ORIGINAL ARTICLE

Janus Kinase Inhibitors and Risk of Venous

Thromboembolism: A Systematic Review
and Meta-analysis
Jawad Bilal, MD; Irbaz Bin Riaz, MD, MS; Syed Arsalan Ahmed Naqvi, MBBS;
Sandipan Bhattacharjee, MS, PhD; Michelle R. Obert, MD; Maryam Sadiq, MD;
Mohamed A. Abd El Aziz, MBBCh; Yahya Nomaan, DO; Lary J. Prokop, MLS;
Long Ge, PhD; Mohammad H. Murad, MD; Alan H. Bryce, MD;
Robert D. McBane, MD; and C. Kent Kwoh, MD

Abstract

Objective: To assess the risk of venous thromboembolism (VTE) in patients treated with Janus kinase
(JAK) inhibitors in clinical trials.
Patients and Methods: We performed a literature search of Ovid MEDLINE and ePub Ahead of Print,
In-Process & Other Non-Indexed Citations, and Daily; Ovid EMBASE; Ovid Cochrane Central Reg-
ister of Controlled Trials; Ovid Cochrane Database of Systematic Reviews; and Scopus, from inception
to December 4, 2019, for randomized, placebo-controlled trials with JAK inhibitors as an intervention
and reported adverse events. Odds ratio with 95% CI was calculated to estimate the VTE risk using a
random effects model. Two independent reviewers screened and extracted data. The GRADE (Grading
of Recommendations Assessment, Development and Evaluation) approach was used to assess certainty
in estimated VTE risk.
Results: We included 29 trials (13,910 patients). No statistically significant association was found
between use of JAK inhibitors and risk of VTE (odds ratio, 0.91; 95% CI, 0.57 to 1.47; P¼.70; I2¼0;
low certainty because of serious imprecision). Results using Bayesian analysis were consistent with
those of the primary analysis. Results of stratified and meta-regression analyses suggested no inter-
action by dose of drug, indication for treatment, or length of follow-up.
Conclusion: We found insufficient evidence to support an increased risk of JAK inhibitoreassociated
VTE based on currently available data.
ª 2021 Mayo Foundation for Medical Education and Research n Mayo Clin Proc. 2021;96(7):1861-1873

J
anus kinase (JAK) inhibitors consist of a myelofibrosis and subsequently has been
group of small molecules that block approved for polycythemia vera. Indications
cytokine-mediated signaling via the for JAK inhibitors have expanded to rheuma- From the Division of
Rheumatology (J.B.,
JAK-STAT (JAKesignal transducer and tologic disorders. Tofacitinib has been FDA C.K.K.), Department of
activator of transcription) pathway.1-3 The approved for rheumatoid arthritis (RA) Pharmacy Practice and
Science, College of Phar-
critical role of the JAK-STAT pathway in with subsequent approval for psoriatic
macy (S.B.), Department
cell growth and differentiation and immuno- arthritis and ulcerative colitis. Baricitinib of Internal Medicine
regulation makes this an attractive therapeu- and upadacitinib have also been approved (M.R.O.), and University of
Arizona Arthritis Center
tic target for a variety of autoimmune- for RA.4 JAK inhibitors are currently under (C.K.K.), University of Ari-
mediated rheumatologic, dermatologic, and investigation for more than 15 indications zona, Tucson; Division of
hematologic disorders as well as for a variety including COVID-19 (coronavirus disease Hematology/Oncology
(I.B.R., R.D.M.), Depart-
of cancers. Ruxolitinib was the first JAK in- 2019), an infection caused by the severe ment of Surgery (M.A.A.),
hibitor approved by the US Food and Drug acute respiratory syndrome coronavirus 2 Affiliations continued at
Administration (FDA) for the treatment of (SARS-CoV-2); thus, the indications for the end of this article.

Mayo Clin Proc. n July 2021;96(7):1861-1873 n https://doi.org/10.1016/j.mayocp.2020.12.035 1861

www.mayoclinicproceedings.org n ª 2021 Mayo Foundation for Medical Education and Research

