Adv Ther
https://doi.org/10.1007/s12325-023-02445-w
BRIEF REPORT
Baricitinib Safety for Events of Special Interest
in Populations at Risk: Analysis from Randomised
Trial Data Across Rheumatologic and Dermatologic
Indications
Peter C. Taylor
. Thomas Bieber . Rieke Alten . Torsten Witte .
James Galloway . Walter Deberdt . Maher Issa . Ewa Haladyj .
Inmaculada De La Torre . Susanne Grond . Andreas Wollenberg
Received: December 5, 2022 / Accepted: January 25, 2023
Ó The Author(s) 2023
ABSTRACT
Introduction: Baricitinib, a Janus kinase (JAK)
1/2 inhibitor, is an approved treatment for
rheumatoid arthritis (RA), atopic dermatitis
(AD), and alopecia areata (AA). Further characterisation of adverse events of special interest
(AESI) for JAK inhibitors in at-risk populations
will improve benefit–risk assessment for individual patients and diseases.
Methods: Data were pooled from clinical trials
and long-term extensions in moderate-to-severe
P. C. Taylor (&)
The Botnar Research Centre, Nuffield Department of
Orthopaedics, Rheumatology and Musculoskeletal
Sciences, University of Oxford, Windmill Road,
Oxford OX3 7LD, UK
e-mail: peter.taylor@kennedy.ox.ac.uk
T. Bieber
Department of Dermatology and Allergy, University
of Bonn, Bonn, Germany
T. Bieber
Christine Kühne-Center for Allergy Research and
Education, Davos, Switzerland
R. Alten
Department of Internal Medicine and
Rheumatology, Schlosspark-Klinik Charité,
University Medicine Berlin, Berlin, Germany
T. Witte
Clinical Immunology, Hannover Medical School,
Hannover, Germany
active RA, moderate-to-severe AD, and severe
AA. Incidence rates (IR) per 100 patient-years of
major adverse cardiovascular event (MACE),
malignancy, venous thromboembolism (VTE),
serious infection, and mortality were calculated
for patients with low risk (younger than
65 years with no specified risk factors), and
patients at risk (C 1 of: aged 65 years or older,
atherosclerotic cardiovascular disease, diabetes
mellitus, hypertension, current smoking, HDL
cholesterol\40 mg/dL, BMI C 30 kg/m2, poor
mobility on EQ-5D, or history of malignancy).
J. Galloway
Centre for Rheumatic Diseases, King’s College
London, London, UK
W. Deberdt M. Issa E. Haladyj I. De La Torre
S. Grond
Eli Lilly and Company, Indianapolis, IN, USA
A. Wollenberg
Department of Dermatology and Allergology,
Ludwig Maximilian University of Munich, Munich,
Germany
A. Wollenberg
Department of Dermatology, Vrije Universiteit
Brussel, Universitair Ziekenhuis Brussel, Brussels,
Belgium
Adv Ther
Results: Datasets included baricitinib exposure
up to 9.3 years with 14,744 person-years of
exposure (PYE) (RA), 3.9 years with 4628 PYE
(AD), and 3.1 years with 1868 PYE (AA). In
patients with low risk (RA: 31%, AD: 48%, AA:
49%), IRs for MACE (0.05, 0.04, 0), malignancies (0.20, 0.13, 0), VTE (0.09, 0.04, 0), serious
infection (1.73, 1.18, 0.6), and mortality (0.04,
0, 0) in the RA, AD, and AA datasets, respectively, were low. In patients at risk (RA: 69%,
AD: 52%, AA: 51%), IRs were for MACE (0.70,
0.25, 0.10), malignancies (1.23, 0.45, 0.31), VTE
(0.66, 0.12, 0.10), serious infection (2.95, 2.30,
1.05), and mortality (0.78, 0.16, 0) for RA, AD,
and AA datasets, respectively.
Conclusion: Populations with low risk have low
incidence of the examined JAK inhibitor-related
AESI. In the dermatologic indications, incidence is also low for patients at risk. Considering individual disease burden, risk factors, and
response to treatment is relevant to make
informed decisions for individual patients treated with baricitinib.
Keywords: Adverse events; Baricitinib; JAK
inhibitors; MACE; Malignancy; Mortality;
Safety; Serious infection; VTE
This analysis examines AESI in the
baricitinib clinical programmes for
rheumatoid arthritis, atopic dermatitis,
and alopecia areata for patients with low
risk (younger than 65 years with no
specified risk factors), and patients at risk
(at least one of: aged 65 years or older,
atherosclerotic cardiovascular disease,
diabetes mellitus, hypertension, current
smoking, HDL cholesterol \40 mg/dL,
BMI C 30 kg/m2, poor mobility on EQ-5D,
or history of malignancy).
What was learned from this study?
Incidence of AESI in patients treated with
baricitinib who were younger than 65
years without risk factors were reduced
compared with the population of patients
with risk factors for all indications, and
the number of AESI is also minimal for
patients with atopic dermatitis and
alopecia areata who have risk factors.
Individual disease burden, risk factors, and
response to treatment should be
considered to make informed decisions for
individual patients treated with
baricitinib.
Key Summary Points
Why carry out this study?
Janus kinase (JAK) inhibitors have been
linked to a possible class effect associated
with particular adverse events, such as
major adverse cardiovascular event
(MACE), venous thromboembolism (VTE),
and malignancy.
Further characterisation of adverse events
of special interest (AESI) for JAK inhibitors
in at-risk populations will improve
benefit–risk assessment for individual
patients and diseases.
