Articles
Efficacy and safety of upadacitinib maintenance therapy
Lancet Gastroenterol Hepatol
2023; 8: 976–89
Published Online
September 5, 2023
https://doi.org/10.1016/
S2468-1253(23)00208-X
This online publication has
been corrected. The corrected
version first appeared at
thelancet.com/gastrohep on
October 1 1, 2023
See Comment page 956
Department of
Gastroenterology &
Hepatology, University
Hospital Leuven, Leuven,
Belgium (Prof S Vermeire MD);
Gastroenterology and
Endoscopy, IRCCS Ospedale
San Raffaele and University
Vita-Salute San Raffaele, Milan,
Italy (Prof S Danese MD);
AbbVie, North Chicago, IL, USA
(W Zhou MD, D Ilo MBBS,
J Klaff MD, G Levy MD, X Yao PhD,
S Chen PhD,
Y Sanchez Gonzalez PhD);
Department of
Gastroenterology and Clinical
Nutrition, CHU de Nice,
Université Côte d’Azur, Nice,
France (Prof X Hébuterne MD);
Department of
Gastroenterology, The Royal
London Hospital, Barts Health
NHS Trust, London, UK
(Prof J O Lindsay FRCP);
Department of Internal
Medicine, Division of
Gastroenterology, University
of Michigan, Ann Arbor, MI,
USA (Prof P D R Higgins MD);
Department of
Gastroenterology,
Sir Run Shaw Hospital,
Zhejiang University School of
Medicine, Hangzhou, China
(Prof Q Cao MD); Department
of Gastroenterology and
Hepatology, Sapporo Medical
976
for moderately to severely active ulcerative colitis in
patients responding to 8 week induction therapy
(U-ACHIEVE Maintenance): overall results from the
randomised, placebo-controlled, double-blind, phase 3
maintenance study
Séverine Vermeire, Silvio Danese, Wen Zhou, Dapo Ilo, Justin Klaff, Gweneth Levy, Xuan Yao, Su Chen, Yuri Sanchez Gonzalez, Xavier Hébuterne,
James O Lindsay, Peter D R Higgins, Qian Cao, Hiroshi Nakase, Jean-Frédéric Colombel, Edward V Loftus Jr, Remo Panaccione
Summary
Background Upadacitinib is an oral, selective, and reversible JAK inhibitor with demonstrated efficacy in patients with
moderately to severely active ulcerative colitis in a phase 2b induction trial, two phase 3 induction trials (U-ACHIEVE
Induction and U-ACCOMPLISH), and a primary analysis of the first 451 patients entering a subsequent maintenance
trial (U-ACHIEVE Maintenance). Here, we present overall results from the entire U-ACHIEVE Maintenance
population.
Methods In this randomised, placebo-controlled, double-blind, phase 3 maintenance study done across Europe,
North and South America, Australasia, Africa, and the Asia-Pacific region at 251 clinical centres in 44 countries,
patients aged 16–75 years with moderately to severely active ulcerative colitis (adapted Mayo score 5–9, centrally
assessed endoscopic subscore of 2 or 3) for 90 days or more were randomly assigned (2:1) to double-blind
upadacitinib 45 mg once daily or placebo induction therapy in the phase 2b induction trial or two phase 3 induction
trials. Patients with a clinical response per adapted Mayo score after 8 weeks were randomly reassigned (1:1:1)
using web-based interactive response technology to 52 week double-blind maintenance therapy with placebo,
upadacitinib 15 mg, or upadacitinib 30 mg once daily. Efficacy was analysed at week 52 in the intention-to-treat
population, which included all patients randomly reassigned who received at least one dose of study drug. The
primary endpoint was clinical remission per adapted Mayo score. Safety through week 52 was assessed with
exposure-adjusted event rates (EAERs; events per 100 patient-years) in upadacitinib 45 mg once daily 8-week
induction responders who were enrolled per protocol for 44-week or 52-week maintenance therapy (ie, the
intention-to-treat population plus patients who received up to 44 weeks’ maintenance therapy under earlier protocol
amendments) and received at least one dose of study drug. The study is registered with ClinicalTrials.gov,
NCT02819635 and is complete.
Findings Between Sept 3, 2016, and Jan 14, 2021 987 patients received the upadacitinib 45 mg once daily induction
therapy in the phase 2b trial, U-ACHIEVE Induction, or U-ACCOMPLISH. 681 patients with a clinical response to
the induction therapy (319 from U-ACHIEVE Induction, 341 from U-ACCOMPLISH, and 21 from the phase 2b
induction trial) received placebo (n=223), upadacitinib 15 mg once daily (n=225), or upadacitinib 30 mg once daily
(n=233) in U-ACHIEVE Maintenance and were included in this analysis. A greater proportion of patients achieved
the primary endpoint with upadacitinib 15 mg (40·4%) and 30 mg once daily (53·6%) versus placebo (10·8%;
both p<0·0001 vs placebo). For safety, 746 patients were analysed, representing 552·9 patient-years of exposure; the
most common grade 3–4 treatment-emergent adverse events were worsening of ulcerative colitis in nine (4%) patients
with placebo, and COVID-19 pneumonia and cryptococcal pneumonia in two (1%) patients each with upadacitinib
30 mg once daily. Higher EAERs of the following treatment-emergent events of special interest were observed with
upadacitinib versus placebo: herpes zoster (6·0 events per 100 patient-years with upadacitinib 15 mg once daily and
7·3 events per 100 patient-years with upadacitinib 30 mg once daily vs none per 100 patient-years with placebo
[12 and 16 vs no events, respectively), hepatic disorders (17·0 and 9·2 vs 5·9 events per 100 patient-years
[34 and 20 vs eight events, respectively), creatine phosphokinase elevation (8·0 and 10·1 vs 3·7 events per 100 patient-
years [16 and 22 vs five events], respectively), and neutropenia (5·5 and 8·7 vs 5·2 events per 100 patient-years
[11 and 19 vs seven events], respectively). One (<1% of patients) adjudicated major adverse cardiovascular event
occurred with placebo and one (<1% of patients) with upadacitinib 30 mg once daily (EAERs 0·7 and 0·5 events per
100 patient-years, respectively). Two (1% of patients) venous thromboembolic events occurred with upadacitinib
15 mg once daily and two (1% of patients) with upadacitinib 30 mg once daily (EAERs 1·0 and 0·9 events per
www.thelancet.com/gastrohep Vol 8 November 2023
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100 patient-years, respectively). All adjudicated major adverse cardiovascular events and venous thromboembolic University School of Medicine,
events with upadacitinib occurred in patients with relevant known risk factors. Sapporo, Japan
(Prof H Nakase MD); Icahn
School of Medicine at
Interpretation Consistent with the primary analysis done among a smaller population, both maintenance doses of Mount Sinai, New York, NY,
upadacitinib showed a positive benefit–risk profile in patients with moderately to severely active ulcerative colitis. USA (Prof J-F Colombel MD);
Upadacitinib represents an effective treatment option for this population, for whom a large unmet need persists. Division of Gastroenterology
and Hepatology, Mayo Clinic
College of Medicine and
Funding AbbVie. Science, Rochester, Minnesota,
USA (Prof E V Loftus Jr MD);
Copyright © 2023 Elsevier Ltd. All rights reserved. Division of Gastroenterology
and Hepatology, University of
Calgary, Calgary, Alberta,
Introduction and was well tolerated.4 Patients in U-ACHIEVE Canada (Prof R Panaccione MD)
Ulcerative colitis is a chronic, idiopathic, relapsing, and Induction, U-ACCOMPLISH, or a phase 2b dose-ranging Correspondence to:
remitting inflammatory bowel disease that results in induction trial (NCT02819635),5 with a clinical response Prof Séverine Vermeire,
mucosal inflammation, which typically extends from the (per adapted Mayo score) after 8 weeks of upadacitinib Department of Gastroenterology
& Hepatology, University
rectum to the proximal colon.1 The estimated incidence 45 mg once daily induction therapy were eligible to be Hospital Leuven, Leuven,
of ulcerative colitis is 1·9–17·2 per 100 000 person-years reassigned randomly to receive 52 weeks of upadacitinib Belgium
in western Europe and 8·8–23·1 per 100 000 person- 15 mg once daily, upadacitinib 30 mg once daily, or severine.vermeire@uzleuven.be
years in North America.2 Hallmark symptoms of placebo maintenance therapy in the U-ACHIEVE
ulcerative colitis include bloody diarrhoea, faecal urgency, Maintenance study (NTC02819635). A prespecified
and abdominal discomfort, which have a substantial primary analysis of the first 8-week induction responders
effect on patients’ quality of life.1 (n=451) who subsequently entered the U-ACHIEVE
Upadacitinib is an oral, selective, and reversible JAK Maintenance study found that upadacitinib 15 mg and
inhibitor.3 In two identical, double-blind, randomised upadacitinib 30 mg once daily showed greater efficacy
clinical trials (U-ACHIEVE Induction [NCT02819635] versus placebo after 52 weeks’ maintenance therapy
and U-ACCOMPLISH [NCT03653026]) of patients with across clinical, endoscopic, histological, and quality of
moderately to severely active ulcerative colitis and an life endpoints, and was well tolerated.4 On the basis of
inadequate response, loss of response, or intolerance to the results of these trials, upadacitinib has been approved
conventional or biological therapy, 8 weeks’ double- for the treatment of adults with moderately to severely
blind induction therapy with upadacitinib 45 mg once active ulcerative colitis in numerous countries.3,6
daily led to a significantly greater proportion of patients Here, we present an updated and final analysis of
achieving clinical remission at week 8 versus placebo, efficacy and safety data from the U-ACHIEVE Maintenance

