This article is more than 5 years old. Information may no longer be current.
Out for Blood: Biomarkers Paving the Road to Personalized Medicine for Rheumatic Diseases
Click Here to Manage Email Alerts
There are endless idioms about blood. It is thicker than water, but one cannot get it from a stone. Truman Capote wrote about the cold version, rock band Foreigner sang about the hot version. When it comes to rheumatic diseases, researchers are out for blood — blood-based biomarkers, that is.
To date, it is impossible to use one blood-based biomarker test for diagnostic and prognostic purposes in the rheumatic diseases. The quest for a comprehensive biomarker assay has led the rheumatology research community to the Vectra DA (Crescendo Bioscience), a multi-biomarker disease activity (MBDA) panel marketed in the U.S. Measuring a number of cytokines, chemokines and soluble cytokine receptors, the MBDA provides rheumatologists with a composite score that can be used to aid in clinical decision-making for patients with rheumatoid arthritis.
Gregg J. Silverman, MD, director of the Laboratory of B Cell Immunobiology at the NYU Langone School of Medicine, believes that, though imperfect, the current formulation of the MBDA is likely a stepping stone toward the goal of personalized medicine in rheumatology, largely due to its comprehensive nature. “While there is evidence that high levels of MBDA can indeed predict radiographic progression, there may be limitations,” he told Healio Rheumatology.
![Biomarker tests could eliminate the tedious trial-and-error treatment process for patients, noted Amr H. Sawalha, MD. “[This] will be a major advance and big leap towards personalized medicine in rheumatology.”](/~/media/images/news/print/healio-rheumatology/2019/09_september/sawalha_amrh.jpg)
One significant drawback is that the MBDA results can be difficult to interpret in patients during treatment with certain targeted biologic agents that directly affect the same factors the test assesses, such as IL-6 blockade. “The test was developed using the DAS28 score as a guide, which has its own strengths and weaknesses,” he said. “It also represents a compromise, in that it can be used in both seropositive and seronegative patients, even though we accept that aspects of pathogenesis certainly differ in these two disease subsets.”
When faced with the range of possible rheumatic diseases in a new patient, however, many rheumatologists prefer to have the option of narrowing that initial margin of error.
“We should use these biomarkers if we have them,” Leonard H. Calabrese, DO, chief medical editor of Healio Rheumatology and director of the RJ Fasenmyer Center for Clinical Immunology at the Cleveland Clinic, said in an interview. “We are perpetually looking for a ‘gold standard’, but often there is no ‘gold standard’ in rheumatology. We have a test in the MBDA that is built on a large database, with known sensitivity and specificity, and if you combine it with your own skill and decision-making powers, it can be very effective.”
He added, “In RA, there is a need for a multiple biomarker test for early diagnosis, for applying prognosis, and for monitoring disease activity. At the moment, the candidates for this are limited. The MBDA seems to fit this bill, at least in part.”
Single-shot Diagnostic Market
However, a growing number of rheumatologists are using the MBDA for one main reason: it measures more than one factor. Clinicians treating RA have long relied on single-factor blood tests such as rheumatoid factor (RF), cyclic citrullinated peptide (CCP), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and antinuclear antibody (ANA). Those treating psoriatic arthritis have used either ESR or CRP, whereas physicians treating lupus may use ESR or ANA. But these tests have limitations.
Amr H. Sawalha, MD, chief of the division of pediatric rheumatology and director of the Comprehensive Lupus Center of Excellence at the University of Pittsburgh School of Medicine, explained why the single-factor tests ultimately fall short. “The diseases we treat in rheumatology are heterogeneous and can sometimes affect multiple organ systems,” he said.
Despite the push for more encompassing tests, an emerging group of single-factor tests have hit the market in recent years, including products like the Sclero-smart (Gemelli Biotech) test that measures anti-vinculin levels in scleroderma; the Avise (Exagen Diagnostics) anticarbamylated antigens (anti-CarP) antibodies test in RA; and a number of products assessing for anti-CCP antibodies, to name a few.
“Discovering and validating novel biomarkers that have the potential to identify or predict specific disease manifestations in systemic autoimmune diseases will be very helpful in the clinic,” Sawalha said. “This will help prioritize monitoring and potentially prevent specific manifestations or initiate early treatment to avoid organ damage and complications.”
