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

Abstract

Rheumatoid arthritis (RA) significantly increases the risk of cardiovascular diseases (CVD), including myocardial infarction (MI), stroke, and heart failure (HF). This association is linked to chronic inflammation, endothelial dysfunction, and accelerated atherosclerosis. Patients with RA have a 1.5-2 times higher risk of CVD compared to the general population, and cardiovascular mortality reaches 40%-50%. However, basic anti-inflammatory drugs such as methotrexate reduce the rate of cardiovascular events by 20%-30% due to suppression of systemic inflammation. Biological medications also demonstrate a cardioprotective effect, reducing the risk of MI by 20%-40%, although some (e.g., tumor necrosis factor α inhibitors) may increase the risk of HF in predisposed patients. Janus kinase inhibitors are associated with an increased risk of thrombosis and cardiovascular events, particularly in patients with pre-existing risk factors. Therefore, optimal control of inflammation in RA can reduce cardiovascular risk; however, drug selection should consider individual safety profiles. Regular monitoring of cardiovascular risk factors and a multidisciplinary approach are key to managing patients with RA and minimizing complications.

Key Words: Rheumatoid arthritis; Disease-modifying antirheumatic drugs; Cardiovascular events; Inflammation; Atherosclerosis

Core Tip: In this review, we analyze both the positive and negative influences on the cardiovascular system of all drugs currently used in rheumatological practice, including the most up-to-date therapies. Particular attention is given to the safety analysis of long-established drugs, whose effectiveness in treating rheumatoid arthritis is well established, while their cardiovascular safety has been studied to a much lesser extent.

INTRODUCTION

Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease characterized by progressive joint destruction due to erosive arthritis and a generalized autoimmune process, in which immune complexes and cytokines damage blood vessels and internal organs. A distinctive feature of RA is systemic inflammation, which contributes to a more severe course of comorbidities, including cardiovascular disease (CVD).

The prognosis in RA is determined less by chronic erosive arthritis and more by comorbid conditions, especially atherosclerosis-related pathology. A meta-analysis of prospective studies showed that the risk of cardiovascular mortality in patients with RA is 48% higher than in the general population[1]. Atherosclerosis in RA is characterized by multiple coronary artery lesions, early recurrence of acute coronary syndrome, increased mortality after the first myocardial infarction (MI), and a high frequency of asymptomatic MI[2-4].

Even before the development of RA or in its early stages, markers of cardiovascular system involvement can be detected in 35%-50% of cases. These markers include endothelial dysfunction, reduced elasticity of both small and large blood vessels, and diastolic myocardial dysfunction, the intensity of which increases with disease duration[5-7].

The accelerated development of atherosclerosis in patients with RA may be partly due to similar pathogenic mechanisms shared by both diseases (Table 1). Atherosclerosis can be considered a chronic inflammatory disease of blood vessels, characterized by lipid accumulation, leukocyte infiltration, and proliferation of vascular smooth muscle cells (VSMC)[8-10].

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.

An association has been established between elevated C-reactive protein (CRP) and erythrocyte sedimentation rate and the increased risk of MI and stroke in patients with RA[11,12]. Furthermore, the asymptomatic carrier state of rheumatoid factor or anti-cyclic citrullinated peptide antibodies is associated with increased CVD morbidity and mortality[13].

Cytokines link the pathogenesis of RA and CVD through shared mechanisms such as chronic inflammation, endothelial dysfunction, and oxidative stress (Table 2)[14-16]. Controlling the cytokine network is a key factor in reducing cardiovascular risk in patients with RA.

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.

The increased risk of CVD typically manifests in the presence of genetic predisposition and largely depends on traditional risk factors, such as arterial hypertension, diabetes mellitus, and obesity. It is further exacerbated by dyslipidemia, smoking, a sedentary lifestyle, family history of CVD, and menopause (Figure 1)[16-18]. However, RA and atherosclerosis share only partial similarities in their pathogenic mechanisms, with different pathways contributing to varying extents. Therefore, it cannot be unequivocally stated that anti-inflammatory therapy always reduces the risk of cardiovascular events, as demonstrated in the CANTOS and CIRT studies (Table 3)[19,20].

