Biologic Agents and Mortality Risk in Rheumatoid Arthritis

Washington, DC—Treatment of rheumatoid arthritis (RA) with biologic agents is associated with a significant reduction in mortality, Canadian researchers reported in a population-based cohort study presented at the ACR meeting.

Although the effectiveness of biologic agents to treat RA suggests that these agents may also reduce the risk of premature mortality associated with RA by reducing inflammation and disease activity, which are predictors of mortality, the side effects of biologic agents could adversely affect mortality risk.

To assess the association between exposure to biologic agents and mortality risk in patients with RA, investigators retrospectively evaluated mortality risk in patients with RA treated with a biologic agent compared with a control group of RA patients not treated with a biologic agent from a population-based cohort in British Columbia, Canada.

Administrative billing data from the Ministry of Health, a universal healthcare system in Canada, was used to identify key data on all RA cases in British Columbia between January 1996 and March 2006, with follow-up until March 2010. Data obtained included all medications used since January 1996, physician visits, hospitalizations, and tests since January 1990.

Patients included in the study had ≥2 physician visits at least 2 months apart with International Classification of Diseases, Ninth Revision (ICD-9) codes for RA. Patients were excluded if they had at least 2 subsequent visits with ICD-9 codes for other inflammatory arthritis, if a rheumatologist did not confirm a diagnosis of RA made by a non-rheumatologist, and if there were no subsequent RA visits over >5 years.

For the study, the investigators identified all patients in the population-based cohort who used a biologic agent (anti-TNF agent, rituximab, anakinra, or abatacept) during follow-up. They matched each biologic user with 1 RA control from the RA population-based cohort who never used a biologic agent but had received ≥3 disease-modifying antirheumatic drugs (DMARDs) and a change in DMARD within 6 months. Using greedy matching, the cohorts (biologic users and controls) were also matched on sex, age, calendar year of inclusion, and closest propensity score (PS). Markers of RA severity and comorbidities increasing the risk of death were used to calculate the PS at time of initiation of biologic use. Matched controls were given the date of initiation of first biologic of the user to which they were matched.

Because of imperfect matching between the biologic users and controls, despite selecting controls with the closest PS, the investigators added PS quintiles to the final multivariate analysis.

The study included 4312 patients with RA, 2156 treated with biologic agents and 2156 controls. Most patients in both groups were female (74.7%) and mean age was 56.3 years. Most of the patients in both groups had prior DMARD treatment, with methotrexate as the most frequently used DMARD (85% for all patients) followed by hydroxychloroquine (70% for all patients).

Among the 2156 patients treated with biologics, 2088 (97%) were treated with an anti-TNF agent, 210 (10%) with rituximab, 118 (6%) with abatacept, and 50 (2%) with anakinra.

According to Diane Lacaille, MD, associate professor and senior scientist at the Arthritis Research Centre of Canada at the University of British Columbia, who presented the results at the ACR meeting, the investigators observed 573 deaths. Of these, 326 people in the control group died and 247 died in the biologic user group.

Using the Cox proportional hazards model (PHM) to estimate the risk of death associated with biologic exposure, the study found that patients exposed to biologic agents had a significant reduction in the risk of death. After adjusting for PS quintiles and variables included in the PS model that were not balanced between the biologic users and controls, the adjusted hazard ratio (aHR) was 0.25 (95% confidence interval [CI], 0.18-0.36; P<.0001). 

To test the robustness of this result, the investigators conducted 2 sensitivity analyses, both of which yielded similar outcomes. One analysis evaluated mortality risk between the biologic users and matched controls that were not required to have used 3 prior DMARDs or a recent change in DMARD, and also found a significant reduction of mortality risk for the biologic users (aHR, 0.26; 95% CI, 0.18-0.36; P<.0001). Mortality risk was also significantly reduced in biologic users in a second sensitivity analysis in which controls were only required to have used 1 DMARD and in which PS scores were not used but PS variables were allowed to enter the PHM model (aHR, 0.31; 95% CI, 0.22-0.34; P<.0001).

Limitations of the study included the use of administrative data, selection bias from non-random allocation of treatment, residual confounding, unmeasured confounding, and the study’s observational design.

According to Dr. Lacaille, these results have important implications for people with RA, along with healthcare providers and policy makers, given the increased mortality risk associated with RA.