Research in context
Evidence before this study patients receiving upadacitinib 15 mg once daily or upadacitinib
Upadacitinib is a JAK inhibitor approved for the treatment of 30 mg once daily achieved clinical remission at week 52 versus
moderately to severely active ulcerative colitis. Approval was placebo; both doses were also significantly more efficacious
based on two induction trials and a prespecified analysis of the versus placebo across all secondary clinical, endoscopic, and
first 8-week induction responders (n=451) who entered the histological endpoints. Upadacitinib was well tolerated, and
subsequent maintenance trial. In the induction trials, 8 weeks’ there were no new safety risks identified with upadacitinib
double-blind therapy with upadacitinib 45 mg once daily led to compared with the previous analysis, or other indications for
a significantly greater proportion of patients achieving the which upadacitinib is approved.
primary endpoint of clinical remission per adapted Mayo score
Implications of all the available evidence
at week 8 versus placebo. In the primary analysis of the
The overall results from the entire population enrolled in this
maintenance trial, upadacitinib 15 mg once daily and
phase 3 maintenance study show the favourable benefit–risk
upadacitinib 30 mg once daily showed greater efficacy versus
profile of upadacitinib in patients with moderately to severely
placebo after 52 weeks’ maintenance therapy for the primary
active ulcerative colitis. These results are consistent with
endpoint of clinical remission per adapted Mayo score, as well
those seen in the primary analysis and support the use of
as all assessed secondary clinical, endoscopic, and histological
upadacitinib as a therapeutic option in patients with
endpoints. Upadacitinib was well tolerated in both induction
moderately to severely active ulcerative colitis, for whom a
studies and the primary analysis of the maintenance study.
large unmet need persists.
Added value of this study
In this analysis of a larger population (n=681) than has been
previously analysed, a significantly greater proportion of

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Induction

8-week responders* 8-week responders* 8-week responders*

319 from U-ACHIEVE induction† 341 from U-ACCOMPLISH† 21 from phase 2b induction study

Maintenance

681 patients randomly assigned (1:1:1) in U-ACHIEVE

Maintenance intention-to-treat population‡

223 assigned to placebo 225 assigned to upadacitinib 233 assigned to upadacitinib

15 mg once daily 30 mg once daily

148 discontinued treatment 70 discontinued treatment 49 discontinued treatment

17 adverse events 5 adverse events 14 adverse events
3 withdrew consent 1 withdrew consent 4 withdrew consent
109 lack of efficacy 51 lack of efficacy 18 lack of efficacy
1 lost to follow-up 13 other reasons 1 lost to follow-up
18 other reasons 1 COVID-19 infection
1 COVID-19 logistical
restriction
10 other reasons

75 completed treatment 155 completed treatment 184 completed treatment

Figure 1: Patient disposition in U-ACHIEVE Maintenance

Patient numbers are given for the U-ACHIEVE Maintenance trial intention-to-treat population, defined as upadacitinib 45 mg once daily 8-week induction
responders who were enrolled per protocol for the 52-week maintenance period, and received ≥1 dose of study drug (placebo, upadacitinib 15 mg once daily, and
upadacitinib 30 mg once daily). Bio-IR=inadequate response, loss of response, or intolerance to ≥1 biologic. RBS=rectal bleeding subscore. RR=re-randomised.
*Clinical response was defined as a decrease from baseline in the adapted Mayo score ≥2 points and ≥30% from baseline, plus a decrease in RBS ≥1 or an absolute
RBS ≤1. †Includes patients who were initially randomly assigned to placebo for 8 weeks but did not achieve a clinical response at week 8 and were subsequently
treated with, and had a clinical response to, 8 weeks’ upadacitinib 45 mg once daily. ‡Re-randomisation was stratified by previous bio-IR status (bio-IR or non-bio-IR),
clinical remission status at week 0 of the maintenance trial (yes or no), and corticosteroid use at week 0 of the maintenance trial (yes or no).

study comprising all patients who had a clinical response
after 8 weeks of induction therapy with upadacitinib
45 mg once daily and were reassigned randomly to receive
maintenance therapy with upadacitinib 15 mg once daily,
upadacitinib 30 mg once daily, or placebo for up to
52 weeks in the maintenance phase. This represents a
larger population (n=681) than has been analysed
previously (n=451),4 and addresses whether the efficacy of
upadacitinib in the entire trial population is consistent
with that observed in the registrational analysis, as well as
whether there are any new safety signals with additional
upadacitinib exposure.
Methods
Study design and participants
Details of the study designs and methodology for the
phase 2b induction trial,5 the double-blind, randomised,
placebo-controlled, induction trials (U-ACHIEVE
Induction and U-ACCOMPLISH) and the maintenance
trial (U-ACHIEVE Maintenance) have been previously
published.4 This was a randomised, placebo-controlled,
double-blind, phase 3 maintenance study done across
Europe, North and South America, Australasia, Africa,
and the Asia-Pacific region at 1251 clinical centres in
44 countries. Briefly, patients eligible for induction were
aged 16–75 years with a confirmed diagnosis of ulcerative
colitis for at least 90 days before study entry, active
disease (defined as an adapted Mayo score of 5–9 and a
centrally assessed Mayo endoscopic subscore of 2 or 3),
and had inadequate response or were intolerant to at
least one oral aminosalicylate, corticosteroid, immuno­
suppressant, or biological therapy. Key exclusion criteria
included a diagnosis of Crohn’s disease or indeterminate
colitis, fulminant colitis, toxic megacolon, disease limited
to the rectum, active infection, or previous exposure to
JAK inhibitors. The study protocol, informed consent
forms, and recruitment materials were approved by the
relevant ethics committees or institutional review boards
of each country before enrolment. The studies were done
in accordance with the International Conference for
Harmonisation guidelines, Declaration of Helsinki,
Good Clinical Practice guidelines, and all applicable
regulations. All patients provided written informed
consent before screening.
Randomisation and masking
In part 1 of the phase 2b induction trial, patients were
randomly assigned 1:1:1:1:1 to receive oral placebo or
upadacitinib 7·5 mg, 15 mg, 30 mg, or 45 mg once
daily induction therapy for 8 weeks. In part 2,

