Trends in All-Cause and Cardiovascular Mortality in Patients With Incident Rheumatoid Arthritis

A 20-Year Follow-Up Matched Case-Cohort Study

Sella A. Provan; Siri Lillegraven; Joe Sexton; Kristin Angel; Cathrine Austad; Espen A. Haavardsholm; Tore K. Kvien; Till Uhlig


Rheumatology. 2020;59(3):505-512. 

In This Article

Abstract and Introduction


Objectives: To examine all-cause and cardiovascular disease (CVD) mortality in consecutive cohorts of patients with incident RA, compared with population comparators.

Methods: The Oslo RA register inclusion criteria were diagnosis of RA (1987 ACR criteria) and residency in Oslo. Patients with disease onset 1994–2008 and 10 matched comparators for each case were linked to the Norwegian Cause of Death Registry. Hazard ratios for all-cause and CVD mortality were calculated for 5, 10, 15 and 20 years of observation using stratified cox-regression models. Mortality trends were estimated by multivariate cox-regression.

Results: 443, 479 and 469 cases with disease incidence in the periods 94–98, 99–03 and 04–08 were matched to 4430, 4790 and 4690 comparators, respectively. For cases diagnosed between 1994 and 2003, the all-cause mortality of cases diverged significantly from comparators after 10 years of disease duration [hazard ratio (95% CI) 94–98 cohort 1.42 (1.15–1.75): 99–03 cohort 1.37 (1.08–1.73)]. CVD related mortality was significantly increased after 5 years for the 94–98 cohort [hazard ratio (95% CI) 1.86 (1.16–2.98) and after 10 years for the 99–03 cohort 1.80 (1.20–2.70)]. Increased mortality was not observed in the 04–08 cohort where cases had significantly lower 10-year all-cause and CVD mortality compared with earlier cohorts.

Conclusion: All-cause and CVD mortality were significantly increased in RA patients diagnosed from 1994 to 2003, compared with matched comparators, but not in patients diagnosed after 2004. This may indicate that modern treatment strategies have a positive impact on mortality in patients with RA.


RA is a chronic, systemic disease characterized by joint inflammation and in some cases, extra-articular manifestations. The mortality rate in patients with RA has in meta-analyses been estimated to be increased by 50–60%, compared with that of the general population.[1,2]About 40% of the deaths in the cohorts included in the meta-analyses were due to cardiovascular disease (CVD), which was the most frequent cause of death.[1] Recent studies suggest that RA patients are still not benefitting fully from the declining mortality rate observed in the general population.[3–5]

The RA treatment strategy has changed dramatically over the past two decades and the importance of early and intensive therapy and frequent assessments, in order to achieve a predefined treatment target and minimize joint damage, has become increasingly recognized.[6–8] The current EULAR recommendations for the treatment of early arthritis advocate rapid referral to a specialist, a minimum of 50% reduction in clinical disease activity after 3 months of treatment and a treatment goal of remission by 6 months.[9] These ambitious goals have been facilitated by the increased use of methotrexate and the introduction of TNF-α inhibitors from the turn of the century.[10] There is, however, a lack of knowledge concerning the effect of the change in treatment strategy on mortality.

The Oslo RA Register (ORAR) contains a large and representative cohort of individuals with RA.[11] Patients included in the register were treated according to the prevailing recommendations at the time of disease onset, and have thus been subjected to change in treatment practices during the longitudinal follow-up.

The objective of this matched case-cohort study was to examine the longitudinal trends in all-cause and CVD mortality in consecutive incidence cohorts of RA patients with disease onset between 1994 and 2008, compared with population comparators in the same geographical area.