patient care perspectives

Biologic and Nonbiologic Interventions for Fatigue in Rheumatoid Arthritis

by Leonard H. Calabrese, DO

Overview

Fatigue is a common manifestation of rheumatoid arthritis (RA) that is tremendously important to patients and substantially impairs quality of life. Management requires both pharmacologic and nonpharmacologic approaches.

Expert Commentary

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

“The importance of fatigue in RA is underscored by several studies that have concluded that patients may value a day without fatigue as much as a day without pain.”

Leonard H. Calabrese, DO

Fatigue is probably the systemic manifestation of RA that rheumatologists have the least confidence in with respect to their approach, and it is a systemic manifestation that patients are profoundly concerned about. The importance of fatigue in RA is underscored by several studies that have concluded that patients may value a day without fatigue as much as a day without pain.

Fatigue is a complicated quality-of-life domain in patients with RA, and there are many things that can influence this. For example, when the disease is active and patients have a lot of inflammation and pain in their joints, they are less likely to exercise, and exercise is clearly inversely related to fatigability. The more you exercise, the less fatigued you are, and that has been demonstrated both experimentally and epidemiologically. Secondly, if you are experiencing significant pain, particularly at night, then you sleep poorly. And it has been shown experimentally that if sleep is disrupted or if the patient has partial insomnia (ie, trouble falling asleep or waking up too early in the predawn hours), then inflammatory markers tend to be increased, especially interleukin 6. For those with RA, the disease scores will rise over several days of sleep disruption. Lastly, patients with RA are more likely to have intercurrent mood disorders, including varying degrees of depression and anxiety. In addition to anhedonia and abulia, common symptoms of depression include pain and fatigability. So, these are areas in which we are very interested in exploring other therapies.

From the pharmacologic perspective, there is great interest in determining whether certain agents, such as interleukin-6 inhibitors, may have something more to offer patients with fatigue, and there are some supportive data to suggest that this may be true for some individuals. Clinically meaningful patient-reported benefits on fatigue have been observed in randomized clinical trials with both sarilumab and tocilizumab.

However, patients need more than just pharmacologic intervention. They need wellness interventions, whether this involves coaching on exercise, cognitive behavioral therapy, sleep therapy, and/or stress modification. Interestingly, as reported by Hewlett and colleagues, there are systems that can be developed that can reduce fatigue over both the short- and long-term. The authors concluded that teams consisting of rheumatology nurses and occupational therapists using cognitive behavioral approaches reduced multiple RA fatigue impacts. Rheumatologists do not currently have access to such systems, but I think that this is an area that is ripe for partnership with the pharmaceutical industry. That is, with the help of industry and its resources, such systems might be developed to improve fatigue and perhaps other outcomes of interest as well.

References

Almeida C, Choy EHS, Hewlett S, et al. Biologic interventions for fatigue in rheumatoid arthritis. Cochrane Database Syst Rev. 2016(6):CD008334. doi:10.1002/14651858.CD008334.pub2

Haack M, Sanchez E, Mullington JM. Elevated inflammatory markers in response to prolonged sleep restriction are associated with increased pain experience in healthy volunteers. Sleep. 2007;30(9):1145-1152. doi:10.1093/sleep/30.9.1145

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. doi:10.1136/annrheumdis-2018-214469

Mullington JM, Simpson NS, Meier-Ewert HK, Haack M. Sleep loss and inflammation. Best Pract Res Clin Endocrinol Metab. 2010;24(5):775-784. doi:10.1016/j.beem.2010.08.014

Pope JE. Management of fatigue in rheumatoid arthritis. RMD Open. 2020;6(1):e001084. doi:10.1136/rmdopen-2019-001084

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(1):198. doi:10.1186/s13075-016-1096-9

Strand V, Michalska M, Birchwood C, et al. Impact of tocilizumab administered intravenously or subcutaneously on patient-reported quality-of-life outcomes in patients with rheumatoid arthritis. RMD Open. 2018;4(1):e000602. doi:10.1136/rmdopen-2017-000602

Strand V, Reaney M, Chen CI, et al. Sarilumab improves patient-reported outcomes in rheumatoid arthritis patients with inadequate response/intolerance to tumour necrosis factor inhibitors. RMD Open. 2017;3(1):e000416. doi:10.1136/rmdopen-2016-000416

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