expert roundtables

Pain, Fatigue, and Depression in Rheumatoid Arthritis

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

Overview

Experts describe a significant psychiatric overlay in a subgroup of patients with rheumatoid arthritis (RA). Perhaps as many as one-fourth of patients with RA have varying levels of central pain sensitization, and within this subgroup, mood disorders are overrepresented. Here, the panelists explore connections between inflammatory cytokines such as interleukin 6 (IL-6) and the overlay of mood, pain, fatigue, and functional disability in patients with RA.

Q: Is RA very much like other chronic pain syndromes in regard to fatigue and depression, or is there also something unique there?

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

“One of the foremost challenges clinically is the concomitant fibromyalgia or chronic muscular pain—which has a good deal of psychological overlay.”

Daniel E. Furst, MD

The only difference between other chronic diseases and this one is the significant pain aspect, which can contribute significantly to psychiatric overlay. One of the foremost challenges clinically is the concomitant fibromyalgia or chronic muscular pain—which has a good deal of psychological overlay. Aside from the consideration of fibromyalgia and psychologically associated illnesses, I don’t think that it’s different from other chronic diseases that involve pain.

Alan L. Epstein, MD

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

“We have come to learn that one of the most important—if not the most important—cytokines in driving many of these extra-articular features of RA is IL-6.”

Alan L. Epstein, MD

Another way to think about this is the way that I was taught a number of decades ago by my teachers, who said, “This is not rheumatoid arthritis; this is rheumatoid disease.” We all know that its major phenotype is joint inflammation. However, this is a systemic illness. We see vasculitis, pericarditis, pleuritis, anemia, etc, that’s related to this disease. We bear in mind that, although the joints are clinically most relevant, there are systemic features in addition to the joints. There are also important comorbidities, such as the increased cardiovascular risk, the increased risk of malignancy, and the increased risks of infection—along with what is being called out in this particular question, which relates to the issues of pain, fatigue, and depression. We have come to learn that one of the most important—if not the most important—cytokines in driving many of these extra-articular features of RA is IL-6.

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

“Yet, as Dr Furst pointed out, we do have perhaps one-fourth of patients with RA who have varying levels of central pain sensitization, and these patients clearly have overrepresented mood disorders. And I would agree with what Dr Epstein said, in that I believe that this phenomenon is not incidental.”

Leonard H. Calabrese, DO

Just to add, in going back to the question of how RA may be different from other chronic, painful diseases—I think that it’s a very interesting question. The epidemiology of intercurrent mood disorders in RA is actually a matter of controversy (ie, whether these disorders are overrepresented or underrepresented). I just saw some data this morning by Clifton O. Bingham 3rd, MD, Director of the Johns Hopkins Arthritis Center. These data relate to the Patient-Reported Outcomes Measurement Information System (PROMIS) scores from their rather large group of patients with RA. And, actually, this group’s mental health profile was almost identical to the population norm. Yet, as Dr Furst pointed out, we do have perhaps one-fourth of patients with RA who have varying levels of central pain sensitization, and these patients clearly have overrepresented mood disorders. And I would agree with what Dr Epstein said, in that I believe that this phenomenon is not incidental. Inflammation and numerous cytokines, including IL-6, may be complicit in disrupting sleep, increasing fatigue, etc. In fact, the role of inflammatory cytokines in the pathogenesis of mood disorders is a whole new, burgeoning area of interest, and there is interest in potentially targeting inflammatory cytokines in the treatment of mood disorders—depression, in particular. It’s a complex area and it’s becoming more interesting as we move along.

Stanley B. Cohen, MD

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

“I always think of my patients with RA as some of the most courageous patients I know.” 

Stanley B. Cohen, MD

I always think of my patients with RA as some of the most courageous patients I know. Most of them are straight shooters, and most of them are stoic. Of course, there is somewhat of a normative distribution within the population, and you get that variation. However, in contrast to other patients with central pain syndromes or somatization disorders and the like, I find the patients with RA who suffer from these phenomena to be somewhat distinct.

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

I agree with what has been said. I would add that another unmet need in this area is that of measurement (ie, the use of quantitative RA measurement tools). Unfortunately, the uptake of these assessment tools in the real world is not as good as we would like. Even with the Routine Assessment of Patient Index Data 3 (RAPID3), which should be an absolute “no-brainer” for the physician, the data suggest that uptake has only been around 30%. And so, we’ve got a ways to go.

References

Bevans M, Ross A, Cella D. Patient-Reported Outcomes Measurement Information System (PROMIS®): efficient, standardized tools to measure self-reported health and quality of life. Nurs Outlook. 2014;62(5):339-345.

Bingham CO 3rd, Bartlett SJ, Merkel PA, et al. Using patient-reported outcomes and PROMIS in research and clinical applications: experiences from the PCORI pilot projects. Qual Life Res. 2016;25(8):2109-2116.

Choy EHS, Calabrese LH. Neuroendocrine and neurophysiological effects of interleukin 6 in rheumatoid arthritis. Rheumatology (Oxford). 2017 Nov 22. doi: 10.1093/rheumatology/kex391. [Epub ahead of print]

Chua JR, Castrejon I, Pincus T. Assessment of pain and other patient symptoms in routine clinical care as quantitative, standardised, “scientific” data. Clin Exp Rheumatol. 2017;35 Suppl 107(5):13-20.

Curtis JR, Chen L, Danila MI, Saag KG, Parham KL, Cush JJ. Routine use of quantitative disease activity measurements among US rheumatologists: implications for treat-to-target management strategies in rheumatoid arthritis. J Rheumatol. 2018;45(1):40-44.

Doss J, Mo H, Carroll RJ, Crofford LJ, Denny JC. Phenome-wide association study of rheumatoid arthritis subgroups identifies association between seronegative disease and fibromyalgia. Arthritis Rheumatol. 2017;69(2):291-300.

Pincus T, Swearingen CJ, Bergman MJ, et al. RAPID3 (Routine Assessment of Patient Index Data) on an MDHAQ (Multidimensional Health Assessment Questionnaire): agreement with DAS28 (Disease Activity Score) and CDAI (Clinical Disease Activity Index) activity categories, scored in five versus more than ninety seconds. Arthritis Care Res (Hoboken). 2010;62(2):181-189.

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, Aletaha D, Barton A, et al. Rheumatoid arthritis. Nat Rev Dis Primers. 2018;4:18001.

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.

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