PSYCHOLOGICAL ASPECTS OF THE PATIENT WITH RHEUMATOID ARTHRITIS

I. Frydas *

Laboratory of Microbiology and Infectious Diseases, School of Veterinary Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece.

*Correspondence to:
Prof. I Frydas,
Laboratory of Microbiology and Infectious Diseases,
School of Veterinary Medicine,
Aristotle University of Thessaloniki,
Thessaloniki, Greece.
e-mail: frydas@vet.auth.gr

ABSTRACT

Rheumatoid arthritis (RA) is an inflammatory autoimmune disease with risk factors of genetics, the female sex, and environmental factors. Lifestyle factors such as obesity, cigarette smoking, alcohol consumption, stress and low socioeconomic status may be implicated in the disease. RA patients have a reduced quality of life and are an economical and health burden for countries. Growing evidence shows that RA patients may present neurological disease with structural differences in the hippocampus and basal ganglia compared to individuals unaffected by RA. The disease involves the immune, nervous, and endocrine systems with physical and psychological discomfort. Emotional stress and anxiety make it a psychosomatic disease with organic damage aggravated by emotional factors. The constant fear and strong concern that afflicts the patient can lead to psychological, physical and mental discomfort. However, more studies need to be done on this topic to understand the real psychological state of the patient and how it is involved in RA. Here, in this article, we report some new evidence on the neurological state of the RA patient.

KEYWORDS: neurology, rheumatoid arthritis, inflammation, immune system, psychological disorders, autoimmunity

INTRODUCTION

Rheumatoid arthritis (RA) is an inflammatory autoimmune disease and a substantial global public health challenge. A recent study examining the worldwide incidence and burden of RA estimated approximately 20 million cases with 3.4 million daily adjusted life years globally (1).

Risk factors for the disease include genetic predisposition, the female sex, and environmental and lifestyle factors, including obesity, smoking, alcohol consumption, stress, and low socioeconomic status.

Patients with this systemic disease suffer from joint swelling and pain, with varying degrees of severity from patient to patient. In addition, RA is associated with various complications, including permanent joint damage that requires surgery, effects on the blood vessels with rheumatoid vasculitis, and Felty syndrome (2).

It is a chronic and progressive disease that begins to affect the small joints initially, followed by larger ones, and can progressively affect other systems such as the skin, eyes, heart, kidneys, and lungs. Bone, ligament, and cartilage damage is common, as well as deformities and severe pain.

RA may lead to compression and invasion of the spinal cord and peripheral nerves, which can cause myelopathy, radiculopathy, and entrapment neuropathies such as carpal tunnel syndrome. The cervical spine is frequently involved in RA and can be affected with diverse ranges of severity, with some studies indicating up to 80% prevalence in cases (3). The atlantooccipital joint, atlantoaxial joint, and subaxial joint can all be affected. There is inflammation and the synovial membranes of joints are affected, with the overproduction of synovial fluid that damages articular structures and ligaments (4). Consequently, there can be compression of the spinal cord, nerve roots, and cervical spine structural alterations. Spinal cord compression can affect the brainstem, spinal nerve roots, cranial nerves, and vertebral arteries (5).

Approximately 40% of RA patients have chronic pain (6) that has physical and psychological consequences, with patients having an increased risk for neurological disease and neuropsychiatric comorbidities. There is no cure for RA and the treatment aims to reduce pain and control joint damage.

RA patients have a reduced quality of life, impacted by the negative physical and mental effects of the disease (7). In turn, patients have an increased rate of use of healthcare resources (8) and psychological disorders such as major depression (9), anxiety (10), and additionally, an increased risk of developing neurodegenerative disease (11).

Neurological disease and structural differences in the brain of RA patients

In RA, the adaptive immune system and the innate immune system interact in a complex mode that involves T-cells, autoantibodies, myeloid cells, and proinflammatory cytokines. There is bidirectional communication between the peripheral and central immune responses that can lead to neuroinflammation and central nervous system (CNS) comorbidity in RA patients (12).

Research has shown structural differences in the brains of RA patients, with changes in the hippocampus and basal ganglia that are not present in healthy, non-arthritic individuals.

Insulin-like growth factor 1 receptor (IGF1R) signaling is enriched in microglia of the hippocampus, and abnormal IGF1R signaling was seen in experimental studies to be associated with hippocampal neurogenesis, reduced hippocampal size, and decreased mobility. Blocking IGF1R was seen to provide some improvement, indicating that hippocampal damage could be reversible to some extent (13).

Another study showed that RA patients with long disease duration had increased ventricle-to-brain ratios in addition to decreased midsagittal cerebellar areas, which may link cerebral and cerebellar atrophy to the disease (14).

