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

Table 1 Pathogenetic similarities between rheumatoid arthritis and atherosclerosis

Pathogenic mechanism	Rheumatoid arthritis	Atherosclerosis	Common features
Chronic inflammation	Synovial membrane activation, TNF-α, IL-1β, IL-6 release	Vascular wall inflammation, same cytokines	Systemic inflammation, TNF-α/IL-6 role
Autoimmune component	Autoantibodies (RF, ACPA)	Autoantibodies to oxidized LDL	Immune complexes, Th1 response
Macrophage activation	Synovial infiltration → pannus formation	Oxidized LDL uptake → foam cells	Macrophages as key effectors
Oxidative stress	ROS-mediated cartilage & synovium damage	LDL oxidation → plaque formation	ROS-driven tissue destruction
Endothelial dysfunction	Microangiopathy, synovial neovascularization	Impaired vascular barrier function	VCAM-1/ICAM-1 upregulation
Neoangiogenesis	Angiogenesis in synovium → arthritis progression	Plaque instability due to new vessels	Pathological vessel growth
Fibrosis/tissue remodeling	Joint deformity (excess collagen)	Fibrous cap formation on plaques	Fibroblast activation
Biomarkers	CRP, ACPA, RF	CRP, oxidized LDL, IL-6	Shared markers (CRP, IL-6)

TNF-α: Tumor necrosis factor-α; IL-1β: Interleukin-1β; IL-6: Interleukin-6; VCAM-1: Vascular cell adhesion molecule-1; ICAM-1: Intercellular adhesion molecule-1; LDL: Low-density lipoprotein; CRP: C-reactive protein; ACPA: Anti-citrullinated protein antibodies; RF: Rheumatoid factor; Th1: T-helper 1 cells; ROS: Reactive oxygen species.

Table 2 Role of cytokines in the pathogenesis of rheumatoid arthritis and cardiovascular disease

Cytokine	Major sources	Effects in RA	Effects in CVD	Common pathogenic effects
TNF-α	Macrophages, Th1 cells, adipocytes	Activates synovial fibroblasts	Endothelial dysfunction	NF-κB activation
		Stimulates osteoclasts (via RANKL)	Increased leukocyte adhesion	Induction of cellular apoptosis
		Induces MMP-9 production	Atherosclerotic plaque destabilization	Stimulation of IL-6 production
IL-6	Macrophages, Th1 cells, adipocytes	Stimulates B-cells (RF production)	Enhances fibrinogen synthesis	JAK/STAT pathway activation
		Induces acute-phase proteins (CRP, SAA)	Promotes cardiomyocyte hypertrophy	Induction of insulin resistance
		Causes anemia of chronic disease	Accelerates atherogenesis
IL-1β	Macrophages, neutrophils	Stimulates chondrocyte protease production	Increases platelet aggregation	NLRP3 inflammasome activation
		Induces fever and pain	Upregulates adhesion molecules (VCAM-1)	Angiogenesis stimulation
		Activates osteoclasts	Plaque destabilization
IL-17	Th17 cells, γδT cells	Promotes synovial neoangiogenesis	Increases endothelial ET-1 production	MAPK pathway activation
		Induces neutrophil infiltration	Promotes myocardial fibrosis	Stimulates IL-6 production
		Synergizes with TNF-α	Enhances oxidative stress
IL-10	Tregs, B-cells, macrophages	Suppresses TNF-α and IL-6 production	Stabilizes atherosclerotic plaques	NF-κB inhibition
		Inhibits Th17 activation	Reduces leukocyte adhesion	SOCS3 stimulation
IFN-γ	Th1, natural killer cells	Activates synovial macrophages	Increases plaque vulnerability	STAT1 activation
		Inhibits Th17 differentiation	Stimulates smooth muscle cell apoptosis	Enhances MHC II expression

