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Risk of venous thromboembolism associated with Janus kinase inhibitors for rheumatoid arthritis: case presentation and literature review

Risk of venous thromboembolism associated with Janus kinase inhibitors for rheumatoid arthritis:... Janus kinase (JAK) inhibitors have been developed as disease-modifying antirheumatic drugs. Despite the positive therapeutic impacts of JAK inhibitors, concerns have been raised regarding the risk of venous thromboembolism (VTE), such as deep vein thrombosis (DVT) and pulmonary embolism (PE). A recent post hoc safety analysis of placebo-controlled trials of JAK inhibitors in rheumatoid arthritis (RA) reported an imbalance in the incidence of VTE for a 4-mg daily dose of baricitinib versus placebo. In a recent postmarketing surveillance trial for RA, a significantly higher incidence of PE was reported in treatment with tofacitinib (10 mg twice daily) compared with tofacitinib 5 mg or tumor necrosis factor inhibitors. We also experienced a case of massive PE occurring 3 months after starting baricitinib (4 mg once daily) for multiple biologic- resistant RA. Nevertheless, the evidence to support the role of JAK inhibitors in VTE risk remains insufficient. There are a number of predisposing conditions and risk factors for VTE. In addition to the known risk factors that can provoke VTE, advanced age, obesity, diabetes mellitus, hypertension, hyperlipidemia, and smoking can also contribute to its development. Greater VTE risk is noted in patients with chronic inflammatory conditions, particularly RA patients with uncontrolled disease activity and any comorbidity. Prior to the initiation of JAK inhibitors, clinicians should consider both the number and strength of VTE risk factors for each patient. In addition, clinicians should advise patients to seek prompt medical help if they develop clinical signs and symptoms that suggest VTE/PE. Key Points • Patients with rheumatoid arthritis (RA) are at increased risk of venous thromboembolism (VTE), especially those with uncontrolled, high disease activity and those with comorbidities. • In addition to the well-known risk factors that provoke VTE events, advanced age and cardiovascular risk factors, such as obesity, diabetes mellitus, hypertension, hyperlipidemia, and smoking, should be considered risk factors for VTE. • Although a signal of VTE/pulmonary embolism (PE) risk with JAK inhibitors has been noted in RA patients who are already at high risk, the evidence is currently insufficient to support the increased risk of VTE during RA treatment with JAK inhibitors. • If there are no suitable alternatives, clinicians should prescribe JAK inhibitors with caution, considering both the strength of individual risk factors and the cumulative weight of all risk factors for each patient. Keywords Baricitinib · Deep vein thrombosis · Janus kinase inhibitors · Pulmonary embolism · Rheumatoid arthritis · Tofacitinib Department of Rheumatology, Clinical Research Center * Shunsuke Mori for Rheumatic Diseases, National Hospital Organization [email protected] Kumamoto Saishun Medical Center, 2659 Suya, Fumihiko Ogata Kohshi Kumamoto 861-1196, Japan [email protected] Divsion of Cardiology, Japanese Red Cross Kumamoto Ryusuke Tsunoda Hospital, Kumamoto, Japan [email protected] Vol.:(0123456789) 1 3 4458 Clinical Rheumatology (2021) 40:4457–4471 it failed to control the disease activity. Next, the patient Introduction attempted four different biological therapies sequentially, starting with etanercept plus MTX, then proceeding to inf- The Janus kinase (JAK)/signal transducer and activator of liximab plus MTX, tocilizumab plus MTX, and abatacept transcription (STAT) pathway is one of the major cascades monotherapy, but every therapy failed and the disease activ- that transfers extracellular cytokine signals from cell surface ity became high. In March 2020, high-throughput leukocyta- receptors to the nucleus. There are four isoforms in the JAK pheresis (LCAP), which is an alternative therapeutic option family, namely, JAK1, JAK2, JAK3, and TYK2, which act for the management of RA with super-resistance to DMARD in pairs either as homodimers or as heterodimers to activate therapies [15], was initiated. After five LCAP procedures STAT proteins. Different cytokine receptor families utilize at 1-week intervals, the patient started baricitinib, a JAK1/ specific pairs of JAK isoforms for signal transduction [1 , 2]. JAK2 inhibitor, 4 mg once daily with oral prednisolone. Over the last decade, JAK inhibitors, small molecules that Eight weeks later, the patient achieved low disease activity. target the JAK-STAT signaling pathway, have been devel- Twelve weeks after starting baricitinib therapy, dyspnea and oped as targeted synthetic disease–modifying antirheumatic chest pain suddenly appeared on lifting heavy objects. The drugs (tsDMARDs) for immune-mediated inflammatory patient had noticed painless swelling of the left leg 1 week diseases (IMIDs) such as rheumatoid arthritis (RA) [3–5]. prior to this attack. The patient was immediately taken to Biological DMARDs (bDMARDs), protein molecules an emergency hospital by ambulance because of worsening that target specific cytokines and cytokine receptors in the dyspnea. inflammatory cascade, have several limitations, including In the emergency room, the patient was in shock. The the need for parenteral administration and the development respiratory rate was 30 breaths/min and SpO was 90% of anti-drug antibodies due to inherent immunogenicity with reservoir mask oxygen at 7 L/min. Arterial blood gas [6]. In the context of these limitations, JAK inhibitors have analysis showed P aO of 77 Torr, P aCO of 29 Torr, and significant advantages over bDMARDs. In addition, recent 2 2 HCO – of 19.2 mmol/L. Elevated levels of serum D-dimer randomized clinical trials of JAK inhibitors for RA demon- (34.6 µg/mL) and brain natriuretic peptide (BNP, 30.1 pg/ strated equivalent or even superior efficacy to adalimumab, mL) were observed. The electrocardiogram indicated right a tumor necrosis factor (TNF) inhibitor [7–10]. Using real- ventricular strain with a heart rate of 126 beats/min. Tran- world registries, we showed that tofacitinib, a first-genera- sthoracic echocardiography showed a dilated right ventricu- tion JAK inhibitor, can induce greater improvements during lar dimension (50.5 mm), McConnell sign (defined as right the r fi st 12-month treatment in bDMARD-naïve RA patients ventricular free wall akinesis with sparing of the apex), and compared with tocilizumab, an anti-interleukin-6 receptor reduced tricuspid annular plane systolic excursion (TAPSE) antibody [11, 12]. Despite these positive therapeutic impacts to 9.3 mm. These results indicate severe right ventricular of JAK inhibitors, concerns have been raised regarding the systolic dysfunction. Contrast-enhanced computed tomog- risk of venous thromboembolism (VTE), such as deep vein raphy revealed thrombi in both main pulmonary arteries, thrombosis (DVT) and pulmonary embolism (PE). In addi- the left popliteal vein, and the left superficial femoral vein tion, previous meta-analyses indicated a higher background (Figs. 1 and 2). The patient was diagnosed as developing risk of VTE among patients with RA or other IMIDs com- acute massive PE caused by DVT [16–18]. Anti-phospho- pared with the general population [13, 14]. lipid syndrome–related tests and anti-SARS-Cov-2 antibody The aim of this review is to provide the latest update tests were negative. The body mass index was 34.2 (obese regarding the risk of VTE events associated with JAK inhibi- class I), and no other cardiovascular or VTE risk factors tors in RA patients, which can guide therapeutic decisions were identified. based on safety considerations. We also share our recent The patient was intravenously administered 120 × 10 experience with a case of massive PE occurring in the treat- units of tissue-type plasminogen activator (t-PA) as ment of multiple biologic-resistant RA with a JAK inhibitor, thrombolytic therapy. On admission day 2, the patient baricitinib, with the intention to discuss the risk manage- recovered from the shock state, and dyspnea was ment of VTE events. improved. No bleeding was observed. Oral rivaroxaban 30 mg daily (Xa inhibitor) was used as anticoagulation therapy. On admission day 6, the patient’s dyspnea and Case presentation: massive PE hypoxia were resolved. Contrast-enhanced computed during baricitinib therapy for RA tomography revealed that the amounts of thrombi had decreased. The findings of right ventricular strain disap- In April 2010, a 46-year-old female was diagnosed with peared. On admission day 10, the patient was discharged seropositive RA. The disease activity was moderate. The with oral rivaroxaban. Certolizumab-pegol plus MTX patient started methotrexate (MTX) monotherapy, but therapy was newly started. Four months later, the patient 1 3 Clinical Rheumatology (2021) 40:4457–4471 4459 achieved low disease activity, and the emboli disappeared Search strategy from the pulmonary arteries and the veins of the left lower limb. The literature search for the current review was carried out The latest postmarketing surveillance data on safety in line with the recommendations for bibliographic searches from pharmaceutical companies in Japan reported six for narrative reviews [19]. Using the PubMed platform, cases of DVT (0.09%), two cases of PE (0.03%), and one the Medline database was searched on April 30, 2020, for case of venous embolism (0.01%) in RA patients receiv- English biomedical literature focusing on VTE risk in RA ing tofacitinib (n = 6989, data cutoff May 5, 2020), and patients receiving and not receiving JAK inhibitors. The 11 cases of severe VTE (0.3%) and seven cases of non- identification of eligible articles was initially carried out by severe VTE (0.2%) in RA patients receiving baricitinib screening titles and abstracts, and finally by reading the full (n = 3445, data cutoff January 1, 2021). In our institution, text of the publication. The references of the eligible articles tofacitinib or baricitinib was used in approximately 200 were screened to ensure that no important research data rel- RA patients and, as mentioned above, one patient devel- evant to the subject were missed. oped massive PE 3 months after starting baricitinib 4 mg To identify English articles relating to the VTE risk once daily. associated with JAK inhibitors, we used the terms (venous Fig. 1 Contrast-enhanced computed tomography reveals prominent emboli in the bilat- eral main pulmonary arteries (yellow arrowheads) Fig. 2 Contrast-enhanced computed tomography reveals occlusive intravenous thrombo- sis in the left popliteal vein and the left superficial femoral vein (yellow arrowheads) 1 3 4460 Clinical Rheumatology (2021) 40:4457–4471 thromboembolism OR venous thromboembolic event OR to 78, and 45 to 117 per 100,000 person-years, respectively. pulmonary embolism OR deep vein thrombosis) AND (Janus The recurrence of VTE occurs frequently: approximately kinase inhibitor OR tofacitinib OR baricitinib OR upadaci- 30% of patients who have a first episode of VTE will experi- tinib OR filgotinib OR peficitinib). Through the Medline ence recurrence within 10 years [22]. A VTE event is a seri- search, a total of 90 articles were identified. Among them, ous medical condition associated with long-term morbidity we found eight post hoc safety analyses, two systematic and increased mortality. In particular, PE is an independent reviews, and seven systematic reviews/meta-analyses using predictor of reduced survival for up to 3 months after the pooled data from clinical trials and long-term extension event [23, 24]. As a result of the westernized lifestyle and (LTE) studies of JAK inhibitors for RA and other IMIDs. In aging society in Japan, the number of patients with PE has addition, six postmarketing studies using real-world regis- increased 4.6-fold in the past 15 years, with an estimated tries of RA and other IMID patients receiving JAK inhibitors annual IR of 12.6 per 100,000 person-years in 2011 [25]. were identified (among these 6, one study was also identified and included as a post hoc analysis). We also found three Risk factors for VTE review articles including detailed data on incidence rates of VTEs associated with JAK inhibitors. All of these studies In the nineteenth century, the German physician Virchow are included in the “VTE events in RA patients receiving explained the pathophysiologic mechanisms of VTE by three JAK inhibitors” section of this review. Individual clinical major determinants, called