower: 36% had a significant effect on diagnosis, but test
results changed immediate treatment in only 1 (6%). In patients being considered
for operative management (n = 8), serologic testing was valuable in clarifying the
diagnosis in 75% of patients and had an impact on the operative plan in 62% of
patients. The authors concluded that serological testing for ANCA/ASCA may have a
significant role in the diagnosis and treatment in individuals presenting with sigmoid
inflammation or atypical inflammation, but was less useful in those with chronic
diarrhea. Serological markers for IBD, including ANCA) and ASCA, although they
might have a high specificity and positive predictive value in diagnosing IBD, neither
indication nor use in clinical practice has still not been clearly established.
The problems of antineutrophil cytoplasmic antibody testing include the diversity of
antineutrophil cytoplasmic antibody target antigens, assay standardization and
performance, the application of antineutrophil cytoplasmic antibody testing in a
clinical setting with a low pretest probability, and, finally, the widespread assumption
that antineutrophil cytoplasmic antibody titers alone may closely reflect disease
activity and therefore may be used to guide therapy. Recent findings demonstrate
that the combined use of indirect immunofluorescence tests and solid phase assays
to detect antineutrophil cytoplasmic antibody directed against myeloperoxidase and
proteinase 3 can minimize the occurrence of false-positive antineutrophil cytoplasmic
antibody results. Furthermore, the yield of antineutrophil cytoplasmic antibody
testing can be improved by the use of a well-standardized test, adherence to
published guidelines, and restricting the use of the tests to clinical situations with a
rather high pretest probability for antineutrophil cytoplasmic antibody-associated
diseases. However, treatment decisions should be still based on the clinical
presentation of the patient and histologic findings and not on the results of
antineutrophil cytoplasmic antibody testing alone.
Scientific Rationale Update February 2006

In their updated practice guidelines for ulcerative colitis in adults (2004), the
American College of Gastroenterology states that:
pANCA have been identified in 60-70% of UC patients but are also
found in up to 40% of patients with CD. These pANCA-positive CD
patients typically resemble left-sided UC patients clinically, so ANCA
detection alone is of little value in distinguishing between UC and CD.
The guideline further states that while pANCA and ASCA assays at this
stage of knowledge are neither a first step nor a definitive step in
differential diagnosis or clinical decision-making, they may be useful in
16
the patient in whom all other clinical features do not allow a distinction
between UC and Crohns colitis.
A clinical review by Escher JC, et al (2003) on the treatment of inflammatory bowel
disease in childhood: best available evidence inflammatory bowel diseases states:
Pharmacogenetic differences in the activity of TPMT may explain why
certain patients are predisposed to AZA/6-MP-induced cytotoxicity,
whereas in others, disease is refractory to therapy. Measurement of
TPMT activity is recommended before instituting therapy.
Immunomodulatory agents commonly used in the long-term care of IBD include 6mercaptopurine (6-MP) and its pro-drug azathioprine (AZA). AZA and 6-MP are
converted intracellularly by thiopurine methyltransferase (TPMT) into nucleotide
metabolites 6-thioguanine (6-TG) and 6- methylmercaptopurine (6-MMP). Both the
therapeutic efficacy and the hematological toxicity of 6-MP are positively related to
serum levels of 6-TG. Measurement of 6-TG levels may aid clinicians in optimizing
the therapeutic response to AZA and 6-MP. In addition, there are established genetic
polymorphisms for TPMT, which result in varied individual responses to these drugs
(Stenson and Korzenik, 2003). Determining the existence of TPMT polymorphisms by
genotyping can assist in identifying patients at risk of toxicity from AZA and 6-MP.
These polymorphisms can be homozygous, heterozygous or absent. Approximately
11% of IBD patients have a heterozygous genotype involving the TPMT-3A allele.
Patients with these heterozygous mutations have approximately half the normal
capacity to methylate 6-MP. Reduction in doses, monitoring of metabolite levels and
frequent blood count analysis can assist in avoiding bone-marrow toxicity in this
population. Homozygous mutations of TPMT, found in 0.3% of the population, have
been shown to cause a much higher risk of severe leukopenia and septic
complications for IBD patients.
Metabolite monitoring includes obtaining blood levels of 6-thioguanine nucleotide (6TGN) and 6-methylmercaptopurine (6-MMP), as well as complete blood counts
(CBCs) to monitor potential side effects. Side effects of the drugs 6-MP and AZA can
include suppression of bone marrow, red blood cell (RBC) macrocytosis, and
leukopenia. Liver and pancreatic function must also be monitored, since those organs
can also react negatively to this therapy. Clinical remission is correlated with an
erythrocyte 6-TG level > 230 pmol/8x108 RBC (Seidman, 2003).
Once therapy begins, patients may continue to deteriorate clinically, as evidenced by
fever, continued weight loss, bloody diarrhea, abdominal pain, or vomiting.
Inadequate dosing is the most common cause of treatment failure. Measuring drug
metabolite levels and adjusting the dose to achieve 6-TGN levels above the
therapeutic threshold (235-400 pmol/8x108 RBC) can convert a treatment failure
into a responder. Other reasons for treatment failure are excessive TPMT activity
and/or non-adherence or inconsistent adherence to therapy (Dubinsky, et al., 2000;
Cuffari, et al., 2001).
When TPMT activity is normal, a ratio of 6-TGN:6-MMP will be between 10:1 and
15:1, with RBC 6-TGN levels > 350 pmol/8x108. Treatment is usually successful,
though the patient must still be monitored for toxicity. Excessive TPMT activity
produces metabolite levels of 6-MMP/6-TGN at ratios of between 30:1 and 100:1.
This increase has been linked to hepatotoxicity, with transaminases elevated by 310%. When TPMT activity is low, then RBC 6-TGN levels can rise (450 pmol/8x108),
causing myelotoxicity (Dubinsky, et al., 2000; Cuffari, et al., 2001)
17
Limited evidence in the published peer-reviewed medical literature suggests that