TNF-α: Tumor necrosis factor-α; IL-6: Interleukin-6; IL-1β: Interleukin-1β; IL-17: Interleukin-17; IL-10: Interleukin-10; IFN-γ: Interferon-gamma; T-helper 1/17: Lymphocyte subsets (Th1; Th17); γδT: Gamma-delta T cells; Tregs: Regulatory T cells; RANKL: Receptor activator of nuclear factor kappa-B ligand; MMP: Matrix metalloproteinase; VCAM-1: Vascular cell adhesion molecule-1; ET-1: Endothelin-1; MHC II: Major histocompatibility complex class II; CRP: C-reactive protein; SAA: Serum amyloid A; CVD: Cardiovascular disease; RA: Rheumatoid arthritis.

Table 3 Comparison of CANTOS and CIRT trials: Impact of anti-inflammatory therapy on cardiovascular outcomes

Criterion	CANTOS (2017)	CIRT (2019)
Study drug	Canakinumab (IL-1β inhibitor)	Methotrexate
Study objective	Evaluate IL-1β suppression on cardiovascular outcomes	Test if low-dose immunosuppression reduces CVD risk
Design	Double-blind, placebo-controlled, multicenter	Double-blind, placebo-controlled, multicenter
Patient population	10061 patients with CAD and hs-CRP ≥ 2 mg/L	4786 patients with CAD/metabolic syndrome + diabetes/obesity
Primary outcomes	15% reduction in acute coronary syndrome (MI, unstable angina, cardiac death) (P = 0.007)	No significant effect: No difference in CVD outcomes vs placebo (P = 0.67)
	37%-41% reduction in hs-CRP
Effect on inflammation	Sustained reduction in IL-6 and hs-CRP	Minimal impact on CRP
Adverse effects	↑ Fatal infections (0.18 vs 0.06 per 100 person-years)	↑ Liver enzyme abnormalities
	↑ LDL levels	↑ Leukopenia risk
Conclusions	Hypothesis confirmed: IL-1β is a valid target for secondary CVD prevention	Hypothesis rejected: Methotrexate does not reduce CVD risk in this population

IL-1β: Interleukin-1β; hs-CRP: High-sensitivity C-reactive protein; CAD: Coronary artery disease; MI: Myocardial infarction; CVD: Cardiovascular disease; LDL: Low-density lipoprotein.

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).

Table 5 The negative effects of methotrexate on the cardiovascular system

Effect	Pathogenesis
Cardiomyopathy	Folate depletion → impaired myocardial energy metabolism Oxidative stress and mitochondrial dysfunction
	Accumulation of adenosine → vasodilation and reduced contractility
Accelerated atherosclerosis	Hyperhomocysteinemia (due to folate antagonism) → endothelial dysfunction
Vascular toxicity	Endothelial injury due to oxidative stress
	Reduced nitric oxide bioavailability
	Increased homocysteine → vascular smooth muscle proliferation
Hypertension	Renal toxicity → sodium retention
	Endothelial dysfunction → impaired vasoregulation
Heart failure	Direct myocardial toxicity (similar to cardiomyopathy)
	Fluid retention due to renal impairment
Arrhythmias	Electrolyte imbalances (e.g., hypokalemia from nephrotoxicity) QT prolongation (rare, linked to high-dose MTX)

MTX: Methotrexate.

Table 6 Comparative safety of disease-modifying antirheumatic drugs: Cardiovascular risks and patient considerations

