Background

RA is characterized by chronic joint inflammation leading to painful symptoms, progressive joint destruction, and loss of function. The disorder is relatively common and associated with a high burden of morbidity for affected patients.

Treatment

Treatment of RA has undergone a shift from symptom management to a more proactive strategy of minimizing disease activity and delaying disease progression.^1, The goal of treatment is to reduce the irreversible joint damage that occurs from ongoing joint inflammation and synovitis by keeping disease activity as low as possible. The availability of an increasing number of effective disease-modifying antirheumatic drugs has made the achievement of remission, or sustained low disease activity, a feasible goal for a large proportion of patients with RA. This treatment strategy has been called a tight control approach.

The concept of tight control in the management of RA has gained wide acceptance. Evidence from clinical trials has demonstrated that outcomes are improved with a tight control strategy, in which treatment targets are mainly based on measures of disease activity. In a systematic review, Schoelsetet al (2010) identified 7 studies that evaluated the efficacy of tight control.^2, Four of these trials randomized patients to tight control using treatment targets or to routine management, two studies compared different treatment targets, and one study compared results from targeted treatment with historical controls. The treatment targets were heterogeneous, including symptom-based measures, joint scores on the exam, validated treatment activity measures, lab values, or combinations of these factors. In all 4 trials that randomized patients to tight control or routine management, there was a significant decrease in the Disease Activity Score (DAS) or its 28 joints version (DAS28) and in the likelihood of achieving remission for patients in the tight control group.

According to the American College of Rheumatology (ACR) guidelines, initial treatment of patients with RA is monotherapy (usually a disease-modifying antirheumatic drug). Treatment may progress to combination therapy if disease activity remains moderate or high despite monotherapy.^3, Combination therapy may consist of additional disease-modifying antirheumatic drugs or the addition of tumor necrosis factors or non-tumor necrosis factors biologics.

Selection of Disease Activity Assessment Tools

For a strategy of tight control to be successful, reliable and valid measurement of disease activity is necessary. Numerous measurements exist that assess various aspects of RA disease activity, including patient self-report of symptom severity and functional capacity, physician examination of joints for swelling and tenderness, laboratory testing of serum biomarkers, and imaging. Various assessment tools exist that range from those that rely only on single types of measurements, to composite tools that combine information from multiple measurement sources. These assessment tools vary in their psychometric properties and their feasibility of implementation and these trade-offs must be considered in their selection for use. For example, although composite tools are more comprehensive, in some cases they may be less feasible for regular use.

Based on a systematic review (2019) of the psychometric properties of 46 tools,^4, an ACR working group determined that the following 11 measures of disease activity fulfilled a minimum standard for regular use in most clinical settings: Disease Activity Score (DAS), Routine Assessment of Patient Index Data 3 (RAPID3), Routine Assessment of Patient Index Data 5 (RAPID5), Clinical Disease Activity Index (CDAI), Disease Activity Score with 28 joints (DAS28-ESR/CRP), Patient Derived DAS28, Hospital Universitario La Princesa Index (HUPI), Multibiomarker Disease Activity Score (MBDA score, Vectra DA), Rheumatoid Arthritis Disease Activity Index (RADAI),Rheumatoid Arthritis Disease Activity Index 5 (RADAI-5), and the Simplified Disease Activity Index (SDAI). Additionally, using a modified Delphi process, the ACR working group further identified the following 5 measures as “preferred” for regular use in most clinic settings: the DAS28-ESR/CRP, CDAI, DSAI, RAPID3, and Patient Activity Scale-II.

Vectra Test

The Vectra Test is a commercially available multibiomarker disease activity (MBDA) test that is an approach to measuring RA disease activity that uses only serum biomarkers obtained through a laboratory blood draw. The manufacturer describes Vectra as a complement to clinical judgment.^5, Although not explicitly stated, it appears that the test may be used as an adjunct to other disease activity measures, to potentially identify patients at high-risk of progression who would, therefore, benefit from a more aggressive treatment strategy.

The Vectra test measures the serum concentrations of the following 12 biomarkers: Interleukin-6 (IL-6), Tumor Necrosis Factor Receptor Type I (TNFRI), Vascular Cell Adhesion Molecule 1 (VCAM-1), Epidermal Growth Factor (EGF), Vascular Endothelial Growth Factor A (VEGF-A), YKL-40, Matrix Metalloproteinase 1 (MMP-1), and Matrix Metalloproteinase 3 (MMP-3), C-reactive protein (CRP), Serum Amyloid A (SAA), Leptin, and Resistin. The concentrations of these 12 biomarkers are measured in serum and, combined with age, gender and adiposity (i.e., leptin) information, are entered in a proprietary formula to generate a score on a scale of 1 to 100 that represents the level of RA disease activity:^6,

Categories of scores were constructed to correlate with the DAS28-CRP scale^5,7,:

• 45-100: high disease activity
• 30-44: moderate disease activity
• 1-29: low disease activity.

In the ACR working group's systematic review reported by England et al (2019),^4, they also graded feasibility of the RA disease activity measurement tools. Any measure not commercially available or requiring advanced imaging was graded as infeasible. All other measures started with 4 points (ie, “++++”) and were downgraded by 1-point for each of the following implementation considerations: requiring a provider joint count, requiring a laboratory test, not possible to complete during a routine clinic visit, not possible to complete on the same day as the clinic visit. The ACR Working Group downgraded the feasibility of the Vectra DA by 3 points (ie, score of “++++" decreased to “+"). This was due to its requirement of a laboratory test and because its result is not available on the same day as the clinic visit. Although the current, commercially available version of the Vectra test was not assessed in the 2019 ACR guideline, because it requires the same laboratory testing that is not available on the same days as the clinic visit, likely it would have a similar feasibility rating as the older version.

Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments. The Vectra^® test (Crescendo Bioscience) is available under the auspices of Clinical Laboratory Improvement Amendments. Laboratories that offer laboratory-developed tests must be licensed by Clinical Laboratory Improvement Amendments for high-complexity testing. To date, the U.S. Food and Drug Administration has chosen not to require any regulatory review of this test.

Related Policies

• None

FIDE-SNP Coverage:
For members enrolled in a Fully Integrated Dual Eligible Special Needs Plan (FIDE-SNP): (1) to the extent the service is covered under the Medicare portion of the member’s benefit package, the above Medicare Coverage statement applies; and (2) to the extent the service is not covered under the Medicare portion of the member’s benefit package, the above Medicaid Coverage statement applies.

[RATIONALE: This policy was created in 2014 and has been updated regularly with searches of the PubMed database. The most recent literature update was performed through April 15, 2020.

Evidence reviews assess whether a medical test is clinically useful. A useful test provides information to make a clinical management decision that improves the net health outcome. That is, the balance of benefits and harms is better when the test is used to manage the condition than when another test or no test is used to manage the condition.

The first step in assessing a medical test is to formulate the clinical context and purpose of the test. The test must be technically reliable, clinically valid, and clinically useful for that purpose. Evidence reviews assess the evidence on whether a test is clinically valid and clinically useful. Technical reliability is outside the scope of these reviews, and credible information on technical reliability is available from other sources.

Multibiomarker Disease Activity Testing in Rheumatoid Arthritis
Clinical Context and Test Purpose

The purpose of the MBDA, specifically the Vectra, in patients who have RA is to determine the level of disease activity (low, medium, or high) in order to inform treatment decisions.

The question addressed in this policy is: Does use of an MBDA (eg, Vectra) test, alone or as an adjunct, to predict disease activity in patients with RA, improve health outcomes compared with the use of other American College of Rheumatology (ACR)-recommended measures of disease activity?

The following PICO was used to select literature to inform this policy.

Patients

The relevant population of interest is individuals with RA who are being managed with a disease-modifying antirheumatic drug (DMARD) and/or biologic agents. The test may be given at an outpatient rheumatology practice or an academic or community setting. Primary care may be the main source of care in some locations.

Management of patients with RA has changed from treatment of symptoms to a tight control strategy. The objective of a tight control strategy is to minimize disease progression and joint damage by monitoring disease activity and treating aggressively if an increase in activity is predicted.

Interventions

Vectra provides a score indicating the level of disease activity, based on blood levels of the following 12 biomarkers: interleukin-6, tumor necrosis factor (TNF) receptor type I, vascular cell adhesion molecule 1, epidermal growth factor, vascular endothelial growth factor A, YKL-40 glycoprotein, matrix metalloproteinase 1, matrix metalloproteinase 3, C-reactive protein (CRP), serum amyloid A, leptin, and resistin. The current, commercially available version of the Vectra test is adjusted for patient age, gender and adiposity, (i.e., leptin), now referred as the "adjusted MBDA score".

Scores range from 1 to 100 (1-29=low disease activity; 30-44=medium disease activity; 45-100=high disease activity).

Comparators

The reference standard for disease activity is radiographic progression at a set point in time, typically three months to one year. In addition, an ACR working group determined that the following 11 measures of disease activity fulfilled a minimum standard for regular use in most clinical settings: Disease Activity Score (DAS), Routine Assessment of Patient Index Data 3 (RAPID3), Routine Assessment of Patient Index Data 5 (RAPID5), Clinical Disease Activity Index (CDAI), Disease Activity Score with 28 joints (DAS28-ESR/CRP), Patient Derived DAS28, Hospital Universitario La Princesa Index (HUPI), the original and no longer commercially available Multibiomarker Disease Activity Score (MBDA score, Vectra DA), Rheumatoid Arthritis Disease Activity Index (RADAI),Rheumatoid Arthritis Disease Activity Index 5 (RADAI-5), and the Simplified Disease Activity Index (SDAI). Additionally, using a modified Delphi process, the ACR working group further identified the following 5 measures as “preferred” for regular use in most clinic settings: the DAS28-ESR/CRP, CDAI, DSAI, RAPID3, and Patient Activity Scale-II.

Outcomes

The goal of treating patients with RA is to improve quality of life and to prevent progression of the disease. Progression of disease causes irreversible joint damage.

If Vectra correctly assesses disease activity as low, the clinician may maintain medications at the same level or consider tapering the patient's medication.

If Vectra correctly assesses disease activity as moderate or high, the clinician may be more aggressive in disease management, by either increasing doses of current medications, switching medications, or adding medications to the treatment plan.

If Vectra incorrectly assesses disease activity as low, the clinician may maintain or decrease medication levels, which will allow progression of the disease and further joint damage.

If Vectra incorrectly assesses disease activity as moderate or high, the clinician may continue to manage the patient with higher levels of medication than is necessary to prevent disease progression, exposing the patient to unnecessary toxins. DMARDs may affect the liver, stomach, and intestines. Biologic agents may increase the risk of infection, lymphoma, and skin cancer.