Research has also shown changes in the subcortical grey matter of RA patients in the basal ganglia, an area involved in motor control, pain processing, and behavioural response to stimuli, which could be the consequences of chronic pain and defects in motor control of these patients (15).

Pain is strongly linked with cognition and emotion, and imaging studies have shown that the emotional and attentional state can alter cerebral pain pathways, with chronic pain sufferers displaying alterations in certain brain regions and showing amplified responses to nociceptive stimuli (15-17).

Chronic pain has been associated with structural changes in the brain, which has been documented in diverse studies (18-21).

Emotional factors of RA

Pain, fatigue, morning stiffness, and disability are often standard conditions for RA patients. Many patients feel constant fear and strong concern relating to pain and their condition, which leads to psychological and physical discomfort.

Chronic pain is characterized by significant emotional distress with feelings including anxiety, anger, frustration, and depressed mood. Somatization and catastrophizing are often common responses to chronic pain and these psychological responses can be destructive to the patient’s well-being. These negative emotional states can hinder patient functioning in the presence of pain, fatigue, and other physical symptoms they are already experiencing.

RA patients are at increased risk for the development of neuropsychiatric comorbidities, including major depressive disorder (MDD) (9), anxiety (10), impaired cognitive performance (22), and neurodegenerative disease such as dementia (23). MDD is often involved, as the rate in RA patients is 17% (24). Studies have also shown conflicting results for the implication of RA in other neurodegenerative diseases such as Alzheimer’s Disease (AD) (25) and Parkinson’s Disease (PD) (26,27).

These psychiatric problems could be due to biological or inflammatory changes or psychological stresses that come with pain and the difficulty of living with medical adversity. But, most likely, it is a combination of these different factors that interact to produce neuropsychiatric comorbidity.

The anxiety, depression, and cognitive impairment that may affect RA patients are, in turn, harmful to their condition, as these disorders can affect responsiveness to treatment and are associated with greater disease activity.

CONCLUSIONS

The chronic musculoskeletal pain experienced in RA is described as “chronic pain in the muscles, bones, joints, or tendons that is characterized by significant emotional distress (i.e., anxiety, anger, frustration, and depressed mood) or functional disability” (28). This pain is subjective and influenced by biological, psychological, and social factors (28).

RA is a multifactorial disease that involves the immune system, nervous system, and endocrine systems, in which patients experience physical and psychological discomfort. The emotional stress and anxiety form RA as a psychosomatic disease, with organic damage that is aggravated by emotional factors.

Chronic pain is implicated in psychological disorders, particularly depression and anxiety, in a bidirectional manner. Chronic pain can initiate and exacerbate depression and anxiety, conditions which, in turn, directly affect the pain level in a negative manner. Peripheral inflammation and sensitization, and central sensitization, can lead to persistent pain. In fact, it was found that patients’ negative emotions relating to their RA state impacted the level of pain they were experiencing (29).

The immune system is also involved in pain regulation. Chronic inflammation and the release of proinflammatory cytokines contribute to pain. In turn, inflammation is also involved in depression and anxiety (24). Proinflammatory cytokines, including interleukin-1 (IL-1), IL-6, and tumor necrosis factor (TNF) are seen to be increased in MDD (30). In the cerebrospinal fluid of RA patients, there are also increased levels of the proinflammatory cytokines IL-1, IL-6, and TNF, substances which have the potential to contribute to cognitive impairment, although more research is needed to elucidate the precise mechanisms (31-33).

Insulin sensitivity is also connected to inflammation, and RA patients have a high prevalence of insulin resistance, above 50%, which is associated with systemic inflammation and cytokine levels (34). Insulin receptors and IGF1R are implicated in neurogenesis and could be associated with neurological diseases, cognitive decline, and regional atrophy (35,36).

This evidence shows the psychosomatic nature of RA, involving psychological disorders, including depression and anxiety.

Conflict of interest

The author declares that they have no conflict of interest.