Virchow’s triad, which included trials as well as LTE studies were not included in this section hypercoagulability (constituents of blood), endothelial because all VTE cases in these studies were incorporated injury (vessel wall), and venous stasis (blood flow) [26]. into the abovementioned post hoc analyses and systematic There are a number of predisposing conditions and risk reviews/meta-analyses. We also excluded studies that only factors for VTE, which can affect one or more elements of focused on patients with non-RA IMIDs. Virchow’s triad. To identify English articles comparing VTE risk between Many episodes of VTE are provoked by a transient or RA patients and non-RA controls as well as those compar- persistent risk factor [27]. Major general surgery, orthope- ing VTE risks among RA patients based on disease activity, dic surgery (hip or knee replacement), major trauma, frac- we used the terms (venous thromboembolism OR venous ture (hip or leg), spinal cord injury, and immobilization are thromboembolic event OR pulmonary embolism OR deep categorized as major setting-related (usually transient) risk vein thrombosis) AND (rheumatoid arthritis OR autoim- factors that can provoke VTE. Active cancer is a well-rec- mune OR immune-mediated OR inflammatory) AND (inci- ognized patient-related (usually permanent or progressive) dence OR rate). Through the Medline search, a total of 1608 risk factor that can provoke VTE [18, 20, 27, 28]. In addi- English articles were identified. Among them, we found 16 tion, congestive heart or respiratory failure, infection (such eligible articles (15 articles comparing the VTE incidence as pneumonia, urinary tract infection, or HIV infection), between RA patients and non-RA controls and one article and acquired thrombophilia (antiphospholipid antibody comparing the VTE incidence among RA patients based on syndrome, etc.) are considered moderate-risk factors that disease activity/severity). These studies are included in the can provoke VTE. Heart disease such as myocardial infrac- “VTE risks in RA patients” section of this review. Stud- tion and atrial fibrillation (within the previous 3 months) ies focusing on postoperative VTE events or recurrent VTE especially increases the risk of PE. In women, pregnancy events were excluded. and puerperium, oral contraceptives, and hormone replace- Additional articles were also selected based on the prior ment therapy are recognized as moderately provoking risk knowledge of the authors, and the information was synthe- factors for VTE [18, 20, 27–29]. A high risk of recurrence sized below. has been noted in patients with persistent risk factor(s). A previous episode of VTE should be considered a major risk factor for a new episode [18, 20, 22, 27]. A brief overview of VTE Approximately 40 to 50% of VTE cases are considered unprovoked or idiopathic, that is, they do not have impor- Epidemiology of VTE tant provoking factors for VTE (either transient or persis- tent) [21, 27, 30]. These patients may, however, have minor VTE is fairly common, and its incidence increases exponen- acquired or inherited predisposing conditions for VTE [25, tially with age [20, 21]. In the majority of cases, VTE mani- 27, 30]. Hereditary thrombophilia (antithrombin, protein fests as DVT of the legs and pelvis; in 30 to 40% of patients, C, or protein S deficiency, Factor V Leiden or prothrom- it appears as PE. The estimated annual incidence rates (IRs) bin G20210A gene mutation, etc.) is considered a minor for VTE, PE (with or without DVT), and DVT alone in inherited risk factor. Increasing age is also associated with Western countries are reported to range from 104 to 183, 29 the risk of VTE [20, 27, 30]. Recently, the contribution of 1 3 Clinical Rheumatology (2021) 40:4457–4471 4461 non-cancer persistent conditions, including chronic inflam- tsDMARD switchers. These findings suggested that switch- matory diseases and traditional cardiovascular risk factors ing bDMARD/tsDMARD may be a proxy for higher disease (such as smoking, obesity, hypertension, diabetes mellitus, severity and poorly controlled disease activity in RA [48]. and hyperlipidemia) to the pathophysiology of VTE, has The increased VTE risk observed in RA patients may be been investigated. These conditions may be insufficient to attributed, at least in part, to uncontrolled disease activity. cause VTE when isolated, but they can be factors that pre- dispose an individual to VTE if combined [30]. It is becoming clear that there is a functional interde- JAK inhibitors currently licensed for RA pendence between inflammation and thrombosis, which treatment is mediated by the loss of normal functions of endothelial cells, leading to the dysregulation of coagulation, platelet Tofacitinib and baricitinib are first-generation JAK inhibi- activation, and leukocyte recruitment in the microvascu- tors, and both have been approved by the US Food and Drug lature. Chronic inflammation appears to be an important Administration (FDA) and the European Medicines Agency determinant of chronic VTE events [30–32]. An imbalance (EMA) [49, 50]. Tofacitinib, a JAK1, JAK2, and JAK3 pan- between pro-thrombotic and anti-thrombotic cytokines may inhibitor, was first approved for the treatment of moderately be involved in the pathophysiology of VTE [32]. to severely active RA by the FDA in 2012. In 2017, the EMA also recommended the approval of tofacitinib for RA. Cur- rently, the recommended dose of tofacitinib in RA treatment VTE risks in RA patients is 5 mg twice daily in most countries. Baricitinib, which has a specificity for JAK 1 and JAK2, is the second approved A number of population-based epidemiological studies JAK inhibitor. The use of this drug was approved by the showed that the risk of VTE is increased in RA patients EMA in 2017 at 2 mg or 4 mg once daily for the treatment compared with the general population. Fifteen studies are of moderately to severely active RA. Subsequently, the FDA summarized in Table  1 [33–47]. RA patients were more recommended the approval of a baricitinib 2-mg once-daily likely to experience VTE compared with age- and sex- dosing regimen for RA treatment in April 2018, but did not matched non-RA subjects, even after adjustment for VTE recommend the use of 4 mg once daily due to safety con- risk factors and comorbidities. In several studies, the VTE cerns related to VTE. In Japan, baricitinib is available in risk was stable over follow-up time [36, 39]. In other stud- 2 mg and 4 mg once-daily dosing regimens for the treatment ies, the VTE risk was highest during the first year, then of RA. attenuated with time but remained statistically elevated even The next-generation JAK inhibitors upadacitinib and fil- 5 years after RA diagnosis [42, 46]. Among hospitalized RA gotinib were designed with selective affinity to JAK1, which patients, the PE risk was highest during the first year after may decrease the risk of unwanted adverse events without hospitalization. This risk decreased over time but persisted compromising clinical efficacy. Upadacitinib was approved up to 10 years [41]. These findings suggested that RA should by the FDA and EMA for the treatment of moderate to be regarded as a hypercoagulable disorder. severe RA in 2019. Filgotinib was approved by the EMA, The VTE risk increased with increased disease activ- but the FDA did not approve this drug because of concerns ity: a twofold increase in VTE risk was observed in RA relating to its testicular toxicity [50, 51]. patients with high disease activity compared with patients These four JAK inhibitors are currently available in the in remission (risk ratio [RR] 2.03, 95% confidence interval treatment of RA in Japan. Peficitinib, a pan JAK inhibitor [CI] 1.73–2.38) [40]. Poorly controlled RA activity may be (a JAK1, JAK2, and JAK 3 inhibitor), is also approved in associated with the risk of VTE. Using the Optum Clin- Japan [50]. formatics Data Mart, a United States (US) claims database that includes patients receiving DMARD treatment after the first diagnosis of RA between 2007 and 2017, Liang VTE events in RA patients receiving JAK et al. showed that, after adjustment for multiple risk fac- inhibitors tors, patients who switched from a bDMARD/tsDMARD to another bDMARD/tsDMARD (bDMARD/tsDMARD Are JAK inhibitors associated with an increased risk switchers) had an increased risk of VTE compared with con- of VTE? ventional synthetic DMARD (csDMARD) users (adjusted hazard ratio [HR] 1.36, 95% CI 1.16–1.58). Compared with Numerically higher rates of VTE/PE events were observed first bDMARD/tsDMARD users, the adjusted HR (95% CI) in some clinical trials of JAK inhibitors versus placebo, sug- for VTE was 1.35 (1.15–1.60) for first bDMARD/tsDMARD gesting an increased risk for developing VTE during treat- switchers and 1.48 (1.19–1.85) for second bDMARD/ ment with JAK inhibitors [5, 52]. Given the rarity of VTE 1 3 4462 Clinical Rheumatology (2021) 40:4457–4471 Table 1 VTE risks in RA patients versus non-RA controls Study Period Database No. of VTEs/total No. of VTEs/total HRs/RRs/ORs/SIR Comments RA patients controls (95% CI)* (Mean follow-up) Country Bacani et al. [33] 1995–2008 Olmsted County, VTE 19/464 7/464 HR 3.6 (1.5–8.6) Incident RA patients Minnesota Matched controls (5.9 years) PE 12/464 5/464 – (1:1) US DVT 11/464 4/464 – Matta et al. [34] 1979–2005 NHDS VTE 110,000 10,226,000 RR 1.99 (1.98– Hospitalized patients 2.00) without joint surgery (NA) PE 41,000 3,366,000 RR 2.25 (2.23– 2.27) US DVT 79,000 7,681,000 RR 1.90 (1.89– 1.92) /4,818,000 /891,055,000 Kim et al. [35] 2001–2008 US insurance VTE 265/22,143 448/88,572 HR 1.4 (1.1–1.7) Matched controls claims database (1:4) (2.0 years) PE 111/22,143 164/88,572 HR 1.9 (1.3–2.7) Adjusted for risk US DVT 197/22,143 364/88,572 HR 1.2 (0.9–1.5) factors Yusuf et al. [36] 2007–2010 Truven Health Mar- VTE 909/70,768 981/198,044 HR 2.13 (1.89– Adjusted for age, ketScan database 2.40) at 1 year sex, and risk fac- (2.6 years) HR 2.03 (1.64– tors US 2.51) at 4 years Bleau et al. [37] 2003–2011 HCUP-NIS data- VTE 9/5780 5716/7,917,453 OR 1.95 (1.01– Pregnant women base 3.75) Adjusted for age (cross-sectional) PE 5/5780 1734/7,917,453 OR 3.62 (1.50– 8.70) US DVT 6/5780 4228/7,917,453 OR 1.75 (0.78– 3.89) Yusuf et al. [38] 2010 HCUP-NIS data- VTE 2.65%/94,585 2.28%/5,539,809 OR 1.17 (1.13– Hospitalized patients base 1.21) Adjusted for age, (cross-sectional) sex, race, and risk US factors Holmqvist et al. 1997–2010 SRQ Register VTE 223/7904 648/37,350 HR 1.6 (1.4–1.9) Incident RA [39] HR 1.6 (1.1–2.5) Matched controls (5.8 years, median) within the first (1:5) Sweden year Adjusted for age HR 1.9 (1.4–2.4) at 5–9 years Molander et al. [40] 2006–2018 SRQ Register VTE 2241/46,316 5301/215,843 RR 1.88 (1.65– Matched controls 2.15) within the (1:5) (1 year) first year RR 2.03 Adjusted for age, Sweden (1.73–2.38) for sex, and calendar high  year of visit DAS28 vs. remis- sion Zoller et al. [41] 1964–2008 MigMed2 database PE 2500/86,366 – SIR 1.91 (1.83– Hospitalized patients 1.98) Adjusted for age, (NA) SIR 5.99 (5.59– sex, entry time, Sweden 6.41) within the and risk factors first year SIR 1.18 (1.06–1.31) at 5–10 years Choi et al. [42] 1986–2010 THIN VTE 176/9589 815/95,776 RR 2.14 (1.80– Incident RA 2.54) Matched controls (1:10) (5.5 years) PE 82/9589 358/95,776 RR 2.16 (1.68– Adjusted for risk 2.79) factors RRs remained high UK DVT 110/9589 512/95,776 RR 2.16 (1.74– at ≥ 5 y ears 2.69) 1 3 Clinical Rheumatology (2021) 40:4457–4471 4463 Table 1 (continued) Study Period Database No. of VTEs/total No. of VTEs/total HRs/RRs/ORs/SIR Comments RA patients controls (95% CI)* (Mean follow-up) Country Ogdie et al. [43] 1994–2014 THIN (Without DMARD) Matched controls Adjusted for age, (No DMARD: VTE 851/20,426 30,356/1,225,571 HR 1.29 (1.18– sex, and risk fac- 5.8 years) 1.39) tors PE 186/20,426 6066/1,225,571 HR 1.45 (1.23– 1.72) (With DMARD: DVT 702/20,426 25,490/1,225,571 HR 1.25 (1.15– 6.2 years) 1.37) (With DMARD) UK VTE 1479/31,336 30,356/1,225,571 HR 1.35 (1.27– 1.44) PE 393/31,336 6066/1,225,571 HR 1.74 (1.55– 1.99) DVT 1162/31,336 25,490/1,225,571 HR 1.29 (1.20– 1.38) Galloway et al. [44] 1999–2019 UK RCGP-RSC VTE 845/23,410 2020/93,640 HR 1.54 (1.40– Matched controls database 1.69) (1:4) Adjusted for age, (8.2 years) PE 373/23,408 916/93,639 HR 1.57 (1.36– sex, race, and risk 1.80) factors UK DVT 542/23,408 1242/93,640 HR 1.64 (1.45– 1.84) Ramagopalan et al. 1999–2008 English national 6825/268,005 – Rate ratio for VTE Hospitalized patients [45] HES 1.75 (1.70–1.80) Adjusted for age, (NA) sex, time period, UK and residential area Li et al. [46] 