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The potential impact of monitoring disease
activity biomarkers on rheumatoid arthritis
outcomes and costs
Gary M Oderda*,1, Grant D Lawless2, Grace C Wright3, Samuel R Nussbaum4, Renwyck
Elder5, Kibum Kim1&D i a n aIB r i x n e r1
1University of Utah College of Pharmacy, Salt Lake City, UT 84112, USA
2University of Southern California School of Medicine, Los Angeles, CA 90033, USA
3NYU School of Medicine, New York, NY 10016, USA
4University of Southern California, Schaeffer Center for Health Policy and Economics, Los Angeles, CA 90089, USA
5AffectRX LLC, Southlake, TX 76092, USA
*Author for correspondence: [anonimizat]
Rheumatoid arthritis (RA) management requires monitoring of disease activity to determine course of
treatment. Global assessments are used in clinical practice to determine RA disease activity. Monitoringdisease activity via biomarkers may also help providers optimize biologic and nonbiologic drug use while
decreasingoveralldrugspendbydelayinguseofexpensivebiologictherapies.Bytestingmultiplebiologic
domains at the same time, a multibiomarker disease activity test may have utility in RA patient manage-ment, through improved intra- and inter-rater reliability. This report provides a comprehensive review
of studies of objective measures, single biomarkers and multibiomarker disease activity tests as disease
activity measures to decrease uncertainty in treatment decisions, and of biomarkers’ potential impact oneconomic and clinical outcomes of treatment choices.
First draft submitted: 1 January 2018; Accepted for publication: 9 April 2018; Published online:
25 April 2018
Keywords: biomarkers •MBDA •outcomes •personalized medicine •rheumatoid arthritis •targeted therapy
Rheumatoid arthritis (RA) is a chronic, progressive and frequently disabling autoimmune disease that results in
joint inflammation and pain and can lead to premature death and disability. RA affects approximately 0.6% of
the US adult population (1.5 million people) [1]. RA is three-times more common in women than in men and
can begin at any age [2]. Patients’ physical and mental health is correlated with pain, loss of function, loss of work
participation and decreased quality of life.
From a societal perspective, both direct and indirect costs (primarily loss of productivity from disability and
absenteeism) due to RA are substantial. A US observational study showed that at a median of 12.8 years after RAonset, 43.8% of patients who had a job at the time of diagnosis were no longer employed. A fourth to a half of all
patients with RA become unable to work within 10–20 years of diagnosis
[3]. A recent study tracking the persistence
of employees with RA showed that 62% were still actively employed at 4 years while only 35% were still workingat 8 years
[4], with a median age of disease onset during prime working years at 45 for females and 50 for males [3].
The estimated total cost attributable to RA and other rheumatic conditions in the USA is $128 billion, with the
majority, $81 billion, from direct medical expenses and $47 billion from indirect costs [5]. Approximately 44% of
RA patients have problems paying medical and drug bills after insurance payments, and 9% report they are unableto purchase all the medications or care they need because of substantial out-of-pocket medical expenses
[3].R A
represents a significant burden to society because of its high medical costs and prevalence, and optimized treatment
strategies are warranted.
Biomarkers have the potential to improve medical and pharmacy payer policies across therapeutic applications
ranging from CNS and cardiovascular disorders to immune system and inflammatory diseases [6]. A quantitative
assessment using objective measures and subgroup discrimination has improved reliability while reducing subjectiveinterpretations by clinicians, and has demonstrated clinical utility. Objective measures can potentially improve
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Special Report Oderda, lawless, Wright et al.
Table 1. Summary of traditional disease activity assessment recommended by American College of Rheumatology.
