MI Risk 39% Lower for Patients With RA Taking TNF Inhibitors

Janis C. Kelly

February 16, 2017

Tumor necrosis factor inhibitors (TNFis) can protect patients with rheumatoid arthritis (RA) from the high cardiovascular risk associated with RA, according to a major analysis of data from the British Society for Rheumatology Biologics Register.

The researchers suggest this might reflect either generally lower inflammation levels resulting from better RA disease control or a direct effect of TNFis on the atherosclerotic process. The TNFis studied included etanercept, infliximab, or adalimumab.

Audrey S. I. Low, MD, from the Arthritis Research UK Centre for Epidemiology, Centre for Musculoskeletal Research, Institute of Inflammation and Repair, University of Manchester, United Kingdom, and colleagues report their analysis in an article published online January 10 in the Annals of the Rheumatic Diseases.

Coauthor Deborah P. M. Symmons, MD, professor of rheumatology and musculoskeletal epidemiology, Arthritis Research UK Centre for Epidemiology, University of Manchester, told Medscape Medical News. "This suggests that cumulative inflammation may play a role in atherosclerosis and that successful suppression of inflammation is beneficial with regards to the heart."

The researchers compared registry data for 11,200 patients with RA who received TNFis and for 3058 similar patients treated with synthetic disease-modifying antirheumatic drugs (sDMARDs) during 2001 to 2009 and found that TNFi treatment was associated with a significant reduction in myocardial infarction (MI) risk compared with sDMARD treatment (hazard ratio, 0.61).

There were no significant differences in MI severity or in mortality during the median follow-up of 5.3 years for TNFi patients and 3.5 years for sDMARD patients. Logistic regression covariates included age, sex, Disease Activity Score 28, disease duration, health assessment questionnaire score, prior use of four or more sDMARDs, entry before the midpoint of the study, hypertension, diabetes, chronic lung disease, smoking, antiplatelet therapy, and use of nonsteroidal anti-inflammatory drugs, cyclooxygenase-2 inhibitors, glucocorticoids, or statins.

Study Highlights Importance of RA Disease Control for the Heart

"The data presented in the study support the concept that disease control is important to reduction of risk for cardiovascular events in patients with rheumatoid arthritis. This supports the findings of other studies of this question," Eric Matteson, MD, a rheumatologist at Mayo Clinic in Rochester, Minnesota, told Medscape Medical News. Dr Matteson was not involved in the study. "In my view, because of potential channelling bias and because of lack of directly comparable intervention groups and comparator subjects, it is unclear how much of this risk reduction may be due to the biologics, but the case is made that they play an important role in the risk reduction."

Dr Symmons said the lack of overall difference in MI severity or mortality may mean that the mechanisms preceding MI (gradual build-up of plaque and occlusion of one or more coronary arteries) might differ from the mechanisms of tissue damage and repair after the episode of ischaemia. "It could be that cumulative inflammation and TNF have a part to play in the mechanisms of MI onset and not in the mechanisms which come into play immediately post-MI," Dr Symmons said.

Suggestion of a Benefit for TNFis on 6-Month Post-MI Mortality

Six-month mortality was 32% lower in patients who were taking TNFis at the time of MI, but this was not statistically significant because of the low numbers of deaths (25 [13%] in those taking TNFis at the time of MI vs 12 [21%] in those who had never taken TNFis). Mortality was three times higher in those who had taken but discontinued TNFis (95% confidence interval, 1.42 - 6.62). Dr Symmons said this higher mortality might reflect the effect of reasons the TNFi was stopped, such as comorbidities.

Dr Symmons said, "This study is in keeping with the hypothesis that cumulative inflammation in patients with RA leads to accelerated atherosclerosis. Suppressing the inflammation (in this case with TNFi) appears to slow down the process, and therefore it delays the time at which the artery may become occluded."

Dr Symmons cautioned against overgeneralizing these results. "Our results can only be generalized to the type of patients who were recruited to the [British Society for Rheumatology Biologics Register]. Our study is large, and patients are followed for longer than some other studies, which mean that the results are robust. However, we cannot automatically generalize our results to situations in which TNFi are prescribed only to much sicker or much healthier subjects."

"The study supports the importance of the approach of achieving best possible disease control in RA, as it reduces not only direct morbidity from the disease but also [comorbidity] from cardiovascular disease," Dr Matteson added.

TNFi Cardioprotection in RA to Be Studied in Randomized Controlled Trial

The apparent protection that TNFis provide against cardiovascular disease in RA will soon be studied in a new prospective, randomized controlled trial supported by the National Institutes of Health. Daniel H. Solomon, MD, MPH, professor of medicine, Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, told Medscape Medical News that the British study "adds to the accumulating evidence that [TNFis] are more effective at reducing cardiac inflammation in RA patients than conventional triple-drug therapy with methotrexate, sulfasalazine, and hydroxychloroquine."

Dr Solomon is coprincipal investigator, with Joan Bathon, MD, for the Treatments Against RA and Effect on imaging (TARGET) Trial. That study will compare the effects on vascular inflammation in patients with RA of TNFis (such as etanercept and adalimumab) with the effects of triple-drug therapy. The TARGET researchers are currently recruiting 200 patients to be randomly assigned to the two treatment groups. They will use imaging to monitor vascular inflammation in patients with RA receiving the two regimens and to compare vascular inflammation in subjects who do vs those who do not achieve remission.

The study was supported by the British Society for Rheumatology, which receives restricted income from AbbVie, Celltrion, Hospira, Pfizer, UCB, and Roche, and in the past Swedish Orphan Biovitrum and Merck; by the National Institute for Health Research; and by the Arthritis Research UK Centre for Epidemiology. One coauthor has received honoraria from Pfizer and AbbVie. One commentator has disclosed research funding, consulting fees, or honoraria from Janssen, Amgen, Roche, Mesoblast, Novartis, Pfizer, Bristol Myers-Squibb, and Genentech. Another commentator has disclosed research grants from Amgen, Lilly, and Corrona; and served in an unpaid position on a trial sponsored by Pfizer, Novartis, Lilly, and Bristol-Myers Squibb. The other authors have disclosed no relevant financial relationships.

Ann Rheum Dis. Published online January 10, 2017. Full text

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