Early detection and aggressive treatment of rheumatic disease are crucial to curtail future damage and mortality; despite the ability to identify levels of inflammation, most biomarker tests are often non-specific to distinct rheumatic diseases, leaving rheumatologists hoping for additional research to pave the way to more customized care.
“There has long been a lot of interest in this,” Daniel G. Arkfeld, MD, associate professor of clinical medicine and director of rheumatological education at Keck Hospital at the University of Southern California, added in an interview. “We have been looking for the perfect biomarker in RA forever. It is a constantly evolving area of science.”
Where that evolution will lead remains to be seen. Exagen Diagnostics is currently exploring a multibiomarker assay for lupus, and other companies are likely to follow suit. It is not difficult to imagine a time when each disease will have its own version of the MBDA. However, whether those tests will have the capacity to identify the myriad subpopulations in any given rheumatic disease is uncertain.
For this reason, many doctors still rely on imaging tests and physical exams to diagnose and monitor patients, so questions persist regarding where blood tests will fit into diagnostic and treatment paradigms. In addition to the clinical concerns, questions pertaining to cost, availability and uptake also must be answered before blood assays can truly stand alone.
A Closer Look at the MBDA
An important question to ask of any novel assay is how it stacks up against traditional methods of disease management. In the OPERA trial, Brahe and colleagues assessed the MBDA in 180 treatment-naive RA patients. Results showed that baseline MBDA score carried an independent association with radiographic progression at 1 year (OR = 1.03/unit; 95% CI, 1.01-1.06).
“There is some evidence from certain studies, such as the OPERA study, that early change in MBDA could predict which patients attain disease remission,” Walter P. Maksymowych, MD, from the division of rheumatology at the University of Alberta, said in an interview with Healio Rheumatology. “In addition, baseline levels of MBDA predicted structural progression of disease independently of other predictors of joint damage.”
Other findings from Brahe and colleagues showed that among anti-CCP-positive patients, 35 of 89 patients with high MBDA scores — defined as greater than 44 — showed evidence of radiographic progression (positive predictive value = 39%). Conversely, no patients with an MBDA score of 44 or lower progressed (P = .003). The researchers added that early changes in MBDA score were associated with clinical remission as assessed by DAS28-CRP at 6 months.
Calabrese
The MBDA is superior to traditional biomarkers such as CRP and combination disease activity measures like CDAI and SDAI, Calabrese noted. “But where we really see the value of this test is helping to manage uncertainty in patients with RA,” he said.
Although many clinicians are skilled at assessing disease activity through physical exam, having a biomarker test that can take the guesswork out of clinical assessment has value. “The MBDA is the closest thing we have to being able to minimize that uncertainty,” Calabrese said.
In study results published in Current Medical Research and Opinion, Curtis and colleagues compared the MBDA with DAS28-CRP and CRP for identifying risk of radiographic progression in 929 patients with RA. Results showed that high MBDA scores were associated with increased risk for radiographic progression, while lower MBDA scores were associated with lower progression risk. The researchers concluded that the MBDA was superior to either of the other measures for predicting radiographic progression.
Despite these encouraging results, Silverman still believes that there may be obvious ways to improve a multiplex test such as the MBDA. “The biggest gap in currently available RA disease activity biomarkers is that no current test incorporates insights into autoimmunity and immunopathogenesis,” he said.
MBDA has also been used to determine which patients are likely to relapse after having achieved remission and then discontinued their TNF inhibitor biologic, according to Maksymowych. “This is very important,” he said. “We need to be able to predict which patients can come off treatment because the cost of treatment, especially the biologics, is a major factor for the health care system.”
“Another concern with MBDA is the lack of consistency of the results,” Maksymowych continued. He cited findings from the AMPLE study, in which Fleischmann and colleagues examined the MBDA in a cohort of patients who were treated with abatacept (Orencia, Bristol-Myers Squibb) against patients treated with adalimumab (Humira, AbbVie).
“The researchers reported that the MBDA had no association with disease activity score and no ability to predict radiographic progression of the disease,” Maksymowych said.