978 www.thelancet.com/gastrohep Vol 8 November 2023


additional patients were randomly assigned 1:1 to oral
upadacitinib 15 mg once daily or 45 mg once daily.
Randomisation was stratified by previous biological
status (patients without inadequate response, loss of
response, or intolerance to a biologic [non-bio-IR] or
patients with inadequate response, loss of response, or
intolerance to at least one biologic [bio-IR], baseline
corticosteroid use (yes or no), and baseline adapted
Mayo score (≤7 and >7). Study investigators, study site
personnel, and patients were masked to treatment
allocation throughout the study.5 Only patients with
a response to 8 weeks’ upadacitinib 45 mg once daily
are analysed here, to align with the populations
included from the other induction studies.
In the phase 3 induction trials, patients were randomly
assigned 2:1 to 8-week double-blind induction therapy
with oral upadacitinib 45 mg once daily or placebo.
Randomisation was stratified by previous biological
status (non-bio-IR or bio-IR), baseline cortico­steroid use
(yes or no), and baseline adapted Mayo score (≤7 or >7).
Baseline was defined as the last non-missing value
collected on or before the first induction dose.
Patients who achieved a clinical response (defined as
a decrease in the adapted Mayo score of at least 2 points
and at least 30% from baseline plus a decrease in rectal
bleeding subscore [RBS] ≥1 or an absolute RBS ≤1) to
upadacitinib 45 mg once daily at week 8 in the phase 2b
induction study,5 or the phase 3 induction studies,4 were
randomly reassigned (1:1:1) to receive double-blind oral
upadacitinib 15 mg once daily, upadacitinib 30 mg once
daily, or placebo for an additional 52 weeks in the phase 3
maintenance trial (figure 1). Patients who were initially
randomised to placebo but did not achieve a clinical
response at week 8 were treated with open-label
upadacitinib 45 mg once daily for 8 weeks; responders after
8 weeks’ open-label upadacitinib induction therapy were
also randomly reassigned into the maintenance trial as
described above and analysed in the same population.
Random reassignment was stratified by previous bio-IR
status (bio-IR or non-bio-IR), clinical remission status at
week 0 of the maintenance trial (yes or no), and cortico­
steroid use at week 0 of the maintenance trial (yes or no).
All patients were randomly assigned with web-based
interactive response technology using block random­
isation methods. Block randomisation schedules (block
size of 3) were generated by randomisation specialists
employed by the sponsor and distributed to the inter­
active response technology vendor for patient random
assignment. As previously described, study investigators,
study site personnel, and patients were masked to
treatment allocation throughout the studies.4 The
upadacitinib and placebo tablets were identical in
appearance to maintain masking.
Procedures
Patients who achieved a clinical response to upadacitinib
45 mg once daily at week 8 in the induction studies4
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received double-blind oral upadacitinib 15 mg once daily,
upadacitinib 30 mg once daily, or placebo for an additional
52 weeks in the maintenance trial (44 weeks under earlier
protocol amendments assessed for safety only). Patients
initially randomly assigned to placebo who did not
achieve a clinical response at week 8 were treated with
open-label upadacitinib 45 mg once daily for 8 weeks;
responders after 8 weeks’ open-label upadacitinib
induction therapy were also randomly reassigned into the
maintenance trial and analysed in the same population.
Non-responders after 8 weeks’ upadacitinib 45 mg once
daily therapy could receive an additional 8 weeks’ open-
label upadacitinib 45 mg once daily therapy (extended
induction) and enter the maintenance trial; these patients
were not analysed as part of the population reported here.
During induction therapy, doses of concomitant
ulcerative colitis-related medications including cortico­
steroids remained stable, but concomitant use of biologics
and immunosuppressants (except metho­ trexate) was
prohibited. From week 0 of the maintenance trial,
corticosteroid use was tapered according to the protocol-
specified schedule (which could be initiated or increased
at the discretion of the investigator if a patient had new or
worsening symptoms of ulcerative colitis). Rescue
therapy could be provided during maintenance to treat
new or worsening symptoms of ulcerative colitis at
the investigator’s discretion. Protocol-permitted rescue
therapies were initiating or increased dosage of cortico­
steroids, aminosalicylates, methotrexate, or ulcerative
colitis-related antibiotics. However, patients were
considered as non-responders for efficacy assessments
on or after dose escalation of ulcerative colitis-related
medication or initiation of rescue therapy.
The primary protocol-defined reasons for study drug
discontinuation included clinically significant abnormal
laboratory results or adverse events; introduction of
prohibited medications or dosages, or non-compliance
with study procedures that could have placed the
patient at risk; patient non-compliance with tuberculosis
prophylaxis (if applicable) or development of active
tuberculosis during the study; or serious infections
which could not be adequately controlled by anti-infective
treatment, malignancy (except for localised non-
melanoma skin cancer or carcinoma in-situ of the cervix),
gastrointestinal perforation (except for appendicitis or
mechanical injury), or confirmed diagnosis of deep vein
thrombosis. Study drug could be interrupted for toxicity
management (eg, because of a treatment-emergent
adverse event including serious infections, herpes zoster,
gastrointestinal perforations, cardiovascular events,
malig­ nancy and gastrointestinal dysplasia, thrombosis
events, electrocardiogram abnormality, or management
of select laboratory abnormalities). If a patient had signs
or symptoms of and suspicion of COVID-19 infection, or
a confirmed diagnosis, study drug was interrupted until
resolution (with no time limit for interruption, providing
no permanent discontinuation criteria were met).
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Adapted Mayo score (full Mayo score excluding
Physician’s Global Assessment) was assessed at
maintenance baseline and week 52. Endoscopic subscore
was calculated on the basis of a centrally reviewed
endoscopy, with a primary central reader masked to the
site’s endoscopy assessment, and the patient’s clinical
data and therapy. Stool frequency subscore, RBS,
abdominal pain, and bowel urgency, assessed at baseline
and week 52, were calculated using mean values reported
by patients in e-diaries from the most recent 3-day
consecutive period in the last 10 days; if data were not
available for consecutive days, the three most recent
non-consecutive days were used. IBD Questionnaire
(IBDQ) and Functional Assessment of Chronic Illness
Therapy—Fatigue (FACIT–F) score were assessed at
baseline and week 52. Full details of assessments and
See Online for appendix timings are listed in the appendix (pp 1–2).
At the time of the protocol-defined primary analysis,
enrolment of 8-week upadacitinib 45 mg once daily
induction responders into the maintenance trial was
complete, and 451 patients had either completed the
study or prematurely ended study participation. Safety
and efficacy data at week 8 of induction therapy, and
maintenance data at week 52 from these 451 patients
have been reported previously.4 Additional patients
ongoing in the maintenance at the time of the primary
analysis are included in this updated and final analysis of
efficacy (post hoc; n=681) and safety (prespecified; n=746)
in the maintenance trial, comprising all 8 week induction
responders in U-ACHIEVE Maintenance.
Outcomes
In the maintenance trial, the primary endpoint was
clinical remission per adapted Mayo score (SFS ≤1 and
not greater than baseline, RBS=0, and endoscopic
subscore ≤1 without friability) at week 52 of maintenance.
Key secondary endpoints at week 52 were maintenance
of clinical response per adapted Mayo score (decrease ≥2
and ≥30% from baseline, plus a decrease in RBS ≥1 or
an absolute RBS ≤1 at week 52, among patients who
achieved clinical response per adapted Mayo score at the
end of the induction period); maintenance of clinical
remission per adapted Mayo score (clinical remission at
week 52 among patients who achieved clinical remission
per adapted Mayo score at the end of the induction
period); corticosteroid-free clinical remission per adapted
Mayo score (clinical remission and corticosteroid-free for
≥90 days immediately before week 52 among patients
who achieved clinical remission per adapted Mayo
score at the end of the induction period); endoscopic
improvement (endoscopic subscore ≤1 without friability);
maintenance of endoscopic improvement (endoscopic
subscore ≤1 without friability at week 52 among patients