metabolite testing is indicated for a subset of patients undergoing azathioprine/6mercaptopurine (AZA/6-MP) therapy for inflammatory bowel disease (IBD). Such
testing may be useful for optimizing therapeutic response to AZA or 6-MP, assessing
individual compliance with drug regimens, and identifying those individuals who are
at increased risk for drug-induced toxicity. Large-scale randomized controlled trials
(RCTs) are needed to further define the role of metabolite testing in the
management of patients with IBD who require immunomodulatory therapy.
Scientific Rationale - Initial

Inflammatory bowel disease (IBD) is a chronic disease of the gastrointestinal tract
that consists of two similar but distinct conditions, ulcerative colitis (UC) and Crohns
disease (CD). Although ulcerative colitis and Crohns disease are generally
considered two separate forms of IBD, their clinical presentations commonly overlap
with symptoms of diarrhea and abdominal pain. In the majority of times, the
definitive diagnosis can usually be established by a combination of radiographic,
endoscopic and histologic criteria. Differentiation of Crohn's disease from ulcerative
colitis is clinically problematic only when inflammation is confined to the colon.
A correct diagnosis of IBD, especially the differentiation between CD and UC, is
highly important toward treatment and prognosis. However, the distinction between
UC and CD cannot be made with certainty in approximately 10-15% of cases. These
patients are given a diagnosis of indeterminate colitis (IC).
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 serological markers known as anti-neutrophil
cytoplasmic antibodies (ANCA), which are specific for granulocyte antigens. ANCA
has 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. It has been proposed that serological markers for IBD
can be utilized both to differentiate UC from CD and also to define patient subgroups.
ANCA and anti-Saccharomycescerevisiae antibodies (ASCA) have been the most
extensively studied serological markers as a first screen in patients with clinical signs
and symptoms suggestive of IBD who have not undergone confirmatory tests such
as contrast radiographic studies or colonoscopy with biopsy. ANCAs can be divided
into 2 types: cytoplasmic staining pattern (cANCA) and perinuclear staining pattern
(pANCA). pANCA has been found to be detectable in 50-80% of patients with UC,
while it has been linked with only 10-40% of patients with CD. ASCA is a more
recently described antibody that has been found to be detectable in 46 to 70% of
patients with CD and 6-12% of patients with UC. Some studies have found that the
majority of Crohn's patients positive for pANCA have ulcerative colitis-like
presentations.
The IBD First Step and IBD Diagnostic System (Prometheus Laboratories, Inc.) are
commercially available diagnostic systems that use combinations of tests for ANCA
and/or ASCA to aid in the diagnosis of IBD. The PRO-Predict series of tests were also
developed by Prometheus, Inc. with the hope of providing guidance in determining
therapeutic direction and predicting therapeutic response in individual patients. PROPredict 6MP is for 6-MP/Azathioprine remission and toxicity monitoring, PRO-Predict
TPMT is for 6-MP/azathioprine response stratification, and PRO-Predict TNF is for
anti-TNF response stratification.
18
At the present time, there is inadequate data in the published medical literature that
diagnostic performance would either alter the standard diagnostic work up or result
in the appropriate classification of patients with indeterminate IBD. No studies have
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. Most published studies have all focused on patients