The test may be run as often as a clinician needs disease activity information, typically every three to six months. A test immediately after diagnosis may serve as a baseline measurement.

For purposes of assessing Vectra against the reference standard of radiographic progression, one year is the typical time frame.

Study Selection Criteria

For the evaluation of the clinical utility of a multibiomarker disease activity test (eg, Vectra), studies would need to use the current commercially available version of the test (including the "adjusted MBDA score") as either an adjunct or a replacement to current disease activity measures to manage treatment decisions in patients with RA. Outcomes would be quality of life and measures of disease progression.

In the absence of direct evidence for the clinical utility of Vectra , evidence for clinical validity is evaluated, in which we can make inferences on clinical utility. For the evaluation of clinical validity, studies would need to compare the current commercially available version of Vectra (including the "adjusted MBDA score") used as an adjunct or as a replacement to ACR-recommended disease activity measures, with radiographic progression as a reference standard. Prognostic studies should report the probability of the outcome measure (with precision) by risk group. Studies reporting other measures (eg, odds ratios) may be included but are less informative.

Technically Reliable

Assessment of technical reliability focuses on specific tests and operators and requires a review of unpublished and often proprietary information. Review of specific tests, operators, and unpublished data are outside the scope of this policy, and alternative sources exist. This policy focuses on the clinical validity and clinical utility.

Clinically Valid
Review of Evidence
Vectra test with "adjusted MBDA score"

Evidence on the evaluation of clinical validity of the current commercially available version of the Vectra test (including the “adjusted MBDA score”) in patients with RA, consists of 1 retrospective cohort study (Table 1).^8, This study by Curtis et al (2018) evaluated the clinical validity of the Vectra test in predicting radiographic progression at 1 year using a convenience sample of combined data from 533 patients enrolled in either the Optimized Treatment in early Rheumatoid Arthritis (OPERA) randomized controlled trial^9, or the Brigham Rheumatoid Arthritis Sequential Study (BRASS) cohort study.^10, The clinical validity of the Vectra test was compared to that of the original Vectra DA test and other measures of DA (Table 2). Among the various disease activity measures assessed, only the new Vectra test (RR 8.38; 95% CI, 1.15 to 60.8), the original Vectra DA test (RR 5.39; 95% CI, 1.3 to 22.29) and CRP (RR 4.15; 95% CI, 1.58 to 10.95) significantly differentiated between the risk of radiographic progression for the high risk groups versus the low risk groups. Based on these outcomes, the study authors concluded that the new Vectra test (“adjusted MBDA score”) may offer “improved clinical utility” over the original and not commercially available Vectra DA test. Although the overlapping confidence intervals suggest at least similar prognostic performance to other DA measures, they indicate uncertainty as to whether Vectra provides prognostic performance superior to the original Vectra DA or CRP. Additionally, the low proportions of patients with radiographic progression in the moderate to high risk patient groups (3.9% to 9.3% for the new Vectra test and 3.5% to 9.7% for the original Vectra DA test group) do not support the use of the test to “rule in” moderate- to high-risk disease. These low rates of patients with radiographic progression the moderate to high risk patient groups suggest that 9 out of 10 patients identified as moderate or high risk could receive intensification of therapy unnecessarily. Likely this is due at least in part to the fact that the overall prevalence of radiographic progression was notably low in this study cohort (6.3%). Although the results from this study by Curtis et al (2018) are initially supportive of the Vectra test’s ability to predict radiographic progression at 1 year, its numerous relevance, design and conduct limitations (Tables 3 and 4) provide an insufficient basis to conclude the clinical validity of the Vectra test.

Table 1. Characteristics of Vectra (“adjusted MBDA score”) Clinical Validity Studies

Study	Study Population	Design	Outcome Measure	Threshold(s) for Risk Categories of Index Test	Timing of Enrollment with respect to course of disease	Blinding of Assessors	Comment
Curtis et al (2018)8,	OPERA, BRASS cohorts	Retrospective cohort with convenience samples	RP (mTSS > 5 units) at 1 y	Low (<30), moderate (30-44), and high (>44)	OPERA: RA < 6 months BRASS: mean disease duration 13.82 y	OPERA: Yes BRASS: No	OPERA involved treatment-naïve patients randomized to MTX plus placebo or MTX plus adalimumab; BRASS: large, single-center, prospective and observational cohort recruited from the practices of rheumatologists; hand and wrist radiographs only were adjusted by a factor of 1.6 to equal mTSS for all joints; DMARD therapy Combined cohort included 555 (92%) of 604 with “suitable radiographic data”

BRASS: Brigham Rheumatoid Arthritis Sequential Study; ICD: International Classification of Disease; DMARD: disease-modifying anti-rheumatic drugs; mTSS: maximal modified total Sharp score; MTS: methotrexate; OPERA: Optimized Treatment in early Rheumatoid Arthritis; RP: radiographic progression; RA: rheumatoid arthritis; US: United States

