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Cited by 45Rheumatoid Arthritis Research and TherapiesDementia and Cognitive Impairment ResearchAlzheimer's disease research and treatments

Comparative risk of alzheimer disease and related dementia among Medicare beneficiaries with rheumatoid arthritis treated with targeted disease-modifying antirheumatic agents

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Desai, Rishi J., Varma, Vijay R., Gerhard, Tobias, Segal, Jodi, Mahesri, Mufaddal, Chin, Kristyn, Horton, Daniel B., Kim, Seoyoung C. +2 more·2022·JAMA Network Open
DOI 10.1001/jamanetworkopen.2022.6567PMC PMC8994126
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Abstract

Importance: Cytokine 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 Measures: The 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. Results: After 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 (analysis 1: HR, 0.90 [95% CI, 0.55-1.51]; analysis 2: HR, 0.78 [95% CI, 0.53-1.13]; analysis 3: HR, 1.29 [95% CI, 0.72-2.33]; analysis 4: HR, 0.50 [95% CI, 0.21-1.20]), tocilizumab (analysis 1: HR, 0.82 [95% CI, 0.55-1.21]; analysis 2: HR, 1.05 [95% CI, 0.81-1.35]; analysis 3: HR, 1.21 [95% CI, 0.75-1.96]; analysis 4: HR, 0.78 [95% CI, 0.44-1.39]), or TNF inhibitors (analysis 1: HR, 0.93 [95% CI, 0.72-1.20]; analysis 2: HR, 1.02 [95% CI, 0.86-1.20]; analysis 3: HR, 1.13 [95% CI, 0.86-1.48]; analysis 4: 0.90 [95% CI, 0.60-1.37]) compared with abatacept. Results from prespecified subgroup analysis by age, sex, and baseline cardiovascular disease were consistent except in patients with cardiovascular disease, for whom there was a potentially lower risk of ADRD with TNF inhibitors vs abatacept, but only in analyses 2 and 4 (analysis 1: HR, 0.76 [95% CI, 0.50-1.16]; analysis 2: HR, 0.74 [95% CI, 0.56-0.99]; analysis 3: HR, 1.03 [95% CI, 0.65-1.61]; analysis 4: HR, 0.45 [95% CI, 0.21-0.98]). Conclusions and Relevance: This cohort study did not find any association of risk of ADRD in patients treated with tofacitinib, tocilizumab, or TNF inhibitors compared with abatacept.

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Cited by

Sorted by citations

Authors
Desai, R. J., Varma, V. R., Gerhard, T., Segal, J., Mahesri, M., Chin, K., Horton, D. B., Kim, S. C., Schneeweiss, S., & Thambisetty, M.
Affiliations
  • Brigham and Women's Hospital (US)
  • National Institute on Aging (US)
  • Rutgers, The State University of New Jersey (US)
  • Johns Hopkins University (US)
Corresponding author
Desai, Rishi J.
ORCID
Venue
JAMA Network Open
Publisher
American Medical Association (AMA)
Published
2022-04-08
Volume
5
Issue
4
Pages
e226567
ISSN
2574-3805 (ISSN-L)
DOI
10.1001/jamanetworkopen.2022.6567
PMC
PMC8994126
OpenAlex
W4223601481
Cited by
45
References
6
Citations by year
2026: 5 · 2025: 8 · 2024: 19 · 2023: 8 · 2022: 5
FWCI
7.28
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • JAMA Network Open (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • Bristol-Myers Squibb
  • Eli Lilly and Company
  • Pfizer
  • Sanofi
  • Laura and John Arnold Foundation
  • Childhood Arthritis and Rheumatology Research Alliance
  • Eisai
  • National Institutes of Health
  • National Institute on Aging
  • National Center for Advancing Translational Sciences
Topics
  • Health Sciences › Medicine › Rheumatology › Rheumatoid Arthritis Research and Therapies
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Keywords
rheumatoid arthritis, tofacitinib, tocilizumab, TNF-alpha inhibitors, abatacept, JAK inhibitors, IL-6 inhibitors, cytokine signaling, dementia risk, older adults, Medicare beneficiaries, drug repurposing, Janus kinase signaling, T cell activation inhibition, anti-TNF therapy, IL-6 inhibition
MeSH terms
Abatacept, Tumor Necrosis Factor Inhibitors, Aged, Alzheimer Disease, Arthritis, Rheumatoid, Cardiovascular Diseases, Female, Medicare, Humans, United States, Cohort Studies, Antirheumatic Agents

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