with established diagnoses of UC or CD, except for a prospective study by Joossens
et al (2002) who identified 97 patients with IC. Using the Prometheus system, a
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.
While the specificity of these tests are relatively high (90-94%), the sensitivity is low
(38%), which indicates that a negative result will not be clinically helpful. The ANCA
and/or ASCA test results cannot be relied upon for confirmation of a diagnosis, thus
patients still require the standardized work-up, including colonoscopy and biopsy.
Studies do not demonstrate any correlation between the presence of these
antibodies and disease activity or duration, proximal versus distal bowel
involvement, and severity of disease, which may provide prognostic information. The
use of ANCA and ASCA for patients with IBD has not shown to improve health
outcomes by reducing the need for other tests.
In his position paper, Griffiths (1999) stated 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 IBD in comparison to clinical acumen and the equally sensitive (albeit
less specific) 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.".."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."
ANCA and ASCA testing has also not been proven to be useful in selecting
therapeutic interventions. Griffiths additionally explains, "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." In addition,
studies have shown that there is no 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 inflammatory bowel disease.
Recently published guidelines from the American College of
Gastroenterology (2001) mention no role for ANCA or ASCA testing in the
screening, diagnosis, or management of patients with Crohn's disease.
19
Furthermore, the American Gastroenterological Associations position statement on

perianal Crohns disease (2003) did not discuss the use of ANCA or ASCA testing as a
diagnostic tool. The optimal mode of therapeutic monitoring remains to be
established through clinical trials.
Guidelines (2001) on Crohn's disease from the American College of Gastroenterology
(ACG) confirms the investigational status of the Pro-Predict tests of azathioprine and
mercaptopurine metabolites:
Azathioprine and mercaptopurine have had demonstrable adjunctive
benefits to steroids in adults but may require up to 4 months to
demonstrate a beneficial effect. Dose-response studies have not been
performed with azathioprine or mercaptopurine. Genetic polymorphisms
for thiopurine methyltransferase, the primary enzyme metabolizing
mercaptopurine, have been identified which may afford the potential to
regulate therapy according to measurement of mercaptopurine
metabolites (6-thioguanine). At present, the optimal dose and mode of
therapeutic monitoring remain to be established although clinical trials
have demonstrated efficacy for oral azathioprine at 2.5 mg/kg.
In 2002, The Institute for Clinical Systems Improvement (ICSI) published its
technology assessment of serologic testing for inflammatory bowel disease and
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 "The clinical utility of serological testing is not yet established
for differentiating between UC and CD in patients with inflammatory bowel disease".
In concusion, there is inadequate scientific evidence in the current medical literature
to validate the routine use of these tests in clinical practice. Large-scale prospective
studies are required to ascertain the predictive value and cost effectiveness of the
use of ANCA and ASCA in screening and monitoring of IBD patients.
Review History
November 2004
September 2005
February 2006
March 2007
December 2010
September 2011
September 2012
September 2013
September 2014
April 2015
Medical Advisory Council for initial approval