Table 2. Results of Vectra (“adjusted MBDA score”) Clinical Validity Studies

Study	Initial N	Final N	Excluded Samples	RP prevalence	% Study Population in Risk Group			Clinical Validity: Outcome Probability (95% CI)
					Low Risk	Intermediate Risk	High Risk	Low Risk	Intermediate Risk	High Risk
Curtis et al (2018)8,	604	533	49 (9%) initially excluded for “unsuitable” samples; 22 (4%) excluded for unspecified reasons	6.3%
Vectra (adjusted MBDA score)					90 (16.9%)	153 (28.7%)	290 (54.4%)	1.1% (0%, 6.0%)	3.9% (1.5%, 8.3%)	9.3% (6.2%, 13.3%)
Original Vectra DA (unadjusted, not commercially available)					111 (20.8%)	144 (27.0%)	278 (52.2%)	1.8% (0.2%, 6.4%)	3.5% (1.1%, 7.9%)	9.7% (6.5%, 13.8%)

CI: confidence interval. RP: radiographic progression

Table 3. Vectra ("adjusted MBDA Score") Clinical Validity - Study Relevance Limitations

Study	Populationa	Interventionb	Comparatorc	Outcomesd	Duration of Follow-Upe
Curtis et al (2018)8,	2. Position in clinical pathway unclear; 4. Unclear if population with low-risk of clinical progression is representative of intended use	3. Not consistent with current use, which is as an adjunct to other disease activity measures		3. Rationale for selecting radiographic progression definition not provided

The evidence limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.

^a Population key: 1. Intended use population unclear; 2. Clinical context is unclear; 3. Study population is unclear; 4. Study population not representative of intended use.
^b Intervention key: 1. Classification thresholds not defined; 2. Version used unclear; 3. Not intervention of interest (e.g., older version of test, not applied as intended).
^c Comparator key: 1. Classification thresholds not defined; 2. Not compared to credible reference standard; 3. Not compared to other tests in use for same purpose.
^d Outcomes key: 1. Study does not directly assess a key health outcome; 2. Evidence chain or decision model not explicated; 3. Key clinical validity outcomes not reported (see template Results tables; 4. Reclassification of diagnostic or prognostic risk categories not reported; 5. Adverse events of the test not described (excluding minor discomforts and inconvenience of venipuncture or noninvasive tests).
^e Follow-Up key: 1. Follow-up duration not sufficient with respect to natural history of disease (true positives, true negatives, false positives, false negatives cannot be determined).

Study	Selectiona	Blindingb	Delivery of Testc	Selective Reportingd	Data Completenesse	Statisticalf
Curtis et al (2018)8,	2. Selection not random or consecutive (ie, convenience).	1. Not blinded to results of reference or other comparator tests in some patients

^a Selection key: 1. Selection not described; 2. Selection not random or consecutive (ie, convenience).
^b Blinding key: 1. Not blinded to results of reference or other comparator tests.
^c Test Delivery key: 1. Timing of delivery of index or reference test not described; 2. Timing of index and comparator tests not same; 3. Procedure for interpreting tests not described; 4. Expertise of evaluators not described.
^d Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication.
^e Data Completeness key: 1. Inadequate description of indeterminate and missing samples; 2. High number of samples excluded; 3. High loss to follow-up or missing data.
^f Statistical key: 1. Confidence intervals and/or p values not reported; 2. Comparison to other tests not reported; 3: Insufficient consideration of potential confounding.

Numerous studies of the validity of the original Vectra DA test (not commercially available) have been conducted based on records and archived samples from randomized controlled trials and cohorts.^{11,12,13,14,15,16,17,18,19,20,21,22,23,}Although the Original Vectra DA test is no longer commercially available, for historical purposes, here we will provide a summary of the key findings from these studies.

The majority of the studies of the original Vectra DA have been previously summarized in 3 recent systematic reviews and pooled analyses.^24,4,25, Overall, findings from the most comprehensive and rigorous review (Johnson et al, 2019) indicated that although the original Vectra DA test has shown a positive correlation with other disease activity measures, results from studies comparing MBDA with radiographic progression are inconsistent.

The most comprehensive review was conducted by Johnson et al (2019),^24, which reported on the results of a systematic review of 22 studies of the clinical validity of the original Vectra DA test. Among those, 9 studies evaluated the ability of the original Vectra DA to predict radiographic progression. Studies were highly heterogenous in their radiographic progression thresholds and definitions, analytic methods, and results. For example, for the comparison of patients with a Vectra DA high-risk score versus patients with Vectra DA low-risk scores, the range of relative risks of radiographic progression was 1.04 to 14.30, and were significant in only 6 studies. Additionally, results of 8 studies that reported correlations of Vectra DA with other RA disease activity measures were included in a meta-analysis (N=3,242). The original Vectra DA test demonstrated modest correlations with the DAS28-CRP (r = 0.41; 95% CI 0.36 to 0.46) and the DAS28-ESR (r = 0.48, 95% CI 0.38 to 0.58). It demonstrated weaker correlations with the SDAI (r = 0.35, 95% CI 0.26 to 0.43), CDAI (r = 0.26, 95% CI 0.19 to 0.33), and RAPID3 (r = 0.23, 95% CI 0.19 to 0.27). Systematic review authors expressed concern that inadequate information about sample handling prevented them from ruling out the potential confounding effects of biased biomarker measurement due to variation in collection, processing, and storage of serum samples. The authors concluded that the findings need further validation in light of the high level of variability in methods and results.