INTRODUCTION
Patients with chronic, systemic, immune-mediated inflammatory conditions have elevated
rates of other comorbidities that increase over
time with longer disease duration and in cases
of refractory disease. Rheumatoid arthritis (RA)
is recognised as an independent risk factor for
major adverse cardiovascular events (MACE) [1],
and has been associated with venous thromboembolism (VTE) [2], certain types of malignancy (lymphoma, lung cancer) [3], and
infections [4] among other comorbidities. For
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patients with atopic dermatitis (AD), the most
common comorbidities include other atopic
disorders, such as asthma or allergic rhinitis [5],
depression and anxiety [5, 6], and AD patients
are more prone to infections, including serious
infections [7, 8]. AD is associated with a moderate increase in MACE, which may be associated with comorbidities and lifestyle factors or
disease severity [9], and has also been linked to
an upregulation of atherosclerosis and cardiovascular risk proteins [10, 11]. While an
increased risk has been described for VTE in
moderate-to-severe AD [12–14], this was not
consistently reported for malignancies, except
lymphoma [15]. Common comorbidities in
alopecia areata (AA) include atopic disorders,
depression, anxiety, overweight/obesity, and
thyroid disease [16, 17]. Risk of MACE and VTE
are not increased in AA [13, 18], but the risks of
infection and malignancy are uncertain
[19–21].
Post-marketing safety studies are important
to better characterise and establish the safety
profile of medications. There have been few
post-marketing safety studies for anti-inflammatory medications following the uncovering
of possible adverse events associated with certain treatments, such as tuberculosis, malignancies [non-melanoma skin cancer (NMSC)],
congestive cardiac failure, or demyelinating
disease for tumour necrosis factor-a inhibitors
(TNFi) [22–24] or diverticulitis, gastrointestinal
perforations, and cardiovascular events with the
interleukin 6 receptor antagonist tocilizumab
[25, 26]. JAK inhibitors (JAKi) have recently
been in the spotlight due to a possible class
effect associated with particular adverse events,
such as MACE, VTE, and malignancy. However,
lack of controlled comparative data has led to
clinical difficulty in making relative benefit–risk
assessments among alternative treatment
options with different mechanisms of action.
Baricitinib, an oral selective JAK 1/2 inhibitor, is approved for the treatment of adults
with moderately-to-severely active RA, moderate-to-severe AD, severe AA, and, in the United
States, hospitalised patients with coronavirus
disease 2019 (COVID-19). This report complements the recently published cross-indication
safety review of baricitinib [28] by expanding on
the safety of baricitinib for adverse events of
special interest (AESI) for JAKi in populations
with risk factors for these AESI, using integrated
clinical trial datasets for the approved systemic
inflammatory indications of RA, AD, and AA.
These safety events, including MACE, VTE,
malignancy, serious infections, and mortality,
were investigated for patients aged 65 years or
older, or with at least one of eight specified risk
factors: history of atherosclerotic cardiovascular
disease (ASCVD), hypertension, diabetes mellitus, current smoking, high-density lipoprotein
(HDL) cholesterol less than 40 mg/dL, history of
malignancy, body mass index (BMI) 30 kg/m2 or
greater, and severe mobility impairment on the
EuroQol-5 Dimension (EQ-5D).
METHODS
Data were analysed from the integrated RA [29],
AD [30], and AA [31] baricitinib trials, which
make up the regulatory submission package for
the clinical development programmes sponsored by Eli Lilly and Company, to yield the
largest possible dataset of patients with reliable
data of exposure to baricitinib to give the best
guidance for future patients. These analysis sets
are not placebo-controlled but provide reliable
estimates for adverse event incidence within the
baricitinib clinical programme, which is particularly relevant for less common event types.
RA Analysis Set
Safety data from nine randomised clinical trials
[Phase
1b:
I4V-MC-JADB;
Phase
2:
NCT01185353, NCT00902486; NCT01469013
(Japan); Phase 3: NCT01710358 (RA-BEAM),
NCT01721044 (RA-BEACON), NCT01721057
(RA-BUILD),
NCT01711359
(RA-BEGIN),
NCT02265705 (RA-BALANCE)] and one completed long-term extension (LTE) trial
[NCT01885078 (RA-BEYOND)] running from
May 2009–November 2020 were pooled. The allbari-RA analysis set includes data of all patients
who received at least one dose of baricitinib
(doses ranged from 1 to 15 mg daily, with 2 mg
and 4 mg daily doses used in the phase 3 and
long-term extension trials) using all available
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data after the first dose without censoring for
rescue or dose change.
AD Analysis Set
Safety data are included from six double-blinded, randomised clinical studies [Phase 2:
NCT02576938;
Phase
3:
NCT03334396
(BREEZE-AD1), NCT03334422 (BREEZE-AD2),
NCT03428100 (BREEZE-AD4), NCT03435081
(BREEZE-AD5), NCT03733301 (BREEZE-AD7)],
one
double-blinded,
randomised
LTE
[NCT03334435 (BREEZE-AD3)], and one openlabel LTE [NCT03559270 (BREEZE-AD6)], with
completed studies running from November
2017–August 2019 and data cut-offs of
15 December 2021 for BREEZE-AD4, and
3 November 2021
(BREEZE-AD3)
and
21 December 2021 (BREEZE-AD6) in the ongoing LTE studies. The all-bari-AD analysis set
includes data for all patients who received at
least one dose of baricitinib (1 mg, 2 mg, or
4 mg) from any of the eight clinical trials at any
time.
AA Analysis Set
Safety data are included from Phase 2 and Phase
3 cohorts of BRAVE-AA1 (NCT03570749) and
Phase 3 BRAVE-AA2 (NCT03899259), with data
cut-offs of 11 November 2021 and 5 November 2021, respectively. The all-bari-AA analysis
set combines all patients exposed to any baricitinib dose (1 mg, 2 mg, or 4 mg) at any time up
to the data cut-off.