1997–2009 British Columbia VTE 1432/39,142 2059/78,078 HR 1.28 (1.20– Incident RA 1.36) Matched controls (1:2) (9.7 years) PE 543/39,142 791/78,078 HR 1.25 (1.13– Adjusted for age, 1.39) sex, and risk fac- Canada DVT 1068/39,142 1484/78,078 HR 1.30 (1.21– tors 1.40) HRs remained high within the first 5  years Chung et al. [47] 1998–2010 Taiwan NHIRD PE 70/29,238 139/116,952 HR 2.07 (1.55– Matched controls 2.76) (1:4) Adjusted for age, (6.6 years) DVT 208/29,238 255/116,952 HR 3.36 (2.79– sex, and risk fac- 4.03) Taiwan tors VTE events included PE and DVT, occurring both individually and in combination The HR, RR, and OR of VTE events in RA patients were calculated compared with those in non-RA patients. Factors used for adjustment are described in the “Comments” column. The SIR was calculated by dividing the observed number of VTE cases in the RA group by the expected number of cases in the reference population with the indirect standardization method. The rate ratio was calculated as the ratio of the observed/ expected numbers in the RA cohort to those in the reference cohort The time-specific RRs were highest within the first year after RA diagnosis (3.27 [95% CI 1.78–6.00] for PE and 3.16 [95% CI 1.95–5.11] for DVT), but persisted at elevated levels at 5 years and more (2.35 [95% CI 1.59–3.46] for PE and 2.32 [95% CI 1.64–3.27] for DVT) The time-specific HRs w ere highest during the first year after RA diagnosis (1.60 [95% CI 1.27–2.00] for VTE, 1.86 [95% CI 1.21–2.86] for PE, and 1.59 [95% CI 1.20–2.10] for DVT), but persisted at high levels within the first 5 years (1.28 [95% CI 1.15–1.42] for VTE, 1.29 [95% CI 1.09–1.53] for PE, and 1.27 [95% CI 1.12–1.43] for DVT) RA, rheumatoid arthritis; VTE, venous thromboembolism; PE, pulmonary embolism; DVT, deep vein thrombosis; HR, hazard ratio; RR, risk ratio; OR, odds ratio; SIR, standardized incidence ratio; DAS28, disease activity score for 28 joints; NHDS, National Hospital Discharge Sur- vey; HCUP-NIS, Health Care Cost and Utilization Project National Impatient Sample; SRQ, Swedish Rheumatology Quality; THIN, The Health Improvement Network; RCGP-RSC, Royal College General Practitioners Research and Surveillance Center; HES, Hospital Episode Statistics; NHIRD, National Health Insurance Research Database; NA, not available 1 3 4464 Clinical Rheumatology (2021) 40:4457–4471 events, however, it is difficult to identify statistically clear VTE events in the tofacitinib development program were signals for increased VTE risks in individual clinical trials. similar between 5 and 10 mg twice-daily doses, and higher In addition, the higher background thromboembolic risk in in patients with cardiovascular or VTE risk factors versus RA patients versus non-RA patients may make it compli- those without. Similar findings were obtained in patients cated to confirm or exclude a significant difference in risk with psoriatic arthritis and those with psoriasis [59]. Similar between JAK inhibitors and placebo [53, 54]. To address IRs were obtained from another integrated safety analysis this issue, a number of post hoc safety analyses and system- of data from phase I, II, III, and IIIb/IV clinical trials (19 atic reviews/meta-analyses of clinical trials and LTE studies studies), and LTE studies (2 studies) of tofacitinib for RA (a as well as postmarketing studies using real-world registries total of 7061 tofacitinib-treated patients) [60]. have been conducted. Upadacitinib Post hoc safety analyses of VTE events in clinical trials and LTE studies In a post hoc safety analysis using integrated data pooled from phase III clinical trials (5 studies) of upadacitinib for There are eight post hoc safety analyses for clinical trials RA (a total of 3834 upadacitinib-treated patients), the IRs and LTE studies of four JAK inhibitors, namely, tofacitinib, of VTE events (per 100 patient-years) in patients receiving baricitinib, upadacitinib, and peficitinib, for RA [55– 62]. upadacitinib 15 mg and 30 mg once daily were 0.6 and 0.3, respectively. The IRs were similar across treatment groups Baricitinib (0.4 for placebo, 0.5 for MTX, and 1.1 for adalimumab) [61]. In post hoc safety analyses using integrated data pooled from Peficitinib phase I, II, and III clinical trials (8 studies) as well as one LTE study of baricitinib for RA, no VTE events occurred In a post hoc pooled safety analysis using integrated data in 1070 placebo-treated patients, but six VTE events were from phase IIb and III clinical trials (3 trials) as well as observed in 997 patients treated with a 4-mg daily dose of one LTE study of peficitinib for RA (a total of 1052 pefi- baricitinib during the 24-week placebo-controlled period. citinib-treated patients), the IR of VTE events was 0.1 per All VTE patients had conventional VTE risk factors. Dur- 100 patient-years for peficitinib-treated patients, and no ing extended observations, the IRs were similar between VTE events were observed in the placebo group. No dose- baricitinib 2 and 4 mg, with IRs of 0.5 per 100 patient-years dependency was observed [62]. versus 0.6 per 100 patient-years. In all patients receiving baricitinib (All-Bari-RA, a total of 3492), the IR was 0.5 Systematic reviews/meta‑analyses of clinical trials per 100 patient-years and stable over time [55, 56]. The IR and LTE studies of VTE events increased with older age in the All-Bari-RA group [63]. In post hoc safety analyses that were limited to Seven meta-analyses using data extracted from clinical trials Japanese or East Asian patients in the ALL-Bari-RA group of JAK inhibitors for RA and other IMIDs were identified (5 phase II and III trials and 1 LTE study), the IRs of DVT in the literature. These studies are summarized in Table 2 were 0.3 to 0.5 per 100 patient-years and there were no PE [64–70]. The meta-analyses for RA showed that there was events [57, 58]. no significant difference in the risk of VTE events between patients receiving JAK inhibitors and those receiving pla- Tofacitinib cebo. During the limited placebo-controlled periods, no dose-dependent impact on the risk of VTE events was In a post hoc safety analysis of pooled data from phase I, II, observed in tofacitinib (5 mg vs. 10 mg twice daily), barici- III, and IIIb/IV clinical trials as well as LTE studies of tofac- tinib (2 mg vs. 4 mg once daily), or upadacitinib (15 mg vs. itinib for RA (a total of 7964 tofacitinib-treated patients), 30 mg once daily) [64, 65]. The meta-analyses for IMIDs the IRs of thromboembolic events (per 100 patient-years) (including RA) showed that VTE risk was unlikely to sub- in patients receiving tofacitinib 5 mg and 10 mg twice daily stantially increase in patients receiving JAK inhibitor during were 0.17 and 0.15 for DVT, 0.12 and 0.13 for PE, and 0.24 the limited placebo-controlled periods [66–69]. In a strati- and 0.26 for VTE, respectively. The IRs in patients with fied and meta-regression analysis, there was no interaction and without cardiovascular risk factors were 0.24 and 0.11 by dose of JAK inhibitors, indication for treatment, or length for DVT, 0.25 and 0.06 for PE, and 0.43 and 0.15 for VTE, of follow-up [68]. In an indirect meta-analysis, the risk of respectively. The IRs in patients with and without VTE risk VTE events in tofacitinib-treated patients was lower than in factors were 0.21 and 0.07 for DVT, 0.16 and 0.04 for PE, baricitinib-treated patients (OR 0.09, 95% CI 0.02–0.51), and 0.35 and 0.10 for VTE, respectively. Thus, the IRs of suggesting the superior safety profile of tofacitinib to 1 3 Clinical Rheumatology (2021) 40:4457–4471 4465 baricitinib [69]. No increased risk was found for PE during the same research group. The crude IRs of VTE (per 100 treatment with JAK inhibitors for IMIDs including RA [70]. patient-years) for tofacitinib and TNF inhibitors were 0.42 and 0.35 in MarketScan, 1.18 and 0.83 in Medicare, and 0.19 VTE events in postmarketing studies using and 0.34 in Optum, respectively. PS-adjusted HRs showed real‑world registries no statistically significant differences in VTE risk between tofacitinib and TNF inhibitors in any database, with a pooled There are six postmarketing studies using real-world regis- HR of 1.13 (95% CI 0.77–1.65) [74]. tries of RA and other IMID patients receiving JAK inhibi- In a post-approval comparative safety study using the US tors [59, 71–75]. In a disproportionality analysis of data Corrona RA Registry, an ongoing longitudinal clinical regis- extracted from the postmarketing FDA’s Adverse Event try from November 2012 through July 2018 (1999 tofacitinib Reporting System (FAERS) from March 2017, no evidence initiators and 8358 TNF-inhibitor initiators), the IRs of VTE for increased reporting rates for DVT or PE was identified per 100 patient-years were 0.29 in tofacitinib initiators (5 mg across three FDA-approved JAK inhibitors, tofacitinib, twice daily in most cases) and 0.33 in bDMARD initiators, tofacitinib extended-release, and ruxolitinib (reporting odds which were numerically similar between tofacitinib initiators ratios [RORs] and empirical Bayesian geometric means < 1). and bDMARD initiators [75]. The IRs of VTE were numeri- However, this study showed that pulmonary arterial throm- cally similar between RA patients in the Corrona Registry bosis (PT) may be a potential safety issue for tofacitinib, and those in the tofacitinib development program [59]. with an ROR of 2.46 (95% CI 1.55–3.91) [71]. A recent ongoing postmarketing safety surveillance trial, In descriptive and disproportionality analysis of data ORAL Surveillance (Study A39212233), which is evaluating extracted in April 2019 from the World Health Organization the safety of tofacitinib versus TNF inhibitors among RA global database (VigiBase) of individual case safety reports patients aged ≥ 50 years and with at least one cardiovascular for tofacitinib and baricitinib, patients with DVT or PT/PE risk factor, raised concerns of a higher incidence of PE and were older and more often received prothrombotic medica- all-cause mortality in patients treated with tofacitinib 10 mg tions or antithrombotic treatment, suggesting a preexisting twice daily compared with tofacitinib 5 mg twice daily or thromboembolic risk/event. In Europe, tofacitinib was asso- TNF inhibitors. In an ad hoc safety analysis (data cuto ff Feb - ciated with elevated reporting for DVT (ROR 2.37, 95% CI ruary 2019), the IRs per 100 person-years in the treatments 1.23–4.56) and PT/PE (ROR 2.38, 95% CI 1.45–3.89). Simi- with tofacitinib 5 mg twice daily, tofacitinib 10 mg twice lar increased reporting for DVT and PT/PE was observed in daily, and TNF inhibitors were 0.30, 0.38, and 0.18 for DVT baricitinib-treated patients (ROR 3.47, 95% CI 2.18–5.52; and 0.27, 0.54, and 0.09 for PE, respectively. Compared with and ROR 3.44, 95% CI 2.43–4.88, respectively). In the USA, TNF inhibitors, the HRs (95% CI) for DVT and PE were tofacitinib was associated with an increased reporting rate 1.66 (0.60–4.57) and 2.99 (0.81–11.06) with tofacitinib 5 mg of PT (ROR 2.05, 95% CI 1.45–2.90), but no evidence for twice daily and 2.13 (0.80–5.69) and 5.96 (1.75–20.33) with elevated reporting was identified for DVT or PE (ROR < 1). tofacitinib 10 mg twice daily, respectively. The IRs of throm- DVT or PT/PE cases were not reported in baricitinib-treated boembolic events observed in the tofacitinib development patients in the US [72]. program for RA patients with cardiovascular or VTE risk In an observational cohort study using claims data from factors were broadly consistent with those observed in the two databases, the crude IRs of VTE (per 100 patient-years) ORAL Surveillance trial. However, the IR of PE was signifi- for tofacitinib and TNF inhibitors in RA patients were 0.60 cantly greater in patients receiving tofacitinib 10 mg twice and 0.34 in the Truven MarketScan database (2012–2016, daily in the ORAL Surveillance trial [59]. 