From joints to vessels: How rheumatoid arthritis therapy alters the fate of the heart

Table 4 Comprehensive classification of disease-modifying antirheumatic drugs by mechanism of action

Drug class/target	Mechanism of action	CVD benefit/risks	Specific drugs (examples)	Key characteristics
Conventional synthetic DMARDs
Folate antagonists	Inhibits dihydrofolate reductase → ↓ purine synthesis → lymphocyte apoptosis	↓Cardiovascular mortality	Methotrexate	Gold standard for RA
	↑ Extracellular adenosine			Weekly dosing (SC/PO)
	↓ TNF-α/IL-6			Requires folate supplementation
Pyrimidine synthesis inhibitors	Blocks dihydroorotate dehydrogenase (DHODH) → ↓ lymphocyte proliferation	Neutral/↑ hypertension	Leflunomide	Teratogenic (requires washout)
				Active metabolite (teriflunomide)
NF-κB inhibitors	Scavenges ROS, inhibits NF-κB → ↓ TNF-α/IL-6	↓ Oxidative stress in endothelium	Sulfasalazine	Split into 5-ASA (gut) + sulfapyridine (systemic)
				Safe in pregnancy
Lysosomotropic agents	↑ Lysosomal pH → ↓ TLR7/9 signaling and antigen presentation	Anti-thrombotic (↓ platelet aggregation)	Hydroxychloroquine	Slow onset (3-6 months)
				Retinopathy risk at high cumulative doses
Biologic DMARDs
TNF-α	Neutralizes soluble/membrane-bound TNF ↓ IL-1/6/8, ↓ metalloproteinases	↑ Endothelial function	Adalimumab, Infliximab	First-line biologics
				Screen for TB/HBV
IL-6 pathway	Blocks IL-6 receptor or ligand: ↓ JAK/STAT3, ↓ Th17 differentiation	↓ LDL oxidation	Tocilizumab, Olokizumab	Rapid CRP reduction
				May ↑ LDL
T-cell Co-stimulation	CTLA4-Ig binds CD80/86 → ↓ T-cell activation	↓ Atherosclerosis progression	Abatacept	Lower infection risk vs anti-TNF
B-cell Depletion	Anti-CD20 → B-cell lysis ↓ Autoantibodies, ↓ Antigen presentation	↓ Atheroma progression	Rituximab	Preferred for seropositive RA
				Prolonged hypogammaglobulinemia risk
IL-1	Recombinant IL-1 receptor antagonist	Reducing atherosclerotic progression and stabilizing plaques	Anakinra	Limited use in RA (more for autoinflammatory diseases)
Targeted synthetic DMARDs
JAK inhibitors	Blocks JAK-STAT signaling: ↓ IFN-γ, IL-6, IL-15 signaling; ↓ GM-CSF, IL-12/23 pathways	↑ LDL Potential ↑ thrombosis	Tofacitinib, Upadacitinib	Oral administration
				Boxed warning for thrombosis
				Avoid in elderly smokers

DMARDs: Disease modifying antirheumatic drugs; CVD: Cardiovascular disease; RA: Rheumatoid arthritis; 5-ASA: 5-aminosalicylic acid; DHODH: Dihydroorotate dehydrogenase; ROS: Reactive oxygen species; TLR7/9: Toll-like receptor 7/9; TNF-α: Tumor necrosis factor-α; IL-1/6/8: Interleukin-1/6/8; TB: Tuberculosis; HBV: Hepatitis B virus; Th17: T-helper 17 cells; CTLA4-Ig: Cytotoxic t-lymphocyte: Associated protein 4 immunoglobulin; IFN-γ: Interferon-Gamma; GM-CSF: Granulocyte-macrophage colony-stimulating factor; LDL: Low-density lipoprotein; CRP: C-reactive protein; ACS: Acute coronary syndrome; SC: Subcutaneous; PO: Per os (oral).