Variables or domains Disease activity cut-offs
Remission Low Moderate High
DAS-28–ESR TJC, SJC, ESR, PtGA 0–2.59 2.60–3.19 3.20–5.09 5.10–9.40
DAS-28–CRP TJC, SJC, CRP, PtGA 0–2.59 2.60–3.19 3.20–5.09 5.10–9.40
SDAI TJC, SJC, PtGA, PrGA, CRP 0–3.30 3.31–11.00 11.01–26.00 26.01–86.00
CDAI TJC, SJC, PtGA, PGA 0–2.80 2.81–10.00 10.01–22.00 22.01–76.00
PAS HAQ, pain VAS, PGA VAS 0–0.25 0.26–3.70 3.71–7.99 8.00–10.00
PASII HAQ-II, pain VAS, PtGA VAS 0–0.25 0.26–3.70 3.71–7.99 8.00–10.00
RAPID 3 MDHAQ-II, pain VAS, PtGA VAS 0–1.00 1.01–2.00 2.01–4.0 4.01–10.0
ACR: American College of Rheumatology; CDAI: Clinical Disease Activity Index; DAS-28: Disease activity score using a 28 joint count; DMARD: Disease -modifying antirheumatic
drug; ESR: Erythrocyte sedimentation rate; HAQ: Health assessment questionnaire; MDHAQ: Multidimensional HAQ; PAS: Patient Activity Scale; PAS I I: Patient Activity Scale II;
PGA: Provider global assessment; PtGA: Patient global assessment; RA: Rheumatoid arthritis; RAPID 3: Routine Assessment of Patient Index Data 3; SD AI: Simplified Disease
Activity Index; SJC: Swollen joint count; TJC: Tender joint count.Data taken from [23,24].
therapeutic outcomes as biomarker applications expand beyond detection and risk identification to prognosis,
therapy selection and disease activity monitoring, resulting in greater preservation of joint space and motility [7].
Previous studies have demonstrated that a ‘treat-to-target’ approach improved patient outcomes [8–10] .I nR A ,
disease activity monitoring based on swelling and /or tender joint count along with global assessment has been
widely used in clinical practice to target therapy. Improved clinical effectiveness may be achieved via the use ofbiomarkers in patients with early RA, in addition to the current assessment tools
[11]. Recent studies have explored
the use of a multibiomarker disease activity (MBDA) measure to assist physicians in treatment decisions between
traditional disease-modifying antirheumatic drugs ( DMARDs) and biologic DMARDs, specifically in patientswho already failed a primary option
[12–14] . Previous reviews introduced MBDA as an option for monitoring disease
activity [12,15]. Unfortunately, they lacked analyses of the MBDA test versus traditional approaches regarding
clinical [16,17]. The objective of this review was to describe the clinical utility of different approaches to monitoring
disease activity in order to guide treatment strategies and to provide insight into the role of the MBDA test in a
practical setting from clinical and cost perspectives.
Traditional disease activity measures in RA
The goal of therapy for RA is to maximize the patient’s long-term health-related quality of life by controlling
symptoms, preventing structural joint damage, normalizing physical function and improving the patient’s ability
to function in social and work activities [18]. Because RA cannot be tracked by a single domain, monitoring RA
disease activity and gauging treatment responses have traditionally relied upon physician- and patient-reported
responses to composite tools, such as the Disease Activity Score (DAS-28), the Clinical Disease Activity Index
and the Simplified DAS [19,20]. Physicians also focus on symptoms and counts of tender and swollen joints using
various imaging techniques to assess joint damage; they may also use the Health Assessment Questionnaire without
Disability Index [21]and criteria from the American College of Rheumatology (ACR) and European League Against
Rheumatism (EULAR) [22]. RA disease activity assessments and cut-offs to decide low, moderate and high RA disease
activity recommended by ACR are summarized in Table 1 [23,24]. Of the assessment tools, DAS-28 augmented by
a biomarker test result, either C-reactive protein (CRP) or erythrocyte sedimentation rate (ESR) has been widely
acknowledged in a clinical setting. By using proper weighting factors, which is a key difference from Simplified
DAS or Clinical Disease Activity Index, DAS-28 demonstrated its performance in measuring response to treatmentand disease activity
[25].
T raditional assessments have been psychometrically validated in a group of RA patients, meaning that such
assessments help physicians consistently monitor a patient’s disease activity as long as the same assessment isperformed regularly
[20,26,27] .