JAK inhibitors are likely to expand further as
data become available from ongoing phase 2
and phase 3 trials.5
The safety profile of JAK inhibitors is
rapidly evolving with data emerging from
clinical trials and registries. A recent safety
report from the FDA Adverse Event Reporting
System (FAERS) database raised concerns
regarding increased venous thromboembo-
lism (VTE) risk with this entire treatment
class. A dose-dependent VTE risk has been
suggested for baricitinib and tofacitinib,6-8
and VTE concerns are now added as a black
box warning on the product label for bariciti-
nib, tofacitinib, and upadacitinib. This
increased VTE risk is particularly concerning
because treatment indications are expanding
for diseases with inherent thrombogenicity,
including rheumatic diseases and cancers.9
Dysregulated thrombopoietin signaling,
impaired platelet homeostasis, and dyslipide-
mia have been proposed as plausible
mechanisms.10,11
Assessing the VTE risk associated with
these agents has been limited for 3 major rea-
sons. First, individual studies are inade-
quately powered to detect this important but
infrequent complication. Second, VTE out-
comes have not been universally collected
across trials. Third, trial durations may not
have been sufficiently long to identify VTE
as a major complication. By combining data
sets, a meta-analysis strategy can provide
adequate power to investigate whether inter-
ventions (ie, JAK inhibitors) increase the
risk of rare events (VTE).12 Hence, we con-
ducted a systematic review and meta-
analysis of published randomized clinical
trials (RCTs) to estimate the overall risk of
VTEs with the use of JAK inhibitors compared
with placebo.
PATIENTS AND METHODS
A systematic review and meta-analysis was con-
ducted using an a priori established protocol
and reported in accordance with PRISMA
(Preferred Reporting Items for Systematic Re-
views and Meta-Analyses) reporting guidelines
(Supplemental Methods 1, available online at
http://www.mayoclinicproceedings.org).13
n n
1862 Mayo Clin Proc.
MAYO CLINIC PROCEEDINGS
Literature Search
We performed a comprehensive search of
Ovid MEDLINE and Epub Ahead of Print,
In-Process & Other Non-Indexed Citations,
and Daily; Ovid EMBASE; Ovid Cochrane
Central Register of Controlled Trials; Ovid
Cochrane Database of Systematic Reviews;
and Scopus for English language articles
from each database's inception to December
4, 2019. The search strategy was designed
and conducted by an experienced librarian
with input from the study's principal investi-
gator (J.B.). Controlled vocabulary supple-
mented with keywords was used to search
for randomized placebo-controlled trials of
JAK inhibitors. A listing of all search terms
used and how they were combined is avail-
able in Supplemental Methods 2. Moreover,
Google Scholar was searched manually to
identify additional trials.
Study Selection
We developed the following a priori inclu-
sion criteria for this study: (1) any phase 2
and phase 3 randomized, placebo-
controlled trials of JAK inhibitors, regardless
of clinical condition, that reported adverse
event data in treatment and control groups;
(2) adult patients (18 years of age); (3) En-
glish language studies only; and (4) studies
that were published from the inception of
the individual databases to December 4,
2019. In instances of multiple reports from
the same study, the safety data from the pub-
lication with the longest follow-up were
included. In studies with more than one
intervention arm, data were extracted from
both the JAK inhibitors arm and the placebo
arm. The safety data obtained from pub-
lished studies were cross-checked with the
results at ClinicalTrials.gov. In cases of
disagreement between 2 sources, data
derived from ClinicalTrials.gov were used.
We excluded abstracts with incomplete
data and trials in which the generic drug
name for the JAK inhibitor had not yet
been assigned as of December 4, 2019. Two
authors (M.S., M.A.) independently screened
titles and abstracts and reviewed full texts of
selected articles to determine whether they
July 2021;96(7):1861-1873 https://doi.org/10.1016/j.mayocp.2020.12.035
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RISK OF VENOUS THROMBOEMBOLISM WITH JAK INHIBITORS
met our inclusion criteria. Any discrepant is-
sues regarding inclusion of studies were
resolved via discussion and arbitration by
the principal investigator (J.B.) of this study.
Data Extraction and Quality Assessment
We abstracted data from the included
studies and coded it into a template of a pre-
viously developed Microsoft Excel (2016)
codebook. The data were coded into 3 broad
categories: (1) study characteristics; (2) pa-
tient characteristics; and (3) outcomes. Our
recorded data included but were not limited
to first author’s last name, publication year,
disease studied, number of patients in treat-
ment and placebo arms, treatment drug, pla-
cebo, dosage of drug, follow-up duration,
number of events of thromboembolism,
and funding sources. Included trials were
assessed for risk of bias using the Cochrane
Collaboration Risk of Bias assessment tool,
version 2 (RoB 2).14
Two authors (M.S., M.A.) coded the data
independently. The principal investigator
(J.B.) assessed and reviewed each coded
item for accuracy and adjudicated any dis-
crepancies. In cases of missing data, the au-
thors of the original studies were not
contacted.
Data Synthesis
Primary Analysis. The main outcome was
VTE risk with JAK inhibitors compared with
placebo. We conducted DerSimonian and
Laird random-effects meta-analysis to esti-
mate odds ratios (ORs) and related 95% CI.
We used the random-effects model because of
anticipated heterogeneity.15-17 Studies that
reported no thromboembolic events in both
JAK inhibitor and placebo arms were excluded
in the main frequentist analysis. In primary
analysis, we did not correct for zero events in
either arm, but we did conduct sensitivity
analysis using continuity correction for zero
events. We used the approach described by
Sweeting et al15 for continuity correction for
either the JAK inhibitor or placebo arm that
reported zero events. Using the ratio (R) of
control to treatment group size, the continuity
correction factor of 1/(R þ 1) and R/(R þ1)
Mayo Clin Proc. n July 2021;96(7):1861-1873 n https://doi.org/10.1016/j.mayocp.2020.12.035
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was used for treatment and control groups,
respectively.
Secondary Analyses. We also performed
sensitivity analysis using the Bayesian
approach with empirical informative priors
for heterogeneity that included the studies
with zero events in both arms.18 We specified
the prior based on the article by Turner et al.18
Data were analyzed using Comprehensive
Meta-Analysis, version 3 software (Biostat).19
Bayesian meta-analysis was conducted using
the bayesmeta R package, version 3.4.3
(RStudio).20
We conducted a cumulative meta-analysis
by adding individual studies chronologically
to provide a visual presentation of the devel-
opment of evidence with time and to deter-
mine point estimates. We summarized the
findings from the cumulative meta-analysis
as each new study was added. In addition,
we conducted leave-one-out analysis to
examine if removing one study at a time
would influence the overall results. Similarly,
stratified analyses were planned a priori and
performed to generate estimates for VTE risk
for each drug and indication.
Assessment of Heterogeneity
Both subgroup analysis and meta-regression
were planned a priori to examine possible
causes of heterogeneity. We performed prespe-
cified subgroup analysis to examine the risk of
VTE by commonly used doses for different
JAK inhibitors when possible. Test of interac-
tion was performed to compare the subgroups.
Meta-regression was performed to assess sta-
tistically whether specific factors (covariates)
influenced the effect size across studies. We
performed meta-regression using the
random-effects model (method of moments)
to evaluate heterogeneity and the association
of the duration of treatment with the risk of
VTE. We converted all ORs by logarithmic
transformation to ensure symmetric distribu-
tion. In the meta-regression, the dependent
variable was the natural logarithm of the OR,
while the duration of follow-up was included
as a predictor variable. We used a weighted
regression model to allow more precise studies
to have higher influence in the analysis.21
1863
 MAYO CLINIC PROCEEDINGS

