expert roundtables

Treatment Advances in Rheumatoid Arthritis

by Leonard H. Calabrese, DO; Jeffrey R. Curtis, MD, MS, MPH; and Eric M. Ruderman, MD

Overview

One of the most significant changes in the approach to the care of patients with rheumatoid arthritis (RA) has been the recognition of the importance of alternative symptoms and domains. Fatigue, sleep disturbance, pain, and mood disturbance are often interlinked and may be crucial to patients with RA.

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Q: What are some recent or currently unfolding RA treatment advances?

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Leonard H. Calabrese, DO

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

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“We now recognize that outcome domains other than joint inflammation and destruction are also operant in RA. These domains, which include pain, sleep, fatigue, and mood, are influenced by disease-related inflammation.”

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Leonard H. Calabrese, DO

We currently know a lot more about the roughly one-third of patients with RA who do not achieve a satisfactory response to treatment. And an important related advance is that we now recognize that outcome domains other than joint inflammation and destruction are also operant in RA. These domains, which include pain, sleep, fatigue, and mood, are influenced by disease-related inflammation. Each of them may have inputs from the inflammatory disease, and this can contribute to a disruption in mood. For example, biomarkers such as interleukin 6 are elevated in patients with depression. There are also biobehavioral aspects of the disease that we are just beginning to learn about and that require further study. These include the role of exercise in decreasing fatiguability and the role of intercurrent mood disorders that may amplify pain, as well as the importance of increased incidence of primary sleep disorders and fatigue in patients with RA. Fatigue is particularly important for patients with RA, and they often prioritize managing their fatigue above managing their pain. Another advance is recognizing that targeting these pathways molecularly with the numerous agents available today shows improvements not only in disease activity, but also in quality-of-life domains. One of the breakout areas of patient care research is the application of patient-reported outcomes to daily practice. These domains can be collected easily with computerized instruments, and we can share these data with our patients, helping them to understand where their deficits are. At the Cleveland Clinic, we routinely collect many quality-of-life measures using Patient-Reported Outcomes Measurement Information System scales and other instruments to assess domains such as global health, global fatigue, scales of mental health, pain, pain interference, and fatigue interference. These can then be shared in a snapshot with the patient, thus becoming instruments for education, engagement, and empowerment. Finally, we are trying to bring wellness measures into the clinic by providing patients with tools to increase their exercise, improve their diets, improve sleep with cognitive behavioral programs, and decrease their stress.

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Jeffrey R. Curtis, MD, MS, MPH

Marguerite Jones Harbert-Gene V. Ball, MD Professor of Medicine
Co-Director, UAB Pharmacoepidemiology and Pharmacoeconomics Research (PEER) Unit
Division of Clinical Immunology and Rheumatology
University of Alabama at Birmingham
Birmingham, AL

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“Beyond new therapies targeting the underlying pathogenesis of RA, the movement around wellness and the concept of holistic care for treating RA-related symptoms such as fatigue is also growing in importance.”

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Jeffrey R. Curtis, MD, MS, MPH

We have numerous effective therapies for RA, so, arguably, there is less new drug development in RA than there was 5 to 10 years ago. The problem is that we are not particularly sure how to use these agents optimally nor how to best sequence them. Research into ways of achieving incrementally increased efficacy (eg, combination therapy) continues to be of interest. For example, can you use low doses of 2 different targeted immunomodulatory agents in combination to get incremental benefit? To date, most of the experiments using 2 targeted therapies together have not shown increased efficacy, but, as long as there are no safety issues such as an increased risk of infection, trials assessing combination therapy are still able to recruit patients and different combinations are still being tested. Other treatment approaches being evaluated include vagus nerve stimulation delivered via implantable medical devices.