The key disadvantage of using traditional disease activity measures is reliability (i.e., predictability and repro-
ducibility). A recent study revealed inconsistencies in DAS from traditional assessments [28]. From the same study,
the agreement of assessments by the same physician on different visits was slightly lower than the agreement betweenphysician and patient
[28]. In conclusion, the scoring systems are meaningful as a supportive tool rather than clear
treatment guidance [29]. More importantly, there has been ongoing concern about the use of a physician assessment
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Biomarkers in rheumatoid arthritis Special Report
Table 2. Biomarkers in multibiomaker disease activity score calculation.
Biomarker Biomarker category Primary role
VCAM-1 Adhesion molecule Cellular influx and tissue expansion
EGF Growth factor Cellular influx and tissue expansion
VEGF-A Growth factor Cellular influx and tissue expansion
IL-6 Cytokine-related protein Local inflammation and destruction
TNF-RI Cytokine-related protein Local inflammation and destruction
MMP-1 Matrix metalloproteinase Cartilage degradation and joint damage
MMP-3 Matrix metalloproteinase Cartilage degradation and joint damage
YKL-40 (chitinase-3-like protein 1) Skeletal-related protein Stromal activity and regulation (fibroblasts,
chondrocytes, and vascular cells)
Leptin Hormone Systemic inflammatory response
Resistin Hormone Systemic inflammatory response
SAA Acute phase protein Systemic inflammatory response
CRP Acute phase protein Systemic inflammatory response
leading to the overestimation of improvement and underestimation of the progression of disease activity, such as
joint damage [29–31] . These traditional disease activity measures are based, in part, upon empirical and qualitative
data. Results can be complicated by comorbidities and the patient’s own perception of illness, resulting in further
uncertainty around the patient- and physician-reported assessments on RA disease activity [32,33].
Single biomarker tests in monitoring RA
Biomarker-based DAS support treatment adjustments, potentially leading to better disease control [33].‘ T r e a t –
to-target’ guidelines specifically recommend regular, documented measurement of disease activity, especially forpatients with moderate /high RA disease activity and for patients in remission
[18].
Each biomarker can be used to achieve a distinct objective. For example, high-titer rheumatoid factor and
anticitrullinated peptide antibody (ACPA) can help in the diagnosis and prognosis of RA [34–37] . Measuring 14-3-
3ηdemonstrated a greater sensitivity and specificity in reference to the ACPA in the diagnosis of RA [38].T h e s e
tests are not commonly used or recommended by guidelines, because they are often positive before RA symptoms
develop and are not specific for RA [25,39]. The utililty of nonspecific biomarkers, such as ESR and CRP , are limited
to define acute phase reactants [25].
Although many individual biomarkers are associated with RA, single biomarkers are incomplete measures of RA
activity, often lacking significant sensitivity and specificity [38]. For example, ESR and CRP often show normal
results despite ongoing disease progression [38]. The sensitivity of the commonly used baseline measure rheumatoid
factor is reported at 60–84% for established disease, falling shorter for new patients at only 57%, while specificityis low at 70–85% for both new and established patients
[40]. These early measures miss 70–85% of patients who
already present with radiographic images with early joint erosions and joint space loss [41]. Sensitivity and specificity
of ACPA in RA diagnosis is dependent on the type of antibody, and on the level of RA progression at the timeof diagnosis
[42,43]. The response operation improved when a diagnostic algorithm included 14-3-3 η[40].W h e t h e r
the test results helped to monitor current RA disease activity, in addition to the role in diagnosis and prognosis,
remains unclear [12].
Biomarkers can address the unmet need for more quantitative identification and classification of the RA dis-
ease state. Combining multiple biomarkers has the potential to allow quantitative care guidelines to be more
systematically applied, while still allowing for personalized care for patients [44].
M B D At e s t i n gi nR A
Our analytic validity study for MBDA identified 25 serum proteins as candidate markers for RA disease activity.