Figure 1 Shared pathogenesis of rheumatoid arthritis and cardiovascular disease. HLA-DRB1: Human leukocyte antigen DR beta 1; SE alleles: Shared epitope alleles; TNF-α: Tumor necrosis factor-α; HDACs: Histone deacetylases; Th17: T-helper 17 cells; IL-17A/F: Interleukin-17A/F; ACPA: Anti-citrullinated protein antibodies; RF: Rheumatoid factor; MMPs: Matrix metalloproteinases; RANKL: Receptor activator of nuclear factor Kappa-B ligand; OPG: Osteoprotegerin; LDL: Low-density lipoprotein; TXA2: Thromboxane A2; PAI-1: Plasminogen activator inhibitor-1; NO: Nitric oxide; ET-1: Endothelin-1; VCAM-1: Vascular cell adhesion molecule-1; ACS: Acute coronary syndrome; CRP: C-reactive protein; SAA: Serum amyloid A; PAD enzymes: Peptidylarginine deiminases; F2RL3: Coagulation factor ii receptor-like 3; VEGF: Vascular endothelial growth factor; FGF: Fibroblast growth factor.

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.

RA is characterized by the so-called lipid paradox: Low levels of total cholesterol, low-density lipoprotein (LDL), and high-density lipoprotein (HDL) in the presence of active inflammation. These levels tend to rise following the initiation of RA treatment, but this does not correlate with increased CVD risk. This paradox is likely due to the effects of cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), which increase LDL and SRB1 receptor activity on hepatocytes, leading to increased hepatic LDL uptake and cholesterol secretion into bile, thus reducing circulating LDL levels.

RA is also associated with an increased risk of heart failure (HF), predominantly with preserved ejection fraction[21]. Some data suggest that RA patients have twice the risk of developing HF compared to the general population[22]. This may result from accelerated atherosclerosis, impaired systolic and diastolic myocardial function, increased interstitial myocardial fibrosis, and reduced myofilament sensitivity to Ca²⁺ ions[23]. Rare complications of RA, such as myocarditis and amyloidosis, can also lead to HF.

Many disease-modifying antirheumatic drugs (DMARDs) are approved for RA treatment in clinical guidelines from different countries[24-26]. Continuous use of drugs from different classes of DMARDs is recommended: (1) Conventional synthetic DMARDs (csDMARDs): Methotrexate (MTX), sulfasalazine (SSZ), leflunomide (LEF), hydroxychloroquine (HCQ); (2) Biologic DMARDs (bDMARDs); (3) TNF inhibitors: Adalimumab, Certolizumab, Etanercept, Golimumab, Infliximab; (4) Cytotoxic T-lymphocyte-associated protein 4 immunoglobulin that inhibits T-cell co-stimulation: Abatacept; (5) Recombinant human IL-1 type I receptor antagonist: Anakinra; (6) IL-6 receptor inhibitors: Sarilumab, Tocilizumab; (7) Anti-IL-6 monoclonal antibody: Olokizumab; (8) Chimeric monoclonal antibody against CD20: Rituximab; (9) Targeted synthetic DMARDs (tsDMARDs); and (10) Janus kinase (JAK) inhibitors: Baricitinib, Tofacitinib, Upadacitinib, Filgotinib.

First-line treatment for RA involves csDMARDs, with MTX being the preferred choice (if no contraindications exist). In cases of MTX intolerance, it may be substituted with LEF, SSZ, or HCQ, either as monotherapy or in combination. If csDMARDs prove insufficiently effective, bDMARDs or tsDMARDs may be added or substituted. TNF inhibitors are the first-line bDMARDs, especially in seropositive RA with high disease activity. Other bDMARDs are typically reserved for patients with an inadequate response or intolerance to TNF inhibitors, with agent selection based on safety profiles and individual risk factors. JAK inhibitors are usually employed following failure of bDMARD therapy. The mechanisms of action of DMARDs in the context of RA and CVD development are summarized in Table 4.

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).

Given the key role of chronic inflammation and autoimmune dysfunction in the development of atherosclerosis and related cardiovascular complications in RA, effective anti-inflammatory therapy plays a vital role in prevention. Adequate inflammation control, tailored to the pathogenic overlap between these diseases, theoretically reduces the risk of cardiovascular events. In this regard, studying the cardiovascular effects of DMARDs is of undeniable importance.

DMARDS IMPACT ON CARDIOVASCULAR RISKS

Conventional synthetic DMARDs: MTX

MTX is currently the most commonly used drug in the treatment of RA. Its high efficiency has earned it the status of the “gold standard” in the treatment of this condition. Over the past decades, MTX has become the first-line drug for RA and the most frequently used component of combination therapy.

As mentioned, the CIRT trial, a double-blind, placebo-controlled study, demonstrated that low doses of MTX did not reduce the frequency of cardiovascular events, nor the levels of inflammatory cytokines such as CRP, IL-1β, and IL-6, compared to the placebo group. However, the study included patients with established ischemic heart disease and diabetes, metabolic syndrome, or both, but not patients with RA[20].

