Relative importance of inflammation and cardiorespiratory fitness for all-cause mortality risk in persons with rheumatoid arthritis: the population-based Trøndelag Health Study

OBJECTIVE: Inflammation and reduced cardiorespiratory fitness (CRF) are associated with increased mortality rates in rheumatoid arthritis (RA). We aimed at directly comparing the relative importance of inflammation and reduced CRF as mediators of all-cause mortality in persons with RA compared with controls, quantifying direct and indirect (mediated) effects. METHODS: Persons with (n=223, cases) and without (n=31 684, controls) RA from the third survey of the Trøndelag Health Study (HUNT3, 2006–2008) were included. Inflammation was quantified using C reactive protein (CRP) and estimated CRF (eCRF) was calculated using published formulae. All-cause mortality was found by linkage to the Norwegian Cause of Death Registry, with follow-up from inclusion in HUNT3 until death or 31 December 2018. Data were analysed using standardised equation modelling, permitting complex correlations among variables. RESULTS: Persons with RA had increased all-cause mortality rates (24.1% vs 9.9%, p<0.001). Both eCRF (p<0.001) and CRP ≥3 mg/L (p<0.001) were mediators of this excess mortality, rendering the direct effect of RA non-significant (p=0.19). The indirect effect of RA mediated by eCRF (standardised coefficient 0.006) was approximately three times higher than the indirect effect mediated by CRP (standardised coefficient 0.002) in a model adjusted for other mortality risk factors. CONCLUSION: Even with CRP concentrations <3 mg/L in all patients with RA, excess mortality mediated by low CRF would still play an important role. Improved inflammation control in RA does not necessarily lead to better CRF. Therefore, our study strongly supports recommendations for development and implementation of exercise programmes aimed at improving CRF in persons with RA.