No revisions
Genotyping for TPMT and monitoring thiopurine methyltransferase metabolite levels become medically necessary
Update no changes
Update. Added Medicare Table. No revisions.
Update. Added Revised Medicare Table. No revisions.
Update. Added NOD2/CARD15 genotyping for Crohn's Disease
as investigational.
Update Added several additional assays to the policy
statement considered medically necessary when criteria is met.
Code updates
Update - no revisions
Added Anser IFX and ADA tests as investigational (i.e. The
Anser IFX test measures serum infliximab (IFX) or [Remicade]
levels and antibodies to infliximab (ATI). The Anser ADA test
measures serum adalimumab (ADA) or [Humira] levels and
antibodies to adalimumab (ATA). Conflicting evidence is
available on the association of ATIs and ADAs with clinical
20
April 2016
response to infliximab and adalimumab in patients with IBD.

Overall quality is low and optimal management of patients who
have lost response to infliximab or adalimumab is unknown.
Detection of ATIs or ADAS may be helpful for physicians who
must decide among these treatment alternatives, however,
more research and ongoing studies are necessary to provide
evidence that altered treatments would result in better
outcomes, for patients with IBD. Codes reviewed.
Update no revisions. Code updates
This policy is based on the following evidenced-based guidelines:

1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
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14.
Asher Kornbluth, M.D. and David B. Sachar, M.D. Ulcerative Colitis Practice
Guidelines in Adults (Update): American College of Gastroenterology, Practice
Parameters Committee. July 2004. American Journal of Gastroenterology. 99(7)
1371 - July 2004. Accessed at:
http://www.acg.gi.org/physicians/guidelines/UlcerativeColitisUpdate.pdf
Hanauer SB, Sandborn W. Management of Crohn's disease in adults. Am J
Gastroenterol 2001 Mar;96(3):635-43.
Society of Surgery of the Alimentary Tract, Inc. (SSAT). Management of
ulcerative colitis. Manchester (MA): Society for Surgery of the Alimentary Tract,
Inc. (SSAT); 2001.
Griffiths AM. Serological diagnosis of IBD. Excerpts from the 1999 NASPGN
Course Syllabus. North American Society for Pediatric Gastroenterology and
Nutrition Position Papers.
American Gastroenterological Association medical position statement: perianal
Crohn's disease. Gastroenterology 2003 Nov;125(5):1503-7. Accessed
at:http://www.gastrojournal.org/article/S0016-5085(03)01366-0/abstract
American Society of Colon and Rectal Surgeons. Practice Parameters for
Treatment of Mucosal Ulcerative Colitis. 1997.
Lashner BA. Inflammatory Bowel Disease. June, 2004.
Institute for Clinical Systems Improvement (ICSI). Serum antibodies for the
diagnosis of inflammatory bowel disease (IBD): pANCA for ulcerative colitis (UC)
and ASCA for Crohns disease (CD). Technology Assessment Report No. 65.
Bloomington, MN: ICSI; November 2002.
Carter MJ, Lobo AJ and Travis SPL. Guidelines for the management of
inflammatory bowel disease in adults. Gut 2004;53:1-16. Accessed at:
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Escher JC, et al (2003) Treatment of Inflammatory Bowel Disease in Childhood:
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World Gastroenterology Organisation (WGO). World Gastroenterology
Organisation Global Guideline: Inflammatory bowel disease: a global
perspective. Munich (Germany): World Gastroenterology Organisation (WGO);
2009 Jun 1. 23 p.
Hayes Search & Summary. Prometheus IBD Serology to Aid in the Diagnosis of
Crohns Disease. January 25, 2010
Hayes GTE Overview. NOD2/CARD15 Testing (Prometheus) for Crohn's Disease.
May 2012. Update May 2015
Lichtenstein GR, Hanauer SB, Sandborn WJ; Practice Parameters Committee of
American College of Gastroenterology. Management of Crohn's disease in adults.
Am J Gastroenterol. 2009 Feb;104(2):465-83. Available at:
http://s3.gi.org/physicians/guidelines/CrohnsDiseaseinAdults2009.pdf
21
15. National Institute for Health and Clinical Excellence (NICE). Crohn's disease:
management in adults, children and young people. National Institute for Health
and Clinical Excellence (NICE); 2012 Oct. 34 p.
16. Gastroenterology & Hepatology August 2013, Volume 9, Issue 8, Supplement 4.
Special Meeting Edition, Clinical Research Highlights in IBD: Diagnosis and AntiTumor Necrosis Factor Monitoring, Digestive Disease Week 2013.
17. Hayes Medical Technology Directory. Serological Assays for the Diagnosis and
Management of Inflammatory Bowel Disease: Crohn's Disease. Mar 2013.
Update Mar 2014. Update Jan 2016
18. Kornbluth A, Sachar DB. Ulcerative colitis practice guidelines in adults: American
College Of Gastroenterology, Practice Parameters Committee. Am J
Gastroenterol. 2010;105(3):501-523. Available at:
http://s3.gi.org/physicians/guidelines/UlcerativeColitis.pdf
19. Hayes. Health Technology Brief. Use of Anti-Infliximab Antibody Levels to
Monitor Infliximab Treatment in Patients with Inflammatory Bowel Disease
(IBD). May 23, 2013. Updated April 30, 2014.
20. Hayes Medical Technology Directory. Serological Assays for the Diagnosis and
Management of Inflammatory Bowel Disease: Ulcerative Colitis. April 2013.
Update March 2016
References Update April 2016

