expert roundtables

Examining the Need for New Treatment Biomarkers in Rheumatoid Arthritis

by Leonard H. Calabrese, DO, Stanley B. Cohen, MD, Alan L. Epstein, MD, Daniel E. Furst, MD


The need for new predictive biomarkers that have real clinical utility remains a foremost topic of interest in rheumatoid arthritis (RA). Using the same treatment strategy does not necessarily achieve similar results in every patient with moderate to severe RA. Despite a large amount of scientific work in this area, there is a scarcity of biomarkers that help guide clinicians on the selection of the most effective, personalized therapies for individual patients who may have differing disease phenotypes.

Q: What are the challenges and unmet needs that affect the care of patients with RA who have had an inadequate response to therapy?

Leonard H. Calabrese, DO

Professor of Medicine
RJ Fasenmyer Chair of Clinical Immunology
Director, RJ Fasenmyer Center for Clinical Immunology
Vice Chair, Department of Rheumatic and Immunologic Diseases
Cleveland Clinic Foundation
Cleveland, OH

While we have been blessed to have had anti–tumor necrosis factor (TNF) agents for 2 decades, it is also true that some patients are more difficult to treat than others, with about one-third not having the gratifying responses to anti-TNF agents that are more typical of the remainder of the population. And, after 20 years, we have yet to identify really good ways to predict these suboptimal outcomes. However, we have been working on it, and I suspect that today we will be talking about some of the creative ways to approach this deficit.

Stanley B. Cohen, MD

Clinical Professor of Medicine
UT Southwestern Medical Center
Co-Director, Division of Rheumatology
Presbyterian Hospital
Dallas Dallas, TX

“We certainly remain a bit jealous of our friends in oncology, who often have so much more in their armamentarium to delineate which treatments might be best for individual patients.”

Stanley B. Cohen, MD

I agree. The biggest disappointment to me, in spite of all of the hard work that has been done in this area, is the lack of treatment biomarkers to help us determine whether or not a specific, individual patient might benefit from the therapeutic targeting of a particular pathway. It would be great to have some kind of treatment biomarker that would help us to discriminate among patients (ie, to help us predict those patients who are going to have an inadequate response to anti-TNF therapy and those who may be inadequate responders to other biologics). So, yes, we are very thankful to have these medications, and we have learned a great deal over the last 20 years. However, we certainly remain a bit jealous of our friends in oncology, who often have so much more in their armamentarium to delineate which treatments might be best for individual patients. The best we have in the way of biomarkers relates to rituximab and abatacept, which are probably better for patients who are seropositive for rheumatoid factor and cyclic citrullinated peptide, but, again, any of the biologics could be used first line, depending on the comfort of the patient and the comfort of the physician. I think that if some of our friends in basic research can help us to elucidate biomarkers that predict response to therapy, to begin to deliver on the promise of personalized medicine that we began hearing about back in the days of my first rheumatology lecture in 1984, that would be exciting for me, personally, as I close out my career.

Alan L. Epstein, MD

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

“Wouldn’t it be nice to be able to predict which patients will do best on which drug? And, I’d perhaps add, at which point in the patient’s disease?”

Alan L. Epstein, MD

Yes, and as Dr Cohen began to illustrate: wouldn’t it be nice to be able to predict which patients will do best on which drug? And, I’d perhaps add, at which point in the patient’s disease? I’d really like it if, for my next patient with RA, I could do a test—perhaps a biomarker test—and predict that, for this individual patient, the disease is predominantly TNF-driven, in which case an anti-TNF agent would be appropriate for him or her. Or, perhaps the next patient with RA who sees me has disease that is more interleukin (IL)-6–driven, so, in that case, maybe an agent that inhibits IL-6 would be preferred. Now, we obviously do not yet have the ability to select patients for individualized treatment, but it would be a wonderful thing. There is now some information to suggest that the immunopathogenesis differs not only among different patients—as I just alluded to—but also among different stages of disease in the same patient.

Daniel E. Furst, MD

Professor of Medicine, University of California (emeritus)
UCLA Medical Center, Department of Medicine
Division of Rheumatology
UCLA Medical Center
Los Angeles, CA

Agreed. And I want to point out that TNF and IL-6 are not the only targets (ie, other targets have been very effective as well), so predictive biomarkers are needed all around.


Cuppen BV, Welsing PM, Sprengers JJ, et al. Personalized biological treatment for rheumatoid arthritis: a systematic review with a focus on clinical applicability. Rheumatology (Oxford). 2016;55(5):826-839.

Demoruelle MK, Harrall KK, Ho L, et al. Anti-citrullinated protein antibodies are associated with neutrophil extracellular traps in the sputum in relatives of rheumatoid arthritis patients. Arthritis Rheumatol. 2017;69(6):1165-1175.

Fleischmann R, Connolly SE, Maldonado MA, Schiff M. Brief report: estimating disease activity using multi-biomarker disease activity scores in rheumatoid arthritis patients treated with abatacept or adalimumab. Arthritis Rheumatol. 2016;68(9):2083-2089.

Jog NR, James JA. Biomarkers in connective tissue diseases. J Allergy Clin Immunol. 2017;140(6):1473-1483.
Singh JA, Saag KG, Bridges SL Jr, et al. 2015 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis. Arthritis Rheumatol. 2016;68(1):1-26.

Smolen JS, Landewé R, Bijlsma J, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2016 update. Ann Rheum Dis. 2017;76(6):960-977.

Strand V, Kosinski M, Chen CI, et al. Sarilumab plus methotrexate improves patient-reported outcomes in patients with active rheumatoid arthritis and inadequate responses to methotrexate: results of a phase III trial. Arthritis Res Ther. 2016;18:198.

Taylor P, Gartemann J, Hsieh J, Creeden J. A systematic review of serum biomarkers anti-cyclic citrullinated peptide and rheumatoid factor as tests for rheumatoid arthritis [published correction appears in Autoimmune Dis. 2012;2012:734069]. Autoimmune Dis. 2011;2011:815038.

Tweehuysen L, van den Ende CH, Beeren FMM, Been EM, van den Hoogen FH, den Broeder AA. Little evidence for usefulness of biomarkers for predicting successful dose reduction or discontinuation of a biologic agent in rheumatoid arthritis: a systematic review. Arthritis Rheumatol. 2017;69(2):301-308.

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