Other studies have shown different results when assessing the impact of MTX on cardiovascular events in patients with rheumatic diseases. A multicenter, prospective cohort study by Johnson et al[27], involving long-term follow-up of 2044 United States veterans with RA receiving MTX therapy, showed a 24% reduction in the risk of cardiovascular events, along with a 57% decrease in hospitalizations due to HF progression. Similar results were reported by the Veterans Affairs RA registry[28], which included 1015 participants. The study found that men with RA had a twofold higher mortality risk compared to the general population, associated with inflammatory activity, the presence of rheumatoid nodules, low body weight, and glucocorticoid use. However, MTX therapy, by effectively controlling chronic rheumatoid inflammation, reduced mortality risk by 40%, primarily due to decreased cardiovascular mortality. A notable limitation of both studies is that most participants were male, which restricts the generalizability of the findings to the broader RA population, where women statistically predominate.

In the study by Wasko et al[29], which included 5626 RA patients (75% women), it was demonstrated that over a 25-year prospective follow-up, long-term MTX use (over 1 year) was associated with a 70% reduction in mortality risk. Male sex, older age, high HAQ scores, glucocorticoid use, presence of HF, and cancer were identified as risk factors for death.

In addition to its impact on prognosis, studies have also examined the effect of MTX on classical CVD risk factors. According to Wållberg-Jonsson et al[30], RA patients receiving MTX demonstrated a 17.6% reduction in carotid intima-media thickness compared to controls, provided effective disease activity suppression was achieved. This highlights the influence of MTX on early atherosclerosis markers through anti-inflammatory mechanisms.

To date, numerous studies have investigated the effects of MTX on blood lipid profiles in RA patients, but the findings remain contradictory. Some report a reduction in the atherogenic index and blood anti-atherogenic lipoproteins in MTX-treated RA patients, correlating with decreased acute-phase reactant levels[31,32]. In contrast, other studies have shown no significant changes in lipid parameters[33,34].

The exact mechanisms by which long-term MTX therapy reduces CVD risk remain unclear. However, it is evident that this effect occurs alongside improved control of RA activity and systemic inflammation. As a result, the intensity of vascular dysfunction, underlying the development and progression of atherothrombosis, is reduced. Moreover, not only long-term but even single-dose MTX administration can lead to a decrease in acute-phase proteins, inhibition of neutrophil chemotaxis, reduction of toxic oxygen metabolite production, and prevention of leukocyte adhesion to the vascular endothelium[35].

Indirect mechanisms by which MTX influences the development of atherosclerosis and its complications in RA have also been discussed. According to Cronstein and Reiss[36], the favorable cardiovascular action of MTX may be linked to its primary pharmacological effects, specifically, the enhanced production of adenosine. This effect is mediated through G-protein signaling, which activates adenylate cyclase and T-cell activation[37]. Adenylate cyclase is abundant in the basal ganglia, vascular walls, and platelets. A2A and A1 receptors for endogenous adenosine play an important role in regulating coronary blood flow, myocardial oxygen consumption, and brain metabolism. Activation of these receptors may contribute to coronary vasodilation and increased cardiac perfusion. Additionally, MTX protects the vascular endothelium by increasing the expression of anti-atherogenic proteins involved in reverse cholesterol transport and by scavenging superoxide, thereby reducing oxidative stress[38].

Despite its anti-inflammatory effects, MTX may have adverse cardiovascular effects by inducing hyperhomocysteinemia, endothelial dysfunction, accelerated atherosclerosis, increased thrombosis risk, and direct cardiotoxicity (Table 5). Nonetheless, most studies demonstrate a positive effect of MTX on cardiovascular event risk, early atherosclerotic changes, and traditional cardiovascular risk factors in RA.

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.

Conventional synthetic DMARDs: LEF

LEF is traditionally considered a second-line drug for monotherapy in RA (e.g., in cases of MTX inefficacy or intolerance) or as an effective component of dual or triple combination therapy. Compared to MTX, the impact of LEF on the development and progression of CVD in patients with rheumatic conditions has been studied to a much lesser extent. Its active metabolite, teriflunomide, exerts anti-inflammatory, antiproliferative, and antioxidant properties, which may contribute to cardiovascular benefits. The following are the key mechanisms of action: (1) Anti-inflammatory effects: LEF inhibits pro-inflammatory cytokines (e.g., TNF-α, IL-6) and reduces endothelial dysfunction, a key factor in atherosclerosis development. Suppression of NF-κB signaling attenuates vascular inflammation and plaque instability; (2) Antiproliferative action on VSMCs: By inhibiting dihydroorotate dehydrogenase, LEF blocks pyrimidine synthesis, reducing VSMC proliferation and migration, thereby slowing atherosclerotic plaque progression; (3) Antioxidant properties: Teriflunomide decreases oxidative stress by scavenging reactive oxygen species and enhancing endogenous antioxidant defenses, improving endothelial function; and (4) Improvement of endothelial function: Enhanced nitric oxide bioavailability and reduced endothelin-1 secretion contribute to vasodilation and improved arterial compliance.