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Scott FI, Lichtenstein GR. Advances in Therapeutic Drug Monitoring of Biologic
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Zhou G, Song Y, Yang W, et al. ASCA, ANCA, ALCA and Many More: Are They
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Infliximab Predict Safety and Success of Re-initiation of Infliximab Therapy. Clin
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Casteele N, Gils A, Singh S, et al. Antibody response to infliximab and its impact
on pharmacokinetics can be transient. Am J Gastroenterol. Feb 19, 2013.
Levesque BG, Greenberg GR, Zou G, et al. A prospective cohort study to
determine the relationship between serum infliximab concentration and efficacy
in patients with luminal Crohn's disease. Aliment Pharmacol Ther. 2014
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McTigue, Sandborn WJ, Levesque BG. Clinical Utility of Next Generation
Infliximab and Antibodies to Infliximab Assay. 2013.
OMeara S, Nanda KS, Moss AC. Inflamm Bowel Dis. Antibodies to infliximab and
risk of infusion reactions in patients with inflammatory bowel disease: a
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Roblin X, Rinaudo M, Del Tedesco E, et al. Development of an algorithm

incorporating pharmacokinetics of adalimumab in inflammatory bowel diseases.
Am J Gastroenterol. Aug 2014; 109(8):1250-1256.
Roblin X, Marotte H, Rinaudo M, et al. Association between pharmacokinetics of
adalimumab and mucosal healing in patients with inflammatory bowel diseases.
Clin Gastroenterol Hepatol. Jan 2014; 12(1):80-84 e82.
Steenholdt C, Bendtzen K, Brynskov J, et al. Clinical implications of measuring
drug and anti-drug antibodies by different assays when optimizing infliximab
treatment failure in Crohn's disease: post hoc analysis of a randomized
controlled trial. Am J Gastroenterol. Jul 2014; 109(7):1055-1064.
Vahabnezhad E, Rabizadeh S, Dubinsky MC. A 10-year, single tertiary care
center experience on the durability of infliximab in pediatric inflammatory bowel
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References Update September 2014