The second most comprehensive systematic review was reported by England et al (2019), which detailed the results of an American College of Rheumatology working group’s systematic review of the psychometric properties of 46 RA disease activity measurement tools.^4, The objective of this ACR review was to determine which measures of disease activity fulfilled a minimum standard for regular use in most clinical settings. The ACR's definition of minimum standard was (1) that the tool provided a numerical value, (2) categorized to ≥3 disease states that separate low, moderate, and high disease activity, (3) was feasible for regular measurement in the clinic, and (4) possessed adequate psychometric properties. The ACR defined the adequacy of psychometric properties as having a level of evidence that suggested at least moderate positive results in hypothesis testing plus 1 of the following: (a) level of evidence suggesting at least moderate positive results in at least 1 of the following additional areas: internal consistency, reliability, measurement error, content validity, structural validity, or responsiveness; (b) level of evidence suggesting at least limited positive results in at least 2 of those additional areas (one of which must be responsiveness), or, (c) a defined minimum important difference/minimum clinically important difference. The ACR systematic review included 14 studies of the original version of the MBDA test, Vectra DA, that were published between 2012 and 2016. The review by England et al (2019) provided data abstraction of performance characteristic results from the individual studies, but did not draw any conclusions about specific clinical validity measures. Based on an overall qualitative assessment of the findings, including correlations and associations to other DA measures and radiographic progression, the ACR workgroup concluded that the original Vectra DA met their criteria for a moderate level of hypothesis testing, based on consistent findings in multiple studies of fair methodologic quality.

Finally, Curtis et al (2019) conducted a pooled analysis on data from studies of Vectra DA and radiographic progression.^25, To be included in the analysis, the cohort studies needed to have patient-level data, more than 100 patients, and the following measures: Vectra DA scores (low/moderate/high: <30, 30-44, >44), DAS28-CRP (low/moderate/high: <2.67, >2.67 to 4.09, >4.09), and CRP (low/moderate/high: <10, >10 to 30, >30 mg/L). Four studies containing 5 cohorts (n=929 patients) were included in the analysis. Relative risks for radiographic progression at one year for each of the measures were calculated based on high vs not high (low and moderate combined) categories. Of the 3 measures, Vectra DA scores best predicted radiographic progression, with a relative risk of 4.6 (95% CI: 2.4 to 8.9, p<0.0001), though DAS28-CRP and CRP alone also reliably predicted radiographic progression, with a relative risk of 1.7 (95% CI: 1.1 to 2.6, p=0.02) and 1.7 (95% CI: 1.2 to 2.4, p=0.002), respectively.

Additionally, findings were also mixed across 3 studies published subsequent to the above-described systematic review and pooled analyses.^17,9,23, For example, in a post hoc analysis of 3 cohort studies by Roodenrijs et al (2018)^23, of 57 RA patients treated with rituximab 1000 mg and methylprednisolone 200 mg, among those with an original Vectra DA score of low, moderate and high MBDA scores, radiographic progression (change in SHS ≥ 5) was observed in 0 (0%), 0 (0%) and 5 (56%) patients, respectively. Additionally, change in the original Vectra DA score from baseline to 6 months was significantly associated with European League Against Rheumatism (EULAR) response (good or moderate) versus non-response at 6 months (OR 0.93; 95% CI, 0.88 to 0.98) per unit change). This association remained statistically significant even after adjustment by age, gender, smoking status, rheumatoid factor (RF) status, autoantibodies against citrullinated peptides (ACPA) status (OR 0.89; 95% CI, 0.81 to 0.98 per unit change). However, in contrast, in the Dose REduction Strategies of Subcutaneous TNF Inhibitors trial (DRESS) RCT by Bouman et al (2017),^17, among 167 randomized, RP occurred in 31% in the dose tapering group and in 16% in the usual care group and the original Vectra DA score was not predictive of successful tapering, flare occurrence, or RP

Section Summary: Clinically Valid

Evidence for the clinical validity of the current commercially available version of the Vectra test (including the “adjusted MBDA score”) in patients with RA, consists of 1 retrospective cohort study that correlated it with other measures of disease activity and with radiographic progression. Results from this study have shown a positive correlation between Vectra and other disease activity measures and have shown that Vectra may be predictive of radiographic progression at 1 year. However, its low PPV (3.9% to 9.3%) indicates that 9 out of 10 patients identified as moderate- to high-risk disease could unnecessarily receive intensification of therapy. Additionally, the study’s numerous relevance, design and conduct limitations provide an insufficient basis to conclude the clinical validity of the Vectra test.

Evidence for the clinical validity of the original Vectra DA test consists of analyses of archived serum samples from RCTs as well as prospective cohort studies that have correlated the original Vectra DA with other measures of disease activity and with radiographic progression. Results from studies comparing the original Vectra DA with other disease activity measures have shown a positive correlation; however, results from studies comparing the original Vectra DA with radiographic progression are inconsistent. Only 1 study reported sensitivity and specificity, with a PPV of 21%, indicating that 4 out of 5 patients identified as positive would receive intensification of therapy unnecessarily.

Currently, MBDA is used as an adjunct to other disease activity measures. No evidence was identified that evaluated the incremental benefit of MBDA when used as an adjunct to other disease activity measures.

Overall, the evidence is insufficient to conclude the clinical validity of Vectra compared with ACR-recommended measures of disease activity.

Clinically Useful

A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary testing.

Review of Evidence
Direct Evidence

Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from RCTs.