1910 tofacitinib initiators and 32,164 TNF-inhibitor initia- tors) and 1.12 and 0.92 in the Medicare Claims database (2012–2015, 995 tofacitinib initiators and 16,091 TNF- Unanswered questions inhibitor initiators), respectively. The PS-adjusted HRs had no statistically significant differences in VTE risk between As summarized above, in the systematic reviews and meta- tofacitinib and TNF inhibitors in either database, with a analyses of data from clinical trials, the evidence was not pooled HR of 1.33 (95% CI 0.78–2.24) [73]. The IRs of sufficient to support the increased risk of VTE events during VTE in these databases were higher compared with those in RA treatment with JAK inhibitors. These studies are limited the tofacitinib development program for RA [59]. With the by the small number of events reported and the limited over- accumulation of additional data from more recent years in all exposure. In addition, patients with substantial cardiovas- these two databases (the MarketScan database [2012–2018] cular risk factors and comorbidities are often excluded from and the Medicare database [2012–2017]) and the inclu- such clinical trials. The postmarketing ORAL Surveillance sion of a third database (the Optum Clinformatics data- analysis reported a significantly higher incidence of PE and base [2012–2019]), an updated analysis was conducted by all-cause mortality in RA patients treated with tofacitinib 1 3 4466 Clinical Rheumatology (2021) 40:4457–4471 Table 2 Meta-analyses of VTE risk in clinical trials of JAK inhibitors for RA and other IMIDs † † † Study JAK inhibitors No. of studyJAK inhibitors Placebo ORs/RRs/RDs Others (95% CI) * Events Total Events Total Xie et al. [64] Overall 25 for RA 12 2193 PYs 3 982 PYs OR 1.16 (0.48–2.81) (Dose dependency: OR) Tofacitinib 9 1 809 PYs 2 205 PYs OR 0.17 (0.03–1.05) 5 vs. 10 mg: 0.81 (0.22–3.03) Baricitinib 6 7 693 PYs 1 561 PYs OR 2.33 (0.62–8.75) 2 vs. 4 mg: 0.23 (0.02–2.17) Upadacitinib 4 4 285 PYs 0 115 PYs OR 1.77 (0.20– 15 vs. 30 mg: 4.36 16.00) (0.47–40) Filgotinib 1 0 178 PYs 0 42 PYs – – Peficitinib 3 0 179 PYs 0 42 PYs – – Decernotinib 2 0 49 PYs 0 17 PYs – – Xie et al. [65] Tofacitinib 12 for RA 1 881 PYs 2 263 PYs OR 0.06 (0.00–0.95) (Dose dependency: OR) 10 vs. 5 mg: 1.47 (0.25–8.50) Yates et al. [66] Overall 18 for IMIDs (11 12 (10) 1950 PYs 4 (3) 709 PYs (625 PYs) RR 0.68 (0.36–1.29) RR 0.44 (0.28–0.70) for RA) (1601PYs) for IMIDs for PE  RR 0.59 (0.31–1.15) for DVT Tofacitinib 7 (3) 2 (1) 1069 (758) 3 (2) 122 (77) – – Baricitinib 2 (2) 3 (3) 234 (234) 0 107 (107) – – Upadacitinib 6 (5) 6 (6) 475 (450) 1 (1) 378 (352) – – Filgotinib 3 (1) 1 (0) 172 (159) 0 102 (89) – – Olivera et al. [67] Overall 10 for IMIDs (6 for 12 (11) n = 3740 (2566) 3 (0) n = 1403 (997) RR 0.90 (0.32–2.54) RR 1.70 (0.48–6.01) RA) for IMIDs for RA Tofacitinib 4 (2) 3 (3) 2060 (1009) 3 (0) 536 (254) – – Baricitinib 1 (1) 2 (2) 374 (374) 0 210 (210) – – Upadacitinib 2 (2) 5 (5) 883 (883) 0 385 (385) – – Filgotinib 3 (1) 2 (1) 423 (300) 0 272 (148) – – Bilal et al. [68] Overall 25 for IMIDs (14 50 (26) n = 8933 (6254) 27 (4) n = 3612 (2490) OR 0.91 (0.57–1.47) OR 1.11 (0.50–2.44) for RA) for IMIDs for RA Tofacitinib 7 (4) 5 (4) 3690 (2301) 5 (2) 908 (521) OR 0.27 (0.08–0.89) OR 0.54 (0.15–1.96) for IMIDs for 10 mg BID OR 0.49 (0.15–1.55) for 5 mg BID Baricitinib 5 (3) 9 (7) 1292 (862) 1 (1) 487 (348) OR 1.12 (0.27–4.69) OR 2.69 for IMIDs (0.42‒17.21) for 4 mg QD OR 3.05 (0.12‒75.43) for 2 mg QD Upadacitinib 4 (4) 12 (12) 2277 (2277) 1 (1) 1256 (1256) OR 2.25 (0.55–9.25) OR2.64 (0.27‒25.45) for IMIDs for 30 mg QD OR2.91 (0.69‒12.21) for 15 mg QD Filgotinib 2 (1) 2 (1) 358 (300) 0 206 (148) OR 2.13 (0.22– – 20.64) for IMIDs Ruxolitinib 4 (0) 19 (0) 591 (0) 20 (0) 482 (0) OR 0.85 (0.31–2.29) – for IMIDs Decernotinib 2 (2) 2 (2) 514 (514) 0 217 (217) OR 1.07 (0.18–6.43) – for IMIDs Abrocitinib 1 (0) 1 (0) 211 (0) 0 56 (0) OR 0.81 (0.03– ‒ 20.03) for IMIDs Gimenez Poderos Tofacitinib 5 for IMIDs (2 for – – – – OR 0.29 (0.10–0.84) OR 1.19 (0.12–11.69) et al. [69] RA) for all doses for 3 mg BID OR 0.18 (0.02–1.60) for 5 mg BID OR 0.19 (0.04–0.91) for 10 mg BID OR 0.32 (0.01–8.05) for 15 mg BID 1 3 Clinical Rheumatology (2021) 40:4457–4471 4467 Table 2 (continued) † † † Study JAK inhibitors No. of studyJAK inhibitors Placebo ORs/RRs/RDs Others (95% CI) * Events Total Events Total Baricitinib 5 for IMIDs (4 for – – – – OR 3.39 OR 3.05 (0.12–75.43) RA) (0.82–14.04) for for 2 mg QD all doses OR 3.64 (0.59–22.46) for 4 mg QD OR 3.00 (0.12–76.49) for 7 mg QD Khoo et al. [70] Overall 27 for IMIDs (21 12 (10) n = 8363 (7270) 3 (3) n = 3314 (2858) RD 0.000 (− 0.002– – for RA) 0.003) Tofacitinib 10 (8) 3 (3) 4178 (3705) 2 (2) 1251 (1095) 0.000 (− 0.003– – 0.003) Baricitinib 7 (6) 3 (2) 2176 (1967) 1 (1) 1354 (1249) 0.000 (− 0.003– – 0.004) Upadacitinib 2 (2) 2 (2) 469 (469) 0 106 (106) 0.005 (− 0.015– – 0.024) Filgotinib 2 (0) 1 (0) 123 (0) 0 124 (0) 0.005 (− 0.020– – 0.030) Peficitinib 1 (1) 0 238 (238) 0 51 (51) 0.000 (− 0.027– – 0.027) Decernotinib 2 (1) 1 (1) 451(163) 0 112 (41) 0.001 (− 0.016– – 0.019) Fostamatinib 3 (3) 2 (2) 728 (728) 0 316 (316) 0.003 (− 0.006– – 0.012) VTE events included PE and DVT, occurring both individually and in combination The ORs, RRs, and RDs of VTE events in patients receiving JAK inhibitors were calculated compared with those receiving placebo The numbers in parentheses represent study numbers, PYs, event numbers, or patient numbers for RA patients Only PE events were included JAK, Janus kinase; RA, rheumatoid arthritis; IMID, immune-mediated inflammatory disease; VTE, venous thromboembolism; PE, pulmonary embolism; DVT, deep vein thrombosis; PYs, person-years; OR, odds ratio; RR, risk ratio; RD, risk difference; 95% CI, 95% confidence interval; BID, twice a day; QD, once a day 10 mg twice daily. The FDA and EMA recommend that JAK risks, possibly related to the specificity of JAK inhibitor inhibitors be avoided in patients with known VTE risk fac- action, remains unanswered [54, 77]. tors if alternative therapies are available. The package inserts for all approved JAK inhibitor products contain a box warn- ing regarding the increased VTE risk [50]. Risk management of VTE in RA patients Nevertheless, it is not entirely clear whether JAK inhibi- tors have a direct causal role in thromboembolic events or When making a therapeutic decision of whether or not to whether this risk simply represents a higher background start a JAK inhibitor for RA patients who are refractory to thromboembolic risk in patients with RA (attributable to biological DMARDs, clinicians should carefully consider RA itself or its comorbidities) [53, 54]. There is a close the following risk factors that predispose them to VTE relationship between the inflammatory activity of a given events. cytokine and its role in thrombus formation. In animal mod- els, anti-inflammatory treatment is effective for thrombus 1. RA disease activity. RA is an independent risk factor for resolution and the reduction of vessel wall damage [32, 76]. VTE. Disease activity is significantly associated with The JAK–STAT pathway can transmit signals from a variety an increased risk of VTE. Our PE case presented in of cytokines that have pro- or anti-thrombotic activity as this review had received four biological DMARDs over well as pro- or anti-inflammatory activity. If blocking the 10 years, but the disease activity was poorly controlled. JAK-STAT pathway results in a reduction of a particular After the commencement of baricitinib, the patient cytokine’s inflammatory activity, it should induce the inhibi- achieved low disease activity, but DVT/PE occurred. tion of prothrombotic activity. The real-world clinical data 2. Comorbidities. Approximately 40% of RA patients suffer indicated that this is not entirely the case, however [77]. from some type of extra-articular manifestations during Whether the thromboembolic complications may be a class the course of their disease. The respiratory system is one effect or a different JAK inhibitor may carry distinct VTE of the most frequent targets of extra-articular manifesta- 1 3 4468 Clinical Rheumatology (2021) 40:4457–4471 tions [78]. In addition, the number of elderly RA patients regarding the risk management of VTE events in RA patients with cardiovascular risk factors is increasing. Older who are scheduled to receive JAK inhibitor therapy. patients are at increased risk of VTE because of mul- There are several limitations to this study. First, we under- tiple comorbid conditions and pharmaceutical changes took literature searches solely through the Medline database, related to drug metabolism and excretion [63]. Chronic and, therefore, we might have missed some relevant studies. kidney disease (CKD) and non-alcoholic fatty liver dis- Second, we mainly focused on VTE events associated with ease (NAFLD) have also been seen more commonly in the five JAK inhibitors approved for RA, namely, tofaci - this patient population [79, 80]. The presence of non- tinib, baricitinib, upadacitinib, filgotinib, and peficitinib. alcoholic steatohepatitis (NASH), a progressive form of Several new JAK inhibitors have been developed for IMIDs, NAFLD, is reported to downregulate the cytochrome but detailed data on VTE risk of individual new-generation P450 (CYP) 3A4 enzyme in the liver [81]. Tofacitinib JAK inhibitors were not available in the literature. Third, our is primarily metabolized through the CYP3A4 enzyme review focused on the VTE risk in RA patients, and did not and excreted via the kidneys. Baricitinib is metabolized cover patients with other IMIDs such as psoriasis, inflamma- not via the CYP system but via the kidneys [50]. Thus, tory bowel diseases, and other inflammatory rheumatic dis- the presence of CKD and NAFLD/NASH can contribute eases. We cannot entirely exclude the possibility that there to the increased risk of VTE associated with these JAK may be a difference in VTE risk between patients with RA inhibitors. Dose adjustment is recommended in patients and those with non-RA IMIDs. with renal impairment and/or NAFLD/NASH. 3. VTE and cardiovascular risk factors. As listed in the “Risk factors for VTE” section, numerous transient and Conclusions persistent risk factors that can provoke VTE have been reported. Additional risk factors to be considered when To date, the evidence is limited and insufficient to support prescribing JAK inhibitors include increased age and the idea that there is an increased risk of VTE during RA traditional cardiovascular risk factors such as obesity, treatment with JAK inhibitors. In addition, the exact mecha- diabetes, hypertension, hyperlipidemia, and smoking. It nisms of how JAK inhibitors might increase the risk of VTE is important to recognize that the predictive values of remain to be clarified. A signal of VTE/PE risk with JAK these factors are not equal. Clinicians should consider inhibitors has been noted in RA patients who are already both the strength of individual risk factors and the cumu- at high risk, however. Clinicians should follow the regula- lative weight of all risk factors for each patient [18, 20]. tory recommendations to avoid the use of JAK inhibitors in 4. Patient education. When a patient complains of warmth patients with cardiovascular and VTE risk factors if alterna- or redness in the leg, dyspnea, chest pain, and/or syn- tive therapies are available. If suitable alternatives are not cope during treatment with JAK inhibitors, clinicians available, clinicians should prescribe JAK inhibitors with should suspect the development of VTE/PE and initiate caution, taking the number and strength of VTE risk factors a rapid diagnostic workup. Prior to the initiation of JAK for each RA patient into careful consideration. inhibitors, we should inform each patient of the number and strength of his/her risk factors for VTE, and advise them to seek prompt medical help if they develop clini- Declarations cal signs and symptoms that suggest VTE/PE. Patient consent Written informed consent for publication was obtained. Limitations Publishing agency We did not use the services of external publishing agents. We performed a literature search to comprehensively collect Conflict of interest The authors have declared that no conflicts of in- and analyze all sources relating to the risk of VTE events in terest exist. RA patients receiving or not receiving JAK kinase inhibi- tors. We obtained relevant data from a variety of articles Disclaimer No part of this manuscript has been copied or published published in rheumatology, pharmacology, cardiology, elsewhere. hematology, and epidemiology journals, which contributed to the reduction of a selection bias. In addition, we included Open Access This article is licensed under a Creative Commons Attri- detailed information on the massive and acute PE case that bution 4.0 International License, which permits use, sharing, adapta- we experienced during baricitinib treatment for multiple tion, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, biologic-resistant RA, which provides critical information provide a link to the Creative Commons licence, and indicate if changes 1 3 Clinical Rheumatology (2021) 40:4457–4471 4469 were made. 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Risk of venous thromboembolism associated with Janus kinase inhibitors for rheumatoid arthritis: case presentation and literature review

