Rheumatoid Arthritis

Treating Rheumatoid Arthritis: What Are Clinicians Overlooking?

Leonard Calabrese, rheumatoid arthritisby Lauren LeBano

Treatment of rheumatoid arthritis has undergone rapid and significant changes in the past decade. With the advent of treat-to-target strategies, patients have seen improved outcomes, and clinicians have tackled the challenges of incorporating precise measurements, including biomarkers, into their daily practice.

Leonard Calabrese, DO, FACR, joined us to discuss overlooked biomarkers, cutting-edge biomarkers, and strategies for educating patients. Dr. Calabrese is the director of the RJ Fasenmyer Center for Clinical Immunology at the Cleveland Clinic and Vice Chairman of the Department of Rheumatic and Immunologic Diseases. He is also a Professor of Medicine at the Lerner College of Medicine at the Cleveland Clinic and Co-Chair of the Interdisciplinary Autoimmune Summit.

What are some currently accepted biomarkers used in treatment of rheumatoid arthritis? Are any biomarkers overlooked?

Treat-to-target strategy is now canonical in the treatment of rheumatoid arthritis.1 We know that patients who are treated with this strategy, which uses defined targets and defined points to modify therapy, have better outcomes than those who are treated with standard of care.

And when we say “better,” we quantify that assessment by measuring the movement of biomarkers. These biomarkers could include disease activity measures such as the Clinical Disease Activity Index (CDAI), the Simplified Disease Activity Index, and the Disease Activity Score (DAS), as well as laboratory markers such as erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP).

Patient-reported outcomes are also part of the biomarker analysis of disease activity. Some patient-reported metrics, such as the Health Assessment Questionnaire (HAQ), examine functional response. Others, such as the Short-Form 36 (SF 36), measure quality of life. Patient-reported outcomes are often dismissed as soft biomarkers, but I believe they are among the most important biomarkers in the management of rheumatoid arthritis, and in all chronic disease. The perspective of an actual patient is critical in assessment.

Even though treat-to-target is orthodoxy, are there any obstacles to embracing this approach in clinical practice?

In clinical practice, there are many patients who are not at target, and one factor may be the slow uptake of treat-to-target on behalf of some physicians. However, it is important for us to remember that establishing a target is not a decision imposed solely by the clinician. We are in an era that emphasizes patient-oriented goals, which means that targets are established based on shared and informed decision-making between doctors and patients.

For example, some patients may not want to take certain medications. As a physician, we can help these patients understand the risks and benefits of various medications, but we do not mandate taking them. Thus, the goal with treat to target is to try to engage most patients, while recognizing that not all patients need the same targets.

Do you have any tips for having productive patient conversations that improve treatment?

Very few patients with rheumatoid arthritis know anything about the parameters that affect their disease.  Patients with diabetes know their hemoglobin A1c, and patients with HIV know their viral load, but patients with rheumatoid arthritis do not know their Multiple Biomarkers of Disease Activity (MBDA) or their CDAI. Understanding these parameters should become part of the fabric of management. Over time, knowledge of the markers and their implications will help patients to understand the goals of treatment.

It is important to have conversations about targets early and ensure that patients are engaged. I mostly educate patients through conversations and through my advanced practitioner.

What recommendations do you have for rheumatologists on how to use biomarkers in clinical practice? Do you have any practical tips on how to organize workflow?

The guidelines in rheumatology suggest that we should use markers frequently, certainly at baseline and at most visits. Many of these biomarkers can be measured quite efficiently. The Routine Assessment of Patient Index Data 3 (RAPID-3) is a completely patient-driven questionnaire that functions well under most circumstances and only takes a few minutes to complete.

Clinicians are often concerned about not having enough time during the patient visit. If clinicians have a workflow that is organized efficiently, the questionnaires don’t detract from the patient visit. I encourage my colleagues to make an investment in the right systems up front.

In our practice, we have patients complete their patient-reported outcome metrics on tablets, with results transmitted directly to electronic medical records. By the time I see the patients, they have already completed Patient Reported Outcomes Measurement Information System (PROMIS) and RAPID 3. I examine the results before I even walk through the door, so it doesn’t cost me any visit time to do these measures with patients. I know I am fortunate to have that system, but such systems are the wave of the future.

Of the biomarkers that are currently available, which one would you highlight for a rheumatologist who wants to be on the cutting edge of practice?

A commercial test called the Multiple Biomarkers of Disease Activity (MBDA) is the most potent at predicting who is most likely to have rapidly progressive disease. There is a significant amount of evidence, based on dozens of peer-reviewed publications, for its utility. The MBDA is easy to use and is helpful in establishing prognosis and identifying discordance of responses (ie, a patient looks good and feels bad, or a patient feels bad and looks good). The MBDA is not a perfect test, but there are growing data evaluating it and sorting out its strengths and weaknesses.2,3

Are there any problems with the current biomarker strategy?

Right now, the field has been relying on composite measures that mix the patient’s global assessment, the doctor’s global assessment, and assessment of tender and swollen joints. A laboratory test, such as ESR or CRP, may also be used. These measures have served us well, but they are imperfect, and there is often discordance between what the patient thinks and what clinicians think might be occurring. We need better biomarkers that can cut through some of the variability.

What is your view on the areas of greatest need for biomarkers?

We have a great need for biomarkers in several areas. We need better and more reliable biomarkers to predict the onset of rheumatoid arthritis and make the diagnosis at an earlier stage. The American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) criteria for diagnosis4 are for patients with well-recognized disease, but rheumatologists are now seeing patients at earlier phases. We have a growing interest in patients who are at a stage of asymptomatic autoimmunity, which means having antibodies without having symptoms. These patients are being discovered because they are first-degree relatives of patients with established disease.

The second area of great need is for prognostic biomarkers. We need to determine which patients are going to have rapidly progressive and severe disease, and which patients are going to have erosive disease.

Thirdly, we need biomarkers that will help us to predict who will respond to certain drugs. We have a wealth of biologic and nonbiologic drugs, and we often switch back-and-forth between them. Biomarkers may help us in making these decisions, and multiple research attempts are underway at the present time. For example, a study presented by Dr. Iain McInnes at the American College of Rheumatology this year demonstrated a promising way to predict who would respond to a TNF inhibitor vs rituximab.

Do you have any final words of advice for clinicians?

Ask yourself this question: what are you measuring? Are you just asking the patient, “How are you doing?” Or are you actually collecting data? If you’re not collecting data, then begin with the low-hanging fruit. Start collecting patient-reported data and eventually incorporate more data into your practice.

When I speak with practitioners around the country, it is clear that people are moving in this direction. Technology is changing and moving in this direction, too.

Going forward, I think we will be obligated to collect more data on patient-reported outcomes, and I don’t think that solo practitioners will be in a good position to do this. There are groups of practitioners that might be sharing these types of resources, and I would encourage you to find the one that works for you.


1. Smolen JS, Breedveld FC, Burmester GR, et al. Treating rheumatoid arthritis to target: 2014 update of the recommendations of an international task force. Ann Rheum Dis. 2015; DOI:10.1136/annrheumdis-2015-207524.

2. Hirata S, Dirven L, Shen Y, et al. A multi-biomarker score measures rheumatoid arthritis disease activity in the BeSt study. Rheumatology (Oxford). 2013;52(7):1202-1207.

3. 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:e000197 DOI:10.1136/rmdopen-2015-000197.

4. Aletaha D, Neogi T, Silman AJ, et al. 2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League against Rheumatism collaborative initiative. Ann Rheum Dis. 2010;69:1580-1588.