Heterogeneity was reported using the I2 including 6 follow-up/long-term extension

statistic and categorized as low, moderate,
and high degree of heterogeneity if the I2
values were less than 50%, 50% to 75%, and
greater than 75%, respectively.22 We gener-
ated the funnel plots for visual inspection of
the presence of publication bias and conduct-
ed the Egger regression test to test for small
study effect. Two-tailed a<.05 was consid-
ered the cutoff for statistical significance. On
an a priori basis, we planned to conduct Duval
and Tweedie’s trim-and-fill method if publica-
tion bias was detected.23
Certainty of Evidence
Certainty of evidence for VTE estimate was
assessed using the GRADE (Grading of Rec-
ommendations Assessment, Development
and Evaluation) approach.24
RESULTS
The initial literature search identified 1175 ti-
tles, from which 57 RCTs (63 references
studies and 31 studies with crossover
design)25-87 met the inclusion criteria
(Figure 1). Of the 57 studies, 2854-81 did not
report the VTE events and were excluded
(Supplemental Table 1, available online at
http://www.mayoclinicproceedings.org). The
quantitative analysis included 25 studies25-33,
35,38-40,42-52,85
using frequentist methods (4
studies with zero events in both arms were
excluded) and 29 studies25-40,42-53,85 using
the Bayesian approach (13,910 patients). The
characteristics of the 29 studies are described
in the Table. A total of 9866 patients were
included in the JAK inhibitors arms and 4044
in the placebo arms. The total number of
VTE events in the JAK inhibitors arms was
50 compared with 27 in the placebo arms
(Supplemental Table 2).
Abrocitinib was investigated in 1 trial,25
baricitinib in 5,26-30 decernotinib in 2,31,32 fil-
gotinib in 3,33-35 peficitinib in 2,36,37 ruxoliti-
nib in 4,38-40,85 tofacitinib in 7,42-47,48 and

Records identified through Records identified through

database searching updated searching
Identification

(n=1034) (n=141)

Records after duplicates were removed

(n=1175)
Screening

Records excluded during

Records screened
title/abstract screening
(n=1175)
(n=724)

Full-text articles assessed for

Eligibility

eligibility Full-text articles excluded, with reasons

(n=451) (n=390):
Reviews/guidelines/editorials/letters/
commentary =3
Abstracts with incomplete data =286
Records identified through Studies included for qualitative Case reports/series =2
Google Scholar analysis n=57 Irrelevant/unrelated =31
(n=2) Investigational =7
Included

(63 references)
Results not published =38
Duplicates =14
Post hoc/subgroup analyses =7
Studies included for quantitative Other language =2
analysis n=29
(33 references)

FIGURE 1. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram.

n n
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Mayo Clin Proc. n July 2021;96(7):1861-1873

