Rheumatoid arthritis (RA) is a chronic autoimmune disorder that mainly affects synovial joints. It is characterized by joint inflammation, pain, swelling, and stiffness that can lead to deformities and functional disability.

The diagnosis of RA is based on clinical manifestations, laboratory tests, and imaging studies. Although the etiology of RA is not fully understood, it is believed to involve genetic, environmental, and immunological factors.

Current treatment approaches for RA involve a combination of pharmacological and non-pharmacological interventions aimed at controlling inflammation, reducing pain, preserving joint function, and preventing complications.

Medications for Rheumatoid Arthritis

The medications used for treating RA can be classified into several categories based on their mechanism of action. Nonsteroidal anti-inflammatory drugs (NSAIDs) are one of the most commonly used medications for RA.

They help to reduce pain and inflammation in the joints by inhibiting the activity of cyclooxygenase (COX) enzymes. However, NSAIDs are associated with gastrointestinal, renal, and cardiovascular adverse effects, especially in high doses or with long-term use.

Corticosteroids are another class of medications that are used for treating RA. They help to reduce inflammation and pain by suppressing the immune system and inhibiting the activity of inflammatory cells.

However, corticosteroids are associated with several adverse effects, such as weight gain, diabetes, osteoporosis, infections, and cardiovascular disease (CVD). Therefore, they should be used in low doses and for a short duration.

Disease-modifying antirheumatic drugs (DMARDs) are a group of medications that are used for treating RA by altering the immune response and inhibiting the progression of joint damage.

They include conventional synthetic DMARDs (csDMARDs) such as methotrexate, sulfasalazine, and leflunomide, as well as biologic DMARDs (bDMARDs) such as tumor necrosis factor (TNF) inhibitors, interleukin-6 (IL-6) inhibitors, and B-cell depleting agents. DMARDs have revolutionized the management of RA by achieving remission or low disease activity in many patients and preventing joint deformities and disability.

However, DMARDs are associated with several adverse effects, such as hematological, hepatic, renal, and infectious complications. Therefore, they should be used under medical supervision with regular monitoring of the patient’s clinical and laboratory parameters.

Janus kinase (JAK) inhibitors are a newer class of DMARDs that act by inhibiting the activity of JAK enzymes, which are involved in cytokine signaling and immune response. They include tofacitinib, baricitinib, and upadacitinib.

JAK inhibitors have shown efficacy in treating RA and other autoimmune disorders, but they are associated with an increased risk of infections, malignancies, and thromboembolic events.

Cardiovascular Risk in Rheumatoid Arthritis

RA is associated with an increased risk of CVD, which is one of the leading causes of morbidity and mortality in RA patients.

The exact mechanisms underlying this association are not clear, but it is believed to involve a combination of traditional and non-traditional risk factors. Traditional risk factors for CVD in RA patients include advanced age, male gender, smoking, hypertension, dyslipidemia, diabetes, and obesity.

Non-traditional risk factors include chronic inflammation, endothelial dysfunction, oxidative stress, and autoantibodies.

Chronic inflammation plays a key role in the pathogenesis of RA and also contributes to the development of atherosclerosis, which is the underlying process of most CVD.

Inflammation causes damage to the endothelium, the inner lining of blood vessels, and impairs its function, leading to reduced production of nitric oxide, a potent vasodilator, and increased expression of adhesion molecules, such as vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1), which promote leukocyte adhesion and infiltration into the vessel wall. This promotes the formation of foam cells, smooth muscle cell proliferation, and extracellular matrix deposition, leading to plaque formation and stenosis.

In addition to chronic inflammation, RA patients are also exposed to several other factors that increase their risk of CVD, such as corticosteroid use, reduced physical activity, depression, and poor sleep quality.

Corticosteroids can cause several metabolic disturbances, such as insulin resistance, dyslipidemia, and hypertension, which promote atherosclerosis. Reduced physical activity and poor sleep quality are associated with endothelial dysfunction, oxidative stress, and pro-inflammatory cytokine production, which contribute to the development of atherosclerosis and CVD.

Thromboembolism Risk in Rheumatoid Arthritis

RA patients are also at an increased risk of thromboembolic events, such as deep vein thrombosis (DVT), pulmonary embolism (PE), and stroke.

The underlying mechanisms of this association are not fully understood but are believed to involve a combination of prothrombotic and antifibrinolytic factors and endothelial dysfunction.

Inflammation can activate the coagulation cascade by increasing the expression of tissue factor, a potent procoagulant, and reducing the expression of thrombomodulin, an anticoagulant.

In addition, inflammation can stimulate platelet activation and aggregation, and reduce the activity of fibrinolysis, leading to thrombus formation and propagation. RA patients are also exposed to several other factors that increase their risk of thromboembolism, such as immobilization, surgery, infections, and comorbidities, such as hypertension, diabetes, and CVD.

Immobilization and surgery can cause stasis of blood flow, leading to DVT and PE. Infections can also activate the coagulation cascade and promote thrombosis. Comorbidities can further increase the risk of thromboembolism by causing endothelial dysfunction, inflammation, and oxidative stress.

Medications and Cardiovascular Risk

Several medications used for treating RA have been associated with an increased risk of CVD. NSAIDs can cause hypertension, heart failure, and myocardial infarction (MI) in high doses or with long-term use.

Corticosteroids can cause hypertension, dyslipidemia, and CVD in a dose-dependent and duration-dependent manner. DMARDs have been associated with different cardiovascular outcomes depending on the class and specific drug. Methotrexate has been shown to reduce the risk of CVD and improve endothelial function.

TNF inhibitors have been associated with an increased risk of heart failure, especially in patients with preexisting heart disease. IL-6 inhibitors have been associated with a reduced risk of CVD and improved lipid profile. JAK inhibitors have been associated with an increased risk of DVT and PE, especially in high-risk patients, such as those with a history of thromboembolism.

Medications and Thromboembolism Risk

Similar to CVD, several medications used for treating RA have been associated with an increased risk of thromboembolism.

NSAIDs can cause DVT and PE, especially in high-risk patients, such as those undergoing surgery or with a history of thromboembolism. Corticosteroids can cause DVT and PE in a dose-dependent and duration-dependent manner. DMARDs have been associated with different thromboembolic outcomes depending on the class and specific drug.

Methotrexate has been shown to reduce the risk of thromboembolism. TNF inhibitors have been associated with an increased risk of DVT and PE, especially in high-risk patients. IL-6 inhibitors have not been associated with an increased risk of thromboembolism.

JAK inhibitors have been associated with an increased risk of DVT and PE, especially in high-risk patients, such as those with a history of thromboembolism.

Conclusion

RA is a chronic autoimmune disorder that is associated with an increased risk of CVD and thromboembolism. The medications used for treating RA have different cardiovascular and thromboembolic risks depending on the class and specific drug.

Healthcare providers should take into consideration the patient’s individual risk profile and comorbidities when selecting the appropriate medication for RA and monitoring the patient for potential adverse effects. Patients with RA should also be educated about the modifiable risk factors for CVD and thromboembolism and encouraged to adopt a healthy lifestyle and adhere to their medication regimen.