Treatment with TNF‐α inhibitors versus methotrexate and the association with dementia and Alzheimer's disease

Abstract

Introduction Peripheral inhibition of tumor necrosis factor (TNF)‐α, outside of the central nervous system, may result in clinical improvement of Alzheimer's disease (AD) outcomes. TNF‐α inhibitors (TNFIs) are effective treatments for various autoimmune conditions and may be effective for preventing and/or treating AD. The objective of this study was to compare the risk of dementia and AD in patients initiating methotrexate versus those initiating TNFIs. Methods Insurance claims data from databases of commercially insured and Medicare‐eligible patients were used to estimate the risk of dementia and AD within patients with rheumatoid arthritis (RA) initiating a TNFI versus initiation of methotrexate. A sensitivity analysis included all patients without the RA diagnosis requirement. The at‐risk period spanned from the index date until a diagnosis of the outcome, loss‐to‐follow‐up, or receipt of the comparator drug. Patients were matched 1‐to‐1 using propensity scores. A Cox proportional hazards model was used to estimate the hazard ratio (HR). Negative controls were used to calibrate the results. Results A total of 11,092 new TNFI patients and 44,023 new methotrexate patients were identified, and 8925 from each group were matched. The outcome of dementia occurred in 1.4% of patients in both groups. The calibrated results from the Cox regression found no difference between the two groups (commercially insured database: calibrated HR = 0.69, 95% confidence interval = 0.45 to 1.05; Medicare‐only database: 1.14, 0.66 to 1.96). Results were similar in all sensitivity analyses: outcome of AD and including patients without RA. Discussion No significant difference for the risk of dementia or AD was seen between patients initiating a TNFI versus methotrexate. Although this study cannot conclude whether use of TNFIs is protective against dementia and AD compared with receiving no treatment, there was no evidence that it is more protective than the active comparator methotrexate.

Association between disease-modifying antirheumatic drugs for rheumatoid arthritis and risk of incident dementia: a systematic review with meta-analysis

“… *Kern et al 32 study reported two separate risk estimates based on two different databases and was therefore regarded as two studies in subgroup analyse. bDMARDs, biological disease-modifying anti-rheumatic drugs; ICD, International Classification of Diseases; RA, rheumatoid arthritis; ROBINS-I, Risk of Bias in Nonrandomised Studies of Interventions.…”

“… *Kern et al 32 study reported two separate risk estimates based on two different databases and was therefore regarded as two studies in subgroup analyse. …”

Association of Tumor Necrosis Factor-α Inhibitors with Incident Dementia: Analysis Based on Population-Based Cohort Studies

“…Relatively few epidemiological studies have so far investigated treatment with TNFi and incident dementia [ 10 – 16 ]. The available data suggest that TNFi may be promising candidates for the treatment of dementia, but there are methodological limitations to the prior studies in terms of the observation period and study design [ 11 – 14 ].…”

Comparative Risk of Alzheimer Disease and Related Dementia Among Medicare Beneficiaries With Rheumatoid Arthritis Treated With Targeted Disease-Modifying Antirheumatic Agents

“…Comparing TDMARDs with nonuse or even with nonbiologic DMARDs is subject to severe bias due to confounding, as the decision to initiate treatment with TDMARDs in old age is likely influenced by RA activity and frailty, which cannot be fully measured with claims data. 44 Some active comparators, for instance methotrexate, which was used in another recent study as a comparator to TNF inhibitors, 45 are likely more appropriate than nonuser comparisons owing to improved confounding adjustment. Indeed, the study comparing TNF inhibitors to methotrexate found no differences in the risk of dementia, unlike previous studies comparing TNF inhibitors with nonuse.…”