To demonstrate clinical utility, there should be evidence that the Vectra score is at least as good a measure of disease activity as other available measures or that the Vectra score demonstrates an incremental benefit when used as an adjunct with other disease activity measures. To demonstrate equivalence with other measures directly, an RCT comparing health outcomes of two groups, one group managed using the Vectra test and the other group managed by another disease activity measure is needed.

To directly demonstrate an incremental benefit when used as an adjunct, an RCT should compare health outcomes in patients receiving treatment guided by the Vectra test plus a disease activity measure with outcomes in patients receiving treatment guided only by the other disease activity measure. No RCTs were identified. No studies of the current commercially available Vectra test ("updated MBDA score") were identified. Below is a retrospective study conducted that evaluated the original Vectra DA test and medication use among patients with RA.

Curtis et al (2018) used Medicare data from 2011 to 2015 to study the original Vectra DA test (not commercially available) scores and biologic and Janus kinase inhibitors use among patients with RA.^26, The database contained 60596 patients with RA who had the original Vectra DA testing results. Among patients not currently taking biologics (n=33728), statistically significant differences in adding or switching medications were detected based on the original Vectra DA scores: 9.0% of patients with low scores, 11.8% with moderate scores, and 19.7% with high scores. Similarly, among patients currently taking biologics, statistically, significant differences in switching medications were detected among the different levels of scores: 5.2% of patients with low scores, 8.3% with moderate scores, and 13.5% with high scores.

Chain of Evidence

Indirect evidence on clinical utility rests on clinical validity. If the evidence is insufficient to demonstrate test performance, no inferences can be made about clinical utility.

Because there is insufficient evidence that the Vectra score is clinically valid, direct evidence is needed to prove clinical utility. No trials were identified that provided direct evidence of clinical utility.

Section Summary: Clinically Useful

There are no RCTs comparing the use of the Vectra test with the "updated MBDA score" or the original Vectra DA score with an alternative method of measuring disease activity. Additionally, there are no RCTs of Vectra or Vectra DA as an adjunct to other disease activity measures compared with using the disease activity measures alone. Absent direct evidence for clinical utility, a chain of evidence could be constructed with indirect evidence proving clinical validity. However, there is insufficient evidence that Vectra or Vectra DAare clinically valid.

Summary of Evidence
Vectra test with adjusted MBDA score

For individuals who have RA who receive the current commercially available Vectra test ("adjusted MBDA score") as an adjunct or as a replacement of other disease activity measures, the evidence includes 1 study that analyzed archived serum samples using combined data from an RCT and a cohort study. Relevant outcomes are test validity, other test performance measures, symptoms, change in disease status, functional outcomes, and quality of life. Analyses comparing Vectra with other previously validated disease activity measures such as the DAS28 or to radiographic progression, consisted mostly of correlations. However, the PPV’s that individuals with Vectra moderate- to high-risk disease scores had radiographic progression were low, at 3.9% and 9.3%, respectively. Additionally, due to numerous relevance, design and conduct limitations of this study, the body of evidence on the Vectra test is insufficient to determine whether it is as good as or better than other disease activity measures. Additionally, there is no evidence evaluating Vectra as an adjunct to other disease activity measures. The evidence is insufficient to determine the effects of the technology on health outcomes.

Original Vectra DA test

For individuals who have RA who receive the original Vectra DA test as an adjunct or as a replacement of other disease activity measures, the evidence includes analyses of archived serum samples from RCTs and prospective cohort studies. Relevant outcomes are test validity, other test performance measures, symptoms, change in disease status, functional outcomes, and quality of life. Analyses comparing Vectra DA with other previously validated disease activity measures such as the DAS28 or to radiographic progression, consisted mostly of correlations, with only 1 study providing sensitivity, specificity, and PPV and NPV. The PPV from this study was 21%. Other analyses of archived serum samples evaluated the use of Vectra DA to predict treatment response. Results from those analyses were inconsistent. The body of evidence on the Vectra DA test is insufficient to determine whether it is as good as or better than other disease activity measures. Additionally, there is no evidence evaluating Vectra DA as an adjunct to other disease activity measures.The evidence is insufficient to determine the effects of the technology on health outcomes.

SUPPLEMENTAL INFORMATION
Practice Guidelines and Position Statements
American College of Rheumatology

In its 2019 guidelines on the treatment of rheumatoid arthritis, the American College of Rheumatology^4, identified the following 11 measures of disease activity as fulfilling a minimum standard for regular use in most clinical settings: , Disease Activity Score (DAS), Routine Assessment of Patient Index Data 3 (RAPID3), Routine Assessment of Patient Index Data 5 (RAPID5), Clinical Disease Activity Index (CDAI), Disease Activity Score with 28 joints (DAS28-ESR/CRP), Patient Derived DAS28, Hospital Universitario La Princesa Index (HUPI), Multibiomarker Disease Activity Score (MBDA score, Vectra DA), Rheumatoid Arthritis Disease Activity Index (RADAI),Rheumatoid Arthritis Disease Activity Index 5 (RADAI-5), Simplified Disease Activity Index (SDAI). Although the original Vectra DA test is included in this list, the current commercially available version of the test that is now called Vectra and that includes the leptin-adjusted MBDA score (now called the "adjusted MBDA score") was not addressed in the 2019 ACR guideline. This is because evidence on Vectra with the adjusted MBDA score was published subsequent to the ACR review end date.