RISK OF VENOUS THROMBOEMBOLISM WITH JAK INHIBITORS

TABLE. Studies Identified Using PRISMA Outcomes of Interest and Included in Quantitative Analysis (N¼29)
Type of Dose of
Reference, year JAK inhibitor JAK inhibitor (mg) Background therapy Follow-up (wk) Indication for therapy Mean patient age (y)
25
Gooderham et al, 2019 Abrocitinib 10, 30, 100, 200 Antihistamine 12 Atopic dermatitis 40.8
Wallace et al,26 2018 Baricitinib 2, 4 Methotrexate, corticosteroids, 28 Systemic lupus erythematosus 44.4
antimalarials, azathioprine,
mycophenolate mofetil, NSAIDs
Papp et al,27 2016 Baricitinib 2, 4, 8, 10 Not reported 52 Psoriasis 47.3
Tanaka et al,28 2016 Baricitinib 1, 2, 4, 8 Methotrexate, corticosteroids 64 Rheumatoid arthritis 54.2
Dougados et al,29 2017 Baricitinib 2, 4 Methotrexate 28 Rheumatoid arthritis 51.6
Genovese et al,30 2016 Baricitinib 2, 4 Not reported 24 Rheumatoid arthritis 55.6
n
https://doi.org/10.1016/j.mayocp.2020.12.035

Fleischmann et al,31 2015 Decernotinib 25, 50, 100, 150 Corticosteroids, NSAIDs 16 Rheumatoid arthritis 56.1
Genovese et al,32 2016 Decernotinib 100, 150, 200 Methotrexate 104 Rheumatoid arthritis 53.1
van der Heijde et al,33 2018 Filgotinib 200 Methotrexate, leflunomide, sulfasalazine, 16 Ankylosing spondylitis 41.5
hydroxychloroquine, NSAIDs
Mease et al,34 2018 Filgotinib 200 Methotrexate, leflunomide, sulfasalazine, 20 Psoriatic arthritis 49.5
corticosteriods
Genovese et al,35 2019 Filgotinib 100, 200 Methotrexate, sulfasalazine, 24 Rheumatoid arthritis 55.6
hydroxychloroquine, leflunomide,
corticosteroids, NSAIDs
Takeuchi et al,36 2019 Peficitinib 100, 150 Methotrexate 52 Rheumatoid arthritis 56.6
Tanaka et al,37 2019 Peficitinib 100, 150 DMARDs 52 Rheumatoid arthritis 55.11
Hurwitz et al,38 2018 Ruxolitinib 15 Capecitabine 6 Metastatic pancreatic cancer Not reported
Hurwitz et al,39 2015 Ruxolitinib 15 Capecitabine 18 Metastatic pancreatic cancer 66
40
O'Shaughnessy et al, 2018 Ruxolitinib 15 Capecitabine 64 HER2-negative breast cancer Not reported
Verstovsek et al,85 2017 Ruxolitinib 15, 20 Not reported 260 Myelofibrosis Not reported
Burmester et al,42 2013 Tofacitinib 5, 10 Methotrexate, antimalarials, NSAIDs, 24 Rheumatoid arthritis 55
corticosteroids
van Vollenhoven et al,43 2012 Tofacitinib 5, 10 Methotrexate, corticosteroids, lipid- 52 Rheumatoid arthritis 53.16
modifying agents
Fleischmann et al,44 2012 Tofacitinib 5, 10 Corticosteroids, antimalarials 24 Rheumatoid arthritis 51.4
Sandborn et al,45 2017 Tofacitinib 5, 10, 15 Aminosalicylates, steriods 52 Ulcerative colitis 41.8
Mease et al,46 2017 Tofacitinib 5, 10 DMARDs 52 Psoriatic arthritis 47.8
Kremer et al,47 2013 Tofacitinib 5, 10 Methotrexate, corticosteriods, DMARDs 52 Rheumatoid arthritis 52.1
Sandborn et al,48 2012 Tofacitinib 0.5, 3, 10, 15 Corticosteriods, TNF-a inhibitors 12 Ulcerative colitis 42.8
Smolen et al,49 2019 Upadacitinib 15, 30 Methotrexate, corticosteroids, NSAIDs, 260 Rheumatoid arthritis 54.3
acetaminophen, folic acid
1865

Continued on next page

 MAYO CLINIC PROCEEDINGS

upadacitinib in 5.49-53 The studies examined

DMARD, disease-modifying antirheumatic drug; HER2, human epidermal growth factor receptor 2; JAK, Janus kinase; NSAID, nonsteroidal anti-inflammatory drug; PRISMA, Preferred Reporting Items for Systematic Reviews and
Mean patient age (y)

JAK inhibitor treatment in RA (n¼16),28-

32,35-37,42-44,49-52,72
inflammatory bowel dis-
ease (n¼2),45,48 psoriatic arthritis (n¼2),34,46
55.7

45.4
57

54

ankylosing spondylitis (n¼2),33,53 pancreatic

cancer (n¼2),38,39 psoriasis (n¼1),27 atopic
dermatitis (n¼1),25 breast cancer (n¼1),40
systemic lupus erythematous (n¼1),26 and
myelofibrosis (n¼1).85 The median duration
Indication for therapy

of follow-up was 48 weeks (range, 6 to 260

Ankylosing spondylitis
Rheumatoid arthritis

Rheumatoid arthritis

Rheumatoid arthritis

weeks; interquartile range, 22 to 56 weeks).

