Successful anti-TNF therapy may cancel excess coronary risk in RA

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.

‘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.”

The Swedish Biologics Register is funded by the Swedish Rheumatology Association, with support from half a dozen pharmaceutical companies. Dr. Ljung disclosed ties with AbbVie and Bristol-Myers Squibb.

http://www.ecardiologynews.com/single-view/successful-anti-tnf-therapy-may-cancel-excess-coronary-risk-in-ra/b5c011441103b562af236684c1920cf3.html

The heart’s intrinsic pacemaker

A specific cell population is responsible for ensuring that our heartbeat remains regular. LMU researchers have now elucidated the mode of action of one of the crucial components of the heart’s intrinsic pacemaker.

The heart possesses a pacemaker of its very own. Specialized pacemaker cells in the so-called sinoatrial node in the left ventricle of the heart control its rate of contraction and relaxation by orchestrating a recurring sequence of electrical signals. Specific proteins known as HCN channels, which are located in the surface membranes of pacemaker cells, play a central role in the generation and transmission of these signals. These proteins function as pores for the passage of electrically charged atoms (ions) across the cell membrane. Because the pore diameter can be regulated, the channels can control the flow of ions across the membrane, and thus determine the difference in electrical potential between the inner and outer surfaces of the cell. Cyclical changes in this parameter give rise to autonomously generated, rhythmic electrical impulses that dictate heartbeat and cardiac rhythmicity.

HCN channels are found primarily in the heart and in the brain, and come in four subtypes, HCN1-4. HCN4 is responsible for about 80% of the total ion current that passes through HCN channels in the sinoatrial node. The other 20% is carried by HCN1 and HCN2. “But while the functions of HCN2 and HCN4 in the sinoatrial node have been extensively studied, the impact of HCN1 on heart rate has so far remained unknown,” says Professor Christian Wahl-Schott of the Department of Pharmacy at LMU, who has now closed this gap in our knowledge of the heart’s intrinsic pacemaker.

Wahl-Schott and his team and also researchers from Professor Martin Biel’s group, tackled the problem by using a mouse strain in which the HCN1 channels in the cells of the sino-atrial node are defective. With the aid of this new experimental model, they were able to demonstrate, for the first time, that HCN1 is involved not in generating the electrical impulse but also in its propagation within the node. Defects in HCN1 function compromise the normal operation of the pacemaker. This results in bradycardia ­- a pathological reduction in heart rate – and increases the incidence of arrhythmias. As a consequence, overall cardiac output is significantly reduced. “We were also able to confirm these effects in vivo by means of telemetric electrocardiography,” Wahl-Schott adds.

Defects in cells of the sino-atrial node are associated with sudden cardiac arrest, and more than half of all implantations of artificial pacemakers worldwide are carried out on patients who suffer from such conditions. But the new findings regarding the role of HCN1 in the regulation of heart function are actually of clinical interest for two reasons. On the one hand, this channel subtype offers a promising target for drugs designed to normalize heartbeat frequency. However, HCN1 is also found in nerve cells in the brain, where it likewise acts to control rates of neural firing. This explains why HCN1 blockers are under consideration for use in the treatment of epilepsy, chronic pain and depression. “In light of our results, the potential effects of HCN1 blockers on cardiac function should be carefully assessed before such agents are used in other contexts,” Wahl-Schott warns.

http://www.medicalnewstoday.com/releases/268746.php