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Study Finds No Association Between Targeted DMARDs, ADRD Risk Among Patients With RA


Researchers found no association between the use of tofacitinib, tocilizumab, or tumor necrosis factor (TNF) inhibitors and risk of developing Alzheimer disease and related dementia (ADRD) among older patients with rheumatoid arthritis (RA).

Among patients with rheumatoid arthritis (RA), there is no association between tofacitinib, tocilizumab, or tumor necrosis factor (TNF) inhibitor use and risk of developing Alzheimer disease and related dementia (ADRD).

These findings were published in JAMA Network Open and were in comparison with abatacept (Orencia), a T-cell activation inhibitor used to treat autoimmune diseases such as RA.

To evaluate any potential association between the 3 included targeted synthetic or biologic disease-modifying antirheumatic drugs (TDMARDs), researchers conducted a cohort study including 22,569 patients with RA aged 65 and older enrolled in Medicare fee-for-service.

Data from between 2007 and 2017 were analyzed between August 2020 and August 2021.

Patients with RA were categorized into 3 cohorts based on their use of JAK inhibitor tofacitinib, IL-6 inhibitor tocilizumab, or TNF inhibitors. Patients were also matched 1:1 within their cohort to patients using abatacept based on propensity score, for a total of 22,569 patient pairs.

The study included 4224 tofacitinib pairs, 6369 tocilizumab pairs, and 11,976 TNF inhibitor pairs. All 3 groups consisted of mostly women and the mean age was around 72 years for all groups.

A majority (73.4%) of patients in the TNF inhibitor cohort were TDMARD naïve, while 34.4% in the tofacitinib cohort and 27.1% in the tocilizumab cohort were TDMARD naïve. According to the authors, this implies that tofacitinib and tocilizumab are frequently used as second-line medications.

They also found that diabetes and hypertension were commonly observed in all cohorts.

Incident ADRD rates ranged from a low of between 2 and 4 per 1000 person-years, to a high of between 14 and 18 per 1000 person-years. According to the authors, incident rates were generally similar within each analysis across all 3 treatment cohorts.

Regarding the comparative risk of ADRD, no evidence pointed towards associations between ADRD risk and tofacitinib, tocilizumab, or TNF inhibitors when compared with abatacept across all 4 analyses.

“Multiple previous investigations using routine health care data have attempted to quantify the associations between TDMARDs, specifically TNF inhibitors, and reduction in ADRD risk, and have reported large effect sizes, ranging from 30% to 70% reduction compared with nonuse,” the authors said. “These implausibly large effect sizes are likely attributable to combinations of various sources of bias identified in these studies, including immortal time bias, reverse causation bias, and severe confounding by indication.”

To address these biases, the authors included abatacept as an active comparator and implemented a new user design. However, they also emphasized the need for “nuanced discussion” of these findings.

They explained that TDMARDs targeting JAK, IL-6, or TNF may potentially not have a causal effect on ADRD risk or trajectory. Additionally, only using abatacept as a comparator could lead to the alternate interpretation that all the included TDMARDs may be lowering ADRD risk to a similar extent as abatacept.

“While these results must be interpreted with caution owing to limitations associated with subgroup analyses, including possibility of type 1 error due to multiple hypothesis testing, further studies in diverse cohorts may clarify whether the interaction of cardiovascular risk factors and TNF signaling is associated with differentially modulating risk of ADRD,” the authors said.


Desai RJ, Varma VR, Gerhard T, et al. Comparative risk of Alzheimer disease and related dementia among Medicare beneficiaries with rheumatoid arthritis treated with targeted disease-modifying antirheumatic agents. JAMA Netw Open. 2022;5(4):e226567. doi:10.1001/jamanetworkopen.2022.6567

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