Despite its potential anti-inflammatory benefits, LEF may have adverse effects, with arterial hypertension being the most frequently reported (occurring in approximately 5% of patients). This is hypothesized to result from fluid retention and endothelial dysfunction due to impaired nitric oxide synthesis[39]. Given its potential cardiovascular protective effects, LEF might be considered for the treatment of RA patients with metabolic syndrome. However, the overall impact of the drug on cardiovascular mortality remains insufficiently studied and should be further investigated in larger clinical studies.

Conventional synthetic DMARDs: SSZ

SSZ is a drug for combination therapy in RA. Consequently, there are no large-scale studies evaluating the effect of this drug as monotherapy on cardiovascular risk in patients with RA.

SSZ suppresses the activation of the NF-κB transcription factor. In both animal models and humans with CVD risk factors, NF-κB activation in the endothelium leads to impaired vasodilatory function[40]. A compound related to SSZ, salsalazine, improves flow-mediated dilation in people with obesity[41], and NF-κB is a central regulator of genes involved in inflammation and adhesion in cells participating in atherogenesis[42]. Suppression of NF-κB is an effective method for preventing the development of atherosclerosis[43]. However, the effect of NF-κB inhibition on established clinical atherosclerotic disease remains incompletely understood. For example, a randomized study by Tabit et al[44], which included patients with stable ischemic heart disease or a history of MI, evaluated the effect of SSZ vs placebo over 6 weeks. The results showed no effect of SSZ on flow-mediated dilation of the brachial artery (a marker of large-vessel endothelial function), the hyperemic response (a marker of small-vessel vasodilatory function), blood pressure (BP), lipid levels, glucose, or insulin levels. However, short-term SSZ treatment did reduce NF-κB activity. The authors suggested that endothelial dysfunction in chronic disease may be more resistant to improvement via NF-κB inhibition, which could explain the lack of a significant clinical effect with this drug.

Moreover, SSZ has been shown to positively influence the lipid profile by increasing HDL levels and reducing the atherogenic index[45]. However, long-term SSZ use may elevate homocysteine levels, as SSZ competitively inhibits folate absorption in the small intestine. Hyperhomocysteinemia, in turn, is associated with an increased risk of CVD and thrombosis[46]. In rare cases, SSZ can induce hypokalemia (due to renal potassium wasting), which may theoretically elevate the risk of arrhythmias. Overall, SSZ appears to have a neutral or possibly beneficial effect on the cardiovascular system due to its anti-inflammatory properties. However, in some cases, monitoring of electrolyte levels and folate status may be necessary.

Conventional synthetic DMARDs: HCQ

HCQ is most widely used in the treatment of systemic lupus erythematosus, and in RA, it is traditionally considered primarily as a component of dual or triple combination therapy. The drug demonstrates potential anti-atherosclerotic properties, which are particularly relevant for patients with chronic inflammatory diseases. These effects are mediated through several key mechanisms. Multiple studies have demonstrated a direct effect of HCQ on lipid metabolism, including reductions in total cholesterol and LDL levels, achieved by inhibiting cholesterol synthesis in the liver via its action on the enzyme 3-hydroxy-3-methyl-glutaryl-CoA reductase similarly to statins, though less potently. As a result, HCQ use in RA patients has been associated with reduced total cholesterol and LDL levels[47,48]. HCQ also improves glucose utilization, resulting in decreased levels of triglycerides and very-LDL[49,50]. The drug helps suppress endothelial dysfunction by inhibiting pro-inflammatory cytokines (TNF-α, IL-6, and interferon-gamma), which contribute to endothelial damage and atherosclerotic plaque formation. HCQ also reduces CRP, a marker of systemic inflammation and atherosclerosis risk[51,52].

There is further evidence that HCQ inhibits nicotinamide adenine dinucleotide phosphate oxidase, an enzyme responsible for generating active oxygen species that accelerate atherosclerosis[53]. HCQ reduces collagen degradation in the fibrous cap of atherosclerotic plaques, and this lowers the risk of plaque rupture and thrombosis[54] by blocking the molecule of vascular cell adhesion protein-1 and intercellular adhesion molecule 1, which hinders the migration of inflammatory cells into the vessel wall[55].