However, he noted that there may be a reason for the inconsistency of results. “A lot of studies that have assessed the MBDA assay have been designed with other objectives in mind and often have not been optimal for the purposes of validating a biomarker,” Maksymowych said. “There are very few studies in the rheumatological literature that have been specifically designed for the purpose of validating a biomarker.”
With conflicting data on the effectiveness of these biomarkers, Silverman noted that some patients may benefit from MBDA testing, while others may not. Similarly, some clinicians find the test beneficial — data vary, but around half of rheumatologists have reported using it — while others do not. “We may certainly use it to help us to decide whether to advance a therapy or switch therapeutic agents,” he said. “But because this is a chronic disease often associated with a lot of joint damage and inflammation, many clinicians still primarily rely on physical exam for diagnosis and management.”
Trailblazing With Anti-CCP Antibodies
When it comes to precision medicine in rheumatology, the single greatest advance is the development of clinical anti-CCP lab tests, according to Silverman. “This test transitioned the shared epitope hypothesis into an in-depth understanding of the interplay of adaptive immunity and predisposing HLA genes and seropositive RA into a practical informative lab test,” he said. “An anti-CCP positive test can predict a worse prognosis, with high likeliness of joint destruction from bony erosions and cartilage destruction, leading to disability.”
An emerging body of data are beginning to confirm the utility of the anti-CCP test. In another analysis from the AMPLE trial, Sokolove and colleagues examined whether baseline anti-CCP2 antibody status impacted outcomes in patients treated with abatacept or adalimumab. Results showed that patients with anti-CCP2 antibody-negative status were less likely to respond to these medications. Among patients with higher baseline anti-CCP2 levels, clinical response to abatacept was improved, while no such association was reported for adalimumab.
“The recent data showing that patients with CCP-positive titers have an improved response to abatacept or rituximab (Rituxan, Genentech) were a little unexpected,” Silverman said. “All things being equal, a high CCP-positive titer could bias your treatment choices.”
In their study published in Rheumatology, Geraldino-Pardilla and colleagues aimed to further elucidate another association observed between RA and CCP antibody titers: The role of anti-citrullinated protein antibodies (ACPAs) in mediating the increased risk of heart failure in patients with RA.
The researchers assessed whether specific ACPAs were associated with subclinical left ventricular phenotypes that could ultimately lead to heart failure. Results showed that increased levels of antibodies targeting citrullinated fibrinogen and vimentin peptides or protein carried an association with increased left ventricular mass index. This could potentially provide a target of citrullinated proteins in myocardial remodeling in RA, they concluded.
“Anti-CCP tests detect the ACPAs that naturally arise and are believed to contribute to pathogenesis in RA,” Silverman said, noting that these antibodies are an important component of ACR/EULAR2010 diagnostic criteria. “Overall, high-titer ACPA patients have traditionally been difficult to treat. If we in rheumatology aspire to personalized medicine, these are the types of patient groups we need to identify and target.”
The association between anti-CCP antibody titers and interstitial lung disease is another area that has generated interest. In their study also published in Rheumatology, Kelly and colleagues assessed patients with RA-associated interstitial lung disease over a recent 25-year period. In univariable analysis, anti-CCP antibody titers proved to be the strongest predictor of this outcome among both men and women.
“Rheumatologists often do not suspect interstitial lung disease or cardiovascular disease in their asymptomatic RA patients,” Silverman said. “This may help us to identify those at greatest risk, and initiate a comprehensive work-up to make those diagnoses earlier.”
Silverman stressed that an additional component of patient management, then, is partnership with a pulmonologist or cardiologist as necessary. “We need to understand what they are doing, and they need to understand what we are doing,” he said. “The anti-CCP test is a good step, but we also need further algorithms for understanding risk of progression and most effective therapeutic intervention.”
In fact, Silverman added that everyone involved needs to understand the implications of the test results and how this contributes to the most efficient patient management. “CCP-positive, RF-positive patients tend to have more disability and there is more likelihood of progression,” he said. “We can’t afford to waste time and delay making treatment decisions, because the patients are suffering. If we use such tests to identify the patients at greatest risk earlier, the better off we will be.”