Compliance with Ethics Guidelines
All studies were conducted in accordance with
ethical principles of the Declaration of Helsinki
and Good Clinical Practice guidelines, and the
research protocols were approved by each centre’s institutional review board or ethics committee. All patients provided written informed
consent.
Statistical Analysis
Each analysis set was reviewed for AESI, defined
as MACE [positively adjudicated events of
myocardial infarction (MI), stroke and cardiovascular deaths combined), MI separately,
malignancies (excluding NMSC), VTE (deep
vein thrombosis (DVT) or pulmonary embolism
(PE)], serious infections, and mortality.
For AESI, the incidence rate (IR) was calculated as standard (number of patients with an
event per 100 patient-years at risk (PYR)],
including follow-up time censored at event
onset date. Poisson distribution was used to
calculate 95% CI.
The IR for AESI was evaluated in subgroups
of patients aged over 65 years or with at least
one of eight specified risk factors [history of
ASCVD, hypertension, diabetes mellitus, current smoking, HDL cholesterol less than 40 mg/
dL, history of malignancy, BMI 30 kg/m2 or
greater, and severe mobility impairment on EQ5D (i.e., responding either ‘I have severe problems in walking about’ or ‘I am unable to walk
about’)] and patients aged below 65 years
without any of the specified risk factors. Past
smoking was not systematically documented in
all studies but was checked for in case histories
of patients with an event. This IR was calculated
as 100 times the number of patients experiencing the event divided by PYR (exposure time up
to the event for patients with the AESI and
exposure time up to the end of the exposure
and 1-month follow-up for patients without the
AESI) in years in the subgroup of the specific
factor. To account for ageing of the cohort, the
number of expected malignancies (excluding
NMSC) were calculated using age-specific
malignancy data from the Surveillance, Epidemiology, and End Results 17 (SEER17),
2013–2017 US population cancer rates [32] and
compared to the number of observed malignancies in the baricitinib clinical programme.
The baricitinib clinical trials for RA did not
exclude patients with any of the above-mentioned risk factors, except for recent comorbidities such as MI or stroke within 12 weeks,
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active or recent (within 30 days) serious infection, or malignant disease [33]. Clinical trials
studying baricitinib in AD and AA also excluded
patients with MI, stroke, or VTE events within
12 weeks of screening, active or recent (within
30 days) serious infection, or malignant disease,
as well as those who had history of, or are
considered at high risk for, VTE [34, 35].
RESULTS
In clinical trials for RA, AD, and AA, 7709
patients received baricitinib and the data
include patients with long-term baricitinib
exposure (Table 1). In the RA dataset, the mean
age of patients at baseline was 53 years and
exposure lasted up to 9.3 years, with a median
exposure of 4.6 years, for a total of 14,744 person-years of exposure (PYE) [29]. The AD dataset
includes exposure up to 3.9 years with a median
exposure of 1.6 years, for a total of 4628 PYE
with a mean age of patients at baseline of
37 years. As the most recently-approved indication for baricitinib, the AA dataset includes a
limited follow-up period (median 1.5 years,
maximum 3.1 years), for a total of 1868 PYE
with mean age of patients at baseline of 38 years
[31]. The proportion of each population with
each specified risk factor at baseline is given in
Table 1.
Across indications, in patients younger than
65 years without one of the eight pre-specified
risk factors, (low-risk) data show low IRs of
MACE, MI, lung cancer, VTE, and overall mortality relative to the literature-reported incidence in these patient populations, and a
reduced incidence of overall malignancy and
serious infections, compared with the at-risk
population (Fig. 1). For AD and AA populations,
the incidence of AESI is low irrespective of the
presence of risk factors.
Approximately 31% (n = 1151) of the allbari-RA dataset were younger than 65 years and
did not have any of the specified risk factors
(low-risk). Very few patients from this low-risk
group had an AESI. There were 2 MACE events
(0.2%, IR = 0.05), both were haemorrhagic
strokes, and no MI (Fig. 1). VTE was recorded in
4 patients (0.3%, IR = 0.09); all 4 had a DVT and
none had a fatal outcome. Serious infection was
reported in 75 low-risk patients (6.5%,
IR = 1.73) compared with 372 patients (9.9%,
IR = 2.58) in the overall study population
(Fig. 1). Mortality was observed in 2 patients
(0.2%, IR = 0.04) (Fig. 1).
For the 69% (n = 2619) of patients in the allbari-RA dataset who were C 65 years or with at
least one risk factor (at-risk), the IRs of AESI
were higher than for the overall all-bari-RA
population (Fig. 1). In this at-risk group, 71
patients (IR = 0.70) recorded a MACE event, 24
of whom were C 65 years (IR = 1.19). A total of
69 patients (IR = 0.66) had VTE, with 87 VTEs
recorded in total (39 PE and 48 DVT). Of the
patients recording VTE, 46 had BMI C 30 kg/m2
(IR = 1.07). There were 130 patients (IR = 1.23)
with malignancies (including respiratory,
breast, gastrointestinal, reproductive, skin,
renal and urinary, lymphomas, and endocrine
neoplasms), 55 of whom were smokers
(IR = 2.01). Serious infection was reported in
297 patients (IR = 2.95), 113 of whom
were C 65 years (IR = 5.49). Mortality was
observed in 83 patients (IR = 0.78), 44 of whom
were C 65 years (IR = 1.97). The majority
([90%) of AESI were observed in patients with
at least one risk factor, but many patients with
an event (60–70%) had two or more risk factors.
The most common risk factors in this group
were hypertension and BMI C 30 kg/m2. Details
on the safety in the all-bari-RA population have
been previously published [29].