European League Against Rheumatism

In 2017, the European League Against Rheumatism updated its guidelines on the management of early arthritis.^27, The League recommended that arthritis activity be assessed at 1- to 3-month intervals to determine target treatment. "Monitoring of disease activity should include tender and swollen joint counts, patient, and physician global assessments, erythrocyte sedimentation rate, and C reactive protein, usually by applying a composite measure." Composite measures recommended include the Disease Activity Score with 28 joints, Clinical Disease Activity Index, and Simplified Disease Activity Index. One item on the research agenda recommended by the League was to evaluate new biomarkers and multibiomarkers for the prognosis and treatment in early arthritis.

National Institute for Health and Care Excellence

In 2018, the National Institute for Health and Care Excellence published guidance on the management of adult patients with rheumatoid arthritis.^28, There is no discussion on the use of a multibiomarker disease activity blood test to monitor patients with rheumatoid arthritis.

U.S. Preventive Services Task Force Recommendations

Not applicable.

Ongoing and Unpublished Clinical Trials

A currently ongoing trial that might influence this policy is listed in Table 5.

Table 5. Summary of Key Trials

NCT No.	Trial Name	Planned Enrollment	Completion Date
Ongoing
NCT03810144a	Impact of Guided Care with the Vectra DA Multi-Biomarker Disease Activity (MBDA) Blood Test on Clinical Outcomes and Pharmaceutical Utilization in Patients with Rheumatoid Arthritis: a Prospective Randomized Study	440	Mar 2021
NCT03631225a	Vectra InVolved Informed Decision Outcome Study (VIVID): A Prospective Randomized Controlled Trial Evaluating the Effect of Guided Care With Vectra Compared to Treatment as Usual in Patients With Rheumatoid Arthritis	1200	Oct 2021
NCT02832297a	Prospective Outcomes Study: Vectra® DA Guided Care Compared to Usual Care	318	Aug 2022

NCT: national clinical trial.
^a Denotes industry-sponsored or cosponsored trial.]
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Horizon BCBSNJ Medical Policy Development Process:

This Horizon BCBSNJ Medical Policy (the “Medical Policy”) has been developed by Horizon BCBSNJ’s Medical Policy Committee (the “Committee”) consistent with generally accepted standards of medical practice, and reflects Horizon BCBSNJ’s view of the subject health care services, supplies or procedures, and in what circumstances they are deemed to be medically necessary or experimental/ investigational in nature. This Medical Policy also considers whether and to what degree the subject health care services, supplies or procedures are clinically appropriate, in terms of type, frequency, extent, site and duration and if they are considered effective for the illnesses, injuries or diseases discussed. Where relevant, this Medical Policy considers whether the subject health care services, supplies or procedures are being requested primarily for the convenience of the covered person or the health care provider. It may also consider whether the services, supplies or procedures are more costly than an alternative service or sequence of services, supplies or procedures that are at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of the relevant illness, injury or disease. In reaching its conclusion regarding what it considers to be the generally accepted standards of medical practice, the Committee reviews and considers the following: all credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, physician and health care provider specialty society recommendations, the views of physicians and health care providers practicing in relevant clinical areas (including, but not limited to, the prevailing opinion within the appropriate specialty) and any other relevant factor as determined by applicable State and Federal laws and regulations.

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Index:
Multibiomarker Disease Activity Blood Test for Rheumatoid Arthritis
Vectra DA Blood Test for Rheumatoid Arthritis
Rheumatoid Arthritis, Vectra DA Blood Test for

References:
1. Upchurch KS, Kay J. Evolution of treatment for rheumatoid arthritis. Rheumatology (Oxford). Dec 2012; 51 Suppl 6: vi28-36. PMID 23221584

2. Schoels M, Knevel R, Aletaha D, et al. Evidence for treating rheumatoid arthritis to target: results of a systematic literature search. Ann Rheum Dis. Apr 2010; 69(4): 638-643. PMID 20237123

3. Singh JA, Saag KG, Bridges SL, et al. 2015 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis.. Jan 2016; 68(1): 1-26. PMID 26545940

4. England BR, Tiong BK, Bergman MJ, et al. 2019 Update of the American College of Rheumatology Recommended Rheumatoid Arthritis Disease Activity Measures. Arthritis Care Res (Hoboken). Dec 2019; 71(12): 1540-1555. PMID 31709779

5. Crescendo Bioscience. Vectra DA Patient Guide: Understanding results. n.d.; https://vectrascore.com/know-your-results/. Accessed May 18, 2020.

6. Crescendo Biosciences, Inc. Vectra Technical Specifications. May 2019. https://vectrascore.com/clinicians/vectra-test-description/. Accessed May 7, 2020

7. Centola M, Cavet G, Shen Y, et al. Development of a multi-biomarker disease activity test for rheumatoid arthritis. PLoS ONE. 2013; 8(4): e60635. PMID 23585841

8. Curtis JR, Flake DD, Weinblatt ME, et al. Adjustment of the multi-biomarker disease activity score to account for age, sex and adiposity in patients with rheumatoid arthritis. Rheumatology (Oxford). May 01 2019; 58(5): 874-883. PMID 30590790

9. Brahe CH, Ostergaard M, Johansen JS, et al. Predictive value of a multi-biomarker disease activity score for clinical remission and radiographic progression in patients with early rheumatoid arthritis: a post-hoc study of the OPERA trial. Scand J Rheumatol. Jan 2019; 48(1): 9-16. PMID 29985080