Anti-vinculin, Anti-CarP Tests Hold Promise
Clinicians treating scleroderma have benefitted from research by Suliman and colleagues, who presented data at the 2018 American College of Rheumatology meeting demonstrating that anti-vinculin is elevated in patients with scleroderma. Moreover, elevated anti-vinculin in these patients may be associated with gastrointestinal complications. The Sclero-smart blood test capitalizes on these associations, measuring anti-vinculin levels and identifying risk of gastrointestinal or vascular complications among patients with scleroderma or systemic sclerosis.
Mark Pimentel, MD, executive director of MAST Program at Cedars-Sinai, was the primary investigator who discovered this marker. “It is not exactly clear why, but anti-vinculin antibody titers are very high in a significant subset of scleroderma patients compared to controls,” he told Healio Rheumatology. “This association with scleroderma is interesting as vinculin is a protein with highest prominence in the nervous system, especially the gut and epithelium. These antibodies are seen in about 40% of known scleroderma patients.”
However, Maksymowych raised a relevant question about the ability of rheumatologists to act on this information. “Since we can do relatively little to intervene in the process, the utility of such a biomarker is unclear to me,” he said.
According to Pimentel, rheumatologists should be paying attention to elevated anti-vinculin, regardless of whether they are able to manage its manifestations. In another data set from Suliman and colleagues, Pimentel highlighted that scleroderma patients with elevated anti-vinculin may be at increased risk for pulmonary hypertension, a potential comorbidity that could be avoided.
However, even he acknowledged the limitations of this information. “Further studies are need to see if these antibodies prospectively provide prognostic information about scleroderma,” he said.
Shifting to anti-CarP, a noteworthy data set came from Truchetet and colleagues published in Arthritis & Rheumatology, demonstrating that elevated anti-CarP antibody levels can signify increased severity of RA, including a higher risk for joint erosions within 3 years of diagnosis. Consequently, these patients with elevated anti-CarP levels often were prescribed more aggressive treatments to maintain disease control.
“This biomarker is relatively specific for RA and when combined with anti-CCP and RF increases specificity for detecting RA from 85-90% to about 95%,” Maksymowych said. “However, this comes at the expense of a reduction in sensitivity from about 60% to about 30% — so, I think its role is limited for the clinician.”
Brian McEvilly, vice president of marketing at Exagen, suggested that having a predictor of poor prognosis is appealing to physicians. “Knowing that patients who are CarP-positive will be more likely to have aggressive, corrosive disease is helpful in the clinic,” he said. “You no longer have to wait for clinical manifestations of joint damage before managing the disease more aggressively.”
For Silverman, the issue for this test, like the others, is how to work it into the algorithm for diagnosis. “We have to ask whether it adds to our diagnostic acumen,” he said. “From one perspective, you see someone who looks like they have an inflammatory polyarthritis and is negative for rheumatoid factor. It does not help you to have another test.”
Although these antibodies may be prevalent in some subpopulations of patients with RA, it is possible to make a diagnosis in the absence of them, according to Silverman. “This test may provide a piece of the puzzle as to what antibodies can contribute to inflammatory arthritis and RA in particular, but you have to wonder about the amount of incremental value it provides,” he said.
Movement Toward Personalized Medicine
Maksymowych believes that the few blood tests that are available are being used effectively by rheumatologists. “My concern relates to use by primary care physicians who often use certain tests in a screening capacity,” he said. “This often culminates in false positive results eliciting patient anxiety, additional health care expenditures and additional investigations.”
Additionally, the cost of the MBDA, at approximately $1,000 per assay, is also problematic, Maksymowych noted. “This makes it prohibitively expensive for monitoring purposes,” he said.
Arkfeld was also cautious in his assessment of these tools. “They are all helpful in that they give us a lot of information, but they are just not 100% for diagnosing lupus or RA,” he said. “We use them, but we do not base our whole practice on them.”
Clinicians will recognize the utility of biomarker tests in eliminating the process of trial and error that often is necessary to find the right treatment regimen for each individual patient, according to Sawalha. “Biomarker tests that can be performed at the first visit and can inform about which specific treatment is most likely to be effective in each patient will be a major advance and big leap towards personalized medicine in rheumatology,” he said.
