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Venous Thromboembolism in Rheumatoid Arthritis: The Added Effect of Disease Activity to Traditional Risk Factors

Abstract Many epidemiological studies have shown an increased risk of venous thromboembolism (VTE) in patients with rheumatoid arthritis (RA). RA and VTE share some background factors, such as increasing age, smoking, and obesity. At the same time, other VTE factors, such as knee replacement and oral contraceptive pills, occur commonly in RA patients. In addition, the chronic inflammatory state of RA might hypothetically lead to endothelial injury and a hypercoagulable state. Two critical pathophysiological pathways lead to VTE. Recently, concerns increased about the increased risk of VTE in patients using Janus Kinase inhibitors. This review aims at reviewing the risk of VTE in RA and the role of traditional risk factors and disease-related inflammation and develops a conceptual framework that describes the interaction between these factors.


RA and the Virchow's Triad
Virchow's triad, comprising venous stasis, endothelial injury, and a hypercoagulable state, was first described in 1856. 19 In this condition, an imbalance between procoagulants and anticoagulants leads to a hypercoagulable state. Venous thrombi comprise two layers: an inner rich platelet layer surrounded by a dense red cell fibrin clot. Clots are usually formed in areas with altered blood flow, such as pockets adjacent to venous valves in the legs. 20 Here we dissect how RA affects each component of Virchow's triad.

Endothelial Injury
Endothelial injury in RA patients primarily occurs secondary to inflammation. It has been linked to the positivity of antiphospholipid antibodies, human leucocyte antigen (HLA) status such as HLA-DRB1*04:01, 21 and some unusual genotypes of tumor necrosis factor inhibitors (TNF) or plasminogen activator inhibitor-1 (PAI-1). 22 In the early stages of RA, a pro-inflammatory state plays a major role in endothelial dysfunction by activating endothelial cells, leading to altered endothelial permeability and increased leukocyte and platelet adhesion, resulting in increased monocyte-endothelial interaction. 23 During inflammation, monocytes express intercellular adhesion molecules, which are induced by pro-inflammatory cytokines such as IL-1β, TNF-α, and C-reactive protein (CRP). 23 The activation of coagulation factors of endothelial origins, such as the von Willebrand factor and PAI-1, may play a significant role in RA and thrombosis. 24

Hypercoagulability
In RA patients, inflammation regulates thrombotic responses by three important components: upregulating procoagulants (homocysteine and P-selectin), downregulating anticoagulants (thrombomodulin and protein C and S), and suppressing fibrinolysis. 25

Upregulating Procoagulants
Fibrinogen, D-dimer, cytokines (such as IL-6, IL-8, and TNF), and CRP, considered inflammatory markers, are associated with an increased risk of thrombosis and may play significant roles in VTE. 26 Homocysteine has been increasingly observed in RA and may increase the risk of venous thrombosis. 27 A high homocysteine level is considered to have a modest association with atherothrombosis or venous thrombosis. 28 P-selectin, a member of adhesion receptors that normally generates procoagulant particles and activates platelets, has been an important predictor of VTE development. 29,30 Furthermore, it was found to be an important biomarker in leucocyte-endothelial interaction and RA-related thrombocytosis. 31,32 Downregulating Anticoagulants Natural anticoagulant mechanisms reduce the thrombotic response but may be depressed by inflammatory mediators. Thrombomodulin is a transmembrane glycoprotein synthesized by vascular endothelial cells and is distributed on the surface of the vein, artery, and capillary endothelial cells. Its gene polymorphism has been associated with an increased risk of VTE. 33 Prothrombotic activities are believed to exert a toxic effect on the endothelium and lead to decreased thrombomodulin expression. 34 Therefore, the protein C pathway is considered a major target. TNF-α specifically downregulates Thrombomodulin and the endothelial cell protein C receptor; while both are needed for optimal protein C activation, they are downregulated by inflammatory mediators. In addition, the protein S glycoprotein is an essential natural anticoagulant for activating the activation protein C pathway, and tissue pathway factor inhibitor can be downregulated in a chronic inflammatory state, resulting in the impaired anticoagulant function of activated protein C. 35,36 Suppressing Fibrinolysis The thrombin activatable fibrinolysis inhibitor (TAFI) is a proenzyme that activates the fibrinolytic system once activated by factors such as thrombin/plasmin and thrombomodulin. 37 TAFI has been found to be elevated in RA patients compared to controls, 38 especially patients with active inflammation. 39 Therefore, higher activated TAFI may cause a transient hypercoagulable state that leads to VTE. 40