A retrospective observational study by Cordova Sanchez et al[56], which included over 2 million patients with RA, showed that HCQ was associated with a slight reduction in the incidence of cardiovascular events and strokes. However, these outcomes were less favorable compared to patients taking MTX or bDMARDs. There is also evidence of potential adverse cardiovascular effects of HCQ, which exhibits dose-dependent cardiotoxicity, with adverse events typically manifesting after prolonged use.

Of particular concern is the potential of HCQ to prolong the QT interval due to blockade of hERG potassium channels, leading to impaired ventricular repolarization. This increases the risk of torsades de pointes and sudden cardiac death, especially in the setting of hypokalemia, concomitant use of other QT-prolonging drugs (e.g., macrolides, class III antiarrhythmics), or congenital long QT syndrome[57,58]. HCQ may also suppress sinoatrial node function and impair atrioventricular (AV) conduction, resulting in sinus bradycardia or first- and second-degree AV block (rarely third-degree). These effects are particularly dangerous in patients with pre-existing conduction abnormalities.

Another serious complication is toxic cardiomyopathy, which is associated with the cumulative dose and duration of therapy, especially in patients treated with HCQ for more than 10 years[59]. Cardiomyopathy usually presents as concentric hypertrophy with restrictive features, with or without conduction abnormalities. While HCQ may offer modest cardiovascular benefits due to its anti-inflammatory, anti-thrombotic, and metabolic effects, its use should be carefully justified and monitored.

TNF inhibitors

TNF-α is one of the key mediators of atherogenesis. It induces endothelial dysfunction, upregulates cell adhesion molecules that facilitate leukocyte migration into the vascular wall, contributes to the destabilization of atherosclerotic plaques, suppresses anticoagulant properties while promoting procoagulant activity of the endothelium, impairs myocardial contractility, and stimulates CRP synthesis[60]. Experimental studies[61] have shown that mice lacking the TNF-α gene do not develop intimal hyperplasia after arterial injury. Clinical studies[62-64] have further demonstrated that elevated TNF-α concentrations correlate with the development of atherosclerosis and its complications. TNF-α also affects lipid metabolism, glucose metabolism, and energy homeostasis. TNF-α inhibitors, widely used biologic drugs for RA, are associated with a reduced overall risk of CVD in RA patients[65]. Anti-TNF-α therapy suppresses the production of pro-inflammatory and pro-atherogenic mediators such as CRP, IL-6, and TNF-α itself, as well as adhesion molecules. It also causes depletion of CD4⁺CD28^- T cells, which play an important role in destabilizing atherosclerotic plaques, and increases the number of endothelial progenitor cells, whose deficiency is linked to higher cardiovascular risk[66]. TNF-α accelerates plaque formation by activating macrophages and promoting LDL oxidation. Blocking TNF-α may help stabilize plaques and reduce the risk of acute coronary events.

Barnabe et al[65] demonstrated that long-term anti-TNF-α therapy reduced cardiovascular event frequency in RA patients. However, a study by Mann et al[67] found no significant effect of etanercept on atherosclerosis progression, suggesting possible differences between agents. A systematic review and meta-analysis by Roubille et al[68], which included 34 studies, confirmed that anti-TNF-α therapy was associated with a decreased risk of overall CVD, including MI, stroke, and major adverse cardiovascular events (MACE). More recent studies reported a 2.1% improvement in endothelium-dependent vasodilation in RA patients receiving anti-TNF-α therapy. Randomized controlled trials have also shown that anti-TNF-α therapy (infliximab, adalimumab, etanercept) reduces markers of subclinical atherosclerosis, such as carotid intima-media thickness and pulse wave velocity[69].

Data on the impact of anti-TNF-α therapy on BP are contradictory. Some studies show a moderate BP reduction due to improved endothelial function and reduced systemic inflammation[70]. However, a study by Faria et al[71] found no significant increase in hypertension risk during treatment, although some patients experienced transient BP elevations requiring adjustment of antihypertensive therapy.

TNF-α also has a negative inotropic effect on the myocardium and contributes to left ventricular remodeling and the progression of HF[72]. Clinical trials, including the anti-TNF Therapy Against Congestive Heart (ATTACH) trial, showed that high-dose infliximab in patients with severe HF worsened outcomes: In the high-dose group (10 mg/kg), hospitalization and mortality rates increased (14% vs 3% in placebo). The trial was terminated early due to the risk of decompensation[73]. Consequently, anti-TNF-α therapy is not recommended for patients with reduced ejection fraction. In addition, TNF-α promotes tissue factor expression and inhibits fibrinolysis, thereby increasing thrombosis risk. Anti-TNF-α therapy may reduce prothrombotic activity, as evidenced by decreased levels of D-dimer and fibrinogen in patients with chronic inflammation[74].