Using a regression methodology, 12 of the candidate biomarkers were selected to generate a single summary scorethat reflects the disease activity in RA patients ( Table 2 ). While none of these biomarkers tell a complete story
individually, the MBDA test, in a patented algorithm, evaluates multiple pathways contributing to the inflammation
in RA, generating a score from 1 to 100, with low ( <30), moderate (30–44) and high ( >44) categories
[45].
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Special Report Oderda, lawless, Wright et al.
We reviewed the MBDA studies that were identified from Medline on 5 March 2018 using search terms including
‘MBDA’, ‘multi-biomarker disease activity’, ‘multibiomarker disease activity’ and ‘multi biomarker disease activity’.
Studies including ‘rheumatoid’ in their text were included in the review. Of the 30 studies identified from the
search, only full text articles for original research relevant to the validity, reliability, clinical decision making, clinicaloutcomes and economics of the MBDA test were included in the review. 23 full-text research articles met this
inclusion; seven did not. When the MBDA test’s brand name was included in the search, the number of articles
found increased to 58. However, the number of original research articles meeting the inclusion criteria remained at23. The review and summary of the MBDA test focused on its usefulness as a disease activity marker or treatment
response marker, which can provide insight into the utility of a laboratory assessment tool in clinical practice.
When the validity of the MBDA test in determining RA disease activity was compared with traditional assess-
ments, a significant correlation between the two was demonstrated
[46]. However, changes in the MBDA score
outperformed the tracked clinical assessment scores in monitoring response to treatment [47–49] . There were also
significant correlations between MBDA score and multiple imaging assessments, including MRI, computed tomog-
raphy, ultrasonography and radiography [50]. Limiting the analysis to each global assessment-based disease activity
group, MBDA was able to provide a more precise distinction that predicted the response to an RA medication [51,52].
Compared to disease activity measures based on joint count, MBDA was not confounded by fibromyalgia or RA co-
morbidities [53,54]. BMI and age influenced the MBDA score, but the original MBDA score is still highly correlated
with (r >0.9) the BMI- and age-adjusted MBDA [53,55].
Although serologic markers alone cannot be used for diagnosis, the MBDA test has high clinical utility for disease
activity monitoring in addition to or as an alternative to traditional clinical markers. Using radiographic progressionas a reference measure, the MBDA test is superior to traditional assessments or CRP in predicting response acrossmultiple medication regimens
[56–60] . A 1-year follow-up study demonstrated that the order of performance in
prediction of radiographic joint damage was ACPA >MBDA >DAS28 [61]. In patients who tapered or stopped
DMARDs, follow-up MBDA scores were associated with RA relapse and had a stronger correlation than theassociation between the level of ACPA and RA relapse
[62]. In the context of anti-TNFi use, the MBDA test could
more accurately assess improvement associated with the use of DAS28-CRP [31].
By monitoring disease activity in RA management, the MBDA test has the potential to influence a clinician’s
decision. After reviewing individual MBDA scores, physicians modified the treatment regiment for 38% of pa-
tients [63]. From three simulated patient scenarios, a 3% improvement in a quality score was observed after using
the MBDA score [64]. The influence of the MBDA score on the clinical decision was associated with a short-term
increase in direct medical cost but predicted longer-term cost–effectiveness [65]. Scenarios employed for these clinical
utility and economic outcomes studies warrant further investigation performed in a real-world setting.
Policy implications of biomarkers in RA
The incorporation of biomarkers into treatment decision-making processes has several applications in oncology.
Targeted therapy, guided by genetic and /or biomarker testing, is commonplace in multiple cancer types including
breast and lung cancer [66–68] . Many of these tests have generated evidence of their cost–effectiveness in treatment
decisions [67]and are part of the evaluation process in oncology value frameworks [68].
As biomarkers are considered as tools to help guide therapy in other disease areas, similar levels of evidence
will be expected and evaluated through various value assessment frameworks. The AMCP Format for FormularySubmissions Version 4.0 incorporated the consideration of diagnostic testing into the description of the value
of new pharmaceuticals and related technologies
[69]. With the growing body of clinical evidence supporting the
utility of composite biomarkers, in 2016, the Centers for Medicare and Medicaid Services began providing ongoingcoverage for the MBDA test
[70]. In addition, organizations such as United Rheumatology are adding biomarker
assessments into clinical pathways for RA management [25].