Approximately 48% (n = 1263) of the allbari-AD dataset had low risk (Fig. 1). The IR for
AESI in this population were in general lower
compared to RA, reflecting different baseline
risk [28]. In this low-risk population, 1 patient
(0.1%, IR = 0.04) reported MACE: a female
patient of 39 years who had a haemorrhagic
stroke due to a ruptured cerebral aneurysm and
hence was not related to a thromboembolic
process. Malignancy was reported for 3 patients
(0.2%, IR = 0.13), 2 of whom had lymphoma
and 1 had testis cancer. Serious infection was
reported in 27 low-risk patients (2.1%,
IR = 1.18) compared with 82 patients (3.1%,
IR = 1.8) in the all-bari-AD population (Fig. 1).
There were no deaths in the low-risk AD patient
group.
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Table 1 Proportion of patients with each of the specified risk factors at baseline from RCT
RA
N 5 3770, PYR 5 14,744
AD
N 5 2636, PYR 5 4628
AA
N 5 1303, PYR 5 1868
ASCVD
119 (3.2)
25 (0.9)
12 (0.9)
Current smoker
603 (16.0)
634 (24.1)
222 (17.0)
Hypertension
1348 (35.8)
349 (13.2)
145 (11.1)
HDL \ 40 mg/dL
308 (8.2)
360 (13.7)
116 (8.9)
Diabetes mellitus
335 (8.9)
71 (2.7)
40 (3.1)
632 (16.8)
101 (3.8)
6 (0.5)
1100 (29.2)
496 (18.8)
266 (20.4)
52 (1.4)
27 (1.0)
17 (1.3)
468 (12.4)
51 (1.9)
4 (0.3)
2619 (69.5)
1373 (52.1)
659 (50.6)
C 65 years
a
BMI C 30 kg/m2
History of malignancy
Severe mobility impairment (EQ-5D)
Any of 9 risk factors
c
b
Data are n (%)
AA alopecia areata; AD atopic dermatitis; ASCVD atherosclerotic cardiovascular disease; BMI body mass index; CV cardiovascular; EQ-5D
EuroQol-5 dimension; HDL high-density lipoprotein; MACE major adverse cerebrocardiovascular event; MI myocardial infarction; N number of
patients in analysis population; n number of patients in the specified category; PYR patient-years of exposure for risk; RA rheumatoid arthritis
a
The age of participants in AA clinical trials was limited to 60 years or younger for males and 70 years or younger for females to reduce
concomitant androgenic alopecia
b
Severe mobility impairment indicated by a response of either ‘I have severe problems in walking about’ or ‘I am unable to walk about’
c
ASCVD, current or past smoking (past smoking was not systematically documented in all trials), hypertension, HDL cholesterol \ 40 mg/dL,
diabetes mellitus, age 65 years or older, BMI 30 kg/m2, history of malignancy, and severe mobility impairment at EQ-5D baseline
In the at-risk AD population (52%,
n = 1373), 6 patients (IR = 0.25) reported
MACE, all of whom presented at least one predefined risk factor (Fig. 1). The 3 patients who
had an MI (IR = 0.06) all had cardiovascular risk
factors at the start of baricitinib treatment.
Malignancy was reported in 11 at-risk patients
(0.8%, IR = 0.45), 5 of whom were 65 years or
older, were current smokers, or both, while the
remaining 6 patients had another of the specified risk factors. Two of these at-risk patients
had lung cancer; both were older than 65 years
and were current or past smokers. A total of 55
of the 82 (67.1%) cases of serious infection in
the all-bari-AD dataset were reported in at-risk
patients, and included infections associated
with AD, such as cellulitis, eczema herpeticum,
and erysipelas, as well as pneumonia, sepsis,
and COVID-19. None of the infections were
fatal. The 4 deaths (IR = 0.16) reported in the
all-bari-AD dataset were at-risk patients who
had presented with at least one of the predefined risk factors. Two of the 4 patients were at
least 65 years of age, 2 had a history of hypertension, and 3 were current smokers.
In the all-bari-AD dataset, 3 of 2561 patients
(0.1%, IR = 0.06) reported a VTE, all of which
were PE. All patients were younger than 65 years
and had none of the predefined risk factors.
However, both female patients who had a VTE
were taking hormonal contraception (as were
approximately 30% of female patients in the allbari-AD dataset that did not have VTEs). These
patients also had other risk factors, including 1
past smoker and 1 with no specified risk factor
but with family history of coagulation disorder.
There were no fatal VTEs. The majority
(67–100%) of AESI were observed in patients
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Fig. 1 Overview of occurrence of events of special interest
in patients younger than 65 years without risk factors (lowrisk) versus patients above 65 years and at least one prespecified risk factor (at-risk) in integrated baricitinib
clinical study datasets. A Number of patients in each risk
group recording events of interest. B Incidence rate of
events of interest per 100 patient-years of exposure for risk
in each risk group. Abbreviations: AA alopecia areata; AD
atopic dermatitis; BMI body mass index; CI confidence
interval; EQ-5D EuroQol-5 dimension; HDL high-density
lipoprotein; MACE major adverse cardiovascular event;
MI myocardial infarction; N number of patients in the
safety analysis set; n number of patients in the specified
category; PYE patient-years of exposure; RA rheumatoid
arthritis; VTE venous thromboembolic event. aFor MACE
and MI in all-bari-RA: patients with low risk, n = 909;
patients at-risk, n = 2342. For MACE, MI, and VTE in
all-bari-AD: patients with low risk, n = 1231; patients atrisk, n = 1330. bExcluding non-melanoma skin cancer.
c
Patients
without
risk
factors
and\65 years.
d
Patients C 65 years or with at least one of the following
risk factors: atherosclerotic cardiovascular disease, diabetes
mellitus, hypertension, current smoking (past smoking was
not systematically documented in all trials),
HDL\40 mg/dL, BMI C 30 kg/m2, poor mobility on
EQ-5D, and history of malignancy. Also including factors
only documented in case narrative, such as past smoking
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with at least one risk factor, but many patients
with an event (31–75%) had two or more risk
factors. The most common risk factors in this
group were smoking and BMI C 30 kg/m2. Even
among this at-risk population, the IRs fall
within, or below, the expected range for
patients with AD.
