Therapeutic potential of folic acid supplementation for cardiovascular disease prevention through homocysteine lowering and blockade in rheumatoid arthritis patients

Abstract

Rheumatoid arthritis (RA) is a chronic inflammatory disease that preferentially affects joints, and characterized by an approximately two-fold increased risk of cardiovascular diseases compared with the general population. Beyond classical cardiovascular risk factors, systemic inflammatory markers are primarily involved. Hence, anti-inflammatory strategies such as homocysteine-lowering interventions are warranted. Indeed, hyperhomocysteinemia is commonly found in RA patients as a result of both genetic and non-genetic factors including older age, male gender, disease-specific features and disease-modifying antirheumatic drugs. Most importantly in the pathophysiology of hyperhomocysteinemia and its related cardiovascular diseases in RA, there is a bi-directional link between immuno-inflammatory activation and hyperhomocysteinemia. As such, chronic immune activation causes B vitamins (including folic acid) depletion and subsequent hyperhomocysteinemia. In turn, hyperhomocysteinemia may perpetrate immuno-inflammatory stimulation via nuclear factor ƙappa B enhancement. This chronic immune activation is a key determinant of hyperhomocysteinemia-related cardiovascular diseases in RA patients. Folate, a homocysteine-lowering therapy could prove valuable for cardiovascular disease prevention in RA patients in the near future with respect to homocysteine reduction along with blockade of subsequent oxidative stress, lipid peroxidation, and endothelial dysfunction. Thus, large scale and long term homocysteine-lowering clinical trials would be helpful to clarify the association between hyperhomocysteinemia and cardiovascular diseases in RA patients and to definitely state conditions surrounding folic acid supplementation. This article reviews direct and indirect evidence for cardiovascular disease prevention with folic acid supplementation in RA patients.

Keywords: Cardiovascular diseases; Folic acid supplementation; Hyperhomocysteinemia; Inflammatory biomarkers; Prevention; Rheumatoid arthritis.

Fig. 1

Homocysteine metabolism and major factors associated with hyperhomocysteinemia in rheumatoid arthritis patients. MTHFR methylene tetrahydrofolate; CBS cystathione β synthase; BHMT betaine homocysteine methyltransferase; MS methionine synthase; Vit vitamin; DMARDs disease-modifying antirheumatic drugs. Vit B9 depletion owing to immuno-inflammatory activation, DMARDs, and gastrointestinal disturbance impairs the MTHFR vit B9-dependent remethylation pathway together with the MTHFR C677T mutation; vit B12 depletion owing to both immuno-inflammatory activation and gastrointestinal disturbance impairs the MS vit B12-dependent remethylation pathway; vit B6 depletion owing to immuno-inflammatory activation and gastrointestinal disturbance impairs the CBS vit B6-dependent transsulfuration pathway

Fig. 2

Mechanisms explaining homocysteine-related cardiovascular diseases at large. Dark arrow main mechanisms; dotted arrow minor mechanism. HHcy Hyperhomocysteinemia; NO nitric oxide; DNA deoxyribonucleic acid; ADMA asymmetric dymethyl arginine; ox-LDL oxidized low density lipoprotein cholesterol; CVD cardiovascular diseases. Through S-nitrosohomocysteine, ADMA and oxidative stress, HHcy reduces NO bioavailability, thus causing endothelial dysfunction. Under high propensity for coagulation (characterized by platelet adhesion and activation, production of clotting molecules, impaired fibrinolysis) that can be exacerbated by HHcy, endothelial dysfunction evolves towards atherothrombosis. Besides, HHcy-related oxidative stress increases ox-LDL production hence leading to formation of the atheromatous plaque which together with arterial smooth muscle cells proliferation trigger atherosclerosis. Atherosclerosis and atherothrombosis (completed atherosclerosis with ruptured plaque and thrombosis) lead to CVD