A challenge that biomarkers present to payers is the lack of consistent balance in policy between medical and
pharmacy benefit for both diagnostic tests and the treatments they guide [71]. Dichotomies often exist between
policy decision makers for coverage decisions of pharmaceuticals and diagnostic tests. Clinical management tools,
including prior authorization and step therapy management, are perceived to be more common under the pharmacybenefit; however, this is changing as payers attempt to address the rapid growth in specialty drug trends, accordingto a recent EMD Serono Specialty Digest Report
[71]. Health plans will need to consider the closer integration of
medical policy decision making and pharmacy spending as a key to optimizing care.
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Biomarkers in rheumatoid arthritis Special Report
A significant challenge for specialty drugs policy will be the demonstration of value, challenging the biomarker
industry to provide evidence of how targeted therapy can improve outcomes at an overall lower cost for RA and
other diseases [71]. Such evidence, targeted to the specific value of composite biomarker testing in RA management,
may justify the use of biomarker testing to facilitate more efficient use of specialty drug spending.
T o aid future policy decisions on how specialty RA drugs would be managed, evidence should focus on how
biomarkers can impact clinical decision making, policies and overall costs by optimizing the use of nonbiologic and
biologic DMARDs. Economic and policy issues related to specialty pharmaceuticals must consider the patient’sneeds and balance innovative pathways and new technologies with affordability
[72].
Health plans will need to take a more integrated, comprehensive approach to documenting the benefits of
early accurate identification of RA patients likely to respond to biologic DMARDs and those that may be treatedeffectively with nonbiologic DMARDs. Hambardzumyan and colleagues suggested that patients with low-activityRA are likely to adequately respond to nonbiologic DMARDs, avoiding high-cost therapies
[58]. This translates
into improved clinical outcomes with the potential for cost-efficient use of therapeutic options.
Despite the promise of biomarkers in RA, challenges to coverage remain. In general, principles of drug coverage
tend to be applied to coverage of diagnostic tests; however, these may not be the most appropriate principles to
assess the value of diagnostic tests. Medical devices often do not undergo the randomized controlled trial process for
regulatory approval, yet the Centers for Medicare & Medicaid Services hierarchy of evidence requests randomizedcontrolled trial evidence of a drug treatment pathway with and without diagnostic testing. Smaller diagnostic
companies with limited resources may be unable to address these hurdles. The US FDA has drafted guidance for
the application of real-world data to regulatory decision making for medical devices for precisely these reasons
[73].
However, in general, there is a lack of cost–effectiveness data justifying coverage for many diagnostics, althoughan example of such evidence in breast cancer is the ‘Oncotype DX’ test
[67], where cost–effectiveness was clearly
demonstrated. The most valuable evidence would be to show clinical utility, demonstrating that clinical decisions
informed by a test result are different than decisions physicians would make without the test, and that the testguided decisions leading to improved health outcomes.
Findings of two recent studies provide insight into the use of biomarkers in cost-effective treatment decisions.
A cost–effectiveness study showed that triple therapy is clinically noninferior to etanercept-methotrexate (MTX)in patients with RA, despite an Institute for Clinical and Economic Review value of over $500,000 per quality-
adjusted life year, or $78,000 per patient over the next 10 covered years
[74]. A supporting study using subgroup
differentiation based on low versus high MBDA scores after MTX failure showed more patients with low scores(88 vs 35%) were likely to respond to triple-therapy than infliximab-MTX
[58]. The subset of all patients studied
showed that 29% had ‘low’ MBDA scores, making them ideal candidates for successful triple-therapy after MTX
failure, while also confirming that the 71% with ‘high’ MBDA scores would benefit most from the high-cost
biologic DMARD therapy. All things considered, later initiation of biologic DMARD for a subgroup defined byMBDA scores may potentially decrease the overall medical expenditure without a loss of clinical effectiveness. This
hypothesis will have to be tested in further economic outcomes studies.