Overall, anti-TNF-α therapy exerts a complex influence on the cardiovascular system, primarily through suppression of systemic inflammation and improvement of endothelial function. However, its use in patients with HF requires caution, and further research is needed to clarify its long-term safety profile.

IL-6 inhibitors

Among IL-6 inhibitors used in rheumatology, the following monoclonal antibodies are of particular interest: Tocilizumab, sarilumab, olokizumab, and levilimab. Most studies have focused on the safety and efficacy of tocilizumab. The literature presents contradictory data regarding its effects on lipid profiles. For example, the randomized placebo-controlled MEASURE trial demonstrated that LDL levels increased by approximately 15%-20% in patients receiving tocilizumab. However, lipoprotein(a) levels decreased by more than 30%, and HDL levels, as well as HDL composition, shifted toward patterns associated with anti-inflammatory effects[75].

The ADACTA trial compared the influence of tocilizumab and adalimumab on lipid profiles in RA patients[76]. During the first 8 weeks of treatment, patients who received tocilizumab monotherapy had higher LDL but lower HDL and lipoprotein(a) levels compared to those treated with adalimumab. Nevertheless, later findings did not show any increased CVD risk associated with tocilizumab-induced hyperlipidemia[77].

A study by Toussirot et al[78] found that tocilizumab treatment in RA patients was associated with a significant increase in total and high-molecular-weight adiponectin levels. These changes in adiponectin may positively influence cardiovascular risk.

Several studies have found no clinically significant differences in treatment-related side effects among sarilumab, olokizumab, and levilimab[79,80]. The MONARCH trial demonstrated a smaller increase in LDL levels in patients treated with sarilumab compared to those receiving tocilizumab[81].

Olokizumab is unique among anti-IL-6 monoclonal antibodies in its mechanism of action. The randomized controlled trials CREDO 1 and CREDO 2 evaluated the efficacy and safety of olokizumab in RA. These studies demonstrated reductions in inflammatory markers, including CRP and fibrinogen, which may theoretically reduce cardiovascular risk[82]. A moderate increase in both LDL and HDL was observed, but without a significant rise in cardiovascular event rates[83].

Despite the absence of a clear increase in cardiovascular risk, some studies have reported a paradoxical rise in LDL without worsening prognosis. This may be related to changes in the functional properties of lipoproteins. Therefore, caution is advised in patients with high cardiovascular risk (e.g., those with diabetes). Long-term data remain limited, highlighting the need for further research.

Interleukin-1 inhibitors

Anakinra is a drug that provides dual inhibition of IL-1α and IL-1β. Several studies have examined its impact on cardiovascular risk, not only in RA patients but also in those with acute MI. For example, a study by Abbate et al[84] demonstrated that IL-1 blockade with anakinra was safe and improved left ventricular remodeling in patients with ST-elevation MI.

A meta-analysis by Zheng et al[85] showed that IL-1 blockers were associated with a reduced risk of adverse cardiovascular events, although they did not significantly reduce all-cause mortality, including mortality from acute MI. The likely mechanism by which IL-1 inhibition lowers CVD risk involves suppression of the inflammatory response and cytokine production, particularly CRP, as confirmed by numerous studies.

The multicenter randomized TRACK trial demonstrated that anakinra therapy significantly improved glycemic control and reduced RA activity, which may counteract the synergy between traditional CVD risk factors and inflammation that accelerates atherosclerosis[86]. A 1% reduction in HbA1c is associated with approximately a 15% decrease in CVD risk[87]. This conclusion is further supported by the CANTOS trial, where IL-1β antagonism reduced CVD risk in post-MI patients with elevated CRP levels, confirming the role of inflammation in CVD development[88]. However, the long-term use of anakinra has also been linked to the development of dyslipidemia[89]. Additional studies are needed to further clarify these risks and benefits.

Anti-CD20-antibodies

Among this class of drugs, rituximab is used in rheumatology and was approved in 2006 for the treatment of patients with RA who had an inadequate response to at least one TNF-α inhibitor. In a study by Provan et al[90], the 12-month effect of rituximab on traditional cardiovascular risk factors and early signs of cardiovascular involvement (e.g., arterial stiffness) was assessed. The results showed no significant changes in CVD risk markers during the first 3 months of therapy. However, after 1 year, there was a trend toward reduced arterial stiffness, with an average decrease of 0.46 m/s, approximately corresponding to a 10-year reduction in vascular aging.