Drug class	Drug	Prevention of adverse cardiovascular effects methods	Preferred patient category	Safety comparison
csDMARDs	Methotrexate	Homocysteine control (target level < 10 μmol/L); Folic acid supplementation (5-10 mg/day)-reduces the risk of hyperhomocysteinemia by 50%-70%. Regular monitoring: Blood pressure (BP), ECG, echocardiography (EchoCG) (with long-term use). Lipid profile, homocysteine levels (every 6-12 months)	Patients without severe cardiovascular disease	Safer than bDMARDs and tsDMARDs but requires monitoring
	Sulfasalazine	Caution in patients with conduction disorders; Use validated risk scores: SCORE2/SCORE2-OP for estimating 10-year CVD risk, QRISK3; Baseline & periodic evaluation: Lipid profile (LDL-C, HDL-C, triglycerides), hs-CRP, homocysteine (if high CVD risk). BP monitoring; ECG/Echocardiography	Patients with mild RA	Safer than biologics but less effective
	Leflunomide	BP control, salt restriction	Patients without a history of HTN	Similar to MTX in safety but more likely to cause HTN
	Hydroxychloroquine	ECG monitoring (QT interval). Before starting therapy: Measure baseline QT (corrected using Fridericia’s formula- QTc). Assess risks if QTc > 450 ms in men or > 470 ms in women (consider alternative medications). Repeat ECG 3-5 days after initiation and after each dose increase. Correction of electrolyte imbalances: Hypokalemia (K+ < 3.5 mmol/L) and hypomagnesemia (Mg2+ < 0.7 mmol/L) increase arrhythmia risk	Patients with very mild RA or SLE	Safest in this group but requires QT interval monitoring
bDMARDs (TNF inhibitors)	Adalimumab	Avoid in patients with HF class III-IV	Patients without severe CVD	Higher infection risk but lower CV risk than JAK inhibitors
	Certolizumab	BP monitoring, cardiac function assessment	Pregnant women (low placental transfer)	Similar to other TNF inhibitors
	Etanercept	Caution in HF	Patients with moderate CV risk	Considered safer than infliximab
	Golimumab	Monitor BP and HF symptoms	Patients intolerant to other TNF inhibitors	Comparable to other TNF inhibitors
	Infliximab	Avoid in HF class II–IV	Patients with severe RA but no CVD	Highest HF risk among TNF inhibitors
Other bDMARDs	Abatacept	BP control, ECG if risk factors present	Patients at high infection risk	Safer than TNF inhibitors regarding HF
	Anakinra	Not required	Patients with concomitant atherosclerosis	One of the safest biologics
	Sarilumab/Tocilizumab	Lipid monitoring, statins if needed	Patients without severe dyslipidemia	Higher CV risk than TNF inhibitors but lower than JAK inhibitors
	Olokizumab	Lipid profile monitoring	Patients resistant to other IL-6 inhibitors	Presumed similar to tocilizumab
	Rituximab	Premedication, slow infusion	Patients with lymphoproliferative disorders	Neutral CV effects but risk of infusion-related hypotension
tsDMARDs (JAK inhibitors)	Baricitinib	Avoid in patients with thrombosis history, BP control, anticoagulants for AF	Younger patients without thrombosis risk factors	Least safe regarding CV risk (FDA, EMA warning-thrombosis, MI, stroke)
	Tofacitinib	Lipid monitoring, BP control, avoid in smokers/obese patients	Patients unresponsive to bDMARDs	High CV risk, especially in smokers
	Upadacitinib	Thrombosis risk assessment before prescribing	Patients intolerant to other JAK inhibitors	Similar to other JAK inhibitors
	Filgotinib	General precautions as for other JAK inhibitors	Limited use, caution required	Presumed similar to tofacitinib

DMARDs: Disease-modifying antirheumatic drugs; RA: Rheumatoid arthritis; SLE: Systemic lupus erythematosus; CVD: Cardiovascular disease; HTN: Hypertension; HF: Heart failure; MI: Myocardial infarction; AF: Atrial fibrillation; LDL-C: Low-density lipoprotein cholesterol; ECG: Electrocardiogram; tsDMARDs: Targeted synthetic DMARDs; bDMARDs: Biologic DMARD; TNF: Tumor necrosis factor; IL-6: Interleukin-6; HDL-C: High-density lipoprotein cholesterol; hs-CRP: High-sensitivity C-reactive protein.