who had achieved endoscopic subscore ≤1 without
friability at the end of the induction period); endoscopic
remission (endoscopic subscore =0); histological–endo­
scopic mucosal improvement (endoscopic subscore ≤1
980
without friability and Geboes score ≤3·1); mucosal
healing (also known as histological–endoscopic mucosal
remission; endoscopic subscore=0 and Geboes score <2);
no abdominal pain (mean score of 0 across 3 days); no
bowel urgency (mean score of 0 across 3 days); change
from baseline in FACIT-F score; and change from
baseline in IBDQ score. Efficacy outcomes were also
analysed by previous bio-IR status (bio-IR and non-bio-IR)
and reported for patients with inadequate response to
anti-TNF (TNF-IR, defined as inadequate response, loss
of response, or intolerance to ≥1 anti-TNF agent).
A subgroup analysis was done for efficacy endpoints by
baseline demographics and clinical characteristics (sex
[self-reported], age, weight, race [self-reported along with
ethnicity and collected as a standard clinical trial
demographic], region, disease duration, adapted Mayo
score, full Mayo score, presence of pancolitis, high-
sensitivity C-reactive protein, albumin concentrations,
corticosteroid use, aminosalicylate use, bio-IR status,
previous exposure to anti-TNF agents in non-bio-IR
patients, and previous exposure to biologics in non-bio-
IR patients). Point estimates and 95% CIs for treatment
differences between each upadacitinib dose and placebo
are presented.
Safety outcomes included treatment-emergent adverse
events, defined as any adverse events that began or
worsened in severity on or after the first dose of study
drug in the maintenance trial and within 30 days after
the last dose for patients who did not participate in the
ongoing long-term extension study, or until first dose of
study drug in the long-term extension study. Adverse
events of special interest (AESIs) were prespecified
and based on previous studies in patients receiving
upadacitinib for other indications or other JAK
inhibitors,5,7,8 and included serious infections, herpes
zoster, malignancy excluding non-melanoma skin cancer,
non-melanoma skin cancer, adjudicated major adverse
cardiovascular events (MACEs, defined as cardiovascular
death, nonfatal myocardial infarction, and non-fatal
stroke), and adjudicated venous thromboembolic events
(VTEs, defined as deep vein thrombosis [DVT] and
pulmonary embolism [ fatal and non-fatal]). Safety
outcomes were also analysed by previous bio-IR status
and reported for anti-TNF-IR patients.
In November, 2022, the European Medicines
Agency (EMA) issued recommendations to minimise
the risk of serious side-effects with JAK inhibitors.9,10
Given the focus of these recommendations on patients
with increased risk of MACE, VTE, and malignancy,
we reviewed baseline data, including previous
cardiovascular events (all events in which the Medical
History Body System or Organ Class [MHBODSYS] was
cardiac disorders) from the safety population for
relevant known risk factors for events of these types. In
addition, full details on all events of MACE, VTE, and
malignancies (excluding non-melanoma skin cancer)
are provided.
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To characterise further the risk of herpes zoster in this
population, herpes zoster rates were analysed by
geographical region, previous herpes zoster, and previous
herpes zoster vaccination.
Statistical analysis
The protocol-defined sample size calculation for the
primary analysis of the first 451 8-week upadacitinib 45 mg
once daily induction responders has been described
previously,4 depicting the pivotal portion of the efficacy
evaluation. Additional patients who had not completed the
study at the time of the primary database lock were
prespecified for safety analyses only, according to the
protocol. The efficacy analyses comprising all 8-week
induction responders presented in this paper were
performed post hoc, and results are nominal in nature.
Efficacy analyses were done in the intention-to-treat
population, defined as upadacitinib 45 mg once daily
8-week induction responders who were enrolled per
protocol for the 52-week maintenance treatment period
and received at least one dose of study drug (placebo,
upadacitinib 15 mg once daily, or upadacitinib
30 mg once daily). The safety analysis population was
defined as the upadacitinib 45 mg once daily 8-week
induction responders who were enrolled per protocol for
44-week or 52-week maintenance therapy (ie, the intention-
to-treat population plus patients who received up to
44 weeks’ maintenance therapy under earlier protocol
amendments) and received at least one dose of study drug
(placebo, upadacitinib 15 mg once daily, or upadacitinib
30 mg once daily).
Efficacy comparisons between upadacitinib 15 mg once
daily versus placebo, and upadacitinib 30 mg once
daily versus placebo were made by means of the
Cochran–Mantel–Haenszel test adjusted by previous
bio-IR status (bio-IR or non-bio-IR), corticosteroid use at
week 0 of the maintenance trial (yes or no), and clinical
remission status at week 0 of the maintenance trial (yes
or no). Continuous endpoints collected at only one post-
baseline visit were analysed by means of an analysis of
covariance model. The study was not designed for
statistical comparisons between upadacitinib 15 mg once
daily and upadacitinib 30 mg once daily, meaning that
any comparisons are descriptive only.
The primary approach for handling missing data was
non-responder imputation, while incorporating multiple
imputation to handle missing data owing to COVID-19.
This approach categorised any patient who did not have
an evaluation during a prespecified visit for any reason
(including initiation of ulcerative colitis-related rescue
medications, lack of efficacy, study drug intolerance, or
early discontinuation from the maintenance study to the
long-term extension study) as a non-responder for
efficacy assessments at that timepoint. For missing data
owing to COVID-19 infection or logistical restrictions
related to the COVID-19 pandemic, under missing at
random assumptions, data were handled by multiple
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imputation; for this, patients were considered responders
or non-responders at that timepoint on the basis of
multiple imputation values.
Data collected at or after ulcerative colitis-related
rescue medication were not used for efficacy analysis.
For binary endpoints, patients who had these events
were considered as not achieving them. For continuous
endpoints, data were analysed by means of multiple
imputation incorporating return-to-baseline to handle
visits on, or after, ulcerative colitis-related rescue
medication use.
Post-hoc analyses of the number needed to treat (NNT)
were done for binary efficacy outcomes in the intention-
to-treat population at week 52. NNT was calculated as the
inverse of the difference in proportions achieving each
outcome with each maintenance dose of upadacitinib
versus placebo.
All efficacy analyses on the overall population were
adjusted for stratification factors. Subgroup analyses were
not adjusted for stratification factors to avoid small sizes
of stratum within each subgroup–treatment combination.
For safety, exposure-adjusted event rates (EAERs,
defined as events per 100 patient-years) and 95% CIs
were calculated. The 95% CIs were calculated by normal
approximation to the Poisson distribution.
Post-hoc analyses of the number needed to harm
(NNH) were done in the safety population at week 52.
NNH was calculated as the inverse of the difference in
proportions of patients having a treatment-emergent
adverse event with each dose of upadacitinib versus
placebo (ie, not exposure adjusted). Negative or positive
NNH values indicate a lower or higher risk, respectively,
of treatment-emergent adverse events for upadacitinib
versus placebo; values closest to 1 indicate that the safety
risk difference between upadacitinib and placebo is
largest (ie, closer to 100%).
All statistical analyses were done with SAS (version 9.4).
These studies are registered with ClinicalTrials.gov
(U-ACHIEVE [Induction and Maintenance] NCT02819635;
U-ACCOMPLISH NCT03653026).
Role of the funding source
The funder of the study was involved in the study
design, data collection, data analysis, data interpretation,
writing of the report, and the decision to submit for
publication.
Results
Between Sept 3, 2016, and June 14, 2018 (phase 2b
induction study), Oct 23, 2018, and Sept 7, 2020
(U-ACHIEVE Induction), and Dec 6, 2018, and
Jan 14, 2021 (U-ACCOMPLISH), 987 patients received
8-week upadacitinib 45 mg once daily induction therapy.
Of these, 681 (69%) patients achieved a clinical response
after 8 weeks and were randomly reassigned to
upadacitinib 15 mg once daily (n=225), upadacitinib
30 mg once daily (n=233), or placebo (n=223) for
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Placebo (n=223) Upadacitinib 15 mg once daily Upadacitinib 30 mg once daily