REFERENCES

1. Safiri S, Kolahi AA, Hoy D, et al. Global, regional and national burden of rheumatoid arthritis 1990–2017: a systematic analysis of the Global Burden of Disease study 2017. Annals of the Rheumatic Diseases. 2019;78(11):1463-1471. doi:10.1136/annrheumdis-2019-215920
2. Bullock J, Rizvi Syed AA, Saleh Ayman M, et al. Rheumatoid arthritis: A brief overview of the treatment. Medical Principles and Practice. 2018;27(6):501-507. doi:10.1159/000493390
3. Joaquim AF, Appenzeller S. Cervical spine involvement in rheumatoid arthritis — A systematic review. Autoimmunity Reviews. 2014;13(12):1195-1202. doi:10.1016/j.autrev.2014.08.014
4. Krauss WE, Bledsoe JM, Clarke MJ, Nottmeier EW, Pichelmann MA. Rheumatoid Arthritis of the Craniovertebral Junction. Neurosurgery. 2010;66(suppl_3):A83-A95. doi:10.1227/01.neu.0000365854.13997.b0
5. DeQuattro K, Imboden JB. Neurologic Manifestations of Rheumatoid Arthritis. Rheumatic Diseases Clinics of North America. 2017;43(4):561-571. doi:10.1016/j.rdc.2017.06.005
6. Vergne‐Salle P, Pouplin S, Trouvin AP, et al. The burden of pain in rheumatoid arthritis: Impact of disease activity and psychological factors. European Journal of Pain. 2020;24(10):1979-1989. doi:10.1002/ejp.1651
7. Uhlig T, Loge JH, Kristiansen IS, Kvien TK. Quantification of reduced health-related quality-of-life in patients with rheumatoid arthritis compares to the general population. J Rheumatol. 2007;34:1241-1247.
8. Ethgen O, Kahler KH, Kong SX, Reginster J, Wolfe F. The effect of health-related quality of life on reported use of health care resources in patients with osteoarthritis and rheumatoid arthritis: a longitudinal analysis. J Rheumatol. 2002;29:1147-1155
9. Nerurkar L, Siebert S, McInnes IB, Cavanagh J. Rheumatoid arthritis and depression: an inflammatory perspective. The Lancet Psychiatry. 2019;6(2):164-173. doi:10.1016/s2215-0366(18)30255-4
10. VanDyke MM, Parker JC, Smarr KL, et al. anxiety in rheumatoid arthritis. Arthritis Care & Research. 2004;51(3):408-412. doi:10.1002/art.20474
11. Wallin K, Solomon A, Kåreholt I, Tuomilehto J, Soininen H, Kivipelto M. Midlife rheumatoid arthritis increases the risk of cognitive impairment two decades later: a population-based study. Journal of Alzheimer’s disease: JAD. 2012;31(3):669-676. doi:10.3233/JAD-2012-111736
12. Süß P, Rothe T, Hoffmann A, Schlachetzki JCM, Winkler J. The Joint-Brain Axis: Insights From Rheumatoid Arthritis on the Crosstalk Between Chronic Peripheral Inflammation and the Brain. Frontiers in Immunology. 2020;11. doi:10.3389/fimmu.2020.612104
13. Andersson KME, Wasén C, Juzokaite L, et al. inflammation in the hippocampus affects IGF1 receptor signaling and contributes to neurological sequelae in rheumatoid arthritis. Proceedings of the National Academy of Sciences. 2018;115(51). doi:10.1073/pnas.1810553115
14. Bekkelund SI, Pierre-Jerome C, Husby G, Mellgren SI. Quantitative cerebral MR in rheumatoid arthritis. AJNR Am J Neuroradiol. 1995;16(4):767-72.
15. Wartolowska K, Hough MG, Jenkinson M, Andersson J, Wordsworth BP, Tracey I. Structural changes of the brain in rheumatoid arthritis. Arthritis & Rheumatism. 2012;64(2):371-379. doi:10.1002/art.33326
16. Hummel T, Schiessl C, Wendler J, Kobal G. Peripheral and central nervous changes in patients with rheumatoid arthritis in response to repetitive painful stimulation. International Journal of Psychophysiology: Official Journal of the International Organization of Psychophysiology. 2000;37(2):177-183. doi:10.1016/s0167-8760(00)00087-8
17. Flodin P, Martinsen S, Altawil R, et al. Intrinsic Brain Connectivity in Chronic Pain: A Resting-State fMRI Study in Patients with Rheumatoid Arthritis. Frontiers in Human Neuroscience. 2016;10. doi:10.3389/fnhum.2016.00107
18. Buckalew N, Haut MW, Morrow L, Weiner D. Chronic Pain Is Associated with Brain Volume Loss in Older Adults: Preliminary Evidence. Pain Medicine. 2008;9(2):240-248. doi:10.1111/j.1526-4637.2008.00412.x
