expert roundtables

Use of Rheumatoid Arthritis Biomarkers to Stratify Patients

by Alan L. Epstein, MD, James O’Dell, MD, MACR, MACP, Vibeke Strand, MD, MACR, FACP


Rheumatoid arthritis (RA) biomarkers have the potential to detect early disease, stratify patients according to their risk, and guide treatment decisions.

Q: How are RA biomarkers currently used to stratify patients with RA, and what are the current capabilities vs the recognized need?

Vibeke Strand, MD, MACR, FACP

Adjunct Clinical Professor, Division of Immunology/Rheumatology
Stanford University School of Medicine
Biopharmaceutical Consultant
Palo Alto, CA

“Patients who are seropositive for RF and/or ACPAs are known to have a more aggressive disease course; they should be treated early and more aggressively with biologic or targeted synthetic disease-modifying antirheumatic drugs.” 

Alan L. Epstein, MD

Even a short delay (of months, not years) in RA diagnosis can lead to significantly worse long-term outcomes. For some patients, such as those with swollen joints and who are seropositive, early diagnosis is easily attainable. However, for other patients, early diagnosis can be challenging. Autoantibodies can be helpful to this end. A recent study by Verheul et al found that triple positivity (for anti–citrullinated protein antibodies [ACPAs], rheumatoid factor [RF], and anti–carbamylated protein antibodies) resulted in a high specificity for RA (98%-100%), which may be useful for early diagnosis. Additionally, patients who are seropositive for RF and/or ACPAs are known to have a more aggressive disease course; they should be treated early and more aggressively with biologic or targeted synthetic disease-modifying antirheumatic drugs. Anti–cyclic citrullinated peptide (anti-CCP) antibody positivity is an established poor prognostic factor in the absence of appropriate treatment. Newer biomarkers, however, such as 14-3-3-eta, have also demonstrated diagnostic and prognostic utility. Approximately 10% of patients who are RF and anti-CCP antibody negative are positive for anti-14-3-3 eta, and these patients have a more aggressive, erosive disease course. Another research biomarker that has shown potential is anti–citrullinated alpha enolase, which is associated with erosive disease and RA-associated interstitial lung disease. Intriguing work by Schett and colleagues recently demonstrated the presence of erosive disease in seropositive (various RA-related autoantibodies) patients before the onset of clinically apparent RA. In these pre-RA patients, anti–citrullinated vimentin antibodies can bind to citrullinated vimentin on the surface of pre-osteoclasts and drive them to differentiate into mature osteoclasts, leading to the development of erosive disease in a patient with no clinical evidence of inflammatory joint disease. This goes against the traditional concept that erosive disease occurs in patients with well-established RA and is being driven by pannus formation.

James O’Dell, MD, MACR, MACP

Stokes Shackleford Distinguished Professor
Chief, Division of Rheumatology and Vice Chair for Education, Department of Internal Medicine
Director, Internal Medicine Residency Program
University of Nebraska Medical Center
Founder and Director, Rheumatoid Arthritis Investigational Network
Omaha, NE

“Seropositivity, in patients who are refractory to initial disease-modifying antirheumatic drugs, predicts a better response to all of our biologics, not just rituximab and abatacept.” 

