Cognitive Decline in Rheumatoid Arthritis: History
View Latest Version
Please note this is an old version of this entry, which may differ significantly from the current revision.
Subjects: Immunology
Contributor:
Maria Sofia Basile

Cognitive decline refers to a deterioration of intellectual and learning abilities and related memory problems, and is often associated with behavioral alterations, which prevents sufferers from carrying out the most common daily activities, such as maintaining normal productive interpersonal relationships, communicating, and leading an autonomous life. Numerous studies have highlighted the association between cognitive decline and autoimmune disorders, including rheumatoid arthritis (RA). RA is a chronic, inflammatory, autoimmune disease that involves systems and organs other than the bones and joints, with varying severity among patients.

  • rheumatoid arthritis
  • cognitive decline
  • pathogenesis

1. Rheumatoid Arthritis (RA)

RA is a chronic, inflammatory, autoimmune disease that involves systems and organs other than the bones and joints, with varying severity between patients [1]. RA is characterized by symmetrical joint pain associated with morning stiffness (joints are affected for >30 min), hyperplasia (swelling), and cartilage and bone destruction that causes rheumatoid nodules under the skin (deformity) [2][3]. However, RA not only affects the joints but is also associated with secondary amyloidosis, lymphomas, cardiovascular and pulmonary disease, vasculitis, and psychological and skeletal disorders that may cause permanent disability in many instances [2]. The presence of RA is relatively constant in the global population, with a prevalence between 0.5% and 1.0% in the European and North American populations [4]. Twice as many women are affected than men, and although it is more common in people in their fifties, it can appear at any age [4].

A complex interaction between genotype and exposure to environmental factors (cigarette smoking, air pollutants, and occupational dust) is likely to determine the onset and development of RA [5]. Genetic studies have found an association of more than 100 polymorphisms with RA, mainly in the major histocompatibility complex (MHC) locus, but also in genes encoding for cytokines/chemokines and their receptors, components of intracellular signaling pathways, and costimulatory factors [6]. The implication of genetic factors in the RA pathogenesis is demonstrated by a positive family history, which increases the risk of RA by about three to five times [4][7]. Along the same lines, a concordance rate of 15% to 30% is observed among monozygotic twins, while only a 5% concordance can be observed among dizygotic twins [1]. The characteristic chronic inflammation of the joints suggests an autoimmune origin of the pathology [8]. Typical histological findings are the symmetrical synovial proliferation, with the destruction of cartilage and bone damage induced by the activation of self-reactive T and B lymphocytes, which produce proinflammatory cytokines and autoantibodies [9] (Figure 1). Evidence obtained from preclinical and clinical studies from animal models of RA and RA patients demonstrates that CD4+ T cells belonging to the proinflammatory subgroups Th1 and Th17, together with M1 macrophages, contribute to the development and maintenance of RA and counteract the action of Th2 and Th3 anti-inflammatory cells and M2 macrophages [8].

Ijms 22 01185 g001 550

Figure 1. Pathogenic role of immune cells in rheumatoid arthritis (RA). The immune cells mainly involved in the pathogenesis of RA are B cells, T cells, and macrophages. These cells are normally present in the synovial tissue. B cells release proteins, such as rheumatoid factor (RF), protein antibodies (ACPAs), and proinflammatory cytokines, that support the establishment of RA. B cells also mediate the activation of T lymphocytes through the expression of costimulatory molecules. In RA, the main function of T lymphocytes is to activate macrophages. Activated T lymphocytes and macrophages release proinflammatory molecules, such as cytokines and chemokines, which keep the osteoarticular tissue inflamed. This condition favors the activation of synoviocytes and osteoclasts, with consequent damage to the osteoarticular tissue and pannus formation [1]. APCs: antigen-presenting cells, ROS: reactive oxygen species.