19. Schmidt-Wilcke T, Leinisch E, Gänbauer S, et al. Affective components and intensity of pain correlate with structural differences in gray matter in chronic back pain patients. Pain. 2006;125(1):89-97. doi:10.1016/j.pain.2006.05.004
20. Schmidt-Wilcke T, Luerding R, Weigand T, et al. Striatal grey matter increase in patients suffering from fibromyalgia – A voxel-based morphometry study. Pain. 2007;132:S109-S116. doi:10.1016/j.pain.2007.05.010
21. Davis KD, Pope G, Chen J, Kwan CL, Crawley AP, Diamant NE. CORTICAL THINNING IN IBS: IMPLICATIONS FOR HOMEOSTATIC, ATTENTION, AND PAIN PROCESSING. Neurology. 2007;70(2):153-154. doi:10.1212/01.wnl.0000295509.30630.10
22. Shin SY, Katz P, Wallhagen M, Julian L. Cognitive impairment in persons with rheumatoid arthritis. Arthritis Care & Research. 2012;64(8):n/a-n/a. doi:10.1002/acr.21683
23. Ungprasert P, Wijarnpreecha K, Thongprayoon C. Rheumatoid arthritis and the risk of dementia: A systematic review and meta-analysis. Neurology India. 2016;64(1):56. doi:10.4103/0028-3886.173623
24. Morris A, Yelin EH, Panopalis P, Julian L, Katz PP. Long-term patterns of depression and associations with health and function in a panel study of rheumatoid arthritis. Journal of Health Psychology. 2011;16(4):667-677. doi:10.1177/1359105310386635
25. Policicchio S, Ahmad AN, Powell JF, Proitsi P. Rheumatoid arthritis and risk for Alzheimer’s disease: a systematic review and meta-analysis and a Mendelian Randomization study. Scientific Reports. 2017;7(1). doi:10.1038/s41598-017-13168-8
26. Rugbjerg K, Friis S, Ritz B, Schernhammer ES, Korbo L, Olsen JH. Autoimmune disease and risk for Parkinson disease: A population-based case-control study. Neurology. 2009;73(18):1462-1468. doi:10.1212/wnl.0b013e3181c06635
27. Chang CC, Lin TM, Chang YS, et al. Autoimmune rheumatic diseases and the risk of Parkinson disease: a nationwide population-based cohort study in Taiwan. Annals of Medicine. 2017;50(1):83-90. doi:10.1080/07853890.2017.1412088
28. International Organization for the Study of Pain (IASP). Available at:(http://www.iasp-pain.org/Education/Content.aspx?ItemNumber=1698&navItemNumber=576). Accessed January 19, 2021.
29. Lee YC, Frits ML, Iannaccone CK, et al. Subgrouping of Patients With Rheumatoid Arthritis Based on Pain, Fatigue, Inflammation, and Psychosocial Factors. Arthritis & Rheumatology. 2014;66(8):2006-2014. doi:10.1002/art.38682
30. Howren MB, Lamkin DM, Suls J. Associations of Depression With C-Reactive Protein, IL-1, and IL-6: A Meta-Analysis. Psychosomatic Medicine. 2009;71(2):171-186. doi:10.1097/psy.0b013e3181907c1b
31. Nieto FR, Clark AK, Grist J, Hathway GJ, Chapman V, Malcangio M. Neuron-immune mechanisms contribute to pain in early stages of arthritis. Journal of Neuroinflammation. 2016;13(1). doi:10.1186/s12974-016-0556-0
32. Lampa J, Westman M, Kadetoff D, et al. Peripheral inflammatory disease associated with centrally activated IL-1 system in humans and mice. Proceedings of the National Academy of Sciences. 2012;109(31):12728-12733. doi:10.1073/pnas.1118748109
33. Felger JC, Lotrich FE. Inflammatory cytokines in depression: Neurobiological mechanisms and therapeutic implications. Neuroscience. 2013;246:199-229. doi:10.1016/j.neuroscience.2013.04.060
34. Giles JT, Danielides S, Szklo M, et al. Insulin Resistance in Rheumatoid Arthritis: Disease-Related Indicators and Associations With the Presence and Progression of Subclinical Atherosclerosis. Arthritis & Rheumatology. 2015;67(3):626-636. doi:10.1002/art.38986
35. Rivera EJ, Goldin A, Fulmer N, Tavares R, Wands JR, de la Monte SM. Insulin and insulin-like growth factor expression and function deteriorate with progression of Alzheimer’s disease: Link to brain reductions in acetylcholine. Journal of Alzheimer’s Disease. 2005;8(3):247-268. doi:10.3233/jad-2005-8304
36. Talbot K, Wang HY, Kazi H, et al. Demonstrated brain insulin resistance in Alzheimer’s disease patients is associated with IGF-1 resistance, IRS-1 dysregulation, and cognitive decline. Journal of Clinical Investigation. 2012;122(4):1316-1338. doi:10.1172/jci59903