Cardiovascular Risk Associated With TNF Alpha Inhibitor Use in Patients With Rheumatoid Arthritis

Abstract

Rheumatoid arthritis (RA) is an autoimmune disease characterized by inflammation and pannus formation, with subsequent joint and cartilage degradation. Treatment commonly targets inflammatory cytokines, including tumor necrosis factor (TNF) alpha, which is a potent inflammatory cytokine required for cell signaling, regulation, and apoptosis, as well as for other cellular functions including immune response. TNF alpha inhibitors have demonstrated benefits in improving RA patient outcomes in terms of immune function and symptomatology. While TNF alpha inhibitors are generally beneficial, some studies have demonstrated that TNF alpha inhibitors may increase the risk of adverse cardiovascular events. While this continues to be debated, our study investigates the role of Tumor Necrosis Factor Receptor 1 (TNFR1) and Tumor Necrosis Factor Receptor 2 (TNFR2) in cardiac tissue. TNFR1 is an apoptotic receptor and its inhibition by TNF alpha inhibitors is subsequently cardioprotective. However, TNF alpha inhibitors may be inhibiting TNFR2 receptors even more so than TNFR1 receptors. TNFR2 is primarily a cardioprotective receptor and its greater inhibition results in the cardiovascular morbidity associated with TNF alpha inhibitors.

Metabolic Abnormalities, Cardiovascular Disease, and Metabolic Syndrome in Adult Rheumatoid Arthritis Patients: Current Perspectives and Clinical Implications

“…That is why they have been involved in deteriorating patients with heart failure. 95 However, other studies have shown that anti-TNF therapy reduces subclinical myocardial inflammation and improves cardiovascular function in patients with rheumatic diseases, including RA. 96 Additionally, it has been demonstrated that TNF-α blocking agents may be related to reduced risk of cardiovascular events compared to non-biological DMARDs.…”

The Effect of TNF-α on CHD and the Relationship between TNF-α Antagonist and CHD in Rheumatoid Arthritis: A Systematic Review

“…TNF- α plays an important role in this pathological process [ 98 ]. Patients with RA are systemically predisposed to high levels of TNF- α [ 99 ]. It is generally accepted that RA and atherosclerosis are autoinflammatory diseases involving multiple inflammatory cytokines, with many common genetic predispositions and environmental factors [ 100 ].…”

“…Cardioprotective effects of TNF- α antagonists may be related to the inhibition of TNFR1 [ 123 ]. However, inhibition of TNFR2, a cardioprotective receptor, by TNF- α antagonists exceeds that of TNFR1, resulting in increased cardiovascular morbidity [ 99 ]. The contrast in the risk of CVD can be explained by the difference in doses administered, causing different degrees of inhibition in TNFR2.…”

Studies of effector molecules exerting autonomous and nonautonomous influence of T lymphocyte apoptosis under the conditions of in vitro “cell neighborhood” in healthy people and patients with rheumatoid arthritis

“…Как известно, фактор некроза опухоли альфа (TNFα), доминирующий медиатор воспаления в патогенезе РА, способствует прогрессированию симптомов РА и является внешним фактором, осуществляющим запуск рецепторного варианта апоптоза через семейство TNF-рецепторов. Специализированные рецепторы из семейства TNF для индукции апоптоза -CD95 (Fas/Apo-l), TNF-R1, TRAIL-Rl, TRAIL-R2Hflp, DR3, DR6, EDA-R и NGF-R, находятся на цитоплазматической мембране клеток [16]. Апоптоз, опосредованный рецептором CD95, Fas и другими членами данного семейства, образует мультибелковый комплекс, необходимый для взаимодействия с обязательными для индукции апоптоза адапторными молекулами, в том числе с доменом цитозольного проэнзима прокаспазы 8.…”

“…Помимо инициации апоптоза, лигирование рецепторов смерти также может вызывать некроптоз, при котором не происходит фрагментация ДНК, а гибель клетки по механизму некроптоза вызывает мощный иммунный ответ, в том числе и пролиферацию. Внешние пути апоптоза и некроптоза регулируют друг друга [16]. В другом исследовании характеризуют каспазу 8 как молекулярный переключатель, контролирующий апоптоз, некроптоз и пироптоз и предотвращающий повреждение тканей во время эмбрионального развития и взросления [12].…”