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10.1007/s10067-021-05911-4
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Abstract

Janus kinase (JAK) inhibitors have been developed as disease-modifying antirheumatic drugs. Despite the positive therapeutic impacts of JAK inhibitors, concerns have been raised regarding the risk of venous thromboembolism (VTE), such as deep vein thrombosis (DVT) and pulmonary embolism (PE). A recent post hoc safety analysis of placebo-controlled trials of JAK inhibitors in rheumatoid arthritis (RA) reported an imbalance in the incidence of VTE for a 4-mg daily dose of baricitinib versus placebo. In a recent postmarketing surveillance trial for RA, a significantly higher incidence of PE was reported in treatment with tofacitinib (10 mg twice daily) compared with tofacitinib 5 mg or tumor necrosis factor inhibitors. We also experienced a case of massive PE occurring 3 months after starting baricitinib (4 mg once daily) for multiple biologic- resistant RA. Nevertheless, the evidence to support the role of JAK inhibitors in VTE risk remains insufficient. There are a number of predisposing conditions and risk factors for VTE. In addition to the known risk factors that can provoke VTE, advanced age, obesity, diabetes mellitus, hypertension, hyperlipidemia, and smoking can also contribute to its development. Greater VTE risk is noted in patients with chronic inflammatory conditions, particularly RA patients with uncontrolled disease activity and any comorbidity. Prior to the initiation of JAK inhibitors, clinicians should consider both the number and strength of VTE risk factors for each patient. In addition, clinicians should advise patients to seek prompt medical help if they develop clinical signs and symptoms that suggest VTE/PE. Key Points • Patients with rheumatoid arthritis (RA) are at increased risk of venous thromboembolism (VTE), especially those with uncontrolled, high disease activity and those with comorbidities. • In addition to the well-known risk factors that provoke VTE events, advanced age and cardiovascular risk factors, such as obesity, diabetes mellitus, hypertension, hyperlipidemia, and smoking, should be considered risk factors for VTE. • Although a signal of VTE/pulmonary embolism (PE) risk with JAK inhibitors has been noted in RA patients who are already at high risk, the evidence is currently insufficient to support the increased risk of VTE during RA treatment with JAK inhibitors. • If there are no suitable alternatives, clinicians should prescribe JAK inhibitors with caution, considering both the strength of individual risk factors and the cumulative weight of all risk factors for each patient. Keywords Baricitinib · Deep vein thrombosis · Janus kinase inhibitors · Pulmonary embolism · Rheumatoid arthritis · Tofacitinib Department of Rheumatology, Clinical Research Center * Shunsuke Mori for Rheumatic Diseases, National Hospital Organization [email protected] Kumamoto Saishun Medical Center, 2659 Suya, Fumihiko Ogata Kohshi Kumamoto 861-1196, Japan [email protected] Divsion of Cardiology, Japanese Red Cross Kumamoto Ryusuke Tsunoda Hospital, Kumamoto, Japan [email protected] Vol.:(0123456789) 1 3 4458 Clinical Rheumatology (2021) 40:4457–4471 it failed to control the disease activity. Next, the patient Introduction attempted four different biological therapies sequentially, starting with etanercept plus MTX, then proceeding to inf- The Janus kinase (JAK)/signal transducer and activator of liximab plus MTX, tocilizumab plus MTX, and abatacept transcription (STAT) pathway is one of the major cascades monotherapy, but every therapy failed and the disease activ- that transfers extracellular cytokine signals from cell surface ity became high. In March 2020, high-throughput leukocyta- receptors to the nucleus. There are four isoforms in the JAK pheresis (LCAP), which is an alternative therapeutic option family, namely, JAK1, JAK2, JAK3, and TYK2, which act for the management of RA with super-resistance to DMARD in pairs either as homodimers or as heterodimers to activate therapies [15], was initiated. After five LCAP procedures STAT proteins. Different cytokine receptor families utilize at 1-week intervals, the patient started baricitinib, a JAK1/ specific pairs of JAK isoforms for signal transduction [1 , 2]. JAK2 inhibitor, 4 mg once daily with oral prednisolone. Over the last decade, JAK inhibitors, small molecules that Eight weeks later, the patient achieved low disease activity. target the JAK-STAT signaling pathway, have been devel- Twelve weeks after starting baricitinib therapy, dyspnea and oped as targeted synthetic disease–modifying antirheumatic chest pain suddenly appeared on lifting heavy objects. The drugs (tsDMARDs) for immune-mediated inflammatory patient had noticed painless swelling of the left leg 1 week diseases (IMIDs) such as rheumatoid arthritis (RA) [3–5]. prior to this attack. The patient was immediately taken to Biological DMARDs (bDMARDs), protein molecules an emergency hospital by ambulance because of worsening that target specific cytokines and cytokine receptors in the dyspnea. inflammatory cascade, have several limitations, including In the emergency room, the patient was in shock. The the need for parenteral administration and the development respiratory rate was 30 breaths/min and SpO was 90% of anti-drug antibodies due to inherent immunogenicity with reservoir mask oxygen at 7 L/min. Arterial blood gas [6]. In the context of these limitations, JAK inhibitors have analysis showed P aO of 77 Torr, P aCO of 29 Torr, and significant advantages over bDMARDs. In addition, recent 2 2 HCO – of 19.2 mmol/L. Elevated levels of serum D-dimer randomized clinical trials of JAK inhibitors for RA demon- (34.6 µg/mL) and brain natriuretic peptide (BNP, 30.1 pg/ strated equivalent or even superior efficacy to adalimumab, mL) were observed. The electrocardiogram indicated right a tumor necrosis factor (TNF) inhibitor [7–10]. Using real- ventricular strain with a heart rate of 126 beats/min. Tran- world registries, we showed that tofacitinib, a first-genera- sthoracic echocardiography showed a dilated right ventricu- tion JAK inhibitor, can induce greater improvements during lar dimension (50.5 mm), McConnell sign (defined as right the r fi st 12-month treatment in bDMARD-naïve RA patients ventricular free wall akinesis with sparing of the apex), and compared with tocilizumab, an anti-interleukin-6 receptor reduced tricuspid annular plane systolic excursion (TAPSE) antibody [11, 12]. Despite these positive therapeutic impacts to 9.3 mm. These results indicate severe right ventricular of JAK inhibitors, concerns have been raised regarding the systolic dysfunction. Contrast-enhanced computed tomog- risk of venous thromboembolism (VTE), such as deep vein raphy revealed thrombi in both main pulmonary arteries, thrombosis (DVT) and pulmonary embolism (PE). In addi- the left popliteal vein, and the left superficial femoral vein tion, previous meta-analyses indicated a higher background (Figs. 1 and 2). The patient was diagnosed as developing risk of VTE among patients with RA or other IMIDs com- acute massive PE caused by DVT [16–18]. Anti-phospho- pared with the general population [13, 14]. lipid syndrome–related tests and anti-SARS-Cov-2 antibody The aim of this review is to provide the latest update tests were negative. The body mass index was 34.2 (obese regarding the risk of VTE events associated with JAK inhibi- class I), and no other cardiovascular or VTE risk factors tors in RA patients, which can guide therapeutic decisions were identified. based on safety considerations. We also share our recent The patient was intravenously administered 120 × 10 experience with a case of massive PE occurring in the treat- units of tissue-type plasminogen activator (t-PA) as ment of multiple biologic-resistant RA with a JAK inhibitor, thrombolytic therapy. On admission day 2, the patient baricitinib, with the intention to discuss the risk manage- recovered from the shock state, and dyspnea was ment of VTE events. improved. No bleeding was observed. Oral rivaroxaban 30 mg daily (Xa inhibitor) was used as anticoagulation therapy. On admission day 6, the patient’s dyspnea and Case presentation: massive PE hypoxia were resolved. Contrast-enhanced computed during baricitinib therapy for RA tomography revealed that the amounts of thrombi had decreased. The findings of right ventricular strain disap- In April 2010, a 46-year-old female was diagnosed with peared. On admission day 10, the patient was discharged seropositive RA. The disease activity was moderate. The with oral rivaroxaban. Certolizumab-pegol plus MTX patient started methotrexate (MTX) monotherapy, but therapy was newly started. Four months later, the patient 1 3 Clinical Rheumatology (2021) 40:4457–4471 4459 achieved low disease activity, and the emboli disappeared Search strategy from the pulmonary arteries and the veins of the left lower limb. The literature search for the current review was carried out The latest postmarketing surveillance data on safety in line with the recommendations for bibliographic searches from pharmaceutical companies in Japan reported six for narrative reviews [19]. Using the PubMed platform, cases of DVT (0.09%), two cases of PE (0.03%), and one the Medline database was searched on April 30, 2020, for case of venous embolism (0.01%) in RA patients receiv- English biomedical literature focusing on VTE risk in RA ing tofacitinib (n = 6989, data cutoff May 5, 2020), and patients receiving and not receiving JAK inhibitors. The 11 cases of severe VTE (0.3%) and seven cases of non- identification of eligible articles was initially carried out by severe VTE (0.2%) in RA patients receiving baricitinib screening titles and abstracts, and finally by reading the full (n = 3445, data cutoff January 1, 2021). In our institution, text of the publication. The references of the eligible articles tofacitinib or baricitinib was used in approximately 200 were screened to ensure that no important research data rel- RA patients and, as mentioned above, one patient devel- evant to the subject were missed. oped massive PE 3 months after starting baricitinib 4 mg To identify English articles relating to the VTE risk once daily. associated with JAK inhibitors, we used the terms (venous Fig. 1 Contrast-enhanced computed tomography reveals prominent emboli in the bilat- eral main pulmonary arteries (yellow arrowheads) Fig. 2 Contrast-enhanced computed tomography reveals occlusive intravenous thrombo- sis in the left popliteal vein and the left superficial femoral vein (yellow arrowheads) 1 3 4460 Clinical Rheumatology (2021) 40:4457–4471 thromboembolism OR venous thromboembolic event OR to 78, and 45 to 117 per 100,000 person-years, respectively. pulmonary embolism OR deep vein thrombosis) AND (Janus The recurrence of VTE occurs frequently: approximately kinase inhibitor OR tofacitinib OR baricitinib OR upadaci- 30% of patients who have a first episode of VTE will experi- tinib OR filgotinib OR peficitinib). Through the Medline ence recurrence within 10 years [22]. A VTE event is a seri- search, a total of 90 articles were identified. Among them, ous medical condition associated with long-term morbidity we found eight post hoc safety analyses, two systematic and increased mortality. In particular, PE is an independent reviews, and seven systematic reviews/meta-analyses using predictor of reduced survival for up to 3 months after the pooled data from clinical trials and long-term extension event [23, 24]. As a result of the westernized lifestyle and (LTE) studies of JAK inhibitors for RA and other IMIDs. In aging society in Japan, the number of patients with PE has addition, six postmarketing studies using real-world regis- increased 4.6-fold in the past 15 years, with an estimated tries of RA and other IMID patients receiving JAK inhibitors annual IR of 12.6 per 100,000 person-years in 2011 [25]. were identified (among these 6, one study was also identified and included as a post hoc analysis). We also found three Risk factors for VTE review articles including detailed data on incidence rates of VTEs associated with JAK inhibitors. All of these studies In the nineteenth century, the German physician Virchow are included in the “VTE events in RA patients receiving explained the pathophysiologic mechanisms of VTE by three JAK inhibitors” section of this review. Individual clinical major determinants, called Virchow’s triad, which included trials as well as LTE studies were not included in this section hypercoagulability (constituents