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

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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.

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Authors and Affiliations

  1. Section of Rheumatology, Dartmouth-Hitchcock Medical Center, One Medical Center Drive, Lebanon, NH, 03756, USA

    Richard C. Chou

  2. Department of Medicine, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA

    Richard C. Chou

  3. Division of Rheumatology, Massachusetts General Hospital, Boston, MA, USA

    Michael Kane

  4. Department of Medicine, Harvard Medical School, Boston, MA, USA

    Michael Kane & Shiva Gautam

  5. Verisk Health, Waltham, MA, USA

    Sanjay Ghimire

  6. Harvard CTSC Biostatistics Program, Beth Israel Deaconess Medical Center, Boston, MA, USA

    Shiva Gautam

  7. Department of Biomedical Data Science, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA

    Jiang Gui

  8. Department of Community and Family Medicine, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA

    Jiang Gui

  9. The Dartmouth Institute for Health Policy and Clinical Practice, Lebanon, NH, USA

    Jiang Gui

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  1. Richard C. Chou
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Correspondence to Richard C. Chou.

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Funding

This work was partially supported by Grant No. UL1 RR025758–Harvard Clinical and Translational Science Center, from the National Center for Research Resources for Shiva Gautam.

Conflict of interest

Richard C. Chou, Michael Kane, Sanjay Ghimire, and Jiang Gui have no conflicts of interest to declare. Shiva Gautam was partially supported by the aforementioned grant. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health. The funder had no role in the study design, data collection and analysis, decision to publish, or preparation of the article.

Ethical approval

Analysis of de-identified data was exempted from continuing review by the Committee for the Protection of Human Subjects at Dartmouth College and Beth Israel Deaconess Medical Center Committee on Clinical Investigation.

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Chou, R.C., Kane, M., Ghimire, S. et al. Treatment for Rheumatoid Arthritis and Risk of Alzheimer’s Disease: A Nested Case-Control Analysis. CNS Drugs 30, 1111–1120 (2016). https://doi.org/10.1007/s40263-016-0374-z

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