James O’Dell, MD, MACR, MACP

We have shown in studies, both in vitro and in vivo, that double positivity for RF and anti-CCP is synergistic in terms of erosive disease. We have also done some work looking at triple positivity using anti–malondialdehyde-acetaldehyde adducts as the third marker. Positivity for these markers is highly predictive for the presence of RA and for predicting worse outcome. These newer biomarkers are, however, primarily limited to the research setting, unfortunately. When it comes to biomarkers, the most clinically useful development has been anti-CCP antibody testing in primary care, which makes early diagnosis much easier. When a patient has ACPAs and inflamed joints, you have a good sense of what you are dealing with. We know from the 2004 study by Nielen et al, and from more recent studies, that, if the patient has joint symptoms and is anti-CCP positive, they will almost certainly develop classical RA. Nielen and colleagues examined banked blood samples from individuals who subsequently developed RA and found that nearly 50% of the patients were positive for RF and/or anti-CCP antibodies several years in advance of clinical symptom onset. Samples were positive for RF and/or anti-CCP a median of 4.5 years prior to symptom onset. Thus, if patients have joint symptoms and are anti-CCP positive, I will aggressively treat them. Seropositivity, in patients who are refractory to initial disease-modifying antirheumatic drugs, predicts a better response to all of our biologics, not just rituximab and abatacept. I am most concerned about the refractory seronegative patients, as these individuals can be more challenging to treat. I am convinced that we do not really know what disease these patients have—it may be somewhat distinct from RA.

Alan L. Epstein, MD

Clinical Professor of Medicine
University of Pennsylvania School of Medicine
Attending Physician and Chief of Rheumatology
Pennsylvania Hospital
Philadelphia, PA

“We need biomarkers to guide initial therapy and to guide second-line therapy for those who fail their initial treatment.” 

Vibeke Strand, MD, MACR, FACP

The big problem is that, although we have all of these biomarkers for helping to make the diagnosis more certain and for identifying patients who have a poorer prognosis, we do not currently have the types of markers that we really need, which are biomarkers that guide treatment. In particular, we need biomarkers to guide initial therapy and to guide second-line therapy for those who fail their initial treatment. It would really be useful to have tests that identify the driver of a particular patient’s disease, such as tumor necrosis factor and interleukin 6, so that we could select a class of therapeutic agents that is specific to the patient’s individual disease characteristics. This has been an ongoing challenge for many years. Progress has been slow, but it remains a goal that would make our practice easier and more logical. There has also been an effort to diagnose patients with preclinical RA who are going to progress to clinical RA. Despite valuable ongoing efforts, including trials of more widespread screening, we really have not made significant progress yet. Although the use of early treatment regimens to prevent RA onset is being explored in Europe, this strategy has not panned out yet, and I would be reluctant to give these preclinical patients any medical treatment—especially a treatment such as methotrexate. I would prefer to follow such patients closely and then treat aggressively at the first onset of clinical disease.


Alunno A, Bistoni O, Pratesi F, et al. Anti-citrullinated alpha enolase antibodies, interstitial lung disease and bone erosion in rheumatoid arthritis. Rheumatology (Oxford). 2018;57(5):850-855.

Deane KD, Norris JM, Holers VM. Pre-clinical rheumatoid arthritis: identification, evaluation and future directions for investigation. Rheum Dis Clin North Am. 2010;36(2):213-241.

Engdahl C, Bang H, Dietel K, Lang SC, Harre U, Schett G. Periarticular bone loss in arthritis is induced by autoantibodies against citrullinated vimentin. J Bone Miner Res. 2017;32(8):1681-1691.

Jog NR, James JA. Biomarkers in connective tissue diseases. J Allergy Clin Immunol. 2017;140(6):1473-1483.

Nielen MM, van Schaardenburg D, Reesink HW, et al. Specific autoantibodies precede the symptoms of rheumatoid arthritis: a study of serial measurements in blood donors. Arthritis Rheum. 2004;50(2):380-386.

Thiele GM, Duryee MJ, Anderson DR, et al. Malondialdehyde-acetaldehyde adducts and anti- malondialdehyde-acetaldehyde antibodies in rheumatoid arthritis. Arthritis Rheumatol. 2015;67(3):645-655.

Verheul MK, Böhringer S, van Delft MAM, et al. Triple positivity for anti-citrullinated protein autoantibodies, rheumatoid factor, and anti-carbamylated protein antibodies conferring high specificity for rheumatoid arthritis: implications for very early identification of at-risk individuals. Arthritis Rheumatol. 2018 May 21. doi: 10.1002/art.40562. [Epub ahead of print]

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