2. Diagnosis and Treatment of RA

RA is a symmetrical polyarthritis with a gradual and persistent chronic course that primarily involves the joints of the hands and feet [4]. The key features of inflammatory arthritis are the presence of early morning stiffness, joint swelling affecting more than three joints, and tenderness across the metacarpo- and metatarso-phalangeal joints, as evaluated by the “squeeze test.” Axial joint involvement is less common, with cervical spine involvement occurring in 30–50% of cases, but rarely in isolation. Temporo-mandibular and crico-arytenoid joints may also be affected [10]. However, the clinical presentation and the course of the disease vary among patients, with some having very acute onset polyarthritis [4].

The European League Against Rheumatism (EULAR) Disease Activity Score (DAS-28) includes the evaluation of the number of affected joints, the level of acute inflammatory markers, and the patient global well-being score [10]. RA is characterized by the presence of rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPAs). Positive serology for RF can be found in 60–80% of patients with established RA, but it is less frequently present in early RA (<50%). ACPAs have a specificity of 94–97% and a sensitivity of 62–72% in early RA. ACPAs can be detected early in the course of RA, often appearing before RF, and may be observed before clinical manifestations of the disease. In ACPAs-negative patients, other autoantibodies have been observed, including anti-carbamylated proteins [11], anti-malondialdehyde acetaldehyde [12], anti BRAF [13], 14-3-3eta, anti-CarP, anti-Sa [14], and anti PAD3/PAD4 [15] antibodies.

Non-steroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen, naproxen, ketoprofen, piroxicam, diclofenac, and Celecoxib, are widely used as symptomatic therapies [16]. Disease-modifying antirheumatic drugs (DMARDs) are a heterogeneous collection of agents that represent the mainstay of treatment for RA [16]. DMARDs can be classified as conventional synthetic DMARDs (csDMARDs, which include methotrexate, sulfasalazine, leflunomide, and hydroxychloroquine), targeted synthetic DMARDs (tsDMARDs, which include tofacitinib and baricitinib), and biological DMARDs (bDMARDs, such as adalimumab, tocilizumab, secukinumab, abatacept, and anakinra). Methotrexate represents the first choice csDMARD. Leflunomide or sulfasalazine is used in the case of contraindication to methotrexate. In patients not responding to treatment, or in the presence of poor prognostic factors, it is recommended to add a bDMARD or tsDMARD. Steroids, although effective in reducing pain and disease progression, are used temporarily as an adjunctive treatment because of their side effects [17].

3. Cognitive Decline

Cognitive decline can be defined as a psychophysical condition that is characterized by an alteration in the orientation, attention, problem-solving abilities, memory, and executive functions [18]. Cognitive impairment may range from a subtle decline in a single cognitive domain to impairment in multiple cognitive domains (mild cognitive impairment (MCI)) to frank dementia, which is characterized by cognitive decline and the loss of function. To diagnose MCI, the following parameters should be met: complaint of a decline in cognitive function, impairment of one or more cognitive domains, and independent function preserved, with no alteration in social and work skills [19].

Impaired episodic memory is typically seen in patients with MCI, who may later progress to dementia. Alzheimer’s disease (AD) is the most common form of dementia and accounts for 50–70% of dementia cases [20].

The growth of the aging population has been associated with an increased burden from cognitive disorders. The prevalence of MCI ranges from 12% to 18% among the older adults (≥65 years old) with an annual 10–15% conversion rate to AD [20].

Cognitive impairment can arise from many chronic diseases, such as hypertension, dyslipidemia, vascular disease, diabetes, chronic obstructive lung disease, depression, anxiety, autoimmune diseases, epilepsy, and drug dependency. Head injuries can lead to impaired cognition. Furthermore, anti-depressants, anticonvulsants, and antipsychotics are associated with cognitive decline. However, in most of these conditions, cognitive disorders are treatable, particularly when they are detected early through monitoring.