(n=225) (n=233)
Sex*
Male 123 (55%) 146 (65%) 141 (61%)
Female 100 (45%) 79 (35%) 92 (39%)
Age, years 40·0 (32·0–54·0) 39·0 (30·0–53·0) 42·0 (31·0–55·0)
Age
<18 years 4 (2%) 0 2 (1%)
≥18 – <40 years 103 (46%) 113 (50%) 100 (43%)
≥40 – <65 years 97 (43%) 92 (41%) 110 (47%)
≥65 years 19 (9%) 20 (9%) 21 (9%)
Race†
American Indian or Alaskan Native 1 (<1%) 0 0
Asian 65 (29%) 70 (31%) 74 (32%)
Black or African American 7 (3%) 9 (4%) 6 (3%)
Native Hawaiian or Other Pacific Islander 1 (<1%) 0 1 (<1%)
Multiple 8 (4%) 0 1 (<1%)
White 141 (63%) 146 (65%) 151 (65%)
Ethnicity†
Hispanic or Latinx 15 (7%) 19 (8%) 16 (7%)
Not Hispanic or Latinx 208 (93%) 206 (92%) 217 (93%)
BMI, kg/m² 23·9 (21·2–27·8) 23.8 (21·0–27·6) 24·5 (20·9–28·1)
Disease duration, years 5·9 (2·8–11·3) 6·3 (2·8–12·1) 5·9 (2·7–11·0)
Faecal calprotectin, mg/kg n=195; 1679·0 (658·0–3338·0) n=197; 1707·0 (724·0–3067·0) n=193; 1580·0 (809·0–2913·0)
High-sensitivity C-reactive protein, mg/L 3·9 (1·4–9·2) 3·6 (1·2–9·3) 4·1 (1·2–8·6)
Aminosalicylate use 146 (65%) 160 (71%) 168 (72%)
Methotrexate use 0 2 (1%) 1 (<1%)
Corticosteroid use‡ 84 (38%) 84 (37%) 84 (36%)
Corticosteroid dose, mg/day prednisone equivalent§ n=83; 20·0 (10·0–25·0) n=81; 15·0 (10·0–30·0) n=81; 20·0 (10·0–20·0)
Bio-IR 116 (52%) 109 (48%) 111 (48%)
Number of previous biologics in bio-IR patients
1 45 (39%) 43 (39%) 40 (36%)
≥2 71 (61%) 66 (61%) 71 (64%)
Adapted Mayo score 7·0 (1·2) 6·9 (1·2) n=231; 7·0 (1·3)
≤7 131 (59%) 140 (62%) 137 (59%)
>7 92 (41%) 85 (38%) 94 (41%)
Mayo score endoscopic subscore 2·7 (0 5) 2·7 (0·5) 2·7 (0·5)
Presence of bowel urgency n=215; 201 (93%) n=221; 204 (92%) n=230; 213 (93%)
Presence of abdominal pain n=215; 197 (92%) n=221; 202 (91%) n=230; 202 (88%)
Inflammatory Bowel Disease Questionnaire n=222; 123·0 (98·0–145·0) n=222; 126·5 (102·0–151·0) n=229; 122·0 (97·0–147·0)
total score
Functional Assessment of Chronic Illness n=221; 30·0 (21·0–40·0) n=222; 33·0 (25·0–40·0) n=228; 31·0 (22·0–39·5)
Therapy—Fatigue score
Data are n (%), median (IQR), or mean (SD) for the intention-to-treat population, defined as upadacitinib 45 mg once daily 8-week induction responders who were enrolled
per protocol for the 52-week maintenance treatment period and received ≥1 dose of study drug (placebo, upadacitinib 15 mg once daily, or UPA 30 mg once daily). Baseline
is defined as the last non-missing value collected on or before the first induction dose. Bio-IR=inadequate response, loss of response, or intolerance to ≥1 biologic.
*Self-reported. †Self-reported and collected as a standard clinical trial demographic. ‡Corticosteroid use was tapered from week 0 of the U-ACHIEVE Maintenance study
according to the protocol-specified schedule (which could be adapted based on the discretion of the investigator). §Among patients receiving corticosteroids at baseline.
Two patients (placebo, n=1; upadacitinib 15 mg once daily, n=1) had reported baseline corticosteroid doses substantially greater than the usual maximum administered daily
dose (>80 mg of prednisone or equivalent).

Table 1: Baseline demographics and clinical characteristics (intention-to-treat population; n=681)

52 weeks of maintenance therapy in the U-ACHIEVE included 319 patients from U-ACHIEVE Induction,
Maintenance trial (Dec 14, 2016–Dec 13, 2021) and 341 patients from U-ACCOMPLISH, and 21 patients
included in the 8-week induction responder intention-to- from the phase 2b induction study. Details on the
treat efficacy population (figure 1). These responders numbers of participants from each country are included