Risk of Bias
The risk of bias was low or with some con-
cerns in most of the RCTs included in our
study, as assessed with the Cochrane Collab-
Follow-up (wk)

oration’s tool (Supplemental Figures 1 and 2,

available online at http://www.
24

48

60

104

mayoclinicproceedings.org).

Primary Analysis
With low certainty of evidence, meta-
Methotrexate, sulfasalazine, leflunomide,

Methotrexate, sulfasalazine, leflunomide,

Methotrexate, corticosteroids, NSAIDs,

analysis revealed no statistically significant

hydroxychloroquine, chloroquine,

hydroxychloroquine, chloroquine,

DMARDs, corticosteroids, NSAIDs

difference in VTE risk with JAK inhibitors

Background therapy

relative to placebo (OR, 0.91; 95% CI, 0.57

acetaminophen, folic acid

to 1.47; P¼.70; I2¼0; 1 fewer per 1000 per-

sons, 95% CI: 3 fewer to 3 more)
corticosteroids

corticosteroids

(Figure 2). The certainty in evidence using

the GRADE approach was rated as low for
risk of VTE with JAK inhibitors vs placebo
considering serious imprecision as a result
of the relatively small number of events in
the treatment and placebo arms and a wide
JAK inhibitor (mg)

confidence interval (Supplemental Table 3).

Dose of

15, 30

15, 30
15

15

Secondary Analyses
Cumulative meta-analysis revealed that the
findings were stable, and the OR did not
change after the first 18 studies
JAK inhibitor
Upadacitinib

Upadacitinib
Upadacitinib

Upadacitinib
Type of

(Supplemental Figure 3). The sensitivity ana-

Meta-Analyses; TNF-a, tumor necrosis factor a.

lyses revealed consistent results of a lack of as-

sociation, with an overall OR with continuity
correction (OR, 0.87; 95% CI, 0.53 to 1.45;
P¼.60; I2¼0) (Supplemental Figure 4); using
van der Heijde et al,53 2019
Fleischmann et al,51 2019

Burmester et al,52 2018

the Bayesian random-effects model (OR,

2018
Reference, year
TABLE. Continued

0.88; 95% CI, 0.55 to 1.42) (Supplemental

50

Figure 5); after exclusion of cancer studies

Genovese et al,

(OR, 0.88; 95% CI, 0.45 to 1.70; P¼.70;