In the all-bari-AA dataset, approximately
49% (n = 644) of the population is low risk for
AESI (Fig. 1). There were 6 cases of serious
infection reported in this group (IR = 0.62). No
other AESI were reported.
The majority of the AESI in the all-bari-AA
dataset were reported for at-risk patients (51%,
n = 659). The single patient with MACE (MI)
(IR = 0.10) had multiple cardiovascular risk
factors at the start of the baricitinib treatment.
All the patients with malignancy (excluding
NMSC) had at least one risk factor; there was no
patient with lung cancer. The patient with VTE
(IR = 0.10) had BMI C 30 kg/m2 and experienced a PE temporally associated with COVID19 pneumonia; coagulation tests revealed a
prothrombin gene heterozygosity that may
impart an approximately threefold increased
risk of VTE. The IR of serious infections (0.8)
was clearly lower than in RA (2.6) and AD (1.8),
and there were no deaths. The most common
risk factors in this at-risk population were
BMI C 30 kg/m2 and smoking. Even among this
at-risk population, the IRs fall within, or below,
the expected range for a population in this age
category. Details on the safety in the all-bari-AA
population have been previously published
[31].
DISCUSSION
In this analysis of data from the baricitinib
clinical trial programme for RA, AD, and AA,
patients who were younger than 65 years and
without any of the risk factors pre-specified had
relatively low incidence of the AESI examined,
particularly compared with the incidence
reported in literature for these patient populations. In the dermatologic indications, the
incidence of AESI is also low for patients aged
65 years or older or with another of the eight
specified risk factors; however, the incidence of
AESI for patients at risk with RA is increased in
comparison with the patients with low risk.
Patients with inflammatory diseases such as
RA often have many comorbidities. Systemic
inflammation with increased proinflammatory
mediators and endothelium damage leads to
accelerated atherosclerosis in RA and to some
degree for AD [11, 36]. Endothelial injury
and hypercoagulability due to chronic inflammation contributes to double risk of VTE in RA
when compared with age- and sex-matched
controls [37]. Early and adequate treatment of
inflammatory conditions can lower the incidence of these comorbidities by halting systemic inflammation. In a randomised trial, a
treat-to-target approach of patients with RA and
cardiovascular disease risk factors led to reduced
subclinical and clinical atherosclerosis compared to usual care of cardiovascular disease
[38], and can also reduce the burden of associated comorbidities and normalise survival [39].
Specifically for cardiovascular risk, long-lasting
disease, seropositivity, and presence of extraarticular manifestations multiply independent
risk of MACE by 1.5-fold [40]. Risk of VTE has
been associated with RA disease activity, and in
ORAL Surveillance, the risks of MACE, VTE, and
non-serious infections excluding herpes zoster
were higher in patients with active disease than
when in remission, confirming that disease
control is critical to prevent adverse events [27].
Among patients with RA, the risk (and risk ratio)
increased with increasing RA disease activity,
from 0.52% following visits in DAS28 ESR
remission to 1.08% in another study following
visits with DAS28 ESR high disease activity [41].
However, different anti-inflammatory agents
and immune modulators may be linked with
different AESI. Many efforts have been made to
characterise the risk of AEs with different treatments through both clinical trials and observational studies. The recent randomised study of
patients with RA aged 50 years or older enriched
for cardiovascular risk factors, ORAL Surveillance, reported a small increased risk of MACE
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and malignancy, which did not meet non-inferiority criteria, as well as higher incidences of
serious infection, VTE, and all-cause mortality
in patients being treated with tofacitinib compared with TNFi-treated patients [27]. This
trend towards increase in MACE, although not
significant, was also observed in a similar population of patients aged 50 years or older with
cardiovascular risk factors receiving tofacitinib
compared with TNFi analysed from routine care
data, but not in the overall RA population
treated with tofacitinib in routine care compared with those who received TNFi [42]. The
AESI for JAKi, mainly MACEs, VTEs, and
malignancies, are most predominant in the RA
clinical programme, although these are still
uncommon in general, particularly in patients
with no risk factors.
MACE in the Baricitinib RA Clinical
Programme
In the baricitinib long-term clinical trial dataset,
over 60% of patients with RA treated with
baricitinib who recorded AESI had at least two
risk factors, the most common of which were
hypertension and BMI of at least 30 kg/m2.
These risk factors are not only easily identifiable
in this patient population but can be managed
to minimise the risk of AESI in these patients.
The proportion of patients with RA at risk,
specifically those with long-established disease,
was higher than for AD and AA, where the AESI
were much lower for both the low-risk and atrisk populations.