982 www.thelancet.com/gastrohep Vol 8 November 2023


in the appendix (pp 3–8). 746 patients (representing
552·9 patient-years of exposure) who achieved a clinical
response after 8 weeks of upadacitinib 45 mg once daily
induction therapy were enrolled for 44-week or 52-week
maintenance therapy and were included in the 8-week
induction responder safety population (upadacitinib
15 mg once daily, n=250; upadacitinib 30 mg once daily,
n=251; placebo, n=245). The difference between the
intention-to-treat and safety populations (n=65) was due to
patients being enrolled for 44-week maintenance therapy
under earlier protocol amendments (n=61) and site non-
compliance issues relating to informed consent (n=4).
Demographics and clinical characteristics at baseline
of patients entering U-ACHIEVE Maintenance were
generally well balanced across treatment groups in the
8-week induction responder intention-to-treat efficacy
population (table 1). Across treatment groups, 35–45%
of patients were female, and the median age was
39·0–42·0 years; patients had a median disease duration
of 5·9–6·3 years and 38–41% of patients had a baseline
adapted Mayo score greater than 7. Approximately half of
the patients in each treatment group had previously
had an inadequate response, loss of response or
intolerance to biologics (48–52%); of these, almost
two-thirds had received at least two biologics (61–64%).
A significantly greater proportion of patients in
the 8-week induction responder population (n=681)
achieved clinical remission per adapted Mayo score at
week 52 with upadacitinib 15 mg once daily (40·4%) and
upadacitinib 30 mg once daily (53·6%) versus placebo
(10·8%; both p<0·0001; figure 2). A greater proportion of
patients who received upadacitinib achieved endoscopic
improvement than did those who received placebo
(upadacitinib 15 mg once daily 48·5%; upadacitinib
30 mg once daily 63·3%; vs 14·1% for placebo; both
p<0·0001); this was also seen with maintenance of
endoscopic improvement (upadacitinib 15 mg once
daily 61·2%; upadacitinib 30 mg once daily 71·0%;
vs 18·4% for placebo; both p<0·0001), and histologic–
endoscopic mucosal improvement (upadacitinib
15 mg once daily 40·5%; upadacitinib 30 mg once
daily 56·0%; vs 12·3%; both p<0·0001). Achievement of
all other clinical, endoscopi c, and histological endpoints
was also significantly higher with both upadacitinib
maintenance doses versus placebo (all p<0·0001; table 2).
At week 52, a significantly greater proportion of patients
with upadacitinib achieved no abdominal pain (45·8% for
upadacitinib 15 mg once daily and 59·7% for upadacitinib
30 mg once daily, vs 20·6% for placebo; both p<0·0001)
and no bowel urgency (53·8% for upadacitinib
15 mg once daily and 66·9% for upadacitinib 30 mg once
daily, vs 18·4% for placebo; both p<0·0001). Improvements
in both FACIT-F and total IBDQ scores were significantly
greater with upadacitinib than placebo (p<0·0001;
table 2). Across all analysed efficacy endpoints, out­comes
were numerically better with upadacitinib 30 mg once
daily than upadacitinib 15 mg once daily (table 2).
www.thelancet.com/gastrohep Vol 8 November 2023
Articles
100
90
80
70 42·9% (35·4–50·4)*†
53·6%
60
30·1% (22·7–37·4)*†
Patients (%)
50 40·4%
40
30
20
10·8%
10
n=223 n=225 n=233
0
Placebo Upadacitinib 15 mg Upadacitinib 30 mg
once daily once daily
Week 52 clinical remission
Figure 2: Clinical remission per adapted Mayo score at week 52
(intention-to-treat population; n=681)
Data are provided for the intention-to-treat population, defined as upadacitinib
45 mg once daily 8-week induction responders who were enrolled per protocol
for the 52-week maintenance treatment period and received ≥1 dose of study
drug (placebo, upadacitinib 15 mg once daily, or upadacitinib 30 mg once daily).
Results are based on non-responder imputation incorporating multiple
imputations to handle missing data owing to COVID-19 (appendix p 21). The
adjusted differences, 95% CI (normal approximation to the binomial distribution)
and p value were calculated according to the Cochran–Mantel–Haenszel test
adjusted for strata (corticosteroid use at week 0 [yes or no], clinical remission
status at week 0 [yes or no], bio-IR status at baseline [bio-IR or non-bio-IR]).
Bio-IR=inadequate response, loss of response, or intolerance to ≥1 biologic.
*p<0·0001 vs placebo. †Adjusted difference (95% CI) vs placebo.
Both upadacitinib 15 mg once daily and 30 mg once
daily were more efficacious than placebo across all
subgroups for achievement of the primary endpoint of
clinical remission per adapted Mayo score when stratified
by baseline demographics and clinical characteristics,
including sex (appendix pp 22–23). Across bio-IR (n=336),
non-bio-IR (n=345), and anti-TNF-IR (n=306; 91% of
bio-IR population) subgroups within the 8-week
induction responder population, both upadacitinib
15 mg once daily and 30 mg once daily were more
efficacious than placebo after 52 weeks of maintenance
treatment across the primary endpoint of clinical
remission, and all key secondary endpoints (figure 3;
appendix pp 9–10). Upadacitinib 30 mg once daily had
numerically better efficacy than upadacitinib 15 mg once
daily across all endpoints in each subgroup, except for
maintenance of endoscopic improvement in the bio-IR
and anti-TNF-IR subgroups. Generally, efficacy was
similar in the bio-IR and anti-TNF-IR subgroups
(although this should be interpreted with respect to the
fact that 91% of the bio-IR population was made up of
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Placebo (n=223) Upadacitinib 15 mg Adjusted difference Upadacitinib 30 mg Adjusted difference

once daily (n=225) vs placebo* once daily (n=233) vs placebo*
Maintenance of clinical response per n=204; 21·5% n=197; 65·6% 43·9† (35·4–52·5) n=217; 77·5% 55·6† (47·8–63·4)
adapted Mayo score
Maintenance of clinical remission per n=85; 18·8% n=76; 53·6% 34·9† (21·2–48·5) n=87; 65·8% 46·9† (34·0–59·8)
adapted Mayo score
Corticosteroid-free clinical remission per n=85; 18·8% n=76; 52·3% 33·7† (20·0–47·3) n=87; 64·6% 45·5† (32·6–58·5)
adapted Mayo score
Endoscopic improvement 14·1% 48·5% 34·4† (26·7–42·1) 63·3% 49·0† (41·4–56·7)
Maintenance of endoscopic improvement n=115; 18·4% n=97; 61·2% 42·2† (30·4–53·9) n=118; 71·0% 51·5† (40·9–62·1)
Endoscopic remission 6·1% 24·9% 18·6† (12·2–25·0) 28·3% 21·9† (15·4–28·5)
Histologic–endoscopic mucosal 12·3% 40·5% 28·5† (21·1–35·9) 56·0% 43·8† (36·1–51·5)
improvement
Mucosal healing 5·1% 18·8% 13·5† (7·8–19·3) 22·6% 17·2† (11·2–23.3)
No abdominal pain 20·6% 45·8% 24·7† (16·5–33·0) 59·7% 38·9† (30·7–47·1)
No bowel urgency 18·4% 53·8% 35·3† (27·3–43·4) 66·9% 48·2† (40·4–56·0)
Change from baseline in Functional 2·6 8·1 5·5† (3·5–7·5) 9·8 7·2† (5·3–9·2)
Assessment of Chronic Illness
Therapy—Fatigue score
Change from baseline in Inflammatory 16·3 48·2 31·8† (23·9–39·8) 59·4 43·1† (35·4–50·8)
Bowel Disease Questionnaire total score
Data are n (%), % adjusted (95% CI), least squares mean, and least squares mean (95% CI). Data are provided for the intention-to-treat population, defined as upadacitinib
45 mg once daily 8-week induction responders who were enrolled per protocol for the 52-week maintenance treatment period and received ≥1 dose of study drug (placebo,
upadacitinib 15 mg once daily, or upadacitinib 30 mg once daily). Baseline is defined as the last non-missing value collected on or before the first induction dose. Results for
categorical endpoints are based on non-responder imputation incorporating multiple imputations to handle missing data owing to COVID-19 (appendix p 21). The adjusted
differences, 95% CI (normal approximation to the binomial distribution within each stratum) and p value were calculated according to the Cochran–Mantel–Haenszel test
adjusted for strata (corticosteroid use at week 0 [yes or no], clinical remission status at week 0 [yes or no], bio-IR status at baseline [bio-IR or non-bio-IR]). Results for
continuous endpoints are based on return-to-baseline multiple imputation; least squares mean, adjusted 95% CI and p values are the synthetic results based on ANCOVA
with baseline, week 0, treatment, and strata (corticosteroid use at week 0 [yes or no], clinical remission status at week 0 [yes or no], bio-IR status at baseline [bio-IR or non-
bio-IR]) in the model using the PROC MIANALYZE procedure. Bio-IR=inadequate response, loss of response, or intolerance to ≥1 biologic. *Adjusted difference in percentage
points for categorical endpoints. †p<0·0001 vs placebo.