I2¼0) (Supplemental Figure 6); after exclusion
of tofacitinib studies (OR, 1.15; 95% CI, 0.68 to
1.93; P¼.60; I2¼0) (Supplemental Figure 7);
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RISK OF VENOUS THROMBOEMBOLISM WITH JAK INHIBITORS
and with the inclusion of events (placebo and
treatment arms) based exclusively on the dura-
tion of the placebo-controlled phase of the trial
(OR, 0.87; 95% CI, 0.52 to 1.46; P¼.59; I2¼0)
(Supplemental Figure 8). The results of leave-
one-out analysis were consistent with those of
the primary analysis.
The results of the analyses stratified by
indication were consistent with those of the
primary analysis: RA (OR, 1.10; 95% CI, 0.50
to 2.43; P¼.80; I2¼0) (Supplemental
Figure 9), psoriatic arthritis (OR, 0.69; 95%
CI, 0.07 to 6.67; P¼.75; I2¼0) (Supplemental
Figure 10), and pancreatic cancer (OR, 1.49;
95% CI, 0.67 to 3.30; P¼.33; I2¼0)
(Supplemental Figure 11). The exception
was inflammatory bowel disease, in which pa-
tients receiving JAK inhibitors were found to
have lower risk of VTE compared with placebo
(OR, 0.07; 95% CI, 0.00 to 0.66; P¼.02; I2¼0)
(Supplemental Figure 12).
The stratified analyses by specific JAK in-
hibitor also yielded results consistent with those
of the primary analysis for most of the JAK in-
hibitors: baricitinib (OR, 1.12; 95% CI, 0.27 to
4.69; P¼.88; I2¼0) (Supplemental Figure 13),
decernotinib (OR, 1.07; 95% CI, 0.18 to 6.43;
P¼.94; I2¼0) (Supplemental Figure 14), filgoti-
nib (OR, 2.13; 95% CI, 0.22 to 20.64; P¼.52;
I2¼0) (Supplemental Figure 15), ruxolitinib
(OR, 0.85; 95% CI, 0.31 to 2.29; P¼.74;
I2¼44.7%) (Supplemental Figure 16), and upa-
dacitinib (OR, 2.25; 95% CI, 0.55 to 9.25;
P¼.26; I2¼0) (Supplemental Figure 17). The
exception was tofacitinib, which had a lower
risk of VTE compared with placebo (OR, 0.27;
95% CI, 0.08 to 0.89; P¼.03; I2¼0)
(Supplemental Figure 18).
There was no significant subgroup effect
in the stratified analysis by dose for individ-
ual JAK inhibitors (P>.1 for interaction)
(Supplemental Figures 19-22).
The meta-regression analysis revealed no
significant association of duration of drug
use with risk of thromboembolism
(coefficient, 0.0037; 95% CI, 0.0118 to
0.0044; P¼.37) (Supplemental Figure 23).
Heterogeneity was low across studies for
primary outcome (Supplemental Figure 24).
The funnel plot analysis revealed no evidence
of publication bias for primary outcome
Mayo Clin Proc. n July 2021;96(7):1861-1873 n https://doi.org/10.1016/j.mayocp.2020.12.035
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(Supplemental Figure 25). Similarly, the
Egger regression test for small-study effect
was also found to be statistically nonsignifi-
cant (P¼.43; Supplemental Figure 26).
DISCUSSION
The primary finding of this meta-analysis
including 29 RCTs totaling 13,910 patients
is that there is insufficient evidence to sup-
port an increased risk of VTE with use of
JAK inhibitors as a class of agent compared
with placebo. The incidence of VTE in trial
participants was 0.51% in the JAK inhibitors
group compared to 0.67% in the placebo
group (OR, 0.91; 95% CI, 0.57 to 1.47).
Most of the subgroup analyses based on spe-
cific drugs (including high vs low dose) and
disease states had similar results. These find-
ings were also consistent across different
sensitivity analyses. These conclusions are
based on study-level data with short
follow-up duration and a relatively small
number of events.
Our results are consistent with those of
prior studies involving fewer types of JAK in-
hibitors, smaller patient samples, and fewer
disease conditions.88-94 Two prior meta-
analyses were unable to identify excess
VTE risk for patients with RA93 or other
rheumatic diseases.94 Agent-specific risk
has been assessed for baricitinib in patients
with RA, analyzing by patient-level data
(3492 patients) from 8 RCTs and 1 ongoing
long-term extension trial with follow-up of
5.5 years (96 patients). No dose or temporal
dependency in deep venous thrombosis or
pulmonary embolism risk was observed
with prolonged administration. Venous
thromboembolism incidence rates for vary-
ing doses of baricitinib (0.5 per 100
patient-years) were comparable to back-
ground rates for RA (0.3 to 0.8 per 100
patient-years) in real-world studies.95 Pooled
data from 6 placebo-controlled studies of
baricitinib found no association between
thrombocytosis and thromboembolic
events.96 Similar results have been found
for tofacitinib in trials of RA, psoriasis, pso-
riatic arthritis, and ulcerative colitis.34 An
open-label long-term extension study of
tofacitinib treatment in RA (4000 patients)
1867

