Rheumatoid arthritis is a chronic disease that causes pain, stiffness, swelling and limitation in the motion and function of multiple joints. Though joints are the principal body parts affected by RA, inflammation can develop in other organs as well. An estimated 1.3 million Americans have RA, and the disease typically affects women twice as often as men.
Researchers in the Netherlands conducted the Behandel Strategieen (BeSt) Study, including 508 patients with recent active-onset RA from March 2000 to August 2002. They compared survival rates of these patients with that of the general Dutch population and sought to define risk factors for mortality during the 10-year duration of the study. “The BeSt study was set up as a four armed comparison study, aiming to find which is the optimal order of use of available anti-rheumatic therapies, with outcomes improvement of functional ability and prevention of radiological damage,” said C.F. Allaart, MD of the Leiden University Medical Center and a lead author of the study.
The study’s arms mainly differed in initial treatment strategies: arms one and two started with a single anti-rheumatic drug, methotrexate, (and switched to, or added, other therapies if necessary) while arms three and four started with a combination of methotrexate with either sulfasalazine plus prednisone or TNF blocker infliximab, combinations that would be tapered to monotherapy if the clinical response was sufficient.
Response to treatment was measured every three months using a Disease Activity Score (DAS) target of 2.4 or lower. If DAS was higher than 2.4, the researchers took the next treatment step in the respective arm. If low disease activity was achieved for at least six consecutive months, medication was tapered to a monotherapy maintenance dose. From year three, the protocol was extended with the requirement that patients who had achieved at least six consecutive months on monotherapy maintenance dose had to stop that last drug too. Across time, some 80 percent of participating patients were in low disease activity, 45 percent were in remission and 15 percent in drug-free remission.
During the 10-year study, 72 of the 508 RA patients died at a mean age of 75 years. The different treatment strategies used to achieve the DAS goal did not result in a difference in survival rates. Compared with mortality rates in the general population, 62 deaths would have been expected, resulting in a standard mortality ratio of 1.16 for the RA patient population, with a 95-percent confidence interval of 0.92 to 1.46, so the difference was not statistically significant. Several risk factors were associated with higher mortality: higher age, male gender, smoking and worse functional ability scored on the Health Assessment Questionnaire. The researchers concluded that in RA patients treated at a target of low disease activity, the mortality rate is similar to that in the general population. Because the treatment was targeted to keep the patient at DAS ≤2.4, inflammation was better controlled than in earlier cohorts where there was increased mortality. The medication used to treat to target does not increase mortality, they concluded.
Rheumatologists might reduce mortality by treating all RA patients to a target of low disease activity and encouraging RA patients to stop smoking, the study’s authors further concluded.
“Historically, mortality risk in RA was significantly increased when inflammation was not as effectively suppressed as for instance in the BeSt cohort to date. RA was a deadly disease,” said Dr. Allaart. “But with earlier treatment and targeted treatment, where medication is intensified until low disease activity is achieved and maintained (and this appears independent of treatment strategy or the order in which medication is used), inflammation can be so well controlled that it no longer affects overall survival.”
Funding sources for this study included a government grant from the Dutch College of Health Insurance Companies, with additional funding from Schering-Plough/MSD and Centocor/Janssen.
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Paper Number: 817
Mortality in a Large Cohort of Patients with Early Rheumatoid Arthritis That Were Treated-to-Target for 10 Years
I.M. Markusse1, L. Dirven1, J.H. van Groenendael2, K.H. Han3, H.K Ronday4, P.J.S.M. Kerstens5, W.F. Lems6, T.W.J. Huizinga1 and C.F. Allaart1, 1Leiden University Medical Center, Leiden, Netherlands, 2Fransiscus Hospital, Roosendaal, Netherlands, 3MCRZ hospital, Rotterdam, Netherlands, 4Haga Hospital, The Hague, Netherlands, 5Jan van Breemen Research Institute | Reade, Amsterdam, Netherlands, 6VU Medical Center, Amsterdam, Netherlands
Background/Purpose: Recent studies showed diverging results about mortality trends in patients with rheumatoid arthritis (RA). Our aim was to determine survival after 10 years of treat-to-target therapy in patients with early RA, to compare these survival rates with the general population and to define risk factors for mortality during the 10 years duration of the BeSt study.
Methods: The BeSt study enrolled 508 Dutch patients with recent-onset active RA (1987 criteria) who were randomized to: sequential monotherapy, step-up therapy, initial combination including either prednisone or infliximab. During 10 years, all patients were treated-to-target, aiming at a disease activity score (DAS) ≤2.4. Kaplan-Meier curves and the log-rank test were used to compare survival rates in the four treatment strategies. Standardized mortality ratios (SMR) were calculated to compare the BeSt population to the general Dutch population, matched by age, gender and calendar year. Cox regression was used to calculate hazard ratios (HR) to determine baseline risk factors for increased mortality in the BeSt population.
Results: During 10 years, 72 of 508 patients died at a mean age of 75 years. No difference in survival was observed between the treatment strategies (p=0.805) (figure), with 16/126, 15/121, 21/133 and 20/128 deaths in arm 1 to 4, respectively. Based on the general Dutch population, 62 deaths were expected and 72 deaths occurred, resulting in an overall SMR of 1.16 (95% confidence interval, CI 0.92 – 1.46). Comparing the general population to each of the treatment strategies resulted in a SMR (95% CI) of 1.00 (0.61 – 1.64), 1.02 (0.61 – 1.69), 1.30 (0.85 – 1.99) and 1.32 (0.85 – 2.04) in arm 1 to 4, respectively.
In the BeSt population, baseline age (HR 1.13, 95% CI 1.10-1.16), male gender (HR 1.78, 95% CI 1.06-2.99), smoking at baseline (HR 5.19, 95% CI 3.08-8.75) and health assessment questionnaire at baseline (HR 1.89, 95% CI 1.29-2.76) were associated with an increased risk of mortality. Randomization arm was not associated with an increased risk of mortality (arm 1 as reference category; arm 2 HR 0.99, 95% CI 0.49 – 2.00; arm 3 HR 1.27, 95% CI 0.66 – 2.44; arm 4 HR 1.25, 95% CI 0.65 – 2.41).
Conclusion: After 10 years of continued tight controlled treatment in patients with rheumatoid arthritis in the BeSt study, the survival rate was comparable to the general Dutch population, without differences between the treatment strategies. Higher age, male gender, smoking and worse functional ability were associated with an increased risk of mortality within our study population. These results suggest that treatment targeted at DAS ≤2.4 prevents increased mortality previously associated with RA, and that the medication used in these strategies does not increase mortality. Disclosures: I. M. Markusse, None.L. Dirven, None.J. H. van Groenendael, None.K. H. Han, None.H. K. Ronday, None.P. J. S. M. Kerstens, None.W. F. Lems, None.T. W. J. Huizinga, None.C. F. Allaart, None.
Journal Link: American College of Rheumatology Annual Meeting
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