In contrast, an earlier study by Mathieu et al[91] demonstrated no reduction in arterial stiffness after 6 and 12 months of rituximab therapy. Moreover, a significant increase in total cholesterol and LDL levels was observed, while HDL and triglyceride levels remained unchanged. Kerekes et al[92] and Gonzalez-Juanatey et al[69] reported significant improvements in endothelial function, as measured by flow-mediated dilation, indicating reduced CVD risk in patients treated with rituximab. Additionally, in the study by Kerekes et al[92], a 3%-11% reduction in total cholesterol and a 14%-35% increase in HDL levels were observed. Similar anti-atherogenic effects of rituximab were demonstrated in a study by Raterman[93].

Rituximab rarely causes direct cardiotoxic effects, but infusion reactions may lead to hemodynamic disturbances. Reported complications following drug administration include the following: (1) Arrhythmias (rare)-including cases of atrial fibrillation and ventricular tachycardia; (2) Hypotension due to cytokine release syndrome; and (3) Cute coronary syndrome (very rare), triggered by histamine and other mediator release.

Thus, in patients with autoimmune diseases, rituximab may reduce systemic inflammation, potentially lowering cardiovascular risk. However, in patients with pre-existing cardiac conditions, close monitoring during infusion is essential.

T-Helper cell co-stimulation blockers

Within this class, abatacept is the only drug currently used in rheumatology. The literature presents conflicting data regarding its influence on cardiovascular risk across different patient age groups. A study by Kang et al[94] showed that patients treated with abatacept had a lower risk of MI compared to those treated with TNF-α inhibitors. However, for other secondary endpoints (such as stroke and venous thromboembolism), the risk was similar between the two groups. The authors also conducted a stratified analysis of high-risk patients (age > 65 years and/or a history of diabetes mellitus). In this subgroup, the risk of combined cardiovascular outcomes was 26% lower with abatacept compared to TNF-α inhibitors. Conversely, among patients without diabetes, the combined cardiovascular risk was similar in both treatment groups[94]. These findings may be explained by the additional metabolic effects of abatacept. Evidence suggests that abatacept improves insulin sensitivity in target cells and may exert anti-atherogenic effects[95].

The risk of venous thromboembolism is significantly higher in patients receiving abatacept compared to those treated with TNF-α inhibitors, both in patients with and without diabetes[94]. In a retrospective cohort study by Shih et al[95], cardiovascular risk was assessed in RA patients with interstitial lung disease who were treated with abatacept, compared with those receiving TNF-α inhibitors. The study found a higher risk of all-cause mortality among patients without cardiovascular risk factors who were treated with abatacept, compared with TNF-α inhibitors. However, among patients with cardiovascular risk factors, this difference was not statistically significant. Additionally, in patients aged 18-64 years, abatacept use was associated with a higher likelihood of requiring mechanical ventilation. The authors suggested that abatacept may provide relatively greater benefits in patients over 65 years of age, consistent with the findings of Kang et al[94].

A study by Mathieu et al[96] evaluated the 6-month effect of abatacept on traditional cardiovascular risk factors and early signs of cardiovascular involvement (e.g., arterial stiffness). After 6 months of treatment, with concurrent reductions in RA disease activity, there was a modest increase in arterial stiffness parameters, a slight elevation in total cholesterol, LDL, and HDL, and a decrease in the atherogenic index. The authors suggested that the lack of improvement in arterial stiffness could be due to insufficient reduction of systemic inflammation. At the same time, abatacept showed favorable effects on lipid profiles, warranting longer-term studies for clearer conclusions.

Unlike TNF-α inhibitors, which may exacerbate HF, abatacept has not been associated with an increased risk of decompensation. Therefore, abatacept may be a preferable option for patients with high cardiovascular risk or those experiencing adverse lipid profile changes with other therapies.

JAK inhibitors

Among tsDMARDs, the following are currently included in various international clinical guidelines for the treatment of RA: Tofacitinib, baricitinib, upadacitinib, and filgotinib. All of them belong to the class of JAK inhibitors. This group of drugs demonstrates efficiency comparable to that of other DMARDs in the treatment of RA[97].

One practical advantage of JAK inhibitors is their oral formulation, which improves adherence. This allows for long-term outpatient treatment (no need for hospital visits or parenteral administration), eliminates the requirement for refrigerated storage, and offers a more convenient option for patients who dislike injections. A specific drawback of tofacitinib is its twice-daily dosing, though an extended-release formulation requiring once-daily administration is now available. However, the cardiovascular safety profile of this drug class remains inconclusive, prompting close scrutiny by regulatory authorities (FDA, EMA).