The IR of MACE in the baricitinib clinical
data for the at-risk RA subpopulation
of C 65 years old with at least one risk factor was
0.70 per 100 PY and much lower for the RA lowrisk population, 0.05 per 100 PY. Both fall
within the expected IR of MACE in patients
with RA reported in real-world settings
(0.27–3.2 per 100 PY) [28]. A retrospective
observational study pooling data from disease
registries and claims databases, with the French
SNDS and Swedish ARTIS data sources contributing the most patients, has investigated the
safety of baricitinib compared with TNFi in a
matched RA population based on propensity
scores for confounding factors. The study
showed a numerically, but not significantly,
greater risk of MACE in patients receiving
baricitinib (incidence rate ratio 1.54, 95% CI
0.93–2.54; incidence rate difference 0.22, 95%
CI - 0.07 to 0.52 per 100 PY) [43]. Recently,
Hoisnard et al., using data from SNDS after
inverse propensity score treatment weighting,
showed that there was no difference in risk of
MACE (or VTE) between patients initiating a
JAKi (60% baricitinib, 40% tofacitinib) and initiating the TNFi adalimumab. A subgroup
analysis of patients aged 65 years or older, and
with at least one risk factor for cardiovascular
disease, also found no evidence of a difference
in risk between the JAKi and adalimumab
cohorts [44]. Further contextualization of these
observational cohort studies with respect to
ORAL Surveillance is hard to elucidate due to
different study designs and endpoints (Cox
model and time to event vs. incidence rates, as
well as length of follow-up and methods of
addressing confounding factors through
propensity scores vs. inverse probabilities).
MACE in the Baricitinib AD and AA
Clinical Programmes
For the baricitinib clinical programme in
patients with AD, IR for MACE in the at-risk
subpopulation (0.25 per 100 PY) lies within the
expected rates for the AD patient population
reported in real-world settings (IR of 0.15–0.63
per 100 PY), with the low-risk AD baricitinib
clinical population having a much lower IR
(0.04) [28]. The IRs for patients with AA in the
baricitinib clinical studies (subpopulation atrisk and low-risk, 0.10 and 0 per 100 PY,
respectively) are the lowest of those observed in
the baricitinib studies, and reflect that the
general population of patients with AA do not
have an increase in risk of MACE.
VTE in the Baricitinib RA Clinical
Programme
For VTEs, the IR in the baricitinib clinical programme for the at-risk RA subgroup (0.66 per
100 PY) falls within the expected IR reported in
Adv Ther
the literature for patients with RA of 0.33–0.79
per 100 PY, with a minimal IR in the low-risk
patient population from the baricitinib studies
(0.09 per 100 PY). However, a recent study using
data from the Swedish Rheumatology Quality
Register found a higher incidence of VTE in
patients receiving JAKi (IR = 11.33 per 1000 PY)
compared with both TNFi (IR = 5.15) and the
general RA population (IR = 5.86) [45]. Similarly, Salinas et al. found increased risk of VTE
with baricitinib versus TNFi (incidence rate
ratio 1.51, 95% CI 1.10–2.08; incidence rate
difference 0.26, 95% CI - 0.04 to 0.57 per 100
PY) [43]. However, Salinas et al. made no
adjustment based on previous treatment failures or disease activity, nor carried out any
analysis on patient subpopulations with or
without relevant risk factors. As highlighted
before, Hoisnard et al. did not show differences
for VTEs in patients treated with JAKi compared
with those who received adalimumab using
SNDS data, including in a subpopulation similar
to the at-risk population of the baricitinib
studies presented here (aged 65 years or older
with at least one risk factor for cardiovascular
disease) [44]. The occurrence of VTE in at-risk
patients who received baricitinib treatment in
the RA clinical programme is thus associated
with previously identified independent VTE risk
factors, such as previous VTE, older age, obesity,
malignancy, and immobility [46]. The risk of
VTE is reflected in the current SmPC for baricitinib due to an imbalance in observed events
during the placebo-controlled period of RA
Phase 3 studies [29].
VTE in the Baricitinib AD and AA Clinical
Programmes
In the baricitinib AD and AA clinical trial programmes, the IRs of VTE in at-risk baricitinib
treatment groups were low (IR of 0.08 and 0.10
per 100 PY, respectively), as expected due to the
younger age and lower vulnerability of these
study populations, both in the clinical studies
and the general populations of patients with
these conditions. These are in line with, or
below, the background IR of 0.18–0.24 per 100
PY in patients with AD and 0.09 per 100 PY in
patients with AA. Although 2 of the patients
with VTE in the AD population were receiving
hormonal contraception, overall approximately
30% of female patients were taking hormonal
contraceptives during these studies. A risk factor
analysis performed on data from the baricitinib
RA clinical programme did not identify oral
contraceptive use as an independent risk factor
in RA [46]. This analysis was not performed for
the AD baricitinib data due to the low number
of events.
Malignancy in the Baricitinib RA, AD,
and AA Clinical Programmes
In this analysis of the baricitinib clinical trial
programmes, the IR of malignancies excluding
NMSC in the LTE at-risk RA population was 1.23
per 100 PY, which is slightly elevated compared
to the all-bari-RA population (IR = 0.92 per 100
PY). When comparing the all-bari-RA population to the expected number of malignancies
based on SEER17 data, the age-adjusted standardised IR was 1.07 (95% CI 0.90–1.26) [29],
suggesting a modest increase in incidence for
these at-risk patients. The IR of malignancies
excluding NMSC in the at-risk group in AD
(0.45) and AA (0.31) baricitinib clinical trials
appear to be at the lower end of the reported IR
in these disease populations (AD: 0.33–0.85 per
100 PY [47, 48]; and AA: 0.37–0.43 per 100 PY
[20]).
Mortality in the Baricitinib RA, AD,
and AA Clinical Programmes
The mortality rate for the baricitinib LTE at-risk
RA subpopulation (0.78) is lower than expected
when compared with the general population
calculated from the SEER incidence distribution
(2013–2017) (83 observed deaths vs. 105.9
expected) [32]. IRs of mortality for baricitinib
at-risk groups in AD and AA clinical studies are
low (0.16 and 0, respectively) and in line with
the younger age and lower vulnerability of these
study populations.
