Time-Varying Association of Rheumatoid Arthritis Disease Activity to Subsequent Cardiovascular Risk

Abstract

Objective: It is unknown how the relationship between disease activity in rheumatoid arthritis (RA) and cardiovascular (CV) events may change over time. We examined the potentially time-varying association of RA disease activity to CV events.

Methods: We used the CorEvitas prevalent RA registry. The Clinical Disease Activity Index (CDAI) score category, averaged within each 6-month window since enrollment, was the exposure, and the outcome was major adverse CV events (MACEs). We used marginal structural models to estimate the hazard ratio (HR), comparing each CDAI score category with remission, allowing for differential association over time. We predicted MACE-free survival under several CDAI score scenarios.

Results: We found 44,816 eligible patients (77% female; mean age 58 years) with a crude event rate of 5.3/1000 person-years (median follow-up 3.4 years). The strongest association between higher CDAI score and MACEs was observed during the first 6 months of enrollment (HR for CDAI score low 2.29 [95% CI: 1.21-4.36], moderate 2.81 [95% CI: 1.46-5.43], and high 2.99 [95% CI: 1.48-6.02]). These estimates gradually diminished; by year 5, the HRs were 1.00 (95% CI: 0.49-2.05) for low, 1.18 (95% CI: 0.51-2.71) for moderate, and 1.04 (95% CI: 0.45-2.40) for high CDAI score. Predicted MACE-free survival suggested a potential decrease in MACEs with a hypothetical earlier transition to remission.

Conclusion: The association of higher disease activity with CV events may be stronger earlier in the disease course of RA. Interventional studies may be warranted to precisely determine the effect of disease activity suppression on CV events in RA.

Figure 1

Time‐varying hazard ratio estimates for MACEs associated with each CDAI score level compared with remission for each 6‐month interval. See Supplementary Figure 2 for a non‐superimposed version. The Y axis is on the log HR scale with the ticks at representative HR values. CDAI, Clinical Disease Activity Index for rheumatoid arthritis; HR, hazard ratio; MACE, major cardiovascular event.

Figure 2

Predicted MACE‐free survival under hypothetical sustained CDAI score levels based on time‐varying hazard ratio estimates from the final model (estimates in Figure 1). CDAI, Clinical Disease Activity Index for rheumatoid arthritis; MACE, major adverse cardiovascular event.

Figure 3

Predicted MACE‐free survival under hypothetical transition to sustained remission at 24 months and 6 months in comparison to hypothetical scenarios of having always‐remission‐level CDAI score (top curve: best‐case scenario) and having always high CDAI score (bottom curve: worst‐case scenario). A hypothetical transition to sustained remission at 24 months (left panel; middle three curves) was predicted to carry less dramatic CV benefit compared with transition to sustained remission at 6 months (right panel; middle three curves), which gave predicted MACE‐free survival curves fairly close to the hypothetical scenario of having always‐remission‐level CDAI score (top curve: best‐case scenario). CDAI, Clinical Disease Activity Index for rheumatoid arthritis; CV, cardiovascular; MACE, major adverse cardiovascular event.