In 2022, to minimize the risk of serious adverse events associated with JAK inhibitors, the Pharmacovigilance Risk Assessment Committee (PRAC) of the European Medicines Agency recommended restrictions on their use for certain indications. These included chronic inflammatory diseases such as RA, psoriatic arthritis, juvenile idiopathic arthritis, axial spondyloarthritis, ulcerative colitis, atopic dermatitis, and alopecia areata. PRAC identified high-risk groups in which JAK inhibitors should be used only if no suitable alternatives exist. These groups include patients aged ≥65 years, those with increased CVD risk (e.g., prior MI or stroke), current or long-term smokers, and patients with high cancer risk. Caution was also recommended when prescribing JAK inhibitors to patients with thromboembolic risk factors.

The basis for this decision was the open-label clinical trial A3921133, which compared the safety of tofacitinib with TNF-α inhibitors in 4362 RA patients aged ≥ 50 years with at least one cardiovascular risk factor[98]. In this study, the incidence of pulmonary embolism per 100 patient-years was 0.54 with tofacitinib 5 mg twice daily, 0.27 with tofacitinib 10 mg twice daily, and 0.09 with TNF-α inhibitors. The incidence of deep vein thrombosis was 0.38, 0.30, and 0.18, respectively. The highest increase in pulmonary embolism risk was observed in patients with pre-existing risk factors for venous thromboembolism. Notably, an observational cohort study using the Truven and Medicare databases found that the risk of venous thromboembolism was comparable between RA patients treated with tofacitinib and those treated with TNF-α inhibitors[99]. Other studies assessing the safety and efficacy of JAK inhibitors have reported more reassuring results. For example, the incidence of MACE in patients receiving tofacitinib was 0.4 per 100 patient-years, with no significant differences between dose regimens and no increase with longer treatment duration[100]. The main cardiovascular events observed were atrial fibrillation, MI, and coronary artery disease. Similarly, clinical trials of baricitinib and upadacitinib have shown a low incidence of cardiovascular complications[101,102]. Moreover, a meta-analysis of randomized clinical trials found no increased risk of cardiovascular outcomes with JAK inhibitor therapy[103].

In the RA-BUILD trial, which studied dose-dependent effects of baricitinib, an elevated risk of venous thromboembolism was observed in patients receiving 4 mg/day. However, comprehensive safety analyses showed that overall risk was not higher than in the general population, regardless of whether baricitinib was taken at 2 mg or 4 mg/day. Risk was more closely associated with age, comorbid conditions (obesity, chronic lung disease, varicose veins), a history of venous thromboembolism, and concomitant use of selective cyclooxygenases-2 inhibitors[104,105].

An analysis of data from a phase III clinical trial of upadacitinib in the SELECT-RA program, in which 54% of patients were considered high risk due to age and smoking status, showed that despite an increased risk of cardiovascular events, venous thromboembolism, and malignant tumors, the incidence rates were comparable across all therapy groups[106].

The cardiovascular safety of filgotinib is currently regarded as satisfactory. The incidence of cardiovascular events and venous thromboembolism in patients treated with this JAK inhibitor did not differ significantly from those observed with adalimumab, MTX, or placebo[107].

The safety profile of various JAK inhibitors in RA was analyzed by Alves et al[108] in a systematic review that included 42 randomized clinical trials. The review found no significant differences among JAK inhibitors with respect to cardiovascular outcomes or venous thromboembolism risk. Moreover, no differences were identified between JAK inhibitors and bDMARDs, including abatacept, adalimumab, and MTX.

The mechanisms potentially linking JAK inhibitor therapy to increased cardiovascular risk remain unclear and require further investigation. Therefore, the current approach to prescribing these drugs involves a careful risk–benefit assessment for each patient.

CONCLUSION

RA is associated with an increased risk of CVD, driven by chronic inflammation, traditional risk factors, and the potential cardiotoxicity of some antirheumatic drugs. Modern treatment strategies should not only focus on controlling inflammation but also on minimizing cardiovascular risk. The use of DMARDs has demonstrated beneficial effects on the cardiovascular system through the reduction of systemic inflammation. However, some drugs, such as JAK inhibitors, require close monitoring due to a possible increase in the risk of thrombosis and other cardiovascular events. To improve prognosis in RA patients, it is essential to conduct regular screening for cardiovascular risk factors (hypertension, dyslipidemia, smoking), tailor therapy to each patient’s cardiovascular profile, and adopt a multidisciplinary approach involving both rheumatologists and cardiologists. A summary of cardiovascular safety profiles for DMARDs, preventive measures, and preferred patient categories is provided in Table 6. Future research should focus on clarifying the mechanisms of cardioprotection in RA, optimizing treatment strategies, and developing personalized approaches for patients at high cardiovascular risk.

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.