Tumor Necrosis Factor (TNF) blocking agents are associated with lower risk for Alzheimer's disease in patients with rheumatoid arthritis and psoriasis

Abstract

This large, retrospective case-control study of electronic health records from 56 million unique adult patients examined whether or not treatment with a Tumor Necrosis Factor (TNF) blocking agent is associated with lower risk for Alzheimer's disease (AD) in patients with rheumatoid arthritis (RA), psoriasis, and other inflammatory diseases which are mediated in part by TNF and for which a TNF blocker is an approved treatment. The analysis compared the diagnosis of AD as an outcome measure in patients receiving at least one prescription for a TNF blocking agent (etanercept, adalimumab, and infliximab) or for methotrexate. Adjusted odds ratios (AORs) were estimated using the Cochran-Mantel-Haenszel (CMH) method and presented with 95% confidence intervals (CIs) and p-values. RA was associated with a higher risk for AD (Adjusted Odds Ratio (AOR) = 2.06, 95% Confidence Interval: (2.02-2.10), P-value <0.0001) as did psoriasis (AOR = 1.37 (1.31-1.42), P <0.0001), ankylosing spondylitis (AOR = 1.57 (1.39-1.77), P <0.0001), inflammatory bowel disease (AOR = 2.46 (2.33-2.59), P < 0.0001), ulcerative colitis (AOR = 1.82 (1.74-1.91), P <0.0001), and Crohn's disease (AOR = 2.33 (2.22-2.43), P <0.0001). The risk for AD in patients with RA was lower among patients treated with etanercept (AOR = 0.34 (0.25-0.47), P <0.0001), adalimumab (AOR = 0.28 (0.19-0.39), P < 0.0001), or infliximab (AOR = 0.52 (0.39-0.69), P <0.0001). Methotrexate was also associated with a lower risk for AD (AOR = 0.64 (0.61-0.68), P <0.0001), while lower risk was found in patients with a prescription history for both a TNF blocker and methotrexate. Etanercept and adalimumab also were associated with lower risk for AD in patients with psoriasis: AOR = 0.47 (0.30-0.73 and 0.41 (0.20-0.76), respectively. There was no effect of gender or race, while younger patients showed greater benefit from a TNF blocker than did older patients. This study identifies a subset of patients in whom systemic inflammation contributes to risk for AD through a pathological mechanism involving TNF and who therefore may benefit from treatment with a TNF blocking agent.

Conflict of interest statement

M.E.G is an employee of Tetra Therapeutics. This commercial affiliation does not alter the adherence of M.E.G to PLOS ONE policies on sharing data and materials.

Figures

Fig 1. A screen shot of cohort identification using the IBM Watson Health Explorys Cohort Discovery fast search tool.

This example selects female White patients with age > 65 years with a diagnosis code for dementia and a prescription for etanercept.

Fig 2. Cumulative age distribution of patients with a diagnosis code for rheumatoid arthritis, dementia or Alzheimer’s disease.

Fig 3

a. Adjusted Odds Ratio (AOR) for a diagnosis of Alzheimer’s disease associated with a diagnosis for an inflammatory disease as compared to the non-inflammatory disease group. Abbreviations: RA -rheumatoid arthritis, AS -ankylosing spondylitis, PA -psoriatic arthritis, IBD -inflammatory bowel disease, UC -ulcerative colitis, Crohn’s -Crohn’s disease. b Adjusted Odds Ratios (AORs) for a diagnosis of Alzheimer’s disease associated with a diagnosis for rheumatoid arthritis as compared to the non-inflammatory disease group, further adjusting for BMI, smoking status, or alcohol use. The added covariate is presented in column 2. We present both adjusted and stratified AOR for each covariate.

Fig 4. Adjusted Odds Ratio (AOR) for a diagnosis code of dementia associated with a diagnosis for an inflammatory disease as compared to the non-inflammatory disease group.

Abbreviations: RA -rheumatoid arthritis, AS -ankylosing spondylitis, PA -psoriatic arthritis, IBD -inflammatory bowel disease, UC -ulcerative colitis, Crohn’s -Crohn’s disease.

Fig 5. Adjusted Odds Ratio (AOR) showing inverse risk associations between Alzheimer’s disease or a diagnosis of dementia and prescription history of a TNF blocker (exclude certolizumab pegol and golimumab) or methotrexate compared to the no-drug group in patients with a diagnosis of rheumatoid arthritis with a prescription.

The analysis excluded patients with a prescription history of a TNF blocker and methotrexate.

Fig 6. Adjusted Odds Ratio (AOR) showing inverse associations between Alzheimer’s disease or a diagnosis of dementia and prescription history of methotrexate and a TNF blocker compared to the methotrexate and no-TNF blocker group in patients with a diagnosis of rheumatoid arthritis.

Fig 7. Adjusted Odds Ratio (AOR) showing inverse associations between Alzheimer’s disease or a diagnosis of dementia and prescription history of a TNF blocker (exclude certolizumab pegol and golimumab) or methotrexate compared to the no-drug group in patients with a diagnosis of psoriasis.

Fig 8. Adjusted Odds Ratio (AOR) showing inverse associations between Alzheimer’s disease or a diagnosis of dementia and prescription history of a TNF blocker in patients with a diagnosis of psoriasis adjusting for methotrexate prescription status.

Fig 9. Effect of age, gender and race on risk for a diagnosis of dementia in rheumatoid arthritis patients treated with etanercept.

Young patients (18–65 years) showed greater benefit than did older patients (over 65 years). The effect of gender and race was not significant.

Fig 10. Crude Odds Ratios (OR) and Adjusted Odds Ratios (AOR) based on insurance status (Medicaid versus no-Medicaid, or private versus no-private insurance) in patients with a diagnosis code for dementia and rheumatoid arthritis.

Fig 11. Comparison of the risk for a diagnosis of Alzheimer’s disease or dementia in patients with a diagnosis of rheumatoid arthritis or psoriasis with a prescription history for etanercept, adalimumab, or infliximab who were not prescribed methotrexate against the general population.