Targeted therapy (personalized medicine) offers tremendous potential to improve the delivery of healthcare
services, with individual patients receiving the most appropriate treatment based on their biologic characteristics,
and to provide optimal clinical outcomes at increased cost efficiency.
Discussion
Our knowledge of RA through clinical staging allows for a more detailed understanding of disease progression
through precision medical testing. The understanding that RA is not a unidirectional linear disease, but rather a
series of dynamic feedback loops, has led to the novel ‘treat to outcome’ imperative. However, much of diseasemodeling from a payer perspective is linear, tracking the group or average patient, rather than the individual patient,
over a predetermined pathway. Patients failing a 3–6 month trial of a traditional nonbiologic DMARD, such as
methotrexate, may be directly prescribed a biologic DMARD without the benefit of other therapeutic options
[75].
Once on that biologic DMARD (typically a TNFi), if patients continue to show signs and symptoms of active
disease, they are either given increasing doses or switched to a second biologic DMARD 94% of the time (typically
to another TNF agent) [76]. Data and the 2015 ACR Guidelines show that many patients with low disease activity
can safely move from a single nonbiologic DMARD to noninferior combination therapy of nonbiologic DMARDs(methotrexate, sulfasalazine and hydroxychloroquine), resulting in significant disease improvements at much lower
cost than biologics
[77,78]. In addition, patients failing a TNFi drug may have other inflammatory mediators driving
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Special Report Oderda, lawless, Wright et al.
the RA disease activity, and thus will gain little or no value from such a change [79]. In these cases, switching to a
non-TNFi biologic DMARD may offer the best response and clinical efficiency at a potentially lower cost [80].
Decades of experience with patients either on methotrexate or a biologic DMARD reveal that only 40–60% of
RA patients achieve a satisfactory response as measured by at least a 50% improvement (by ACR criteria), while15–30% develop adverse drug events
[81]. As the presentation of RA moves from initiation of symptoms (baseline)
to treatment, remission, reactivation or change in status, physicians need a better approach to objectively measure
joint damage progression in order to better support and modify their clinical judgment.
Integrating a multibiomarker RA disease activity test more broadly into the commercial market based on real-
world data may offer providers and payers validated and practical utility of subgroup identification and associated
potential cost savings [46,56–58 ,61,62] . As an objective measure reflecting the level of inflammation, the MBDA test
may be more reliable than the DAS-28 and other clinical measures [33]. Biomarker tests are reproducible numerical
scales and are able to quantify RA disease activity and status.
Of the biomarkers used in RA management, based on this and previous reviews, 14-3-3 ηand the MBDA test
demonstrate utility in clinical practice [15]. However, the selection of biomarker tests must be tailored to optimize the
value of the test. The MBDA test is a dynamic and progressive measure of disease activity versus other biomarkers
that are static and only measure a single point in time. By focusing more on current disease activity monitoring,
the MBDA test helps determine the next treatment decision. On the other hand, 14-3-3 ηhas a greater utility for a
diagnosis of RA and a predictive progression marker. However, there has not yet been a direct comparison between
the two options to show a clear indication for each biomarker test.
Conclusion
The targeted use of composite biomarkers in RA management paves the way for a transition from subjectivemeasures of RA disease activity and treatment selection to more accountable, trackable and reproducible objectivemeasures. Increased use of the MBDA test to better identify the initial inflammation stage at the joint space,
eliminating sometimes misleading physical symptoms, and then using the MBDA test to track response to therapy
may lead to more reliable clinical decisions. T o help public and commercial payers make better informed decisions,additional evidence specifically quantifying the potential economic benefit of this multibiomarker test is required
and underway. As the scientific community continues to create unique and novel medicines based on greater patient
specificity and use of targeted biomarkers, the MBDA test may help standardize individual treatment decisions andserve as a model to guide therapy in diverse clinical domains.
