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

Abstract

IMPORTANCECytokine signaling, including tumor necrosis factor (TNF) and interleukin (IL)-6, through the Janus-kinase (JAK)-signal transducer and activator of transcription pathway, was hypothesized to attenuate the risk of Alzheimer disease and related dementia (ADRD) in the Drug Repurposing for Effective Alzheimer Medicines (DREAM) initiative based on multiomics phenotyping. OBJECTIVE To evaluate the association between treatment with tofacitinib, tocilizumab, or TNF inhibitors compared with abatacept and risk of incident ADRD. DESIGN, SETTING, AND PARTICIPANTS This cohort study was conducted among US Medicare fee-for-service patients with rheumatoid arthritis aged 65 years and older from 2007 to 2017. Patients were categorized into 3 cohorts based on initiation of tofacitinib (a JAK inhibitor), tocilizumab (an IL-6 inhibitor), or TNF inhibitors compared with a common comparator abatacept (a T-cell activation inhibitor). Analyses were conducted from August 2020 to August 2021. MAIN OUTCOMES AND MEASURESThe main outcome was onset of ADRD based on diagnosis codes evaluated in 4 alternative analysis schemes: (1) an as-treated follow-up approach, (2) an as-started follow-up approach incorporating a 6-month induction period, (3) incorporating a 6-month symptom to diagnosis period to account for misclassification of ADRD onset, and (4) identifying ADRD through symptomatic prescriptions and diagnosis codes. Hazard ratios (HRs) with 95% CIs were calculated from Cox proportional hazard regression after adjustment for 79 preexposure characteristics through propensity score matching. RESULTSAfter 1:1 propensity score matching to patients using abatacept, a total of 22 569 propensity score-matched patient pairs, including 4224 tofacitinib pairs (mean [SD] age 72.19 [5.65] years; 6945 [82.2%] women), 6369 tocilizumab pairs (mean [SD] age 72.01 [5.46] years; 10 105 [79.4%] women), and 11 976 TNF inhibitor pairs (mean [SD] age 72.67 [5.91] years; 19 710 [82.3%]women), were assessed. Incidence rates of ADRD varied from 2 to 18 per 1000 person-years across analyses schemes. There were no statistically significant associations of ADRD with tofacitinib

Hydroxychloroquine lowers Alzheimer’s disease and related dementias risk and rescues molecular phenotypes related to Alzheimer’s disease

“…Extending our recent work examining candidate AD treatments targeting the JAK/STAT cytokine signaling pathway [3,9], we now demonstrate that HCQ lowers the incidence of ADRD compared to MTX in older individuals, rescues impaired hippocampal synaptic plasticity in APP/PS1 mice and corrects multiple molecular abnormalities underlying AD. Together, these findings suggest that HCQ may be a promising disease-modifying AD treatment in at-risk individuals.…”

“…Prior studies have suggested that dysregulation in this pathway may be associated with neurodegenerative diseases [4,5] and may therefore may be a plausible therapeutic target [6][7][8]. We recently showed that disease modifying antirheumatic drugs (DMARDs) including tofacitinib (a JAK inhibitor), and 2) tocilizumab (an interleukin [IL]-6 inhibitor) were not associated with risk of AD and related dementias (ADRD) while TNF inhibitors may reduce risk of ADRD among patients with cardiovascular disease [9]. We additionally showed that C188-9, an experimental STAT3 inactivator currently in human clinical trials of cancer, rescued several molecular phenotypes relevant to AD in cell culture-based phenotypic assays [10].…”

Promise and peril of claims-based dementia ascertainment in causal inference

“…Moreover, clinical research has applied this definition to ascertain ADRD among persons for whom this diagnosis has important prognostic and treatment-related implications for comorbid conditions, such as cancer 3. Emerging applications of claims-based ADRD ascertainment now include drug-repurposing and pharmacogenomics 4…”

Risk Factors for Dementia in Patients With Incident Rheumatoid Arthritis: A Population-Based Cohort Study

“…Two recent studies from the US and UK showed a reduced risk of dementia with the use of biologics in RA patients (46) (47). A recent large cohort study using propensity-score matching did not find any difference in the risk of dementia in patients with RA treated with TNFi, IL-6 inhibitor or Janus kinase inhibitor versus abatacept, although patients were followed up for a maximum of only 3 years (48). In our study, we did not find an association between exposure to DMARDs at any time during the follow-up (i.e., "ever use") and incident dementia.…”