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Elkadri AA, Stempak JM, Walters TD, et al. Serum antibodies associated with
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Mokhtarifar A, Ganji A, Sadrneshin M, et al. Diagnostic Value of ASCA and
Atypical p-ANCA in Differential Diagnosis of Inflammatory Bowel Disease. Middle
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Papp M, Lakatos PL. Serological studies in inflammatory bowel disease: how
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Plevy S, Silverberg MS, Lockton S, et al. Combined serological, genetic, and
inflammatory markers differentiate non-IBD, Crohn's disease, and ulcerative
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Kekilli M, Beyazit Y, Tas A, et al. Atypical pANCA as a marker of indeterminate

colitis for the prediction of ulcerative colitis and Crohn's disease. Wien Klin
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Kuna AT. Serological markers of inflammatory bowel disease. Biochem Med
(Zagreb). 2013;23(1):28-42
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in pediatric Crohn's disease in comparison with an adult cohort. Inflamm Bowel
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in children from the Western region of Saudi Arabia. Arab J Gastroenterol. 2013
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van Schaik FD, Oldenburg B, Hart AR, et al. Serological markers predict
inflammatory bowel disease years before the diagnosis. Gut. 2013
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with phenotypes and higher risk for surgery in Crohns disease: a meta-analysis.
Dig Dis Sci. 2012;57(11):2944-2954.
23

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Clinical Trials. Identifying Disease Variants for Familial Crohns Disease

(5RO1DK083553-02). 2011 currently being done at Johns Hopkins University.
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Library of Medicine (NLM) Identifier: NCT00780949. Updated September 24,
2010. Available at: http://www.clinicaltrials.gov/ct2/show/NCT00780949.
Cleveland Clinic Lerner Col/Med-CWRU. Genetic Studies in Crohn's Disease.
Project No. 5K23DK068112-05. 2011. RePORTER.
Farrell RJ, Peppercorn MA. Overview of the medical management of mild to
moderate Crohn's disease in adults. UpToDate. April 27, 2011.
Johns Hopkins University. Identifying Disease Variants for Familial Crohn's
Disease. Project No. 5R01DK083553-02. 2011. RePORTER.
Lauriola M, Ugolini G, Rivetti S. IL23R, NOD2/CARD15, ATG16L1 and PHOX2B
polymorphisms in a group of patients with Crohn's disease and correlation with
sub-phenotypes. Int J Mol Med. 2011;27(3):469-477.
Prometheus Inc. CLIA Accreditation. 2011b.