Table 2: Key secondary efficacy endpoints at week 52 (intention-to-treat population; n=681)

the anti-TNF-IR population) and was consistent with the
overall 8-week induction responder population (figure 3,
appendix pp 9–10).
Calculation of NNT values in the intention-to-treat
population showed greater efficacy at 52 weeks of
maintenance therapy for patients treated with either
upadacitinib 15 mg once daily or 30 mg once daily versus
placebo for the primary endpoint of clinical remission
(NNT 3·4 and 2·4, respectively). Across key secondary
efficacy endpoints, NNT values ranged between
2·3 and 7·5 for upadacitinib 15 mg once daily and
1·8–5·9 for upadacitinib 30 mg once daily (appendix
pp 24–25).
EAERs for any treatment-emergent adverse event,
either serious or leading to discontinuation were
numerically higher with placebo than either upadacitinib
dose; no deaths were reported (table 3). For AESIs, the
EAERs of serious infection were 5·9, 5·0, and 3·2 events
per 100 patient-years with placebo, upadacitinib
15 mg once daily, and upadacitinib 30 mg once daily,
respectively (table 3). Herpes zoster was reported only
with upadacitinib in a dose-dependent manner
(upadacitinib 15 mg once daily 6·0 events per
100 patient-years; upadacitinib 30 mg once daily
7·3 events per 100 patient-years). There were no cases
of adjudicated gastrointestinal perforation in either
upadacitinib group, compared with two cases (1·5 events
per 100 patient-years) with placebo. EAERs of neutropenia
were 5·2, 5·5, and 8·7 events per 100 patient-years with
placebo, upadacitinib 15 mg once daily, and upadacitinib
30 mg once daily, respectively; EAERs of creatine
phospho­kinase elevation were 3·7, 8·0, and 10·1 events
per 100 patient-years, respectively.
Hepatic disorders were more common with upadacitinib
15 mg once daily and upadacitinib 30 mg once daily versus
placebo, with EAERs of 17·0 and 9·2 versus 5·9 events
per 100 patient-years, respectively. Of the 31 patients
receiving upadacitinib treatment with any event of
hepatic disorder, the most frequent events were elevated
alanine aminotransferase (seven events with upadacitinib
15 mg once daily and seven events with upadacitinib
30 mg once daily) and elevated aspartate aminotransferase
(nine events with upadacitinib 15 mg once daily and
five events with upadacitinib 30 mg once daily).
One non-serious case of drug-induced liver injury led to
discontinuation of upadacitinib. There were no confirmed
cases of Hy’s law.
There was one malignancy (excluding non-melanoma
skin cancer) with placebo, one with upadacitinib
15 mg once daily, and two with upadacitinib 30 mg once

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100 UPA 15 mg once daily Overall

UPA 30 mg once daily Non-bio-IR
Bio-IR
Anti-TNF-IR
80
Response rate difference vs placebo (%)

60

40

20

0
Clinical remission Maintenance of Corticosteroid-free Endoscopic Endoscopic remission Histological–endoscopic Mucosal healing
clinical response clinical remission improvement mucosal improvement

Figure 3: Efficacy at week 52 in subgroups by biological status (intention-to-treat population)

The efficacy analysis was done in the non-bio-IR, bio-IR, and anti-TNF-IR subgroups of the intention-to-treat population (upadacitinib 45 mg once daily 8-week induction responders who were
enrolled per protocol for the 52-week maintenance treatment period and received ≥1 dose of study drug [placebo, upadacitinib 15 mg once daily, or upadacitinib 30 mg once daily]). Results are based
on non-responder imputation incorporating multiple imputations to handle missing data owing to COVID-19. For the overall population, adjusted differences, 95% CI (normal approximation to the
binomial distribution within each stratum) and p value were calculated according to the Cochran–Mantel–Haenszel test adjusted for strata (corticosteroid use at week 0 [yes or no], clinical remission
status at week 0 [yes or no], bio-IR status at baseline [bio-IR or non-bio-IR]). For the subgroup data, unadjusted differences are shown with 95% CI calculated by means of normal approximation to the
binomial distribution. Anti-TNF=anti-tumour necrosis factor. Anti-TNF-IR=inadequate response, loss of response, or intolerance to ≥1 TNF inhibitor. Bio-IR=inadequate response, loss of response, or
intolerance to ≥1 biologic.

daily (0·7, 0·5, and 0·9 events per 100 patient-years, (n=53; 7%), hypertension (n=111; 15%), diabetes
respectively). There was one adjudicated MACE with (n=43; 6%), current or former tobacco use (n=305;
placebo and one with upadacitinib 30 mg once daily 41%), and low concentrations of high-density lipo­
(0·7 and 0·5 events per 100 patient-years, respectively); protein cholesterol (n=102; 14%; appendix p 13).
there were no cases with upadacitinib 15 mg once daily. Additionally, five (1%) patients had previous VTE.
There were no cases of adjudicated VTE with placebo, Assessment of the upadacitinib-treated patients who
two cases with upadacitinib 15 mg once daily, and had an adjudicated MACE (one [<1%] of 501 patients) or
two with upadacitinib 30 mg once daily (1·0 and 0·9 events VTE (four [1%] of 501 patients) during maintenance
per 100 patient-years for upadacitinib 15 mg once daily, therapy showed that all had at least one known risk
and upadacitinib 30 mg once daily, respectively). factor (see appendix pp 14–16 for details of these events
Across treatment groups, the EAERs of any and relevant known risk factors). There were
treatment-emergent adverse event, either serious or two adjudicated MACEs: one acute myocardial infarc­
leading to discontinuation, and AESIs were generally tion in a placebo-treated patient and one subarachnoid
similar between each of the bio-IR, non-bio-IR, and haemorrhage in a patient receiving upadacitinib
anti-TNF-IR subgroups and were similar to the overall 30 mg once daily. Four patients had adjudicated VTE:
population, except for lower EAERs of any treatment- two patients receiving upadacitinib 15 mg once daily had
emergent adverse event across treatments in the a pulmonary embolism (both had mild disease [adapted
non-bio-IR subgroup (appendix pp 11–12). Mayo score ≤7] at the time of the event) and two patients
To investigate the safety of upadacitinib in patients at receiving upadacitinib 30 mg once daily had a deep vein
higher risk of MACE, VTE, and malignancies, data thrombosis (one with mild disease at the time of the
from the safety population were reviewed for known event and one with severe [adapted Mayo score >7]).
baseline risk factors that might increase the risk of None of the female patients who had a MACE or VTE
these events. Given that advanced age is a known risk reported use of concomitant oral contraception or
factor for cardiovascular events and VTE, it is of note hormone replacement therapy. Four (1% of patients)
that 243 (33%) of 746 patients in the safety population malignancies (excluding non-melanoma skin cancer)
were aged at least 50 years and 65 (9%) were 65 years or were reported, all of which were considered serious; of
older. The safety population also included a substantial these, three occurred in upadacitinib-treated patients,
proportion of patients with one or more known one invasive breast carcinoma in the upadacitinib
cardiovascular risk factor at baseline (n=417; 56%), 15 mg once daily group, one adenocarcinoma of the
including at least one previous cardiovascular event colon and one small cell carcinoma of the prostate in the

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Placebo (n=245) Upadacitinib 15 mg Upadacitinib 30 mg