Beyond new therapies targeting the underlying pathogenesis of RA, the movement around wellness and the concept of holistic care for treating RA-related symptoms such as fatigue is also growing in importance. These approaches include mindfulness meditation, cognitive behavioral therapy (ie, for the management of chronic pain), and other strategies that are not directly targeting inflammation and cytokines with a drug. I think that these will likely become a more significant component of RA care, recognizing the appreciably unmet need to treat pain, fatigue, and numerous related symptoms in patients with RA that are commonly experienced, even for those who are doing relatively well in terms of inflammatory disease control.

Finally, we are also increasingly recognizing that, while there are important clinical differences between seropositive patients and seronegative patients, the impact of the disease and its manifestations may be as severe in seronegative disease. On expectation, seropositive patients may have more structural damage, but seronegative patients may have more fatigue. Seronegative RA may have as great an impact—or an even greater impact—on work activities and activities of daily living that is not necessarily exclusively driven by RA-related inflammation. The health impact of these symptoms, some of which may closely resemble those for conditions such as fibromyalgia, can be just as important as those caused by the inflammatory component of arthritis. Thus, we now recognize that even those patients with RA who are not seropositive should not necessarily receive less aggressive disease-modifying and targeted RA treatments.

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Eric M. Ruderman, MD

Professor of Medicine
Associate Chief for Clinical Affairs
Division of Rheumatology
Northwestern University Feinberg School of Medicine
Chicago, IL

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An important advance from the last 2 years is the current focus on alternative symptoms and the recognition that these symptoms may also be driven by mechanisms other than inflammation.” 

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Eric M. Ruderman, MD

An important advance from the last 2 years is the current focus on alternative symptoms and the recognition that these symptoms may also be driven by mechanisms other than inflammation. The medical community has always recognized that there is a component of central pain and noninflammatory pain that has been called fibromyalgia or fibromyalgia-like; however, a significant change is that we now recognize that it is important to identify these components and deal with them separately to achieve the best outcomes (ie, if you do not recognize a central pain component and develop your approach accordingly, then you are not necessarily going to get very far). I see more and more recognition of this in the published research and out in the community amongst rheumatologists. Over the years, we have also made some changes in how we approach the treatment of patients who are seropositive because they tend to have more progressive disease and more extra-articular manifestations. Although we should treat all patients aggressively with a treat-to-target approach and evidence suggests that it is not a good idea to treat seronegative patients more gingerly, I do think that we tend to pay closer attention to our seropositive patients. We are also still learning how best to use imaging to treat patients. Currently, imaging is primarily used to confirm an RA diagnosis in those who have a clinical presentation that sounds like inflammatory arthritis. In the future, imaging may be used to identify the appropriate time to change treatment (eg, tapering, switching), but we need more data on this use.

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References

Aletaha D, Smolen JS. Diagnosis and management of rheumatoid arthritis: a review. JAMA. 2018;320(13):1360-1372.

Choy EHS, Calabrese LH. Neuroendocrine and neurophysiological effects of interleukin 6 in rheumatoid arthritis. Rheumatology (Oxford). 2018;57(11):1885-1895.

Hewlett S, Almeida C, Ambler N, et al; RAFT Study Group. Reducing arthritis fatigue impact: two-year randomised controlled trial of cognitive behavioural approaches by rheumatology teams (RAFT). Ann Rheum Dis. 2019;78(4):465-472.

Løppenthin K, Esbensen BA, Østergaard M, et al. Physical activity and the association with fatigue and sleep in Danish patients with rheumatoid arthritis. Rheumatol Int. 2015;35(10):1655-1664.

Mandelin AM II, Homan PJ, Shaffer AM, et al. Transcriptional profiling of synovial macrophages using minimally invasive ultrasound-guided synovial biopsies in rheumatoid arthritis. Arthritis Rheumatol. 2018;70(6):841-854.

Nerurkar L, Siebert S, McInnes IB, Cavanagh J. Rheumatoid arthritis and depression: an inflammatory perspective. Lancet Psychiatry. 2019;6(2):164-173.

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