conference reporter

Patient Management Principles for Difficult-to-Treat Rheumatoid Arthritis

by Alan L. Epstein, MD


A panel discussion titled “How Do I Manage This Patient?: Difficult-to-Treat RA Cases” was moderated by Daniel Solomon, MD, MPH, of the Brigham and Women’s Hospital, and Gordon Starkebaum, MD, of the University of Washington, on November 12 at the 2019 ACR/ARP Annual Meeting in Atlanta, GA. Panelists weighed in on best practices for patients with rheumatoid arthritis (RA) with inadequate response to methotrexate (MTX-IR), the earlier use of biologic disease-modifying antirheumatic drugs (bDMARDs), and principles to guide the selection of therapy in bDMARD-IR patients. Case vignettes were presented throughout the session.  

Following the panel discussion, our featured expert, Alan L. Epstein, MD, who attended this session, was interviewed by Conference Reporter Editor-in-Chief Tom Iarocci, MD. Dr Epstein’s clinical perspectives on the proceedings are presented here.

“If a patient with RA is truly MTX-IR, what is the best next step? The bottom line is that we do not yet know. The panelists shared their thoughts, along with some supportive data. For example, an IL-6 receptor antagonist might be a good choice in a patient with cardiovascular disease, since IL-6 signaling has been linked with cardiovascular comorbidity in RA.” 

Alan L. Epstein, MD

The first case for the panel was that of a 55-year-old female executive in good health, with a 2-month history of polyarthritis, who is found to have seropositive RA. The following question was posed to the panel: Barring contraindication, would you ever start a bDMARD or a targeted synthetic DMARD (tsDMARD) rather than MTX monotherapy? Paul Emery, MA, MD, from Leeds, UK, stated that, if given a free hand (ie, for patients going on a study protocol), he would estimate the likelihood of MTX success using baseline characteristics, including C-reactive protein, number of inflamed joints, and other markers. Then, in patients who are predicted to be MTX-IR, he would start with the combination of MTX with either a bDMARD or a tsDMARD. Dr Emery noted that he would not necessarily worry about maintaining the MTX later, but that its value early in the course of RA was the most important factor. Another panelist questioned the reliability of currently available predictive modeling to identify patients who were not likely to respond to MTX at baseline. Still, another panelist noted that a slightly younger woman in this clinical scenario might be started on biologic monotherapy if planning to become pregnant.

My perspective is that almost all providers in the United States are going to start with MTX initially unless there is a contraindication. Approximately 30% of patients have an adequate response to initial MTX monotherapy; however, an important issue with MTX is the proper use of the drug. Oral absorption depends on transport proteins in the gut that are saturable. Therefore, if used orally, doses of MTX must be split over a 24-hour period. The other option is to use the drug subcutaneously. Additionally, one should make sure that therapeutic levels of MTX have been achieved before concluding that a patient is MTX-IR. The measurement of MTX polyglutamate levels in circulating erythrocytes may be helpful toward this end, and I think that we, as practitioners, could stand to use this test more frequently than we do. It should also be noted that MTX can take a long time to take effect. Bridging therapy with low-dose prednisone may be an option in this setting.

Another vignette for the panel’s consideration was that of a 25-year-old man with a 3-month history of seropositive RA who is doing poorly on subcutaneous MTX, dosed at 20 mg weekly, with a Clinical Disease Activity Index of greater than 10. The case assumption was that there was no uncertainty that he now required a bDMARD or a tsDMARD. Thus, this vignette presents a big question in RA treatment: If a patient with RA is truly MTX-IR, what is the best next step? The bottom line is that we do not yet know. The panelists shared their thoughts, along with some supportive data. For example, an interleukin 6 (IL-6) receptor antagonist might be a good choice in a patient with cardiovascular disease, since IL-6 signaling has been linked with cardiovascular comorbidity in RA. Similarly, the identification of the primary cytokine “driver” of the patient’s disease (eg, tumor necrosis factor, IL-6) may help to determine the optimal choice of therapy. For instance, one panelist felt that a patient with particularly high levels of antibodies to citrullinated proteins might do better on abatacept, and there are some data to support that concept. Tumor necrosis factor inhibitors are commonly prescribed in MTX-IR patients with RA. This has become a habit among the rheumatology community due to our long experience/comfort with these agents, along with formulary availability. If tsDMARDs become available as first-line agents in terms of formulary availability, their oral route of administration might drive a change in the current paradigm.

As the session drew to a close, remarks turned to advances and future directions in RA management. Prior to 1999, agents used in the treatment of patients with RA were primarily discovered by accident. Since then, a markedly increased understanding of the immunopathogenesis of RA has led to the development of a new generation of immunologically targeted therapies that holds much promise for patients with difficult-to-treat RA. With that said, we still have a long way to go.


Bozec A, Luo Y, Engdahl C, Figueiredo C, Bang H, Schett G. Abatacept blocks anti-citrullinated protein antibody and rheumatoid factor mediated cytokine production in human macrophages in IDO-dependent manner. Arthritis Res Ther. 2018;20(1):24.

Kearsley-Fleet L, Davies R, De Cock D, et al. Biologic refractory disease in rheumatoid arthritis: results from the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis. Ann Rheum Dis. 2018;77(10):1405-1412.

Roodenrijs NMT, de Hair MJH, van der Goes MC, et al; whole EULAR Task Force on development of EULAR recommendations for the comprehensive management of difficult-to-treat rheumatoid arthritis. Characteristics of difficult-to-treat rheumatoid arthritis: results of an international survey. Ann Rheum Dis. 2018;77(12):1705-1709.

Rosa M, Chignon A, Li Z, et al. A Mendelian randomization study of IL6 signaling in cardiovascular diseases, immune-related disorders and longevity. NPJ Genom Med. 2019;4:23. doi: 10.1038/s41525-019-0097-4. eCollection 2019.

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.

Solomon D, Starkebaum G. How do I manage this patient?: difficult-to-treat RA cases.: Difficult-to-Treat RA Cases. Session presented at: 2019 American College of Rheumatology/Association of Rheumatology Professionals Annual Meeting; November 12, 2019; Atlanta, GA.

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