Adv Ther
Contextualisation and Clinical
Recommendations
The risk factors presented in this analysis are
those relevant for the adverse events of special
interest investigated, as determined by the recommendation of the safety committee of the
European Medicines Agency (EMA) following
the results of the ORAL Surveillance study to use
JAK inhibitors in the following patients only if
no suitable treatment alternatives are available:
those aged 65 years or above, those at increased
risk of major cardiovascular problems (such as
heart attack or stroke), those who smoke or
have done so for a long time in the past, and
those at increased risk of cancer [49]. The
Committee also recommended using JAK inhibitors with caution in patients with risk factors
for blood clots in the lungs and in deep veins
(VTE). The cardiovascular risk factors included
in our analysis were chosen to reflect the entry
criteria for the ORAL Surveillance study [27]:
risk of VTE is linked to older age, increased BMI
[50], and immobility, represented by the surrogate factor of poor mobility on EQ-5D, while
risk of cancer was determined by age, history of
malignancy, and smoking status as the most
reliable predictive factors for cancer risk.
Per recent recommendations from committees of the EMA [Pharmacovigilance Risk
Assessment Committee (PRAC) and Committee
for Medicinal Products for Human Use
(CHMP)], the benefit–risk profile of baricitinib
for patients with no risk factors remains positive
for patients with RA, AD, and AA who have
responded inadequately to, or who are intolerant to, cDMARDs [51, 52] or topical treatments
[53]. For patients at risk for AESI, benefit–risk
shared decision-making discussions should be
taken into consideration by the prescriber to
evaluate use of baricitinib if no other suitable alternatives are available. Further, PRAC
and CHMP recommend the doses of JAK inhibitors should, where possible, be reduced in
patient groups who are at risk of VTE, cancer, or
major cardiovascular problems [49]. Based on
available data across indications for baricitinib,
including randomised controlled trials, LTE,
and real-world evidence data, a clinically relevant or consistent dose-dependent response
with a higher risk for the 4 mg versus the 2 mg
dose has not been observed for AESI, except for
infections, including herpes zoster, nor for VTE,
for which an imbalance between doses was
observed during the placebo-controlled period
of RA trials [46].
EULAR have recently proposed an updated
approach for the management of RA with targeted synthetic disease-modifying antirheumatic drugs (tsDMARDs) and biological
DMARDs (bDMARDs), aligned with previous
EULAR recommendations in which JAKi remain
on the same level as bDMARDs and can be used
after conventional DMARD failure in patients
who do not have risk factors for cardiovascular
disease, VTE, or malignant diseases [54]. EULAR
emphasises the importance of shared decisionmaking, and that, when making recommendations, clinicians give careful consideration to
specific risk factors of relevance for the individual patient before initiating JAKi. There are
many precedents for the success of mitigation
strategies to prevent treatment-associated risks
in the case of biologic therapies: for example,
screening for latent tuberculosis and hepatitis,
cardiac failure, and demyelination risks [55–57].
Furthermore, regardless of medication, RA
management recommendations emphasise the
importance of careful screening and management of cardiovascular, infection, and malignancy risks [40]. The contribution of specific
risk factors to each of these AESIs remains to be
further elucidated. However, all of these known
risk factors can be identified in routine clinical
practice, and therefore health-care providers
should follow established guidelines to manage
cardiovascular risk, screen for malignancies, and
vaccinate patients, as for any other patients
with
immune-mediated
inflammatory
conditions.
For AD, it is recommended to limit systemic
corticosteroids to use only for 1–2 weeks for
severe acute exacerbations, due to the largely
unfavourable risk–benefit ratio [58, 59]. Treatment duration with cyclosporine, the first-line
systemic option for patients with severe disease,
usually varies from 3 months to 1 year due to
poor drug survival [58, 59]. Long-term use of
cyclosporine is associated with multiple risks,
including
hyperlipidaemia,
hypertension,
Adv Ther
kidney toxicity, and malignancy. Therefore, it is
important to provide access to treatments with
a better long-term benefit–risk balance, including dupilumab and JAKi indicated for AD
[60, 61]. Baricitinib has been shown in clinical
trials to have fast onset of action, especially on
the most limiting AD symptom itch, which is
also recognised in the recently published EuroGuiDerm 2022 guideline on atopic eczema
(atopic dermatitis) [59], and has been shown to
be effective on AD signs and other symptoms,
such as skin pain and sleep, leading to an
overall improved quality of life [62–64]. This
treatment algorithm is recommended by the
European Guidelines for Treatment of AD, who
recommend dupilumab and baricitinib with the
same level of evidence ‘‘in atopic eczema
patients who are candidates for systemic treatment’’, while recommending against the longterm use of systemic glucocorticosteroids [59].
In most geographies, for patients with severe
AA, there is no licensed treatment alternative to
baricitinib. In the baricitinib AA clinical trials,
baricitinib treatment demonstrated significant
hair regrowth of scalp, eyebrows, and eyelashes
compared to placebo up to 36 weeks [35].
Approximately half of the population in the
baricitinib AA clinical programme are younger
than 65 years, have no cardiovascular or
thrombotic risk factors, and have limited risk of
malignancy or infection. Published population
risks for AA differ from the published background risks for the RA population. For example, in a retrospective cohort study, AA was not
associated with an increased risk of heart disease
[18]. Additionally, a study involving a heterogeneous AA population in the US found that AA
was not associated with an increased risk of
stroke and MI [65].
CONCLUSIONS
Using data derived from integrated clinical trial
safety datasets of baricitinib for RA, AD, and AA,
we observed a low IR of MACE, MI, lung cancer,
VTE, and overall mortality in patients younger
than 65 years without risk factors. Incidence of
overall malignancy and serious infections in
patients younger than 65 years without risk
factors were reduced compared with the population of patients with risk factors. Even for
patients with risk factors, the numbers of AESI
are minimal for AD and AA. This raises the
question of whether it is clinically useful to
extrapolate the risk factors identified in RA
patients to AD and AA patient populations.