Antiphospholipid Antibodies
The expression of antiphospholipid antibodies is considered a risk factor for VTE, arterial thrombosis, and pregnancyrelated complications in patients with rheumatic diseases, especially those with background lupus or primary antiphospholipid syndrome (APS). 41 In the case of RA, the literature is scarce, and no solid conclusion has been drawn due to the high variability in the observed results. In a review published in 2006 by Olech and Merrill, the median prevalence of aPL antibodies in RA patients was 22% in samples not exceeding 200 patients, with a few studies showing some relation. [42][43][44] However, the functionality of these antibodies is questionable. However, their persistence is unknown, as aPL antibodies can result from infection or are induced by drugs such as TNF inhibitors (TNFi). 45

Smoking
Smoking is an important environmental risk factor for both RA and VTE. 46,47 Smoking primarily causes a hypercoagulable state through different mechanisms. An increase in procoagulant factors (II, V, VIII, X, and XIII), homocysteine, and tissue factor levels is unbalanced by a decrease in anti-thrombin III and tissue factor pathway inhibitor levels. Epidemiologically, Cigarette smoking (CS), intensity, and duration are directly related to the risk of RA development, even after CS cessation. Di Giuseppe et al found in a meta-analysis including three prospective and seven case-control studies that the risk of developing RA increased by 26% in CS users who smoked 1-10 pack-years and by 94% in those with more than 20 pack-years. A meta-analysis also showed that rheumatoid factor (RF)-positive smokers had a higher risk of RA than RF-negative smokers. 47 On the other hand, Hedström et al conducted a case-control study in a Swedish population with 3655 cases and 5883 controls and showed a dose-dependent increase in RA risk regardless of whether the anti-citrullinated peptide antibodies (ACPA) were positive or negative. When comparing the duration and intensity of CS, duration was found to have a stronger influence on the association between CS and RA.

Hyper-Viscosity and Venous Stasis
The exact mechanisms underlying increased plasma viscosity and subsequent VTE development in RA remain unknown. Two possible factors might explain this phenomenon:

Intrinsic Factors
Acute-phase reactants are elevated in many autoimmune diseases, including RA, contributing to increased plasma viscosity and risk of thrombosis. This includes CRP, erythrocyte sedimentation rate (ESR), coagulation factor VIII, fibrinogen, and von Willebrand factor. 48 Immobility RA causes joint destruction that leads to disability and immobility. 49 Also, RA is the second cause of joint replacement after osteoarthritis, 50 a high-risk surgery for VTE development. Finally, RA patients are at increased risk of infection, 51 osteoporotic fractures, 52 cardiovascular, 53 and pulmonary diseases, 54 all leading to hospitalization and immobility. Figure 1 shows the interaction between intrinsic and extrinsic risk factors for VTE in patients with RA.