For the diagnosis of cognitive decline, different standardized tests have been developed, including the Mini-Mental State Examination (MMSE), the Montreal Cognitive Assessment (MoCA), the Trail-Making Test (TMT), the Victoria Stroop Test (VST), the Wechsler Adult Intelligence Scale (WAIS), and the Benton Visual Retention Test (BVRT) [21]. The Beck Depression Inventory (BDI) and the State-Trait Anxiety Inventory (STAIT/S) are used to assess the presence of depression and anxiety, which are commonly found in RA patients [21].

4. RA and Cognitive Decline

An increased risk of cognitive decline has recently been associated with the presence of rheumatic diseases [22][23]. It is hypothesized that the triggering cause could be represented by the systemic inflammation that is associated with a chronic rheumatological condition [22][23]. In particular, numerous studies have shown the presence of a cognitive decline in RA patients [18].

To date, the molecular pathogenetic mechanisms that underlie the association of cognitive decline and RA are not fully clarified. However, during the last few years, a growing number of studies have investigated the link between these conditions, highlighting the potential pathogenic role of several clinical, psychological, and biological factors (Figure 2). These include cardiovascular complications and chronic pain, along with the involvement of autoimmune and inflammatory factors, changes in hormone levels, drug side effects, genetic factors, and psychiatric disorders [18][22][24][25][26].

Ijms 22 01185 g002 550
Figure 2. Multistep progression of rheumatoid arthritis to cognitive dysfunction.

Among the psychiatric conditions, depression and anxiety are mostly associated with RA patients [27]. Usually, the peak of onset of the disease occurs in individuals during their professional and social life, thus compromising the social sphere [28][29]. It has been observed that depression affects up to 66% of patients, anxiety affects 70% of patients, and nearly 17% of RA patients have a major depressive disorder [30][31][32][33]. Depression is usually associated with higher levels of pain and disability, resulting in a lower health-related quality of life and increased mortality [34][35]. Moreover, RA disease activity has been associated with cognitive decline [36][37].

Several studies have reported that the association between cognitive decline and RA is more evident in patients of advanced age [38][39][40][41]. A debilitating condition leading to cognitive decline is associated with the recorded increase in accelerated inflammatory atherosclerosis with a consequent risk of stroke, especially in elderly RA patients with long-standing illness [42]. However, cognitive decline has also been observed in young RA patients, in particular during the early stages of the disease [43].

Other risk factors for cognitive decline in RA include cardiovascular risk and the use of certain drugs, such as glucocorticoids [38]. However, there are some studies that found no association between cardiovascular risk or medication intake and cognitive decline in RA patients [36][44]. On the other hand, treatment with biological anti-tumor necrosis factor (TNF) therapies in RA patients may be protective, showing a lower risk percentage of developing cognitive decline [39].

In this review, we analyzed and explored the correlation between cognitive decline and RA from a pathogenic point of view, focusing on the main molecular mechanisms involved.