of blood), endothelial because all VTE cases in these studies were incorporated injury (vessel wall), and venous stasis (blood flow) [26]. into the abovementioned post hoc analyses and systematic There are a number of predisposing conditions and risk reviews/meta-analyses. We also excluded studies that only factors for VTE, which can affect one or more elements of focused on patients with non-RA IMIDs. Virchow’s triad. To identify English articles comparing VTE risk between Many episodes of VTE are provoked by a transient or RA patients and non-RA controls as well as those compar- persistent risk factor [27]. Major general surgery, orthope- ing VTE risks among RA patients based on disease activity, dic surgery (hip or knee replacement), major trauma, frac- we used the terms (venous thromboembolism OR venous ture (hip or leg), spinal cord injury, and immobilization are thromboembolic event OR pulmonary embolism OR deep categorized as major setting-related (usually transient) risk vein thrombosis) AND (rheumatoid arthritis OR autoim- factors that can provoke VTE. Active cancer is a well-rec- mune OR immune-mediated OR inflammatory) AND (inci- ognized patient-related (usually permanent or progressive) dence OR rate). Through the Medline search, a total of 1608 risk factor that can provoke VTE [18, 20, 27, 28]. In addi- English articles were identified. Among them, we found 16 tion, congestive heart or respiratory failure, infection (such eligible articles (15 articles comparing the VTE incidence as pneumonia, urinary tract infection, or HIV infection), between RA patients and non-RA controls and one article and acquired thrombophilia (antiphospholipid antibody comparing the VTE incidence among RA patients based on syndrome, etc.) are considered moderate-risk factors that disease activity/severity). These studies are included in the can provoke VTE. Heart disease such as myocardial infrac- “VTE risks in RA patients” section of this review. Stud- tion and atrial fibrillation (within the previous 3 months) ies focusing on postoperative VTE events or recurrent VTE especially increases the risk of PE. In women, pregnancy events were excluded. and puerperium, oral contraceptives, and hormone replace- Additional articles were also selected based on the prior ment therapy are recognized as moderately provoking risk knowledge of the authors, and the information was synthe- factors for VTE [18, 20, 27–29]. A high risk of recurrence sized below. has been noted in patients with persistent risk factor(s). A previous episode of VTE should be considered a major risk factor for a new episode [18, 20, 22, 27]. A brief overview of VTE Approximately 40 to 50% of VTE cases are considered unprovoked or idiopathic, that is, they do not have impor- Epidemiology of VTE tant provoking factors for VTE (either transient or persis- tent) [21, 27, 30]. These patients may, however, have minor VTE is fairly common, and its incidence increases exponen- acquired or inherited predisposing conditions for VTE [25, tially with age [20, 21]. In the majority of cases, VTE mani- 27, 30]. Hereditary thrombophilia (antithrombin, protein fests as DVT of the legs and pelvis; in 30 to 40% of patients, C, or protein S deficiency, Factor V Leiden or prothrom- it appears as PE. The estimated annual incidence rates (IRs) bin G20210A gene mutation, etc.) is considered a minor for VTE, PE (with or without DVT), and DVT alone in inherited risk factor. Increasing age is also associated with Western countries are reported to range from 104 to 183, 29 the risk of VTE [20, 27, 30]. Recently, the contribution of 1 3 Clinical Rheumatology (2021) 40:4457–4471 4461 non-cancer persistent conditions, including chronic inflam- tsDMARD switchers. These findings suggested that switch- matory diseases and traditional cardiovascular risk factors ing bDMARD/tsDMARD may be a proxy for higher disease (such as smoking, obesity, hypertension, diabetes mellitus, severity and poorly controlled disease activity in RA [48]. and hyperlipidemia) to the pathophysiology of VTE, has The increased VTE risk observed in RA patients may be been investigated. These conditions may be insufficient to attributed, at least in part, to uncontrolled disease activity. cause VTE when isolated, but they can be factors that pre- dispose an individual to VTE if combined [30]. It is becoming clear that there is a functional interde- JAK inhibitors currently licensed for RA pendence between inflammation and thrombosis, which treatment is mediated by the loss of normal functions of endothelial cells, leading to the dysregulation of coagulation, platelet Tofacitinib and baricitinib are first-generation JAK inhibi- activation, and leukocyte recruitment in the microvascu- tors, and both have been approved by the US Food and Drug lature. Chronic inflammation appears to be an important Administration (FDA) and the European Medicines Agency determinant of chronic VTE events [30–32]. An imbalance (EMA) [49, 50]. Tofacitinib, a JAK1, JAK2, and JAK3 pan- between pro-thrombotic and anti-thrombotic cytokines may inhibitor, was first approved for the treatment of moderately be involved in the pathophysiology of VTE [32]. to severely active RA by the FDA in 2012. In 2017, the EMA also recommended the approval of tofacitinib for RA. Cur- rently, the recommended dose of tofacitinib in RA treatment VTE risks in RA patients is 5 mg twice daily in most countries. Baricitinib, which has a specificity for JAK 1 and JAK2, is the second approved A number of population-based epidemiological studies JAK inhibitor. The use of this drug was approved by the showed that the risk of VTE is increased in RA patients EMA in 2017 at 2 mg or 4 mg once daily for the treatment compared with the general population. Fifteen studies are of moderately to severely active RA. Subsequently, the FDA summarized in Table  1 [33–47]. RA patients were more recommended the approval of a baricitinib 2-mg once-daily likely to experience VTE compared with age- and sex- dosing regimen for RA treatment in April 2018, but did not matched non-RA subjects, even after adjustment for VTE recommend the use of 4 mg once daily due to safety con- risk factors and comorbidities. In several studies, the VTE cerns related to VTE. In Japan, baricitinib is available in risk was stable over follow-up time [36, 39]. In other stud- 2 mg and 4 mg once-daily dosing regimens for the treatment ies, the VTE risk was highest during the first year, then of RA. attenuated with time but remained statistically elevated even The next-generation JAK inhibitors upadacitinib and fil- 5 years after RA diagnosis [42, 46]. Among hospitalized RA gotinib were designed with selective affinity to JAK1, which patients, the PE risk was highest during the first year after may decrease the risk of unwanted adverse events without hospitalization. This risk decreased over time but persisted compromising clinical efficacy. Upadacitinib was approved up to 10 years [41]. These findings suggested that RA should by the FDA and EMA for the treatment of moderate to be regarded as a hypercoagulable disorder. severe RA in 2019. Filgotinib was approved by the EMA, The VTE risk increased with increased disease activ- but the FDA did not approve this drug because of concerns ity: a twofold increase in VTE risk was observed in RA relating to its testicular toxicity [50, 51]. patients with high disease activity compared with patients These four JAK inhibitors are currently available in the in remission (risk ratio [RR] 2.03, 95% confidence interval treatment of RA in Japan. Peficitinib, a pan JAK inhibitor [CI] 1.73–2.38) [40]. Poorly controlled RA activity may be (a JAK1, JAK2, and JAK 3 inhibitor), is also approved in associated with the risk of VTE. Using the Optum Clin- Japan [50]. formatics Data Mart, a United States (US) claims database that includes patients receiving DMARD treatment after the first diagnosis of RA between 2007 and 2017, Liang VTE events in RA patients receiving JAK et al. showed that, after adjustment for multiple risk fac- inhibitors tors, patients who switched from a bDMARD/tsDMARD to another bDMARD/tsDMARD (bDMARD/tsDMARD Are JAK inhibitors associated with an increased risk switchers) had an increased risk of VTE compared with con- of VTE? ventional synthetic DMARD (csDMARD) users (adjusted hazard ratio [HR] 1.36, 95% CI 1.16–1.58). Compared with Numerically higher rates of VTE/PE events were observed first bDMARD/tsDMARD users, the adjusted HR (95% CI) in some clinical trials of JAK inhibitors versus placebo, sug- for VTE was 1.35 (1.15–1.60) for first bDMARD/tsDMARD gesting an increased risk for developing VTE during treat- switchers and 1.48 (1.19–1.85) for second bDMARD/ ment with JAK inhibitors [5, 52]. Given the rarity of VTE 1 3 4462 Clinical Rheumatology (2021) 40:4457–4471 Table 1 VTE risks in RA patients versus non-RA controls Study Period Database No. of VTEs/total No. of VTEs/total HRs/RRs/ORs/SIR Comments RA patients controls (95% CI)* (Mean follow-up) Country Bacani et al. [33] 1995–2008 Olmsted County, VTE 19/464 7/464 HR 3.6 (1.5–8.6) Incident RA patients Minnesota Matched controls (5.9 years) PE 12/464 5/464 – (1:1) US DVT 11/464 4/464 – Matta et al. [34] 1979–2005 NHDS VTE 110,000 10,226,000 RR 1.99 (1.98– Hospitalized patients 2.00) without joint surgery (NA) PE 41,000 3,366,000 RR 2.25 (2.23– 2.27) US DVT 79,000 7,681,000 RR 1.90 (1.89– 1.92) /4,818,000 /891,055,000 Kim et al. [35] 2001–2008 US insurance VTE 265/22,143 448/88,572 HR 1.4 (1.1–1.7) Matched controls claims database (1:4) (2.0 years) PE 111/22,143 164/88,572 HR 1.9 (1.3–2.7) Adjusted for risk US DVT 197/22,143 364/88,572 HR 1.2 (0.9–1.5) factors Yusuf et al. [36] 2007–2010 Truven Health Mar- VTE 909/70,768 981/198,044 HR 2.13 (1.89– Adjusted for age, ketScan database 2.40) at 1 year sex, and risk fac- (2.6 years) HR 2.03 (1.64– tors US 2.51) at 4 years Bleau et al. [37] 2003–2011 HCUP-NIS data- VTE 9/5780 5716/7,917,453 OR 1.95 (1.01– Pregnant women base 3.75) Adjusted for age (cross-sectional) PE 5/5780 1734/7,917,453 OR 3.62 (1.50– 8.70) US DVT 6/5780 4228/7,917,453 OR 1.75 (0.78– 3.89) Yusuf et al. [38] 2010 HCUP-NIS data- VTE 2.65%/94,585 2.28%/5,539,809 OR 1.17 (1.13– Hospitalized patients base 1.21) Adjusted for age, (cross-sectional) sex, race, and risk US factors Holmqvist et al. 1997–2010 SRQ Register VTE 223/7904 648/37,350 HR 1.6 (1.4–1.9) Incident RA [39] HR 1.6 (1.1–2.5) Matched controls (5.8 years, median) within the first (1:5) Sweden year Adjusted for age HR 1.9 (1.4–2.4) at 5–9 years Molander et al. [40] 2006–2018 SRQ Register VTE 2241/46,316 5301/215,843 RR 1.88 (1.65– Matched controls 2.15) within the (1:5) (1 year) first year RR 2.03 Adjusted for age, Sweden (1.73–2.38) for sex, and calendar high  year of visit DAS28 vs. remis- sion Zoller et al. [41] 1964–2008 MigMed2 database PE 2500/86,366 – SIR 1.91 (1.83– Hospitalized patients 1.98) Adjusted for age, (NA) SIR 5.99 (5.59– sex, entry time, Sweden 6.41) within the and risk factors first year SIR 1.18 (1.06–1.31) at 5–10 years Choi et al. [42] 1986–2010 THIN VTE 176/9589 815/95,776 RR 2.14 (1.80– Incident RA 2.54) Matched controls (1:10) (5.5 years) PE 82/9589 358/95,776 RR 2.16 (1.68– Adjusted for risk 2.79) factors RRs remained high UK DVT 110/9589 512/95,776 RR 2.16 (1.74– at ≥ 5 y ears 2.69) 1 3 Clinical Rheumatology (2021) 40:4457–4471 4463 Table 1 (continued) Study Period Database No. of VTEs/total No. of VTEs/total HRs/RRs/ORs/SIR Comments RA patients controls (95% CI)* (Mean follow-up) Country Ogdie et al. [43] 1994–2014 THIN (Without DMARD) Matched controls Adjusted for age, (No DMARD: VTE 851/20,426 30,356/1,225,571 HR 1.29 (1.18– sex, and risk fac- 5.8 years) 1.39) tors PE 186/20,426 6066/1,225,571 HR 1.45 (1.23– 1.72) (With DMARD: DVT 702/20,426 25,490/1,225,571 HR 1.25 (1.15– 6.2 years) 1.37) (With DMARD) UK VTE 1479/31,336 30,356/1,225,571 HR 1.35 (1.27– 1.44) PE 393/31,336 6066/1,225,571 HR 1.74 (1.55– 1.99) DVT 1162/31,336 25,490/1,225,571 HR 1.29 (1.20– 1.38) Galloway et al. [44] 1999–2019 UK RCGP-RSC VTE 845/23,410 2020/93,640 HR 1.54 (1.40– Matched controls database 1.69) (1:4) Adjusted for age, (8.2 years) PE 373/23,408 916/93,639 HR 1.57 (1.36– sex, race, and risk 1.80) factors UK DVT 542/23,408 1242/93,640 HR 1.64 (1.45– 1.84) Ramagopalan et al. 1999–2008 English national 6825/268,005 – Rate ratio for VTE Hospitalized patients [45] HES 1.75 (1.70–1.80) Adjusted for age, (NA) sex, time period, UK and residential area Li et al. [46] 1997–2009 British Columbia VTE 1432/39,142 2059/78,078 HR 1.28 (1.20– Incident RA 1.36) Matched controls (1:2) (9.7 years) PE 543/39,142 