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

Figures & data

Figure 1 Conceptualization framework describing the interaction between intrinsic and extrinsic venous thromboembolism risk factors in rheumatoid arthritis patients.

Abbreviations: APS, antiphospholipid syndrome; CTD, connective tissue disease; JAKi, Janus kinase inhibitor; OCP, oral contraceptive pills; VTE, venous thromboembolism; CAD, coronary artery disease; CHF, congestive heart failure; COPD, chronic obstructive lung disease; SAD, small airway disease; ILD, interstitial lung disease.

Table 1 Summary of Systematic Reviews Examining Venous Thromboembolism Risk in Rheumatoid Arthritis Patients

First Author	Year	Number of Studies	Inclusion Criteria	Main Outcomes
HU et al^Citation3	2021	12	Studies evaluating the incidence of VTE, DVT, and PE in RA patients	OR of DVT in RA patients relative to controls: (2.25, 95% CI: 1.70 to 2.98, p<0.001) OR of PE in RA patients relative to controls (2.15, 95% CI: 1.39 to 3.49, p=0.001). OR of VTE in RA patients relative to controls (2.23, 95% CI: 1.79 to 2.77, p<0.001)
Lee and Pope.^Citation55	2014	10	Studies evaluating the incidence of VTE, DVT, and PE in RA patients	OR of DVT in RA patients relative to controls: 2.23 (95% CI: 2.02 to 2.47) Cumulative incidence of VTE is 2.18% (95% CI:1.82% to 2.54%)
Ungprasert et al^Citation2	2014	9	Observational studies (case-control, cross-sectional, cohort) evaluating the association between RA and VTE, DVT or PE	Pooled risk ratio for VTE 1.96 (95% CI 1.81–2.11) Pooled risk ratio for DVT= 2.08 (95% CI 1.75–2.47) Pooled risk ratio for PE= 2.17 (95% CI 2.05–2.31)

Abbreviations: RA, rheumatoid arthritis; VTE, venous thromboembolism; DVT, deep venous thrombosis; PE, pulmonary embolism; CI, confidence interval; OR, odds ratio.

Table 2 Summary of Major Epidemiological Studies Evaluating Venous Thromboembolism in Rheumatoid Arthritis Patients