This entry is adapted from the peer-reviewed paper 10.3390/ijms22031185

References

  1. McInnes, I.B.; Schett, G. The Pathogenesis of Rheumatoid Arthritis. N. Engl. J. Med. 2011, 365, 2205–2219.
  2. Smolen, J.S.; Aletaha, D.; McInnes, I.B. Rheumatoid arthritis. Lancet 2016, 388, 2023–2038.
  3. Bullock, J.; Rizvi, S.A.A.; Saleh, A.M.; Ahmed, S.S.; Do, D.P.; Ansari, R.A.; Ahmed, J. Rheumatoid Arthritis: A Brief Overview of the Treatment. Med. Princ. Pract. 2018, 27, 501–507.
  4. Van der Woude, D.; van der Helm-van Mil, A.H.M. Update on the epidemiology, risk factors, and disease outcomes of rheumatoid arthritis. Best Pract. Res. Clin. Rheumatol. 2018, 32, 174–187.
  5. Deane, K.D.; Demoruelle, M.K.; Kelmenson, L.B.; Kuhn, K.A.; Norris, J.M.; Holers, V.M. Genetic and environmental risk factors for rheumatoid arthritis. Best Pract. Res. Clin. Rheumatol. 2017, 31, 3–18.
  6. Mikhaylenko, D.S.; Nemtsova, M.V.; Bure, I.V.; Kuznetsova, E.B.; Alekseeva, E.A.; Tarasov, V.V.; Lukashev, A.N.; Beloukhova, M.I.; Deviatkin, A.A.; Zamyatnin, A.A. Genetic polymorphisms associated with rheumatoid arthritis development and antirheumatic therapy response. Int. J. Mol. Sci. 2020, 21, 4911.
  7. Silman, A.J.; Pearson, J.E. Epidemiology and genetics of rheumatoid arthritis. Arthritis Res. 2002, 4, S265–S272.
  8. Petralia, M.C.; Mazzon, E.; Basile, M.S.; Cutuli, M.; Di Marco, R.; Scandurra, F.; Saraceno, A.; Fagone, P.; Nicoletti, F.; Mangano, K. Effects of Treatment with the Hypomethylating Agent 5-aza-2’-deoxycytidine in Murine Type II Collagen-Induced Arthritis. Pharmaceuticals 2019, 12, 174.
  9. Brennan, F.M.; McInnes, I.B. Evidence that cytokines play a role in rheumatoid arthritis. J. Clin. Investig. 2008, 118, 3537–3545.
  10. Jeffery, R.C. Clinical features of rheumatoid arthritis. Medicine (UK) 2014, 42, 231–236.
  11. Trouw, L.A.; Mahler, M. Closing the serological gap: Promising novel biomarkers for the early diagnosis of rheumatoid arthritis. Autoimmun. Rev. 2012, 12, 318–322.
  12. Thiele, G.M.; Duryee, M.J.; Anderson, D.R.; Klassen, L.W.; Mohring, S.M.; Young, K.A.; Benissan-Messan, D.; Sayles, H.; Dusad, A.; Hunter, C.D.; et al. Malondialdehyde-acetaldehyde adducts and anti-malondialdehyde-acetaldehyde antibodies in rheumatoid arthritis. Arthritis Rheumatol. 2015, 67, 645–655.
  13. Auger, I.; Charpin, C.; Balandraud, N.; Martin, M.; Roudier, J. Autoantibodies to PAD4 and BRAF in rheumatoid arthritis. Autoimmun. Rev. 2012, 11, 801–803.
  14. Salman, E.; Çetiner, S.; Boral, B.; Kibar, F.; Erken, E.; Ersözlü, E.D.; Badak, S.Ö.; Bilici Salman, R.; Sertdemir, Y.; Çetin Duran, A.; et al. Importance of 14-3-3eta, anti-carp, and anti-sa in the diagnosis of seronegative rheumatoid arthritis. Turkish J. Med. Sci. 2019, 49, 1498–1502.
  15. Zhao, J.; Zhao, Y.; He, J.; Jia, R.; Li, Z. Prevalence and Significance of Anti-Peptidylarginine Deiminase 4 Antibodies in Rheumatoid Arthritis. J. Rheumatol. 2008, 35, 969–974.
  16. Alam, J.; Jantan, I.; Bukhari, S.N.A. Rheumatoid arthritis: Recent advances on its etiology, role of cytokines and pharmacotherapy. Biomed. Pharmacother. 2017, 92, 615–633.
