Immunotherapy reduces CVD risk in patients with RA

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Immunotherapy reduces cardiovascular disease (CVD) risk in patients with rheumatoid arthritis (RA), according to research presented at Frontiers in CardioVascular Biology 2016.

Professor Aida Babaeva, head of the department of internal medicine, Volgograd State Medical University, Volgograd, Russia, found that the combination of two extra-low dose anticytokine drugs reduced rheumatoid arthritis disease activity and cardiovascular events.

“Rheumatoid arthritis is an autoimmune disease in which cytokines such as tumour necrosis factor (TNF) and interferon (IFN), which normally protect the body, attack healthy cells,” said Babaeva. “Patients have painful and inflamed joints. They are also at increased cardiovascular risk, particularly if their rheumatoid arthritis is not controlled.”

Babaeva’s previous research showed that treatment with anticytokine drugs can decrease the activity of rheumatoid arthritis. Extra-low dose anti-TNFα reduced levels of inflammatory mediators and cytokines including C-reactive protein (CRP), rheumatoid factor, TNF, interleukin-1 (IL-1), and interleukin-6 (IL-6). The effect was more apparent and developed earlier when patients were treated with a combination of anti-TNFα and anti-IFNƔ, both at extra-low doses.

The current study investigated the impact of the combination of drugs on cardiovascular events. It included 68 patients who had suffered from active rheumatoid arthritis for at least five years. Patients were randomised to receive the combination of anti-TNFα and anti-IFN plus standard disease-modifying therapy (38 patients) or placebo plus standard therapy (30 patients). During the three year follow up period the investigators monitored rheumatoid arthritis disease activity and cardiovascular events.

Patients taking the combination of anticytokines had a lower rheumatoid arthritis disease activity score, as measured by the DAS28,2 and more dramatic decreases in IL-1, IL-6 and TNFα than the group on standard therapy alone.

The incidence of cardiovascular events (unstable angina, severe hypertensive crisis, and deterioration of chronic heart failure) was more than double in the group on conventional disease-modifying drugs alone (37%) compared to those also taking the combination of anticytokines (13%).

Babaeva said: “Our findings suggest that the decreased rheumatoid arthritis disease activity with the combination of anticytokines translates into decreased cardiovascular risk. Rheumatoid arthritis promotes the development of cardiovascular disease in a number of ways. Therefore, decreasing disease activity may also reduce cardiovascular risk by slowing down or halting these processes.”

For example, rheumatoid arthritis is associated with dysfunction of the blood vessel lining (called endothelium), which leads to lipid accumulation in the artery wall, plaque formation and atherosclerosis. Increased disease activity is also linked with a pro-coagulant state in which patients are more prone to blood clots and thrombosis. Patients with active disease have an increase in molecules that promote inflammation, which has been associated with an increased risk of cardiovascular disease.

In patients with hypertension, target blood pressure was reached in 71% of those taking the combination of anticytokines compared to just 32% of patients on standard therapy alone.

Babaeva said: “This doesn’t mean that the two drugs directly impact on blood pressure. But the combination can improve endothelial function and it could be that blood pressure is more stable when disease activity is low.” “We found that the combination of two anticytokines containing extra-low doses of antibodies against TNFα and IFN can improve the efficacy of standard rheumatoid arthritis therapy and decrease cardiovascular risk,” said Babaeva.

She concluded: “We do not think that all patients with rheumatoid arthritis should be treated with this combination. In patients with highly active disease, the standard biologics are better at preventing severe complications such as progressive joint destruction and/or systemic manifestations (vasculitis, uveitis, involvement of internal organs). We recommend this new approach for preventing cardiovascular events in patients with moderate disease activity who are not receiving the standard biologics and who do not have severe complications.”

Background: Rheumatoid arthritis (RA) is characterized by increased cardiovascular risk (CVR), associated with erosive arthritis, high activity and positive rheumatoid factor (RF). These features are considered as additional risk factors for CV events. In our previous studies we defined the efficacy of anti-TNFα antibodies in combination with anti-IFNγ antibodies (both in extra-low dose) in pts with RA.
Aims: to assess the influence of combination of arthtofoon (anti-TNFα in extra-low dose) and anaferon (anti-IFNγ in extra-low dose) on CVR factors in pts with RA in opened placebo-controlled study.
Methods: 68 pts with active RA enrolled into investigation were divided randomly on two cohorts. The 1st cohort (38 pts) was treated with combination of arthrofoon and anaferon, which was added to standard therapy. The 2nd one (30 pts) received placebo of these drugs and standard therapy. We monitored the clinical and laboratory parameters of RA activity, CVR and registered the incidence of CV events during the 3 years period.
Results: All RA pts met the criteria of high/very high CVR. There were no significant differences in demographic and clinical characteristics of compared cohorts as well as in baseline laboratory data. We defined the significant impact of combination of arthrofoon and anaferon on RA activity: disease activity score (DAS28) and plasma levels of IL1β, IL6, TNFα decreased more dramatically in the 1st cohort than in 2nd one. The target blood pressure was reached in 70.6% pts from the 1st cohort (24 pts from 34 pts with AH), whereas in the 2nd one only 32% pts (9 from 28 hypertensives) reached and maintained target BP. The incidence of CV events (unstable angina, sever hypertensive crisis, deterioration of chronic heart failure) was fewer in 1st cohort (13.2%) than in 2nd (36.7%).
Conclusions: Combination of two anti-cytokines, containing extra-low doses of antibodies against TNFα and IFNγ can improve the efficacy of RA therapy and can decrease CVR.

AR Babaeva, KS Solodenkova, EV Kalinina, MN Usachiova

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