First Author	Year	Country	Study Design	Sample Size	Main Outcomes
Matta et al^Citation87	2009	United States	Cohort	895,873,000	Incident of DVT 0.9 in RA vs 0.4 in non-RA, RR 2.25. Incident of PE 1.6 in RA vs 0.9 in non-RA, RR 1.90. Incident of VTE 2.3 in RA vs 1.1 in non-RA, RR 1.99.
Davies et al^Citation74	2011	United Kingdom	Cohort	15,554	IR was 3.7/1000 person-year in RA with TNFi vs 3.7/1000 person-year in RA with csDMARD. Adjusted HR of VTE with TNFi group= 0.8.
Kang et al^Citation88	2012	Taiwan	Case control	25,965	OR of RA in cases of VTE= 1.92 (95% CI, 1.46–2.53; P < 0.001).
Holmqvist et al^Citation64	2012	Sweden	Prospective cohort study	215,175	Prevalent cohort: IR of VTE was 5.9/1000 person-year in RA vs 2.8/1000 person-year in non-RA, HR= 2. Incident cohort: IR of VTE was 4.5/1000 person-year in RA vs 1.6/1000 person-year in non-RA, HR= 1.6.
Choi et al^Citation58	2012	United Kingdom	Cohort	105,365	IR of DVT 2.1/1000 patient-year in RA vs 1.0/1000 patient-year in non-RA. IR of PE 1.5/1000 patient-year in RA vs 0.7/1000 patient-year in non-RA. IR for VTE 3.3/1000 patient-year in RA vs 1.5/1000 patient-year in non-RA. RR of VTE in RA after adjustment for multivariant 2.14.
Bacani et al^Citation56	2012	United States	Cohort	928	Cumulative incidence: DVT 3.1±10 in RA vs 1.7±0.9 in non-RA (P value= 0.034)PE 4.8±1.5 in RA vs 1.6±0.7 in non-RA (P value=0.050). VTE 6.7±1.7 in RA vs 2.8±1.1 in non-RA (P value=0.005). Rate of VTE = 7.4/1000 patient-year. HR of VTE= 3.6 (95% confidence interval [95% CI] 1.5–8.6) in RA group.
Chung et al^Citation59	2013	Taiwan	Cohort	146,190	IR of DVT 1.7/1000 person-years in RA vs 0.322/1000 person-years in non-RA, HR = 3.36. IR of PE 0.36/1000 person-years in RA vs 0.175/1000 in non-RA, HR= 2.07.
Kim et al^Citation67	2013	United States	Retrospective cohort	110,715	IR of DVT 4.5/1000 person-year in RA vs 2.1/1000 person-year in non-RA, Risk ratio= 2.2. IR of PE 2.6/1000 person-year in RA vs 0.9/1000 person-year in non-RA, Risk ratio= 2.7. IR of VTE 6.1/1000 person-year in RA vs 2.5/1000 person-year in non-RA, Risk ratio= 2.4.
Yusuf et al^Citation89	2015	United States	Cohort	296,352	IR of VTE was 4.90/1000 person-year in RA vs 1.91/1000 person-year in controls. IR of VTE was 19.74/1000 person-year in autoimmune hemolytic anemia. IR of VTE was 7.72/1000 person-year in immune thrombocytopenic purpura. IR of VTE was 9.89/1000 person-year in lupus patients.
Ogdie et al^Citation90	2018	United States	Retrospective Cohort	1,483,705	IR of DVT was 3.7 and 3.4/10,000 person-year in RA with DMARDs vs no DMARDs, respectively, and 2.1/10,000 person-year in non-RA. IR of PE was 1.3 and 0.9/10,000 person-year in RA with DMARDs vs no DMARDs, respectively, and 0.5/10,000 person-year in non-RA. IR of VTE was 4.7 and 4.2/10,000 person-year in RA with DMARDs vs no DMARDs, respectively, and 2.5/10,000 person-year in non-RA. HR of VTE in RA = 1.29 in no DMARD group vs 1.35 in DMARD group.
Mansour et al^Citation91	2019	Israel	Cohort	69,755	IR of VTE was 6.92% in RA vs 3.18% in non-RA. OR of VTE in RA = 2.27.
Galloway et al^Citation66	2020	United Kingdom	Cohort	266,890	HR of VTE was 1.54 in RA. HR of PE was 1.57 in RA. HR of DVT was 1.64 in RA vs HR= 1 in control. HR of VTE was 1.27,1.73, 1.20 in UC, CD, PsA respectively. HR of PE was 1.23, 1.69,1.34 in UC, CD, PsA respectively. HR of DVT was 1.33,1.96,1.34 in UC, CD, PsA respectively. vs HR =1 in control.
Molander et al^Citation62	2020	Sweden	Cohort	262,159	IR of DVT 0.45/1000 person-year in RA vs 0.22/1000 person-year in non-RA. IR of PE 0.26/1000 person-year in RA vs 0.14/1000 person-year in non-RA. IR of VTE 0.71/1000 person-year in RA vs 0.36 in non-RA. Adjusted RR for VTE in RA = 1.88. Within RA cohort: IR of VTE was 0.52, 0.63, 0.80,1.08 in remission, low, intermediate, and high disease activity, respectively. Adjusted RR of VTE was 1.12,1.48, and 2.03 in low, intermediate, and high disease activity, respectively.
Chen et al^Citation72	2021	Taiwan	Cohort	28,873	IR of VTE in RA with csDMARD was 12.61/10,000 person-year vs 14.33 was 12.61/10,000 person-year in RA with bDMARDs. HR of VTE in bDMARDs was= 1.11 (not statically significant).
Dore et al^Citation92	2021	United States	Retrospective cohort		VTE incident in csDMARD naive = 0.8 (0.7 for DVT, 0.3 for PE) VTE incident in csDMARD switchers= 0.7 (0.6 for DVT, 0.3 for PE) VTE incident in bDMARD switchers= 0.9 (0.7 for DVT, 0.3 for PE).
Conforti et al^Citation63	2021	Italy	Retrospective Cohort		IR of VTE was 7.8 per 1000 person-year in the RA cohort. IR of VTE was 1 per 1000 person-year in the general population from previous data. HR for predictive factors: Age = 1.07 (P value= 0.015) BMI = 1.37 (P value= 0.025) Disease duration= 1.13 (P value= 0.006).
Ozen et al^Citation61	2021	United States	Cohort		Number of VTE events = 539 HR of BMI >30 and VTE= 1.47 HR of steroid use and VTE= 1.99 HR of age >65 and VTE= 2.32 HR of RDCI and VTE= 1.20 HR of recent fracture and VTE= 1.62 HR of hospitalization and VTE= 1.09 HR of recent surgery and VTE= 1.18. HR of moderate/sever disease activity and VTE = 1.31
Li et al^Citation60	2021	Canada	Cohort	117,220	IR of DVT 2.82 per 1000 person-year in RA vs.1.94/1000 person-year in non-RA. IR of PE 1.43/1000 person-year in RA vs 1.03/1000 person-year in non-RA. IR of VTE 3.79/1000 person-year in RA vs 2.70/1000 person-year in non-RA. Fully adjusted HR of VTE = 1.28.

