Treatment for Rheumatoid Arthritis and Risk of Alzheimer’s Disease: A Nested Case-Control Analysis

Abstract

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.

Peripheral inflammatory markers in Alzheimer’s disease: a systematic review and meta-analysis of 175 studies

“…In clinical studies, individuals with severe AD have been shown to have greater levels of TNF-α compared with those with mild-to-moderate AD 76–78. Certain medical conditions such as inflammatory bowel disease, rheumatoid disease or cancer are also known to be involved with elevated inflammatory marker concentrations and patients with rheumatoid arthritis can be at an elevated risk of AD 79. It is also possible that additional factors such as acute infections may have elevated inflammatory markers (eg, CRP and hsCRP) and were not reported in these studies.…”

TNF alpha inhibitors in Alzheimer's disease: A systematic review

“…The confounding factors were well controlled in one study . It is unclear whether participants of the 2 remaining studies were exposed to any factors that may have affected the results . Blinding was adequate in only one study and partially adequate in the 2 remaining ones .…”

New insights into the impact of neuro-inflammation in rheumatoid arthritis

“…Several groups have utilized animal models to discover that although certain features of inflammation are typical for the pro-inflammatory response systemically e.g., interleukin-6 (IL-6), interferon-β (IFNβ), these are not observed in the brain, but activation of TNFα does appear to maintain pro-inflammatory activity in the brain as it does systemically (Skelly et al, 2013; Thomson et al, 2014). Some of the basic science observations can be extended to RA, where Chou et al (2010) observed that people with RA receiving TNF inhibitor treatment (infliximab, etanercept, adalimumab) showed a reduction in the risk of developing AD compared to controls (Chou et al, 2010). The risk of AD was not affected by exposure to other Disease-Modifying Anti-Rheumatic Drugs (DMARDs) used in RA.…”