10. Iannaccone CK, Lee YC, Cui J, et al. Using genetic and clinical data to understand response to disease-modifying anti-rheumatic drug therapy: data from the Brigham and Women's Hospital Rheumatoid Arthritis Sequential Study. Rheumatology (Oxford). Jan 2011; 50(1): 40-6. PMID 20847201

11. Bakker MF, Cavet G, Jacobs JW, et al. Performance of a multi-biomarker score measuring rheumatoid arthritis disease activity in the CAMERA tight control study. Ann Rheum Dis. Oct 2012; 71(10): 1692-7. PMID 22596166

12. Markusse IM, Dirven L, van den Broek M, et al. A multibiomarker disease activity score for rheumatoid arthritis predicts radiographic joint damage in the BeSt study. J Rheumatol. Nov 2014; 41(11): 2114-9. PMID 25128518

13. Hambardzumyan K, Bolce R, Saevarsdottir S, et al. Pretreatment multi-biomarker disease activity score and radiographic progression in early RA: results from the SWEFOT trial. Ann Rheum Dis. Jun 2015; 74(6): 1102-9. PMID 24812287

14. Hambardzumyan K, Bolce RJ, Saevarsdottir S, et al. Association of a multibiomarker disease activity score at multiple time-points with radiographic progression in rheumatoid arthritis: results from the SWEFOT trial. RMD Open. 2016; 2(1): e000197. PMID 26958364

15. Fleischmann R, Connolly SE, Maldonado MA, et al. Brief Report: Estimating Disease Activity Using Multi-Biomarker Disease Activity Scores in Rheumatoid Arthritis Patients Treated With Abatacept or Adalimumab.. Sep 2016; 68(9): 2083-9. PMID 27111089

16. Hirata S, Li W, Kubo S, et al. Association of the multi-biomarker disease activity score with joint destruction in patients with rheumatoid arthritis receiving tumor necrosis factor-alpha inhibitor treatment in clinical practice. Mod Rheumatol. Nov 2016; 26(6): 850-856. PMID 26873570

17. Bouman CAM, van der Maas A, van Herwaarden N, et al. A multi-biomarker score measuring disease activity in rheumatoid arthritis patients tapering adalimumab or etanercept: predictive value for clinical and radiographic outcomes. Rheumatology (Oxford). Jun 01 2017; 56(6): 973-980. PMID 28339738

18. Hambardzumyan K, Saevarsdottir S, Forslind K, et al. A Multi-Biomarker Disease Activity Score and the Choice of Second-Line Therapy in Early Rheumatoid Arthritis After Methotrexate Failure.. May 2017; 69(5): 953-963. PMID 27992691

19. van der Helm-van Mil AH, Knevel R, Cavet G, et al. An evaluation of molecular and clinical remission in rheumatoid arthritis by assessing radiographic progression. Rheumatology (Oxford). May 2013; 52(5): 839-46. PMID 23287359

20. Li W, Sasso EH, van der Helm-van Mil AH, et al. Relationship of multi-biomarker disease activity score and other risk factors with radiographic progression in an observational study of patients with rheumatoid arthritis. Rheumatology (Oxford). Feb 2016; 55(2): 357-66. PMID 26385370

21. Krabbe S, Bolce R, Brahe CH, et al. Investigation of a multi-biomarker disease activity score in rheumatoid arthritis by comparison with magnetic resonance imaging, computed tomography, ultrasonography, and radiography parameters of inflammation and damage. Scand J Rheumatol. Sep 2017; 46(5): 353-358. PMID 27682742

22. Reiss WG, Devenport JN, Low JM, et al. Interpreting the multi-biomarker disease activity score in the context of tocilizumab treatment for patients with rheumatoid arthritis. Rheumatol Int. Feb 2016; 36(2): 295-300. PMID 26026604

23. Roodenrijs NMT, de Hair MJH, Wheater G, et al. The multi-biomarker disease activity score tracks response to rituximab treatment in rheumatoid arthritis patients: a post hoc analysis of three cohort studies. Arthritis Res Ther. Nov 20 2018; 20(1): 256. PMID 30458871

24. Johnson TM, Register KA, Schmidt CM, et al. Correlation of the Multi-Biomarker Disease Activity Score With Rheumatoid Arthritis Disease Activity Measures: A Systematic Review and Meta-Analysis. Arthritis Care Res (Hoboken). Nov 2019; 71(11): 1459-1472. PMID 30320973

25. Curtis JR, Brahe CH, Ostergaard M, et al. Predicting risk for radiographic damage in rheumatoid arthritis: comparative analysis of the multi-biomarker disease activity score and conventional measures of disease activity in multiple studies. Curr Med Res Opin. Sep 2019; 35(9): 1483-1493. PMID 30777458

26. Curtis JR, Xie F, Yang S, et al. Uptake and Clinical Utility of Multibiomarker Disease Activity Testing in the United States. J Rheumatol. Mar 2019; 46(3): 237-244. PMID 30442830

27. Combe B, Landewe R, Daien CI, et al. 2016 update of the EULAR recommendations for the management of early arthritis. Ann Rheum Dis. Jun 2017; 76(6): 948-959. PMID 27979873

28. National Institute for Health and Care Excellence. Rheumatoid arthritis in adults: management [NG100]. July 2018, https://www.nice.org.uk/guidance/ng100. Accessed May 19, 2020.