Abbreviations: RA, rheumatoid arthritis; VTE, venous thromboembolism; DVT, deep venous thrombosis; PE, pulmonary embolism; CI, confidence interval; OR, odds ratio; RR, relative risk; HR, hazard ratio; IR, incidence rate; DMARDs, disease-modifying anti-rheumatic drugs; csDMARDs, conventional synthetic DMARDs; bDMARDs, biological DMARDs; TNFi, tumor necrosis factor inhibitors; UC, ulcerative colitis; CD, Crohn’s disease; PsA, psoriatic arthritis; BMI, body mass index; RDCI, rheumatic disease comorbidity index.

Table 3 Systematic Reviews Assessing Venous Thromboembolism Risk in Patients Treated with Janus Kinase Inhibitors

First Author	Year	Number of Studies	Inclusion Criteria	Main Outcomes
Alves et al^Citation79	2022	42	RA RCTs of baricitinib, filgotinib, peficitinib, tofacitinib, and upadacitinib.	No differences were observed between different JAKis regarding the risk of VTE compared with placebo
Bilal et al^Citation80	2021	29	RCTs of JAK inhibitors, regardless of clinical condition, that reported adverse event data for the treatment and control groups	No association between the use of JAK inhibitors and the risk of VTE (odds ratio, 0.91; 95% CI, 0.57 to 1.47), even when cancer studies were excluded and analysis was stratified according to underlying disease.
Giménez et al^Citation81	2020	59	RCTs and non-RCTs and controlled cohort studies (prospective or retrospective) comparing oral baricitinib or tofacitinib at any dose with another active drug or placebo in which patients received at least one dose of oral baricitinib or tofacitinib for any indication.	Overall, an odds ratio (OR) for VTE events of 0.29 (95% CI 0.10–0.84) for tofacitinib. -The ORs for VTE events for baricitinib was 3.39 (95% CI 0.82–14.04) overall. -The indirect meta-analysis comparing tofacitinib with baricitinib showed an OR for VTE events of 0.086 (95% CI 0.02–0.51) for tofacitinib and a superior safety profile for VTE events. -In the meta-regression analysis, the effect was 0.02 (95% CI −0.04 to 0.08) for tofacitinib and 0.01 (95% CI −1.29 to 1.26 for baricitinib. -Plotting data for tofacitinib showed that VTE risk increased with high doses. -The effect, however, was less than 1 for the 10- and 20-mg doses, indicating a protective effect. This effect was not observed for baricitinib.
Yates et al^Citation82	2020	42	RCTs of JAKi therapy with a placebo comparator arm	IRR of VTE, PE and DVT in patients receiving JAKi were 0.68 (95% CI 0.36 to 1.29), 0.44 (95% CI 0.28 to 0.70) and 0.59 (95% CI 0.31 to 1.15), respectively.
Wang et al^Citation83	2020	20	RTCs of tofacitinib or baricitinib, or upadacitinib in RA patients	VTE data were unavailable for tofacitinib or baricitinib, but there was no increase in risk with upadacitinib (15 mg daily: RR, 2.34; 95% CI, 0.34 to 15.92).
Xie et al^Citation84	2019	29	RCTs in adult patients with immune-mediated inflammatory disorders using tofacitinib	There was a decreased rate of VTEs (OR 0.03, 95% CI 0.00–0.21) in patients initiating tofacitinib. Tofacitinib 10 twice daily was associated with an increase in VTEs risk (OR = 1.47, 95% CI 0.25–8.50) compared with the 5 mg regimen.
Xie et al	2019	25 for placebo comparison 18 for dose dependence	RTCs of tofacitinib or baricitinib, or upadacitinib in RA patients	There was no increased risk of VTEs in users of the 3 JAKi (OR 1.16 (0.48 to 2.81), p = 0.74). There was no dose dependent increase of VTE in any JAKi

Abbreviations: RCT, randomized controlled trial; RA, rheumatoid arthritis; JAKi, Janus kinase inhibitor; VTE, venous thromboembolism; DVT, deep venous thrombosis; PE, pulmonary embolism; CI, confidence interval; OR, odds ratio; RR, relative risk; HR, hazard ratio; IR, incident rate.

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