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Treatment for Rheumatoid Arthritis and Risk of Alzheimer’s Disease: A Nested Case-Control Analysis
Open accessAbstract
Introduction It is increasingly becoming accepted that inflammation may play an important role in the pathogenesis of Alzheimer's disease (AD), as several immune-related genes have been associated with AD. Among these is tumor necrosis factor (TNF)-α, a proinflammatory cytokine known to play an important role in autoimmune disorders, including rheumatoid arthritis (RA). Although AD and RA appear to involve similar pathological mechanisms through the production of TNF-α, the relationship between AD and RA remains unknown.Objective To determine the relative risk of AD among RA patients and non-RA patients, and whether anti-TNF therapy for RA was associated with a lower risk of AD in RA patients.Methods We performed a nested case-control study of more than 8.5 million commercially insured adults (aged ≥18 years) in all 50 US states, Puerto Rico, and US Virgin Islands in the Verisk Health claims database. We derived a sub-cohort of subjects with a diagnosis of RA (controls), or RA and AD (cases), matching cases and controls based on age, sex, exposure assessment period, and methotrexate treatment. We also assessed relative risk of AD following exposure to standard RA therapies, including anti-TNF agents (infliximab, adalimumab, etanercept), methotrexate, prednisone, sulfasalazine, and rituximab. Odds ratios were adjusted for comorbidities, including coronary artery disease, diabetes mellitus, and peripheral vascular disease.Results AD was more prevalent (p < 0.0001) among RA patients (0.79 %) than among those without RA (0.11 %). Chronic conditions such as coronary artery disease (odds ratio [OR] 1.48; 95 % confidence interval [CI] 1.04-2.05; p = 0.03), diabetes (OR 1.86; 95 % CI 1.32-2.62; p = 0.0004), and peripheral vascular disease (OR 1.61; 95 % CI 1.06-2.43; p = 0.02) significantly increased the relative risk of AD among RA patients. Exposure to anti-TNF agents as a class, but not other immunosuppressive drugs studied, was associated with lowered risk of AD among RA patients (unadjusted OR 0.44; 95 % CI 0.22-0.87; p = 0.02; adjusted OR 0.45; 95 % CI 0.23-0.90; p = 0.02). Sub-group analysis demonstrated that of the three anti-TNF agents studied, only etanercept (unadjusted OR, 0.33; 95 % CI 0.08-0.94; p = 0.03; adjusted OR 0.30; 95 % CI 0.08-0.89; p = 0.02) was associated with a decreased risk of AD in RA patients.Conclusion There is an increased risk of AD in the studied RA population. The relative risk of AD among RA subjects was lowered in those exposed to etanercept. Anti-TNF therapy with etanercept shows promise as a potential treatment for AD.
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“The risk for developing Alzheimer’s disease was also significantly lower among patients with rheumatoid arthritis treated with the TNF-α inhibitor etanercept43.”
From Chronic inflammation in the etiology of disease across the life span (2019) · cites this paper as [43]
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“In one study, patients with rheumatoid arthritis treated with etanercept, TNFα decoy receptor, had lower incidence of AD, but no effect was noted with use of other anti-rheumatic medications (prednisone, sulfasalazine, rituximab) or anti-TNF agents (infliximab, adalimumab) (Chou et al., 2016).”
From Alzheimer Disease: An Update on Pathobiology and Treatment Strategies (2019) · cites this paper as Chou et al., 2016
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Metadata
- Authors
- Chou, R. C., Kane, M., Ghimire, S., Gautam, S., & Gui, J.
- Affiliations
- Dartmouth College (US)
- Harvard University (US)
- Beth Israel Deaconess Medical Center (US)
- Corresponding author
- Chou, Richard C.
- ORCID
- Gui, Jiang
- Venue
- CNS Drugs
- Published
- 2016-07-28
- Volume
- 30
- Issue
- 11
- Pages
- 1111-1120
- ISSN
- 1172-7047 (ISSN-L)
- 1179-1934
- PMC
- PMC5585782
- OpenAlex
- W2489613804
- Cited by
- 194
- References
- 53
- Citations by year
- 2026: 14 · 2025: 14 · 2024: 17 · 2023: 24 · 2022: 33 · 2021: 27 · 2020: 23 · 2019: 21 · 2018: 12 · 2017: 6 · 2016: 1
- FWCI
- 14.19
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- CNS Drugs (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (P30CA023108)
- U.S. National Library of Medicine (R01LM012012)
- National Center for Research Resources (UL1RR025758)
- Topics
- Health Sciences › Medicine › Rheumatology › Rheumatoid Arthritis Research and Therapies
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Keywords
- rheumatoid arthritis, Alzheimer's disease, anti-TNF therapy, TNF-α, inflammation, methotrexate, infliximab, adalimumab, etanercept, rituximab, sulfasalazine, prednisone, comorbidities, coronary artery disease, diabetes mellitus, peripheral vascular disease, immunosuppressants
- MeSH terms
- Adult, Aged, Alzheimer Disease, Arthritis, Rheumatoid, Female, Humans, Male, Middle Aged, Risk, Tumor Necrosis Factor-alpha, Cohort Studies, Case-Control Studies, Antirheumatic Agents
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