with nearly 9.5-year follow-up97 reported
similar VTE rates comparing pooled phase
2 and 3 monotherapy data with combination
therapy including disease-modifying anti-
rheumatic drugs. Two large observational
cohorts (ie, Truven Marketscan and Medi-
care claims database [parts A, B, and D]) re-
ported a nonsignificant difference of VTE
rates from 50,865 patients with RA treated
with tofacitinib or a tumor necrosis factor
(TNF) inhibitor.88
In contrast, a postmarketing safety review
of the FAERS indicated that pulmonary throm-
bosis might potentially be a class-wide compli-
cation of JAK inhibitors.6 There are several
limitations of the FAERS report, however,
including a small number of patients, lack of
a denominator, and the uncertain impact of pa-
tient or disease-related risk factors for VTE. A
safety trial of tofacitinib vs adalimumab and
etanercept (NCT02092467) is ongoing.8,98
This study includes patients older than 50
years with RA and with one cardiovascular
risk factor. An interim analysis reported an
increased risk of VTE and mortality in patients
treated with tofacitinib at 10 mg twice daily
compared with patients treated with tofaciti-
nib at 5 mg twice daily or a TNF blocker. There
were 19 cases of pulmonary embolism during
3884 patient-years of follow-up in patients
who received tofacitinib at 10 mg twice daily,
compared with 3 cases during 3982 patient-
years in patients who received TNF blockers.99
A potential dose-dependent risk of VTE with
tofacitinib was suggested, and the FDA subse-
quently restricted the use of tofacitinib to a
5-mg twice daily dosing.8 In our study, short-
term use of tofacitinib (5 and 10 mg) did not
appear to increase the risk of VTE compared
with placebo in a subanalysis. It should be
noted that the interpretation of our subanaly-
ses is limited by few events, limited exposure,
and a small number of studies. The final report
of the tofacitinib safety trial may provide addi-
tional insights that will further characterize the
benefit/risk profile across doses of tofacitinib.
The existing literature suggests that there
is an increased natural background rate of
thromboembolic events in individuals with
inflammatory diseases, ie, RA, psoriasis,
and psoriatic arthritis.95,98,100-102 A literature
n n
1868 Mayo Clin Proc.
MAYO CLINIC PROCEEDINGS
review by Scott et al9 summarized the risk of
VTE in the general population and in indi-
viduals with RA with and without treatment.
They reported a rate of 1 to 4 VTE events per
1000 patient-years in the general population.
The rate of VTE events increases to 3 to 7
per 1000 patient-years in patients with RA,
with minimal change in risk when biologics
and disease-modifying antirheumatic drugs
are used (ie, between 4 and 8 VTE events
per 1000 patient-years). In addition, epide-
miological data indicate that the baseline
risk of VTE varies among different ethnic-
ities.103 The inherent risk of VTE, both arte-
rial and venous, is higher in individuals with
myeloproliferative neoplasms, reflecting the
natural course of disease.104
To date, JAK inhibitors are being used pri-
marily for rheumatic and hematologic dis-
eases. It is challenging to establish the safety
profile of any novel drug in this patient popu-
lation because of the difficulty in distinguish-
ing between the potential harm of a new drug
and the effects of the disease and other drug
treatments. The overall mortality associated
with most rheumatic and hematologic dis-
eases is higher than that of the healthy popu-
lation.105,106 The FDA-approved drugs used
for treatment (biologics and other immuno-
suppressive medications) also carry an
increased mortality risk among other safety
concerns.107,108 Despite the existence of
safety signals, the benefits from these treat-
ments are substantial and outweigh the
risks.109 It is important to consider a similar
approach in defining the safety profile for
JAK inhibitors. The efficacy of JAK inhibitors
should be weighed against any potential harm
after recognizing the potential role of other
confounding factors, including the risk of
premature mortality associated with these
diseases, the risk compared with other avail-
able treatments, the baseline risk of adverse
events in healthy individuals, and the pres-
ence of comorbidities.
There are several noteworthy limitations
of this analysis. First, the outcome of interest
(risk of VTE) was a rare event; therefore, the
results may be impacted by small changes in
event distribution. Second, VTE events were
not centrally adjudicated in most trials, and
July 2021;96(7):1861-1873 https://doi.org/10.1016/j.mayocp.2020.12.035
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RISK OF VENOUS THROMBOEMBOLISM WITH JAK INHIBITORS

Study Statistics for each study Odds ratio and 95% CI

JAK Odds Lower Upper
inhibitors Placebo ratio limit limit z value P value
Burmester 2013 2/399 0/132 1.667 0.080 34.937 0.329 0.74
Burmester 2018 2/440 0/221 2.526 0.121 52.834 0.597 0.55
Dougados 2017 1/456 0/228 1.505 0.061 37.088 0.250 0.80
Fleischmann 2012 0/610 2/122 0.039 0.002 0.827 –2.082 0.04
Fleischmann 2015 1/163 0/41 0.766 0.031 19.151 –0.162 0.87
Fleischmann 2019 2/954 1/650 1.363 0.123 15.068 0.253 0.80
Genovese 2016 [1] 1/351 0/176 1.511 0.061 37.274 0.252 0.80
Genovese 2016 [2] 5/265 1/71 1.346 0.155 11.710 0.269 0.79
Genovese 2018 7/451 0/169 5.720 0.325 100.698 1.192 0.23
Genovese 2019 1/300 0/148 1.487 0.060 36.735 0.243 0.81
Gooderham 2019 1/211 0/56 0.805 0.032 20.034 –0.132 0.89
Huwitz 2015 7/59 3/60 2.558 0.628 10.411 1.311 0.19
Huwitz 2018 9/195 8/197 1.143 0.432 3.027 0.269 0.79
Krener 2013 1/779 0/159 0.615 0.025 15.156 –0.298 0.77
Mease 2017 1/316 0/105 1.003 0.041 24.813 0.002 1.00
O'Shaughnessy 2018 2/71 7/71 0.265 0.053 1.323 –1.619 0.11
Papp 2016 [1] 1/221 0/34 0.469 0.019 11.756 –0.460 0.65
Sandborn 2012 0/146 1/48 0.108 0.004 2.698 –1.355 0.18
Sandborn 2017 0/927 2/234 0.050 0.002 1.048 –1.930 0.05
Smolen 2019 1/432 0/216 1.505 0.061 37.103 0.250 0.80
Tanaka 2016 1/141 0/49 1.057 0.042 26.373 0.034 0.97
van der Heijde 2018 1/58 0/58 3.052 0.122 76.485 0.679 0.50
van Vollenhoven 2012 1/513 0/108 0.635 0.026 15.695 –0.277 0.78
Verstovsek 2017 1/266 2/154 0.287 0.026 3.189 –1.016 0.31
Wallace 2018 1/209 0/105 1.518 0.061 37.583 0.255 0.80
0.911 0.566 1.465 –0.386 0.70