Eliminating trial and error in treatment decision making will reduce costs, Maksymowych added. “The alternatives to serological biomarkers often focus on imaging, which is, of course, a good deal more expensive,” he said. “But often there is little choice because of the lack of availability of appropriately validated biomarkers — including prognostic biomarkers for RA or diagnostic biomarkers for spondylitis.”
All of this begs the question of whether any one blood test, in any of the rheumatic diseases, will lead to the kind of clearly defined treatment algorithms that will allow clinicians to treat each patient individually and also, perhaps more importantly, satisfy payers, according to Arkfeld. “I think of rheumatology as gray, whereas insurance companies want to have black and white protocols,” he said.
Silverman brought the clinical and financial issues together. “If you want the targeted biologic and signal transduction blocking medications to continue to be covered, you have to show insurance companies that your patients are maintaining clinical response on such an agent,” he said. “If a test can help us do that, to better quantitate the level of disease activity, then such tests are likely to have a place in our practice.”
“Rheumatologists have an increasing number of options with blood tests and treatments, but none of them are really standardized,” Arkfeld said. “If we can develop more biomarkers that improve the sensitivity and specificity of prediction, they could be used in treatment paradigms, but we are not there yet.”
Silverman agreed. “The way we conceptualize the pathogenesis of RA has gotten more complicated,” he said. “We understand more molecules and cells are involved, but we do not yet fully understand all of the drivers of this molecular disease. We aspire to integrate the principles of precision medicine into diagnosis and treatment. As more of these tests emerge and clinicians grow more comfortable with them, we may get there.” – by Rob Volansky
- References:
- Brahe CH, et al. Scand J Rheumatol. 2019;doi:10.1080/03009742.2018.1464206.
- Curtis J, et al. Curr Med Res Op. 2019; doi: 10.1080/03007995.2019.1585064.
- Fleischmann R, et al. Arthritis Rheumatol. 2016;doi: 10.1002/art.39714.
- Geraldino-Pardilla L, et al. Rheumatology. 2017;doi:10.1093/rheumatology/kew436.
- Kelly CA, et al. Rheumatology (Oxford). 2014 doi: 10.1093/rheumatology/keu165.
- Sokolove J, et al. Ann Rheum Dis. 2016;75:709-714.
- Suliman YA, et al. Abstracts #2908 and #2937. Presented at: ACR/ARHP Annual Meeting, Oct. 20-24, 2018; Chicago.
- Truchutet ME, et al. Arthritis Rheumatol. 2017; doi:10.1002/art.40237.
- For more information:
- Daniel G. Arkfeld, MD, can be reached at 2020 Zonal Ave. # 620, Los Angeles, CA 90089; email: meg.aldrich@med.usc.edu.
- Walter P. Maksymowych, MD, can be reached at 8440 112 St. NW, Edmonton, Alberta, Canada T6G 2R7; email: walter.maksymowych@ualberta.ca.
- Brian McEvilly can be reached at 1261 Liberty Way, Suite C, Vista, CA 92081; email: bmcevilly@exagen.com.
- Mark Pimentel, MD, can be reached at 8730 Alden Drive, Suite 240E, Los Angeles, CA 90048; email: panditji@gemellibiotech.com.
- Amr H. Sawalha, MD, can be reached at 4401 Penn Ave., Pittsburgh, PA 15224; email: asawalha@med.umich.edu.
- Gregg J. Silverman, MD, can be reached at 435 East 30th St., New York, NY 10016; email: gregg.silverman@nyumc.org.
Disclosure: Arkfeld reports no relevant financial disclosures. Maksymowych reports receiving royalties from the University of British Columbia. McEvilly reports being an employee of Exagen. Pimentel reports being the PI who discovered the Gemelli Biotech marker, and that it is licensed from Cedars-Sinai to Gemelli Biotech. He holds equity in Gemelli Biotech. Sawalha reports being listed as inventor on a patent application to use IFI44L methylation as a diagnostic tool for lupus. Silverman reports consulting for Lilly, Onyx, Pfizer, Quest and Roche and receiving grant support from the American College of Rheumatology Research Foundation, the Lupus Research Institute, and NIH.