Risk of VTE in RA Patients
It has been proposed that patients with RA have an increased risk of VTE. Lee  Furthermore, the risk of VTE was increased in RA patients independent of other traditional risk factors, such as chronic comorbidities, recent fractures, and use of oral contraceptive pills. 59,60 In addition, the occurrence of the first VTE was associated with a threefold increased risk of cardiovascular disease in patients. 61 RA disease activity is associated with an increased risk of VTE. 61,62 In a recent Swedish cohort, the risk of VTE increased twofold in patients with evidence of disease activity compared to patients in remission. 62 Although it has been proposed that longer disease duration increases the risk of VTE, 59,63 many studies have shown that the relative risk is higher in the first year and remains relatively stable  in subsequent years. 56,58,60,64,65 Several studies have observed an association between increased body mass index and risk of VTE. 56,61,63,66,67 In a recent Italian cohort, obesity was associated with a hazard ratio (HR) of 1.37 for developing VTE. 63 In another study by Ozen et al, obesity was found to be associated with an increased risk of VTE (HR 1.46 (95% CI), (1.13-1.87)) 61 (Table 2).

RA Treatment and the Risk of VTE
Glucocorticoids (GCs) play an essential role in the management of RA. Efforts have been made to limit their use as bridging therapy or during flares; 68 their chronic use is still significant but decreases over time. 69 GC use increases VTE risk 2-3-fold in different patient populations. 70 GCs further increase endothelial injury by decreasing nitric oxide levels and increasing adhesion molecule expression. Finally, GCs cause hypercoagulability by increasing factors II and VIII and the von Willebrand factor, critical procoagulant factors. 71 bDMARDs have not been linked to an increased risk of VTE in RA. 56,[72][73][74][75] In a large Chinese cohort studying the risk of VTE with bDMARDs compared to csDMARDs, there was no statistically significant association between biologic use and VTE (HR, 1.11 (95% CI 0.79-1.55); (p > 0.05). 72 In another cohort study on the risk of VTE and TNFi use, there was no significant association between TNFi and VTE (HR of TNFi group was 0.8). 74 The significant effect of JAKi on different cytokine pathways may hypothetically reduce the risk of thrombosis. However, the outcome could not be predicted as some cytokines have a pleiotropic effect, and some have both pro-and anti-inflammatory effects. 76 The increased risk was particularly observed in the group treated with tofacitinib 10 mg twice daily in an extensive analysis that included clinical trial programs and the (Consortium of Rheumatology Researchers of North America) CORRONA registry. 77 The Oral Surveillance Study confirmed these findings, a randomized, open-label, non-inferiority, postauthorization, safety end-point trial that compared the long-term safety of tofacitinib 5 mg and 10 mg twice daily compared to TNFi in an enriched population of patients with increased risk for major adverse cardiovascular events and cancer (age ≥50 years and at least one cardiovascular risk factor). VTE had a numerically higher Hazard ratio for the 5 mg dosing group (HR 1.66 (0.76-3.63)) and a statistically significant Hazard ratio for the 10 mg dosing (HR 3.52 (1.74-7.12)). 78 These findings prompted the Food Drug Administration and the European Medicine Agency to select patients for the entire JAKi class cautiously. In contrast, multiple systematic reviews showed no increased risk of VTE in different JAKi, and variable patient populations compared to controls, even when assessing different dosing arms (Table 3). [79][80][81][82][83][84][85] These conflicting findings could be explained by the dilutional effect of low-risk patients in clinical trial programs who are classically young with high disease activity and lack significant comorbidities. In this subset of patients, the anticytokine effect of JAKi leads to a reduction in VTE following the control of RA-related inflammation. In patients with multiple risk factors, the impact on the JAK/STAT pathway and the inhibitory effect on some cytokines may be responsible for potentiating the risk of VTE. Therefore, it is important to stratify patients' risk prior to JAKi initiation. 86

Conclusion
The increased risk of VTE in RA patients can be explained by a complex interaction between intrinsic and extrinsic factors. Therefore, Modification of risk factors, adequate disease control, and appropriate risk stratification is recommended for VTE prevention.

Disclosure
Mohammed A. Omair received speaker honoraria from Abbvie, Actelion, Amgen, Bristol Myers Squibb, Glaxo-Smith-Kline, Hekma, Janssen, Lilly, New Bridge, Novartis, Pfizer, and Roche. The other authors have no conflicts of interest to declare.