  17. Smolen, J.S.; Landewé, R.B.M.; Bijlsma, J.W.J.; Burmester, G.R.; Dougados, M.; Kerschbaumer, A.; McInnes, I.B.; Sepriano, A.; Van Vollenhoven, R.F.; De Wit, M.; et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2019 update. Ann. Rheum. Dis. 2020, 79, S685–S699.
  18. Meade, T.; Manolios, N.; Cumming, S.R.; Conaghan, P.G.; Katz, P. Cognitive Impairment in Rheumatoid Arthritis: A Systematic Review. Arthritis Care Res. 2018, 70, 39–52.
  19. Albert, M.S.; DeKosky, S.T.; Dickson, D.; Dubois, B.; Feldman, H.H.; Fox, N.C.; Gamst, A.; Holtzman, D.M.; Jagust, W.J.; Petersen, R.C.; et al. The diagnosis of mild cognitive impairment due to Alzheimer’s disease: Recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimer’s Dement. 2011, 7, 270–279.
  20. Tavares-Júnior, J.W.L.; De Souza, A.C.C.; Alves, G.S.; de Carvalho Bonfadini, J.; Siqueira-Neto, J.I.; Braga-Neto, P. Cognitive Assessment Tools for Screening Older Adults with Low Levels of Education: A Critical Review. Front. Psychiatry 2019, 10, 878.
  21. Oláh, C.; Kardos, Z.; Andrejkovics, M.; Szarka, E.; Hodosi, K.; Domján, A.; Sepsi, M.; Sas, A.; Kostyál, L.; Fazekas, K.; et al. Assessment of cognitive function in female rheumatoid arthritis patients: Associations with cerebrovascular pathology, depression and anxiety. Rheumatol. Int. 2020, 40, 529–540.
  22. Oláh, C.; Schwartz, N.; Denton, C.; Kardos, Z.; Putterman, C.; Szekanecz, Z. Cognitive dysfunction in autoimmune rheumatic diseases. Arthritis Res. Ther. 2020, 22, 78.
  23. Sood, A.; Raji, M.A. Cognitive impairment in elderly patients with rheumatic disease and the effect of disease-modifying anti-rheumatic drugs. Clin. Rheumatol. 2020.
  24. Lwin, M.N.; Serhal, L.; Holroyd, C.; Edwards, C.J. Rheumatoid Arthritis: The Impact of Mental Health on Disease: A Narrative Review. Rheumatol. Ther. 2020, 7, 457–471.
  25. Baptista, T.S.A.; Petersen, L.E.; Molina, J.K.; de Nardi, T.; Wieck, A.; do Prado, A.; Piovesan, D.M.; Keisermann, M.; Grassi-Oliveira, R.; Bauer, M.E. Autoantibodies against myelin sheath and S100β are associated with cognitive dysfunction in patients with rheumatoid arthritis. Clin. Rheumatol. 2017, 36, 1959–1968.
  26. Yang, L.; Zou, Q.H.; Zhang, Y.; Shi, Y.; Hu, C.R.; Hui, C.X.; Liu, X.F.; Fang, Y.F. Proteomic analysis of plasma from rheumatoid arthritis patients with mild cognitive impairment. Clin. Rheumatol. 2018, 37, 1773–1782.
  27. Fiest, K.M.; Hitchon, C.A.; Bernstein, C.N.; Peschken, C.A.; Walker, J.R.; Graff, L.A.; Zarychanski, R.; Abou-Setta, A.; Patten, S.B.; Sareen, J.; et al. Systematic review and meta-analysis of interventions for depression and anxiety in persons with rheumatoid arthritis. J. Clin. Rheumatol. 2017, 23, 425–434.
  28. Eberhardt, K.; Larsson, B.M.; Nived, K.; Lindqvist, E. Work disability in rheumatoid arthritis—Development over 15 years and evaluation of predictive factors over time. J. Rheumatol. 2007, 34, 481–487.
  29. Pollard, L.; Choy, E.H.; Scott, D.L. The consequences of rheumatoid arthritis: Quality of life measures in the individual patient. Clin. Exp. Rheumatol. 2005, 23, S43–S52.
  30. Isik, A.; Koca, S.S.; Ozturk, A.; Mermi, O. Anxiety and depression in patients with rheumatoid arthritis. Clin. Rheumatol. 2007, 26, 872–878.