791/78,078 HR 1.25 (1.13– Adjusted for age, 1.39) sex, and risk fac- Canada DVT 1068/39,142 1484/78,078 HR 1.30 (1.21– tors 1.40) HRs remained high within the first 5  years Chung et al. [47] 1998–2010 Taiwan NHIRD PE 70/29,238 139/116,952 HR 2.07 (1.55– Matched controls 2.76) (1:4) Adjusted for age, (6.6 years) DVT 208/29,238 255/116,952 HR 3.36 (2.79– sex, and risk fac- 4.03) Taiwan tors VTE events included PE and DVT, occurring both individually and in combination The HR, RR, and OR of VTE events in RA patients were calculated compared with those in non-RA patients. Factors used for adjustment are described in the “Comments” column. The SIR was calculated by dividing the observed number of VTE cases in the RA group by the expected number of cases in the reference population with the indirect standardization method. The rate ratio was calculated as the ratio of the observed/ expected numbers in the RA cohort to those in the reference cohort The time-specific RRs were highest within the first year after RA diagnosis (3.27 [95% CI 1.78–6.00] for PE and 3.16 [95% CI 1.95–5.11] for DVT), but persisted at elevated levels at 5 years and more (2.35 [95% CI 1.59–3.46] for PE and 2.32 [95% CI 1.64–3.27] for DVT) The time-specific HRs w ere highest during the first year after RA diagnosis (1.60 [95% CI 1.27–2.00] for VTE, 1.86 [95% CI 1.21–2.86] for PE, and 1.59 [95% CI 1.20–2.10] for DVT), but persisted at high levels within the first 5 years (1.28 [95% CI 1.15–1.42] for VTE, 1.29 [95% CI 1.09–1.53] for PE, and 1.27 [95% CI 1.12–1.43] for DVT) RA, rheumatoid arthritis; VTE, venous thromboembolism; PE, pulmonary embolism; DVT, deep vein thrombosis; HR, hazard ratio; RR, risk ratio; OR, odds ratio; SIR, standardized incidence ratio; DAS28, disease activity score for 28 joints; NHDS, National Hospital Discharge Sur- vey; HCUP-NIS, Health Care Cost and Utilization Project National Impatient Sample; SRQ, Swedish Rheumatology Quality; THIN, The Health Improvement Network; RCGP-RSC, Royal College General Practitioners Research and Surveillance Center; HES, Hospital Episode Statistics; NHIRD, National Health Insurance Research Database; NA, not available 1 3 4464 Clinical Rheumatology (2021) 40:4457–4471 events, however, it is difficult to identify statistically clear VTE events in the tofacitinib development program were signals for increased VTE risks in individual clinical trials. similar between 5 and 10 mg twice-daily doses, and higher In addition, the higher background thromboembolic risk in in patients with cardiovascular or VTE risk factors versus RA patients versus non-RA patients may make it compli- those without. Similar findings were obtained in patients cated to confirm or exclude a significant difference in risk with psoriatic arthritis and those with psoriasis [59]. Similar between JAK inhibitors and placebo [53, 54]. To address IRs were obtained from another integrated safety analysis this issue, a number of post hoc safety analyses and system- of data from phase I, II, III, and IIIb/IV clinical trials (19 atic reviews/meta-analyses of clinical trials and LTE studies studies), and LTE studies (2 studies) of tofacitinib for RA (a as well as postmarketing studies using real-world registries total of 7061 tofacitinib-treated patients) [60]. have been conducted. Upadacitinib Post hoc safety analyses of VTE events in clinical trials and LTE studies In a post hoc safety analysis using integrated data pooled from phase III clinical trials (5 studies) of upadacitinib for There are eight post hoc safety analyses for clinical trials RA (a total of 3834 upadacitinib-treated patients), the IRs and LTE studies of four JAK inhibitors, namely, tofacitinib, of VTE events (per 100 patient-years) in patients receiving baricitinib, upadacitinib, and peficitinib, for RA [55– 62]. upadacitinib 15 mg and 30 mg once daily were 0.6 and 0.3, respectively. The IRs were similar across treatment groups Baricitinib (0.4 for placebo, 0.5 for MTX, and 1.1 for adalimumab) [61]. In post hoc safety analyses using integrated data pooled from Peficitinib phase I, II, and III clinical trials (8 studies) as well as one LTE study of baricitinib for RA, no VTE events occurred In a post hoc pooled safety analysis using integrated data in 1070 placebo-treated patients, but six VTE events were from phase IIb and III clinical trials (3 trials) as well as observed in 997 patients treated with a 4-mg daily dose of one LTE study of peficitinib for RA (a total of 1052 pefi- baricitinib during the 24-week placebo-controlled period. citinib-treated patients), the IR of VTE events was 0.1 per All VTE patients had conventional VTE risk factors. Dur- 100 patient-years for peficitinib-treated patients, and no ing extended observations, the IRs were similar between VTE events were observed in the placebo group. No dose- baricitinib 2 and 4 mg, with IRs of 0.5 per 100 patient-years dependency was observed [62]. versus 0.6 per 100 patient-years. In all patients receiving baricitinib (All-Bari-RA, a total of 3492), the IR was 0.5 Systematic reviews/meta‑analyses of clinical trials per 100 patient-years and stable over time [55, 56]. The IR and LTE studies of VTE events increased with older age in the All-Bari-RA group [63]. In post hoc safety analyses that were limited to Seven meta-analyses using data extracted from clinical trials Japanese or East Asian patients in the ALL-Bari-RA group of JAK inhibitors for RA and other IMIDs were identified (5 phase II and III trials and 1 LTE study), the IRs of DVT in the literature. These studies are summarized in Table 2 were 0.3 to 0.5 per 100 patient-years and there were no PE [64–70]. The meta-analyses for RA showed that there was events [57, 58]. no significant difference in the risk of VTE events between patients receiving JAK inhibitors and those receiving pla- Tofacitinib cebo. During the limited placebo-controlled periods, no dose-dependent impact on the risk of VTE events was In a post hoc safety analysis of pooled data from phase I, II, observed in tofacitinib (5 mg vs. 10 mg twice daily), barici- III, and IIIb/IV clinical trials as well as LTE studies of tofac- tinib (2 mg vs. 4 mg once daily), or upadacitinib (15 mg vs. itinib for RA (a total of 7964 tofacitinib-treated patients), 30 mg once daily) [64, 65]. The meta-analyses for IMIDs the IRs of thromboembolic events (per 100 patient-years) (including RA) showed that VTE risk was unlikely to sub- in patients receiving tofacitinib 5 mg and 10 mg twice daily stantially increase in patients receiving JAK inhibitor during were 0.17 and 0.15 for DVT, 0.12 and 0.13 for PE, and 0.24 the limited placebo-controlled periods [66–69]. In a strati- and 0.26 for VTE, respectively. The IRs in patients with fied and meta-regression analysis, there was no interaction and without cardiovascular risk factors were 0.24 and 0.11 by dose of JAK inhibitors, indication for treatment, or length for DVT, 0.25 and 0.06 for PE, and 0.43 and 0.15 for VTE, of follow-up [68]. In an indirect meta-analysis, the risk of respectively. The IRs in patients with and without VTE risk VTE events in tofacitinib-treated patients was lower than in factors were 0.21 and 0.07 for DVT, 0.16 and 0.04 for PE, baricitinib-treated patients (OR 0.09, 95% CI 0.02–0.51), and 0.35 and 0.10 for VTE, respectively. Thus, the IRs of suggesting the superior safety profile of tofacitinib to 1 3 Clinical Rheumatology (2021) 40:4457–4471 4465 baricitinib [69]. No increased risk was found for PE during the same research group. The crude IRs of VTE (per 100 treatment with JAK inhibitors for IMIDs including RA [70]. patient-years) for tofacitinib and TNF inhibitors were 0.42 and 0.35 in MarketScan, 1.18 and 0.83 in Medicare, and 0.19 VTE events in postmarketing studies using and 0.34 in Optum, respectively. PS-adjusted HRs showed real‑world registries no statistically significant differences in VTE risk between tofacitinib and TNF inhibitors in any database, with a pooled There are six postmarketing studies using real-world regis- HR of 1.13 (95% CI 0.77–1.65) [74]. tries of RA and other IMID patients receiving JAK inhibi- In a post-approval comparative safety study using the US tors [59, 71–75]. In a disproportionality analysis of data Corrona RA Registry, an ongoing longitudinal clinical regis- extracted from the postmarketing FDA’s Adverse Event try from November 2012 through July 2018 (1999 tofacitinib Reporting System (FAERS) from March 2017, no evidence initiators and 8358 TNF-inhibitor initiators), the IRs of VTE for increased reporting rates for DVT or PE was identified per 100 patient-years were 0.29 in tofacitinib initiators (5 mg across three FDA-approved JAK inhibitors, tofacitinib, twice daily in most cases) and 0.33 in bDMARD initiators, tofacitinib extended-release, and ruxolitinib (reporting odds which were numerically similar between tofacitinib initiators ratios [RORs] and empirical Bayesian geometric means < 1). and bDMARD initiators [75]. The IRs of VTE were numeri- However, this study showed that pulmonary arterial throm- cally similar between RA patients in the Corrona Registry bosis (PT) may be a potential safety issue for tofacitinib, and those in the tofacitinib development program [59]. with an ROR of 2.46 (95% CI 1.55–3.91) [71]. A recent ongoing postmarketing safety surveillance trial, In descriptive and disproportionality analysis of data ORAL Surveillance (Study A39212233), which is evaluating extracted in April 2019 from the World Health Organization the safety of tofacitinib versus TNF inhibitors among RA global database (VigiBase) of individual case safety reports patients aged ≥ 50 years and with at least one cardiovascular for tofacitinib and baricitinib, patients with DVT or PT/PE risk factor, raised concerns of a higher incidence of PE and were older and more often received prothrombotic medica- all-cause mortality in patients treated with tofacitinib 10 mg tions or antithrombotic treatment, suggesting a preexisting twice daily compared with tofacitinib 5 mg twice daily or thromboembolic risk/event. In Europe, tofacitinib was asso- TNF inhibitors. In an ad hoc safety analysis (data cuto ff Feb - ciated with elevated reporting for DVT (ROR 2.37, 95% CI ruary 2019), the IRs per 100 person-years in the treatments 1.23–4.56) and PT/PE (ROR 2.38, 95% CI 1.45–3.89). Simi- with tofacitinib 5 mg twice daily, tofacitinib 10 mg twice lar increased reporting for DVT and PT/PE was observed in daily, and TNF inhibitors were 0.30, 0.38, and 0.18 for DVT baricitinib-treated patients (ROR 3.47, 95% CI 2.18–5.52; and 0.27, 0.54, and 0.09 for PE, respectively. Compared with and ROR 3.44, 95% CI 2.43–4.88, respectively). In the USA, TNF inhibitors, the HRs (95% CI) for DVT and PE were tofacitinib was associated with an increased reporting rate 1.66 (0.60–4.57) and 2.99 (0.81–11.06) with tofacitinib 5 mg of PT (ROR 2.05, 95% CI 1.45–2.90), but no evidence for twice daily and 2.13 (0.80–5.69) and 5.96 (1.75–20.33) with elevated reporting was identified for DVT or PE (ROR < 1). tofacitinib 10 mg twice daily, respectively. The IRs of throm- DVT or PT/PE cases were not reported in baricitinib-treated boembolic events observed in the tofacitinib development patients in the US [72]. program for RA patients with cardiovascular or VTE risk In an observational cohort study using claims data from factors were broadly consistent with those observed in the two databases, the crude IRs of VTE (per 100 patient-years) ORAL Surveillance trial. However, the IR of PE was signifi- for tofacitinib and TNF inhibitors in RA patients were 0.60 cantly greater in patients receiving tofacitinib 10 mg twice and 0.34 in the Truven MarketScan database (2012–2016, daily in the ORAL Surveillance trial [59]. 