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Cytoplasmic Antibody Testing. Current Opinion in Rheumatology 2004
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3. Vergara T, Cofre P, Cifuentes S, et al. Presence of antineutrophil cytoplasmic
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2004;17 Suppl 1:22-6.
6. Sandborn WJ. Serologic markers in inflammatory bowel disease: state of the art.
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and anti-OmpC in children and young adults with Crohn's disease and ulcerative
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6. Dubinsky MC, Ofman JJ, Urman M, et al. Clinical utility of serodiagnostic testing in
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8. Sandborn WJ, Loftus EV, Colombel JF, et al. Evaluation of serologic disease
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10. Reumaux D, Colombel JF, Masy E et al. Anti-neutrophil cytoplasmic autoantibodies (ANCA) in ulcerative colitis (UC): no relationship with disease activity.
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inflammatory bowel disease: clinical role and review of the literature. Dis Colon
Rectum 2000; 43(7):999-1007.
12. Nielsen OH, Vainer B, Madsen SM, et al. Established and emerging biological
activity markers of inflammatory bowel disease. Am J Gastroenterol
2000;95(2):359-67
13. Check W. Shades of gray in gastrointestinal testing. CAP Today, August 2000.
Accessed at:
http://www.cap.org/apps/docs/cap_today/feature_stories/feat1800.html
14. Hoffenberg EJ. Serologic testing for inflammatory bowel disease. J Pediatr.
1999;134(4):447-452.
15. Stein RB. Medical therapy for inflammatory bowel disease. Gastroenterol Clin
North Am. 1999;28(2):297-321.
16. Lamers CB, Griffioen G, van Hogezand RA, Veenendaal RA. Azathioprine: An
update on clinical efficacy and safety in inflammatory bowel disease. Scand J
Gastroenterol Suppl. 1999;230:111-115.
17. MacDermott RP. Lack of current clinical value of serological testing in the
evaluation of patients with IBD. Inflamm Bowel Dis. 1999;5(1):64-67.
18. 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.
19. Ringel M. 'Jury is out' on value of combination GI test panel. CAP Today.
1998;12(6):26-28, 32.
20. Rutgeerts P, Vermeire S. Clinical value of the detection of antibodies in the serum
for diagnosis and treatment of inflammatory bowel disease. Gastroenterol.
1998;115(4):1006-1009.
21. Ruemmele FM, Targan SR, Levy G, et al. Diagnostic accuracy of serological
assays in pediatric inflammatory bowel disease. Gastroenterology.
1998;115:822-829.
28
22. Olives JP, Breton A, Hugot JP, et al. Antineutrophil cytoplasmic antibodies in
children with inflammatory bowel disease: Prevalence and diagnostic value. J
Pediatr Gastroenterol Nutr. 1997;25(2):142-148.
23. Abad E, Tural C, Mirapeix E, Cuxart A. Relationship between ANCA and clinical
activity in inflammatory bowel disease: Variation in prevalence of ANCA and
evidence of heterogeneity. J Autoimmun. 1997;10(2):175-180.
24. Freeman H, Roeck B, Devine D, Carter C. Prospective evaluation of neutrophil
autoantibodies in 500 consecutive patients with inflammatory bowel disease. Can
J Gastroenterol. 1997;11(3):203-207.
25. Bansi DS, Chapman RW, Fleming KA. Prevalence and diagnostic role of
antineutrophil cytoplasmic antibodies in inflammatory bowel disease. Eur J
Gastroenterol Hepatol. 1996;8(9):881-885.
26. Hanauer SB. pANCA and classification resistance in ulcerative colitis. Mayo Clin
Proc. 1996;71(5):517-518.
27. Andreani ML, Frasca G, Brusco G, et al. Antineutrophil cytoplasmic antibodies in
inflammatory bowel disease: Diagnostic tool or research procedure? Ann Ital Med
Int. 1996;11(4):254-257.
28. Vasiliauskas EA, Plevy SE, Landers CJ, et al. Perinuclear antineutrophil
cytoplasmic antibodies in patients with Crohn's disease define a clinical subgroup.
Gastroenterology. 1996;110:1810-1819.
29. Castellino F, Rosina F, Bansi DS, et al. Anti-neutrophil cytoplasmic antibodies in
inflammatory bowel disease: Do they recognize different subsets of a
heterogeneous disease? Eur J Gastroenterol Hepatol. 1995;7(9):859-864.
30. Hertervig E, Wieslander J, Johansson C, et al. Anti-neutrophil cytoplasmic
antibodies in chronic inflammatory bowel disease. Prevalence and diagnostic role.
Scand J Gastroenterol. 1995;30(7):693-698.
31. Deusch K, Oberstadt K, Schaedel W, et al. p-ANCA as a diagnostic marker in
ulcerative colitis. Adv Exp Med Biol. 1993;336:527-531.
32. Oudkerk Pool M, Ellerbroek PM, Ridwan BU, et al. 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
treatment. Gut. 1993;34(1):46-50.
33. Cambridge G, Rampton DS, Stevens TR, et al. Antineutrophil antibodies in
inflammatory bowel disease: Prevalence and diagnostic role. Gut. 1992;33:668674.
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ANCAfor Crohns Diseaseand Ulcerative Colitis