  31. Lok, E.Y.C.; Mok, C.C.; Cheng, C.W.; Cheung, E.F.C. Prevalence and Determinants of Psychiatric Disorders in Patients with Rheumatoid Arthritis. Psychosomatics 2010, 51, 338.
  32. VanDyke, M.M.; Parker, J.C.; Smarr, K.L.; Hewett, J.E.; Johnson, G.E.; Slaughter, J.R.; Walker, S.E. Anxiety in rheumatoid arthritis. Arthritis Care Res. (Hoboken) 2004, 51, 408–412.
  33. Matcham, F.; Rayner, L.; Steer, S.; Hotopf, M. The prevalence of depression in rheumatoid arthritis: A systematic review and meta-analysis. Rheumatology 2013, 52, 2136–2148.
  34. Mok, C.; Lok, E.; Cheung, E. Concurrent psychiatric disorders are associated with significantly poorer quality of life in patients with rheumatoid arthritis. Scand. J. Rheumatol. 2012, 41, 253–259.
  35. van den Hoek, J.; Boshuizen, H.C.; Roorda, L.D.; Tijhuis, G.J.; Nurmohamed, M.T.; Dekker, J.; van den Bos, G.A.M. Association of Somatic Comorbidities and Comorbid Depression with Mortality in Patients with Rheumatoid Arthritis: A 14-Year Prospective Cohort Study. Arthritis Care Res. (Hoboken) 2016, 68, 1055–1060.
  36. Lee, J.H.; Kim, G.T.; Kim, Y.K.; Lee, S.G. Cognitive function of patients with rheumatoid arthritis is associated with disease activity but not carotid atherosclerotic changes. Clin. Exp. Rheumatol. 2018, 36, 856–861.
  37. Katchamart, W.; Narongroeknawin, P.; Phutthinart, N.; Srinonprasert, V.; Muangpaisan, W.; Chaiamnauy, S. Disease activity is associated with cognitive impairment in patients with rheumatoid arthritis. Clin. Rheumatol. 2019, 38.
  38. Shin, S.Y.; Katz, P.; Wallhagen, M.; Julian, L. Cognitive impairment in persons with rheumatoid arthritis. Arthritis Care Res. (Hoboken) 2012, 64, 1144–1150.
  39. Vitturi, B.K.; Nascimento, B.A.C.; Alves, B.R.; de Campos, F.S.C.; Torigoe, D.Y. Cognitive impairment in patients with rheumatoid arthritis. J. Clin. Neurosci. 2019, 69, 81–87.
  40. Wallin, K.; Solomon, A.; Kreholt, I.; Tuomilehto, J.; Soininen, H.; Walin, K. Midlife rheumatoid arthritis increases the risk of cognitive impairment two decades later: A population-based study. J. Alzheimer’s Dis. 2012, 31, 669–676.
  41. Min, C.; Bang, W.J.; Kim, M.; Oh, D.J.; Choi, H.G. Rheumatoid arthritis and neurodegenerative dementia: A nested case-control study and a follow-up study using a national sample cohort. Clin. Rheumatol. 2020, 39, 159–166.
  42. Joaquim, A.F.; Appenzeller, S. Neuropsychiatric manifestations in rheumatoid arthritis. Autoimmun. Rev. 2015, 14, 1116–1122.
  43. Simos, P.; Ktistaki, G.; Dimitraki, G.; Papastefanakis, E.; Kougkas, N.; Fanouriakis, A.; Gergianaki, I.; Bertsias, G.; Sidiropoulos, P.; Karademas, E.C. Cognitive deficits early in the course of rheumatoid arthritis. J. Clin. Exp. Neuropsychol. 2016, 38, 820–829.
  44. Said, F.A.; Betoni, T.B.; Magalhaes, V.; Nisihara, R.; Skare, T.L. Rheumatoid arthritis and cognition dysfunction: Lack of association with cumulative glucocorticoid use. Immunopharmacol. Immunotoxicol. 2019, 41, 565–567.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license; additional terms may apply. By using this site, you agree to the Terms and Conditions and Privacy Policy.
This entry is offline, you can click here to edit this entry!
ScholarVision Creations
Feedback