Future perspective
The use of biomarkers has increased significantly in the area of oncology. In fact, recent FDA new drug approvals
have been for cancers with specific biomarker and molecular determinants, not by the specific organ of origin of the
cancer. As biomarkers become more prevalent in disease areas such as cardiovascular disease and RA, we may see asimilar trend where patterns of biomarkers indicate treatment choice. In RA, where prevalence is high and biologicmedications are expensive, we may see a faster uptake of biomarker testing to ensure the appropriate clinical use of
more costly medicines.
Authors’ contributions
Authors Lawless, Wright, Nussbaum, Elder, Oderda and Brixner made substantial contributions to the concept and design of theworkaswellastheanalysisandinterpretationofdataanddraftedsectionsoftheworkandcriticallyrevisedtheworkforimportant
intellectual content. Author Kim made substantial contributions to the concept and design of the work and critically revised the
work for important intellectual content. All the authors gave final approval and agreed to be accountable for all aspects of thework.
Acknowledgements
The authors wish to thank Kelley JP Lindberg for her assistance in editing this manuscript.
Financial & competing interests disclosure
CrescendoBiosciencesprovidedfinancialsupportforthiswork,andalloftheauthorsdisclosehavingreceivedpaymentforconsult-
ingoradvisoryrolesforCrescendoBiosciences,butpublicationofthismanuscriptwasnotcontingentuponCrescendoBiosciences’
10.2217/pme-2018-0001 Per. Med. (Epub ahead of print) future science group

Biomarkers in rheumatoid arthritis Special Report
Executive summary
Background
•Rheumatoid arthritis (RA) is a chronic, progressive autoimmune disease affecting approximately 0.6% of US
adults (1.5 million people).
•Estimated annual direct and indirect costs (i.e., loss of productivity and absenteeism) due to RA and other
rheumatic conditions in the USA is $128 billion.
•Biomarker tests may improve disease monitoring and assist clinicians in determining future treatment plans for
patients who previously failed a primary treatment option, but payers need evidence of biomarker performancebefore using biomarkers to guide coverage decisions.
•A composite biomarker test used in RA care may be an ‘optimal practice’ example for policy development
discussions.
Traditional disease activity measures in RA
•Traditional methods to monitor RA disease activity and gauge treatment response rely upon clinical criteria and
physician judgment.
•Global assessments are complicated by comorbidities and confounded by patients’ perception of the symptoms
and disease progression.
Single biomarker tests in monitoring RA
•Biomarkers reliably identify and classify the RA disease state and improve disease activity monitoring. However, a
single biomarker may not address all relevant domains in RA.
Multibiomarker disease activity testing in RA
•A multibiomarker approach could be a promising alternative to single marker tests and /or traditional
assessments.
•By monitoring disease activity and response to therapy in a less subjective manner across multiple biologic
domains, multibiomarker testing may help optimize the use of nonbiologic and biologic drugs for RA patients.
Policy implications of biomarkers in RA
•Cost–effectiveness evidence showing how biomarker-influenced targeted therapy may help physicians and health
plans make more informed decisions in RA management.
•Future evidence should focus on how biomarkers can impact clinical decision making, policies and overall costs by
optimizing the use of nonbiologic and biologic disease-modifying antirheumatic drugs.
Discussion
•Because biologic drugs for RA are significantly more expensive than nonbiologic drugs, objective tools that help
guide treatment and optimize the use of biologic and nonbiologic drugs may improve outcomes and patient
quality of life while reducing costs.
•Research quantifying the potential economic benefit of RA multibiomarker testing is needed.
Conclusion
•Composite biomarkers present an opportunity to monitor RA disease activity and guide healthcare providers to
make more informed decisions between biologic and nonbiologic drugs for RA patients, improving patientoutcomes and affordability.
approval. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial
interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
Writing assistance was utilized in the production of this manuscript. KL was paid for her editing assistance by MOG, whose
principalsreceivedfundingfromthesponsorfortheproductionofthemanuscript.However,publicationwasnotcontingentupon
sponsors’ approval.
Open access
This work is licensed under the Attribution-NonCommercial-NoDerivatives 4.0 Unported License. To view a copy of this license,
visit http://creativecommons.org/licenses/by-nc-nd/4.0/
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