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National Medical Policy

ANCA for Crohns Disease and Ulcerative

This National Medical Policy is subject to the terms in the

Use Health Net Policy

Crohn's Disease and Ulcerative Colitis Serum Antibodies Apr 16

Current Policy Statement

Subsequent to colonoscopy in adult patients with indeterminate colitis;

In adult patients who present acutely with significant symptoms of

In the initial work up of pediatric patients with inflammatory bowel

Crohn's Disease and Ulcerative Colitis Serum Antibodies Apr 16

Codes Related To This Policy

Regional enteritis (i.e., Crohns disease)

Crohns disease (regional enteritis)

Immunoassay for analyte other than infectious agent antibody

2016 CPT Codes

Immunofluorescence, per specimen; each additional single

Scientific Rationale Update April 2016

Crohn's Disease and Ulcerative Colitis Serum Antibodies Apr 16

Paul et al (2015) reported the usefulness of anti-glycan antibodies alone or combined

Scientific Rationale Update April 2015

Crohn's Disease and Ulcerative Colitis Serum Antibodies Apr 16

Crohn's Disease and Ulcerative Colitis Serum Antibodies Apr 16

Crohn's Disease and Ulcerative Colitis Serum Antibodies Apr 16

U/mL; 95% CI 0 to 23.7 U/mL; P<0.001). Receiver operating characteristic (ROC)

Crohn's Disease and Ulcerative Colitis Serum Antibodies Apr 16

There is insufficient evidence in the peer reviewed published medical literature to

Scientific Rationale Update September 2014

Scientific Rationale Update September 2013

Crohn's Disease and Ulcerative Colitis Serum Antibodies Apr 16

antineutrophil cytoplasmic antibody (pANCA). Subsequent research has identified a

Crohn's Disease and Ulcerative Colitis Serum Antibodies Apr 16

in 60 70 % of UC patients, but are also found in up to 40% of patients with

Crohn's Disease and Ulcerative Colitis Serum Antibodies Apr 16

Scientific Rationale Update September 2012

Scientific Rationale Update September 2011

Crohn's Disease and Ulcerative Colitis Serum Antibodies Apr 16

Scientific Rationale Update December 2010

Crohn's Disease and Ulcerative Colitis Serum Antibodies Apr 16

Scientific Rationale Update March 2007

Crohn's Disease and Ulcerative Colitis Serum Antibodies Apr 16

Crohn's Disease and Ulcerative Colitis Serum Antibodies Apr 16

Gupta et al (2005) determine the clinical impact of ANCA/ASCA testing by evaluating

Scientific Rationale Update February 2006

Crohn's Disease and Ulcerative Colitis Serum Antibodies Apr 16

Crohn's Disease and Ulcerative Colitis Serum Antibodies Apr 16

Limited evidence in the published peer-reviewed medical literature suggests that

Scientific Rationale - Initial

Crohn's Disease and Ulcerative Colitis Serum Antibodies Apr 16

Crohn's Disease and Ulcerative Colitis Serum Antibodies Apr 16

Furthermore, the American Gastroenterological Associations position statement on

Medical Advisory Council for initial approval

Crohn's Disease and Ulcerative Colitis Serum Antibodies Apr 16

response to infliximab and adalimumab in patients with IBD.

This policy is based on the following evidenced-based guidelines:

Crohn's Disease and Ulcerative Colitis Serum Antibodies Apr 16

References Update April 2016

El-Matary W, Dupuis K, Sokoro A. Anti-Saccharomyces cerevisiae antibody titres

References Update April 2015

Baert F, Drobne D, Gills A, et al. Early Trough Levels and Antibodies to

Crohn's Disease and Ulcerative Colitis Serum Antibodies Apr 16

Roblin X, Rinaudo M, Del Tedesco E, et al. Development of an algorithm

References Update September 2014

References Update September 2013