SAN DIEGO – Rheumatoid arthritis patients with a good response to tumor necrosis factor inhibitor therapy when assessed roughly 5 months into treatment had an acute coronary syndrome risk during the next 2 years that was no different than that of the matched general population in a large, Swedish national registry study.
"We could see that the risk of acute coronary syndrome in the TNF inhibitor–exposed population was doubled in the first year compared to the general population. But all this increased risk was carried by patients with a moderate or nonresponse to therapy. We saw no difference in risk between the general population and patients with a good response to treatment. My belief is that this benefit is not due to the TNF inhibitor as such, but rather it’s the control of inflammation that is crucial," Dr. Lotta Ljung said at the annual meeting of the American College of Rheumatology.
Dr. Lotta Ljung
‘Good response’ was defined in this study via the EULAR response criteria: that is, a greater than 1.2-point improvement in the widely used Disease Activity Score 28 (DAS28) over baseline to a score of 3.2 or less at the 5-month evaluation.
Dr. Ljung, a senior consultant in rheumatology at Umea (Sweden) University Hospital, presented two analyses drawn from the Swedish Biologics Register, a national registry that captures 90% of all Swedes on biologic therapy for rheumatoid arthritis (RA). The study population included 7,704 RA patients with no history of ischemic heart disease when they started on their first TNF inhibitor during 2001-2010. They were matched by age, gender, and location to 23,112 RA patients who never took a biologic agent and to a second matched control group comprised of 38,520 individuals in the general population.
The crude incidence rate of acute coronary syndrome (ACS) in patients actively on TNF inhibitor therapy throughout follow-up was 5.7 events per 1,000 person-years, compared with 8.6 per 1,000 in biologic-naive RA patients and 3.3 per 1,000 in the matched general population.
In a fully adjusted Cox multivariate regression analysis factoring in socioeconomic variables, RA duration, joint surgery, and baseline atherosclerotic disease and other comorbid conditions, patients on anti-TNF therapy had a highly significant 27% reduction in ACS risk, compared with biologic-naive RA patients.
Nonetheless, patients on TNF inhibitor therapy remained at an adjusted 1.5-fold increased risk of ACS, compared with general population controls. However, this was significantly lower than the 2.3-fold elevated risk in biologic-naive RA patients.
In a separate analysis, the investigators took a closer look at the Swedish Biologics Register subgroup of the 4,931 RA patients on anti-TNF therapy for whom EULAR response data 5 months into treatment were available. Thirty-eight percent of these patients had a EULAR good response, 37% had a moderate response, and 25% had no response.
During 2 years of follow-up starting at the time of the EULAR response evaluation, the crude incidence rate of ACS among all TNF inhibitor–exposed RA patients, with close to 8,600 person-years of follow-up, was 6.9 cases per 1,000 person-years, compared with 3.4 per 1,000 among the matched general population controls. In an adjusted multivariate regression analysis, the ACS risk was 1.94-fold greater in moderate responders to anti-TNF therapy than in the general population and 2.53-fold greater in the nonresponders, but not significantly different between good responders and controls.
In addition, patients with an erythrocyte sedimentation rate (ESR) below 20 mm/hour at the time of their EULAR response evaluation had a subsequent 66% lower 1-year risk of ACS than did those with a higher ESR. And patients with a DAS28 remission at the 5-month evaluation – that is, a DAS28 below 2.6 – had a 79% lower ACS risk than did those with a DAS28 of 2.6 or above.
"This is dramatic," Dr. Ljung said in an interview. "I think it’s the first time we see a population in our RA cohorts that doesn’t have any proven cardiovascular risk increase compared with the general population. But it raises additional questions, of course, such as who are these patients who receive the good response: Is it due to factors related to their disease or background that gives them the opportunity to have the good response? We adjusted for a number of factors, but still ..."
She added that these studies contain two key take-home messages for rheumatologists: "I think the first thing for us to do is to treat our patients’ inflammation perfectly using traditional and biologic DMARDs. And the second thing is to be more aware of the traditional risk factors and start modifying those more aggressively for our patients."