Initiation of targeted disease-modifying antirheumatic drugs in patients with rheumatoid arthritis not associated with reduced risk of Alzheimer disease and related dementia

1. There were no differences in the risk of Alzheimer disease and related dementia in patients with rheumatoid arthritis treated with inhibitors of Janus-kinase (tofacitinib), interleukin-6 (tocilizumab), or tumor necrosis factor compared with those treated with a T-cell activation inhibitor (abatacept).

2. In subgroup analysis in patients with cardiovascular disease, there was a potentially lower risk of Alzheimer disease and related dementia with tumor necrosis factor inhibitors.

Evidence Rating Level: 2 (Good)

Study Rundown: The Drug Repurposing for Effective Alzheimer Medicines (DREAM) study is aimed at identifying drug repurposing candidates for Alzheimer disease and related dementia (ADRD). Testable hypotheses are generated based on multiomics phenotyping where abnormal metabolic pathways associated with ADRD neuropathogenesis are targeted. This study compared the risk of ADRD in patients with rheumatoid arthritis (RA) who were treated with biologic disease-modifying antirheumatic drugs (TDMARDs) and potential repurposing candidates through the JAK/STAT pathway, including tofacitinib (JAK inhibitor), tocilizumab (IL-6 inhibitor), and TNF inhibitors, compared with an active comparator abatacept (T-cell activation inhibitor). The main outcome was incident ADRD based on diagnosis codes evaluated via 4 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. Among 22 569 propensity score-matched patient pairs, initiation of tofacitinib, tocilizumab, and TNF inhibitors used for the treatment of RA was not associated with reduced risk of ADRD compared with abatacept. A limitation of this study was the possibility of outcomes misclassification in identifying ADRD through Medicare claims that may confound associations.

Click to read the study in JAMA Network Open

Relevant Reading: Treatment for rheumatoid arthritis and risk of Alzheimer’s disease: a nested case-control analysis

In-Depth [retrospective cohort]: This cohort study included 22 569 US Medicare fee-for-service patients with rheumatoid arthritis aged ≥65 years between 2007 to 2017. After 1:1 propensity score matching to patients using abatacept, 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. Overall, incidence rates of ADRD varied from 2 to 18 per 1000 person-years across multiple analysis schemes. Compared with abatacept, there were no statistically significant associations between 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]). In subgroup analysis in patients with cardiovascular disease, there was a potentially lower risk of ADRD with TNF inhibitors (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]).

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