Risk factors established for the RA population are identifiable through health screening;
thus, the physician and patient can make a
decision on the appropriateness and acceptability of initiation or continuation of treatment with baricitinib, taking into account the
particularities of the individual disease burden,
risk factors, and response to treatment.
ACKNOWLEDGEMENTS
Eli Lilly and Company would like to thank the
clinical trial participants and their caregivers,
without whom this work would not be possible.
Funding. Sponsorship for this study and its
publication, including the journal’s Rapid Service Fee, were funded by Eli Lilly and Company.
Medical Writing, Editorial, and Other
Assistance. Medical writing support was provided by Catherine Lynch, PhD, a full-time
employee of Eli Lilly and Company.
Author Contributions. Peter C. Taylor,
Thomas Bieber, Rieke Alten, Torsten Witte,
James Galloway, Walter Deberdt, Maher Issa,
Ewa Haladyj, Inmaculada De La Torre, Susanne
Grond, and Andreas Wollenberg contributed to
the study conception and design. Material
preparation, data collection and analysis were
performed by Walter Deberdt and Maher Issa.
The first draft of the manuscript was written by
Inmaculada De La Torre and all authors commented on previous versions of the manuscript.
All authors read and approved the final
manuscript.
Prior Presentation. These data were previously presented in part at the European Academy of Dermatology and Venereology (EADV)
Adv Ther
Congress; Milan, Italy; 7–10 September 2022
(Bieber T, et al. EADV 2022. Safety of baricitinib
for the treatment of atopic dermatitis over a
median of 1.6 and up to 3.9 years treatment: an
updated integrated analysis of 8 clinical trials.
FC03.03).
Disclosures. Peter C. Taylor has been a consultant for or has received grant/research support from AbbVie, Biogen, Celgene, Eli Lilly and
Company, Galapagos NV, Gilead Sciences,
GlaxoSmithKline, Janssen, Novartis, Pfizer,
Sandoz, and UCB Pharma.
Thomas Bieber was speaker or consultant or
Investigator for AbbVie, Affibody, Allmiral,
AnaptysBio, Arena, Asana Biosciences, ASLAN
pharma, Bayer Health, BioVerSys, BöhringerIngelheim, Bristol-Myers Squibb, Connect Pharma, Dermavant, Domain Therapeutics, EQRx,
Eli Lilly and Company, Galderma, Glenmark,
GSK, Incyte, Innovaderm, IQVIA, Janssen, Kirin, Kymab, LEO, LG Chem, LOréal, MSD,
Novartis, Numab, OM-Pharma, Pfizer, Pierre
Fabre, Q32bio, RAPT, Sanofi/Regeneron, UCB.
He is founder and chairman of the board of the
non-profit biotech ‘‘Davos Biosciences’’.
Rieke Alten has been a consultant for or
received grant or research support from AbbVie,
Bristol Myers Squibb, Celltrion, Chugai, Eli Lilly
and Company, Galapagos NV, Gilead Sciences,
Janssen, Novartis, Pfizer, Roche, and UCB
Pharma.
Torsten Witte has received grant/research support or received honoraria or support for
attending meetings or participated on a data
safety monitoring board or advisory board for
AbbVie, Chugai, Eli Lilly and Company, Galapagos, Medac, Janssen, Novartis, Pfizer, Roche,
and UCB Pharma.
James Galloway has been a consultant for or
has received grant/research support or received
honoraria from AbbVie, Eli Lilly and Company,
Galapagos, and Pfizer.
Walter Deberdt, Maher Issa, Ewa Haladyj,
Inmaculada De La Torre, and Susanne Grond
are employees and shareholders of Eli Lilly and
Company.
Andreas Wollenberg has served as an advisor or
paid speaker for or participated in clinical trials
sponsored by AbbVie, Almirall, Amgen, Beiers-
dorf, Bioderma, Boehringer Ingelheim, Bristol
Myers Squibb, Celgene, Chugai, Eli Lilly and
Company, Galapagos, Galderma, Glenmark,
Janssen-Cilag, L’Oreal, LEO Pharma, Maruho,
MedImmune/AstraZeneca, Merck, Novartis, Pfizer, Pierre Fabre, Regeneron, Sanofi-Aventis/
Genzyme, and UCB.
Compliance with Ethics Guidelines. All
studies were conducted in accordance with
ethical principles of the Declaration of Helsinki
and Good Clinical Practice guidelines, and the
research protocols were approved by each centre’s institutional review board or ethics committee. All patients provided written informed
consent.
Data Availability. Lilly provides access to
all individual participant data collected during
the trial, after anonymization, with the exception of pharmacokinetic or genetic data. Data
are available to request 6 months after the
indication studied has been approved in the US
and EU and after primary publication acceptance, whichever is later. No expiration date of
data requests is currently set once data are made
available. Access is provided after a proposal has
been approved by an independent review committee identified for this purpose and after
receipt of a signed data sharing agreement. Data
and documents, including the study protocol,
statistical analysis plan, clinical study report,
blank or annotated case report forms, will be
provided in a secure data sharing environment.
For details on submitting a request, see the
instructions provided at www.vivli.org.
Open Access. This article is licensed under a
Creative Commons Attribution-NonCommercial 4.0 International License, which permits
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to the original author(s) and the source, provide
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licence, unless indicated otherwise in a credit
line to the material. If material is not included
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regulation or exceeds the permitted use, you
will need to obtain permission directly from the
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visit http://creativecommons.org/licenses/bync/4.0/.
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