1910 tofacitinib initiators and 32,164 TNF-inhibitor initia- tors) and 1.12 and 0.92 in the Medicare Claims database (2012–2015, 995 tofacitinib initiators and 16,091 TNF- Unanswered questions inhibitor initiators), respectively. The PS-adjusted HRs had no statistically significant differences in VTE risk between As summarized above, in the systematic reviews and meta- tofacitinib and TNF inhibitors in either database, with a analyses of data from clinical trials, the evidence was not pooled HR of 1.33 (95% CI 0.78–2.24) [73]. The IRs of sufficient to support the increased risk of VTE events during VTE in these databases were higher compared with those in RA treatment with JAK inhibitors. These studies are limited the tofacitinib development program for RA [59]. With the by the small number of events reported and the limited over- accumulation of additional data from more recent years in all exposure. In addition, patients with substantial cardiovas- these two databases (the MarketScan database [2012–2018] cular risk factors and comorbidities are often excluded from and the Medicare database [2012–2017]) and the inclu- such clinical trials. The postmarketing ORAL Surveillance sion of a third database (the Optum Clinformatics data- analysis reported a significantly higher incidence of PE and base [2012–2019]), an updated analysis was conducted by all-cause mortality in RA patients treated with tofacitinib 1 3 4466 Clinical Rheumatology (2021) 40:4457–4471 Table 2 Meta-analyses of VTE risk in clinical trials of JAK inhibitors for RA and other IMIDs † † † Study JAK inhibitors No. of studyJAK inhibitors Placebo ORs/RRs/RDs Others (95% CI) * Events Total Events Total Xie et al. [64] Overall 25 for RA 12 2193 PYs 3 982 PYs OR 1.16 (0.48–2.81) (Dose dependency: OR) Tofacitinib 9 1 809 PYs 2 205 PYs OR 0.17 (0.03–1.05) 5 vs. 10 mg: 0.81 (0.22–3.03) Baricitinib 6 7 693 PYs 1 561 PYs OR 2.33 (0.62–8.75) 2 vs. 4 mg: 0.23 (0.02–2.17) Upadacitinib 4 4 285 PYs 0 115 PYs OR 1.77 (0.20– 15 vs. 30 mg: 4.36 16.00) (0.47–40) Filgotinib 1 0 178 PYs 0 42 PYs – – Peficitinib 3 0 179 PYs 0 42 PYs – – Decernotinib 2 0 49 PYs 0 17 PYs – – Xie et al. [65] Tofacitinib 12 for RA 1 881 PYs 2 263 PYs OR 0.06 (0.00–0.95) (Dose dependency: OR) 10 vs. 5 mg: 1.47 (0.25–8.50) Yates et al. [66] Overall 18 for IMIDs (11 12 (10) 1950 PYs 4 (3) 709 PYs (625 PYs) RR 0.68 (0.36–1.29) RR 0.44 (0.28–0.70) for RA) (1601PYs) for IMIDs for PE  RR 0.59 (0.31–1.15) for DVT Tofacitinib 7 (3) 2 (1) 1069 (758) 3 (2) 122 (77) – – Baricitinib 2 (2) 3 (3) 234 (234) 0 107 (107) – – Upadacitinib 6 (5) 6 (6) 475 (450) 1 (1) 378 (352) – – Filgotinib 3 (1) 1 (0) 172 (159) 0 102 (89) – – Olivera et al. [67] Overall 10 for IMIDs (6 for 12 (11) n = 3740 (2566) 3 (0) n = 1403 (997) RR 0.90 (0.32–2.54) RR 1.70 (0.48–6.01) RA) for IMIDs for RA Tofacitinib 4 (2) 3 (3) 2060 (1009) 3 (0) 536 (254) – – Baricitinib 1 (1) 2 (2) 374 (374) 0 210 (210) – – Upadacitinib 2 (2) 5 (5) 883 (883) 0 385 (385) – – Filgotinib 3 (1) 2 (1) 423 (300) 0 272 (148) – – Bilal et al. [68] Overall 25 for IMIDs (14 50 (26) n = 8933 (6254) 27 (4) n = 3612 (2490) OR 0.91 (0.57–1.47) OR 1.11 (0.50–2.44) for RA) for IMIDs for RA Tofacitinib 7 (4) 5 (4) 3690 (2301) 5 (2) 908 (521) OR 0.27 (0.08–0.89) OR 0.54 (0.15–1.96) for IMIDs for 10 mg BID OR 0.49 (0.15–1.55) for 5 mg BID Baricitinib 5 (3) 9 (7) 1292 (862) 1 (1) 487 (348) OR 1.12 (0.27–4.69) OR 2.69 for IMIDs (0.42‒17.21) for 4 mg QD OR 3.05 (0.12‒75.43) for 2 mg QD Upadacitinib 4 (4) 12 (12) 2277 (2277) 1 (1) 1256 (1256) OR 2.25 (0.55–9.25) OR2.64 (0.27‒25.45) for IMIDs for 30 mg QD OR2.91 (0.69‒12.21) for 15 mg QD Filgotinib 2 (1) 2 (1) 358 (300) 0 206 (148) OR 2.13 (0.22– – 20.64) for IMIDs Ruxolitinib 4 (0) 19 (0) 591 (0) 20 (0) 482 (0) OR 0.85 (0.31–2.29) – for IMIDs Decernotinib 2 (2) 2 (2) 514 (514) 0 217 (217) OR 1.07 (0.18–6.43) – for IMIDs Abrocitinib 1 (0) 1 (0) 211 (0) 0 56 (0) OR 0.81 (0.03– ‒ 20.03) for IMIDs Gimenez Poderos Tofacitinib 5 for IMIDs (2 for – – – – OR 0.29 (0.10–0.84) OR 1.19 (0.12–11.69) et al. [69] RA) for all doses for 3 mg BID OR 0.18 (0.02–1.60) for 5 mg BID OR 0.19 (0.04–0.91) for 10 mg BID OR 0.32 (0.01–8.05) for 15 mg BID 1 3 Clinical Rheumatology (2021) 40:4457–4471 4467 Table 2 (continued) † † † Study JAK inhibitors No. of studyJAK inhibitors Placebo ORs/RRs/RDs Others (95% CI) * Events Total Events Total Baricitinib 5 for IMIDs (4 for – – – – OR 3.39 OR 3.05 (0.12–75.43) RA) (0.82–14.04) for for 2 mg QD all doses OR 3.64 (0.59–22.46) for 4 mg QD OR 3.00 (0.12–76.49) for 7 mg QD Khoo et al. [70] Overall 27 for IMIDs (21 12 (10) n = 8363 (7270) 3 (3) n = 3314 (2858) RD 0.000 (− 0.002– – for RA) 0.003) Tofacitinib 10 (8) 3 (3) 4178 (3705) 2 (2) 1251 (1095) 0.000 (− 0.003– – 0.003) Baricitinib 7 (6) 3 (2) 2176 (1967) 1 (1) 1354 (1249) 0.000 (− 0.003– – 0.004) Upadacitinib 2 (2) 2 (2) 469 (469) 0 106 (106) 0.005 (− 0.015– – 0.024) Filgotinib 2 (0) 1 (0) 123 (0) 0 124 (0) 0.005 (− 0.020– – 0.030) Peficitinib 1 (1) 0 238 (238) 0 51 (51) 0.000 (− 0.027– – 0.027) Decernotinib 2 (1) 1 (1) 451(163) 0 112 (41) 0.001 (− 0.016– – 0.019) Fostamatinib 3 (3) 2 (2) 728 (728) 0 316 (316) 0.003 (− 0.006– – 0.012) VTE events included PE and DVT, occurring both individually and in combination The ORs, RRs, and RDs of VTE events in patients receiving JAK inhibitors were calculated compared with those receiving placebo The numbers in parentheses represent study numbers, PYs, event numbers, or patient numbers for RA patients Only PE events were included JAK, Janus kinase; RA, rheumatoid arthritis; IMID, immune-mediated inflammatory disease; VTE, venous thromboembolism; PE, pulmonary embolism; DVT, deep vein thrombosis; PYs, person-years; OR, odds ratio; RR, risk ratio; RD, risk difference; 95% CI, 95% confidence interval; BID, twice a day; QD, once a day 10 mg twice daily. The FDA and EMA recommend that JAK risks, possibly related to the specificity of JAK inhibitor inhibitors be avoided in patients with known VTE risk fac- action, remains unanswered [54, 77]. tors if alternative therapies are available. The package inserts for all approved JAK inhibitor products contain a box warn- ing regarding the increased VTE risk [50]. Risk management of VTE in RA patients Nevertheless, it is not entirely clear whether JAK inhibi- tors have a direct causal role in thromboembolic events or When making a therapeutic decision of whether or not to whether this risk simply represents a higher background start a JAK inhibitor for RA patients who are refractory to thromboembolic risk in patients with RA (attributable to biological DMARDs, clinicians should carefully consider RA itself or its comorbidities) [53, 54]. There is a close the following risk factors that predispose them to VTE relationship between the inflammatory activity of a given events. cytokine and its role in thrombus formation. In animal mod- els, anti-inflammatory treatment is effective for thrombus 1. RA disease activity. RA is an independent risk factor for resolution and the reduction of vessel wall damage [32, 76]. VTE. Disease activity is significantly associated with The JAK–STAT pathway can transmit signals from a variety an increased risk of VTE. Our PE case presented in of cytokines that have pro- or anti-thrombotic activity as this review had received four biological DMARDs over well as pro- or anti-inflammatory activity. If blocking the 10 years, but the disease activity was poorly controlled. JAK-STAT pathway results in a reduction of a particular After the commencement of baricitinib, the patient cytokine’s inflammatory activity, it should induce the inhibi- achieved low disease activity, but DVT/PE occurred. tion of prothrombotic activity. The real-world clinical data 2. Comorbidities. Approximately 40% of RA patients suffer indicated that this is not entirely the case, however [77]. from some type of extra-articular manifestations during Whether the thromboembolic complications may be a class the course of their disease. The respiratory system is one effect or a different JAK inhibitor may carry distinct VTE of the most frequent targets of extra-articular manifesta- 1 3 4468 Clinical Rheumatology (2021) 40:4457–4471 tions [78]. In addition, the number of elderly RA patients regarding the risk management of VTE events in RA patients with cardiovascular risk factors is increasing. Older who are scheduled to receive JAK inhibitor therapy. patients are at increased risk of VTE because of mul- There are several limitations to this study. First, we under- tiple comorbid conditions and pharmaceutical changes took literature searches solely through the Medline database, related to drug metabolism and excretion [63]. Chronic and, therefore, we might have missed some relevant studies. kidney disease (CKD) and non-alcoholic fatty liver dis- Second, we mainly focused on VTE events associated with ease (NAFLD) have also been seen more commonly in the five JAK inhibitors approved for RA, namely, tofaci - this patient population [79, 80]. The presence of non- tinib, baricitinib, upadacitinib, filgotinib, and peficitinib. alcoholic steatohepatitis (NASH), a progressive form of Several new JAK inhibitors have been developed for IMIDs, NAFLD, is reported to downregulate the cytochrome but detailed data on VTE risk of individual new-generation P450 (CYP) 3A4 enzyme in the liver [81]. Tofacitinib JAK inhibitors were not available in the literature. Third, our is primarily metabolized through the CYP3A4 enzyme review focused on the VTE risk in RA patients, and did not and excreted via the kidneys. Baricitinib is metabolized cover patients with other IMIDs such as psoriasis, inflamma- not via the CYP system but via the kidneys [50]. Thus, tory bowel diseases, and other inflammatory rheumatic dis- the presence of CKD and NAFLD/NASH can contribute eases. We cannot entirely exclude the possibility that there to the increased risk of VTE associated with these JAK may be a difference in VTE risk between patients with RA inhibitors. Dose adjustment is recommended in patients and those with non-RA IMIDs. with renal impairment and/or NAFLD/NASH. 3. VTE and cardiovascular risk factors. As listed in the “Risk factors for VTE” section, numerous transient and Conclusions persistent risk factors that can provoke VTE have been reported. Additional risk factors to be considered when To date, the evidence is limited and insufficient to support prescribing JAK inhibitors include increased age and the idea that there is an increased risk of VTE during RA traditional cardiovascular risk factors such as obesity, treatment with JAK inhibitors. In addition, the exact mecha- diabetes, hypertension, hyperlipidemia, and smoking. It nisms of how JAK inhibitors might increase the risk of VTE is important to recognize that the predictive values of remain to be clarified. A signal of VTE/PE risk with JAK these factors are not equal. Clinicians should consider inhibitors has been noted in RA patients who are already both the strength of individual risk factors and the cumu- at high risk, however. Clinicians should follow the regula- lative weight of all risk factors for each patient [18, 20]. tory recommendations to avoid the use of JAK inhibitors in 4. Patient education. When a patient complains of warmth patients with cardiovascular and VTE risk factors if alterna- or redness in the leg, dyspnea, chest pain, and/or syn- tive therapies are available. If suitable alternatives are not cope during treatment with JAK inhibitors, clinicians available, clinicians should prescribe JAK inhibitors with should suspect the development of VTE/PE and initiate caution, taking the number and strength of VTE risk factors a rapid diagnostic workup. Prior to the initiation of JAK for each RA patient into careful consideration. inhibitors, we should inform each patient of the number and strength of his/her risk factors for VTE, and advise them to seek prompt medical help if they develop clini- Declarations cal signs and symptoms that suggest VTE/PE. Patient consent Written informed consent for publication was obtained. Limitations Publishing agency We did not use the services of external publishing agents. We performed a literature search to comprehensively collect Conflict of interest The authors have declared that no conflicts of in- and analyze all sources relating to the risk of VTE events in terest exist. RA patients receiving or not receiving JAK kinase inhibi- tors. We obtained relevant data from a variety of articles Disclaimer No part of this manuscript has been copied or published published in rheumatology, pharmacology, cardiology, elsewhere. hematology, and epidemiology journals, which contributed to the reduction of a selection bias. In addition, we included Open Access This article is licensed under a Creative Commons Attri- detailed information on the massive and acute PE case that bution 4.0 International License, which permits use, sharing, adapta- we experienced during baricitinib treatment for multiple tion, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, biologic-resistant RA, which provides critical information provide a link to the Creative Commons licence, and indicate if changes 1 3 Clinical Rheumatology (2021) 40:4457–4471 4469 were made. 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Journal

Clinical Rheumatology – Springer Journals

Published: Nov 1, 2021

Keywords: Baricitinib; Deep vein thrombosis; Janus kinase inhibitors; Pulmonary embolism; Rheumatoid arthritis; Tofacitinib

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