0.01 0.1 1 10 100

Favors JAK inhibitors Favors placebo

FIGURE 2. Risk of venous thromboembolism. JAK, Janus kinase.

the trials were not originally designed to
explore VTE as an outcome. Third, access
to source data was not available such that
statistically robust patient-level analysis
could not be performed. Fourth, follow-up
duration was limited, and therefore a long-
term safety profile of JAK inhibitors cannot
be extrapolated. Because the longest avail-
able event data for treatment groups was
included, the true risk may have been over-
estimated. Follow-up in the treatment arms
was longer than in the placebo arms for
most studies. To address this concern, a
sensitivity analysis was conducted to include
the data from only the placebo-controlled
duration of the trials; the results were similar
(Supplemental Figure 6). Fifth, effect modi-
fication by different profiles of JAK
inhibitors (JAK 1, 2, and 3) were not
explored. Lastly, a large number of studies
Mayo Clin Proc. n July 2021;96(7):1861-1873
www.mayoclinicproceedings.org
(n¼28)54-81 evaluating the efficacy and
safety of JAK inhibitors did not report spe-
cific data on VTE events and therefore
were not included in our analyses.
However, this study provides the most up-
to-date evidence on the risk of VTE in patients
using JAK inhibitors across a broad range of
diseases. Our study addresses the urgent
need for clarifying the safety of JAK inhibitors
with regard to the risk of VTE. By pooling the
data from randomized placebo-controlled
clinical trials, we were able to perform various
subgroup analyses to address pragmatic clin-
ical questions. Despite the large number of tri-
als, there is consistency across the analyses,
indicating the robustness of the results.
CONCLUSION
The results of our study are reassuring and
support a favorable benefit/risk profile of
n https://doi.org/10.1016/j.mayocp.2020.12.035 1869

JAK inhibitors in the short term. However,
owing to the intrinsic limitations of meta-
analysis from study-level data, additional ev-
idence from large databases and real-world
experience is needed before definite conclu-
sions on the long-term safety of JAK inhibi-
tors can be drawn.
SUPPLEMENTAL ONLINE MATERIAL
Supplemental material can be found online
at http://www.mayoclinicproceedings.org.
Supplemental material attached to journal
articles has not been edited, and the authors
take responsibility for the accuracy of all
data.
Abbreviations and Acronyms: FAERS = FDA Adverse
Event Reporting System; FDA = Food and Drug Adminis-
tration; JAK = Janus kinase; OR = odds ratio; R = ratio; RA =
rheumatoid arthritis; RCT = randomized clinical trial; TNF =
tumor necrosis factor; VTE = venous thromboembolism
Affiliations (Continued from the first page of this
article.): Mayo Clinic Libraries (L.J.P.), Evidence-based Prac-
tice Center (M.H.M.), and Vascular Medicine Division,
Gonda Vascular Center (R.D.M.), Mayo Clinic, Rochester,
MN; Dow University of Health Sciences, Karachi, Pakistan
(S.A.A.N.); Department of Pediatrics, Wayne State Univer-
sity, Detroit, MI (M.S.); Department of Pediatrics, Phoenix
Children’s Hospital, Phoenix, AZ (Y.N.); Evidence-Based So-
cial Science Research Center, School of Public Health, Lanz-
hou University, Lanzhou, China (L.G.); and Division of
Hematology/Oncology, Mayo Clinic, Phoenix, AZ (A.H.B.).
Potential Competing Interests: Dr McBane has received
research funding from Bristol-Myers Squibb Company
related to the EVE trial. Dr Kwoh has been a consultant
for EMD Serono, Inc, Amzell, Kolon TissueGene, Inc, Ex-
press Scripts, LG Chem, and Regeneron Pharmaceuticals,
Inc, and has received/has pending grants from Pfizer, Eli Lilly
and Company, and GlaxoSmithKline plc. The rest of the au-
thors report no competing interests.
Correspondence: Address to Jawad Bilal, MD, Division of
Rheumatology, University of Arizona, 1501 N Campbell
Ave, PO Box 245093, Tucson, AZ 85724-5093 (jawad.
bilal@hotmail.com).
ORCID
Jawad Bilal: https://orcid.org/0000-0001-7015-8151;
Irbaz Bin Riaz: https://orcid.org/0000-0003-4249-0311;
Syed Arsalan Ahmed Naqvi: https://orcid.org/0000-
0002-3131-2088; Mohamed A. Abd El Aziz: https://orci-
d.org/0000-0003-4477-0114; Mohammad H. Murad:
https://orcid.org/0000-0001-5502-5975; Robert D. McBane:
https://orcid.org/0000-0001-8727-8029
n n
1870 Mayo Clin Proc. July 2021;96(7):1861-1873
MAYO CLINIC PROCEEDINGS
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