135·0 patient-years once daily (n=250) once daily (n=251)
199·4 patient-years 218·5 patient-years
Event
Any treatment-emergent adverse event 674 (499·4, 461·7–537·1) 626 (313·9, 289·3–338·5) 691 (316·2, 292·7–339·8)
Serious treatment-emergent adverse events 28 (20·7, 13·1–28·4) 24 (12·0, 7·2–16·8) 22 (10·1, 5·9–14·3)
Treatment-emergent adverse events leading to discontinuation 26 (19·3, 11·9–26·7) 11 (5·5, 2·3–8·8) 19 (8·7, 4·8–12·6)
Treatment-emergent adverse events leading to death 0 0 0
Adverse event of special interest
Serious infection 8 (5·9, 1·8–10·0) 10 (5·0, 1·9–8·1) 7 (3·2, 0·8–5·6)
Opportunistic infection (excluding tuberculosis and herpes zoster) 2 (1·5, 0·0–3·5) 2 (1·0, 0·0–2·4) 2 (0·9, 0·0–2·2)
Herpes zoster 0 12 (6·0, 2·6–9·4) 16 (7·3, 3·7–10·9)
Malignancy (excluding non-melanoma skin cancer) 1 (0·7, 0·0–2·2) 1 (0·5, 0·0–1·5) 2 (0·9, 0·0–2·2)
Non-melanoma skin cancer 0 0 3 (1·4, 0·0–2·9)
Renal dysfunction 1 (0·7, 0·0–2·2) 1 (0·5, 0·0–1·5) 1 (0·5, 0·0–1·4)
Hepatic disorder 8 (5·9, 1·8–10·0) 34 (17·0, 11·3–22·8) 20 (9·2, 5·1–13·2)
Adjudicated gastrointestinal perforation 2 (1·5, 0·0–3·5) 0 0
Adjudicated major adverse cardiovascular event* 1 (0·7, 0·0–2·2) 0 1 (0·5, 0·0–1·4)
Adjudicated venous thromboembolic event† 0 2 (1·0, 0·0–2·4) 2 (0·9, 0·0–2·2)
Anaemia 19 (14·1, 7·7–20·4) 12 (6·0, 2·6–9·4) 10 (4·6, 1·7–7·4)
Neutropenia 7 (5·2, 1·3–9·0) 11 (5·5, 2·3–8·8) 19 (8·7, 4·8–12·6)
Lymphopenia 5 (3·7, 0·5–7·0) 10 (5·0, 1·9–8·1) 7 (3·2, 0·8–5·6)
Creatine phosphokinase elevation 5 (3·7, 0·5–7·0) 16 (8·0, 4·1–12·0) 22 (10·1, 5·9–14·3)
Data are events (events per 100 patient-years; 95% CI). Data are from the safety population, defined as the upadacitinib 45 mg once daily 8-week induction responders
per protocol for 44-week or 52-week maintenance therapy, and received ≥1 dose of study drug (placebo, upadacitinib 15 mg once daily, and upadacitinib 30 mg once daily).
The 95% CIs were calculated by normal approximation to the Poisson distribution, so 95% CIs were not calculated for event rates of 0. *Defined as cardiovascular death,
nonfatal myocardial infarction, and non-fatal stroke. †Defined as deep vein thrombosis and pulmonary embolism (fatal and non-fatal).

Table 3: Treatment-emergent adverse events and adverse events of special interest over 52 weeks (safety population; n=746)

upadacitinib 30 mg once daily group. All three patients
had at least one relevant known risk factor, and a time
to onset from the first upadacitinib dose within
approximately 1 year. No malignancies (excluding non-
melanoma skin cancer) with upadacitinib were
considered by the investigator as having a reasonable
possibility of being related to upadacitinib treatment
(appendix pp 14–16).
Most events of herpes zoster involved a single
dermatome and were not serious. Of the cases with more
extensive dermatomal involvement, there were two cases
of herpes zoster with unilateral involvement of multiple
dermatomes in the upadacitinib 15 mg once daily group
and five cases in the upadacitinib 30 mg once daily
group. In addition, in the upadacitinib 30 mg once daily
group, there were two cases of disseminated herpes
zoster with cutaneous involvement only (ie, without
central nervous system involvement) and one case of
herpes zoster with meningoencephalopathic involve­
ment. No events had lung or liver involvement. EAERs of
herpes zoster in upadacitinib-treated patients varied by
geographical region, with the highest rates seen in
western Europe and Oceania for upadacitinib 15 mg
once daily (12·3 events per 100 patient-years) and Japan
for upadacitinib 30 mg once daily (14·9 events
per 100 patient-years; appendix p 17). No herpes zoster
cases were reported in Latin America, although few
upadacitinib-treated patients were included from that
region (upadacitinib 15 mg once daily n=9; upadacitinib
30 mg once daily n=10). Less than 5% (n=24) of patients
in this study were vaccinated against herpes zoster or
had previous history of herpes zoster (appendix p 13),
making it difficult to assess the effect of these factors on
the incidence of herpes zoster. For patients treated with
upadacitinib, two herpes zoster events occurred among
17 patients with previous vaccination, and four events
occurred among the 15 patients with previous history of
herpes zoster (appendix p 17).
Overall, calculation of NNH showed generally similar
safety at 52 weeks for patients treated with upadacitinib
15 mg once daily or upadacitinib 30 mg once daily versus
placebo, with no risk differences in overall or serious
treatment-emergent adverse events (appendix pp 18–20).
There was a lower risk of treatment-emergent adverse
events leading to discontinuation with upadacitinib
15 mg once daily versus placebo (NNH –16·1). Higher
risks were seen for upadacitinib 15 mg once daily and
upadacitinib 30 mg once daily versus placebo for herpes
zoster (NNH 21·2 and 17·8, respectively), as well as
hepatic disorders with upadacitinib 15 mg once daily
(NNH 20·8) and neutropenia with upadacitinib
30 mg once daily (NNH 25·6; appendix pp 18–20).

986 www.thelancet.com/gastrohep Vol 8 November 2023


Discussion
In this final efficacy analysis of 681 patients with
moderately to severely active ulcerative colitis who achieved
clinical response after 8 weeks of induction treatment with
upadacitinib 45 mg once daily, both maintenance doses
(upadacitinib 15 mg once daily and 30 mg once daily)
showed efficacy across the primary endpoint of clinical
remission and all key secondary endpoints assessed at
week 52. Both upadacitinib maintenance doses were well
tolerated up to week 52 with no new safety signals
observed. Efficacy results and the safety profile of
upadacitinib for the entire patient population were
consistent with those previously reported by Danese and
colleagues4 in the smaller primary registrational study
analysis of the first 451 patients randomly assigned into the
maintenance trial.
In this analysis, significantly higher proportions of
patients achieved clinical remission with upadacitinib
15 mg once daily and upadacitinib 30 mg once daily
compared with placebo, with similar proportions
reported as in the primary analysis.4 Similar proportions
of patients achieved clinical remission in subgroup
analyses of baseline demographics and clinical charac­
teristics. The proportions of patients achieving key
secondary efficacy endpoints with both upadacitinib
maintenance doses were also consistent with those
previously reported4 and, for some endpoints, were
numerically higher in this final, larger analysis. Although
both upadacitinib maintenance doses (15 mg once daily
and 30 mg once daily) showed efficacy, numerically
greater efficacy was seen with the higher dose across all
assessed endpoints, both in the current analysis and the
primary analysis.4 However, these comparisons are
descriptive in nature given that the study was not
designed to statistically compare upadacitinib doses.
Consistent with other approved upadacitinib
indications,12–14 dose dependence was observed for AESIs
of neutropenia, creatine phosphokinase elevations, and
herpes zoster. Alanine aminotransferase and aspartate
aminotransferase elevations were more common with
upadacitinib than with placebo, with more events
observed in patients receiving upadacitinib 15 mg once
daily than with upadacitinib 30 mg once daily. In this
analysis, non-melanoma skin cancer was observed only
in patients receiving upadacitinib 30 mg once daily
(two out of three cases in patients ≥70 years old), with no
cases in patients receiving upadacitinib 15 mg once
daily or placebo. Most events of herpes zoster involved a
single dermatome and were non-serious. Of note, few
patients (3%) in the trial had been vaccinated against
herpes zoster. This was because most patients in the trial
were younger than 60 years at baseline, and U-ACHIEVE
Induction and U-ACCOMPLISH started in close
proximity to approval of the vaccine in patients aged
50 to 60 years (2017 onwards depending on region),
and before the vaccine was approved for patients between
the ages of 18 and 50 years with increased risk of
www.thelancet.com/gastrohep Vol 8 November 2023
Articles
immunosuppression (2021). Current recommendations
state that patients are brought up to date with all relevant
immunisations, including prophylactic herpes zoster
vaccinations, before initiating advanced therapies,
including upadacitinib.15,16
In November, 2022, the EMA issued recommendations
to minimise the risk of serious side-effects with JAK
inhibitors, particularly relating to MACEs, VTEs, and
malignancy, based on potential safety issues reported
in ORAL Surveillance.9–11 Consequently, the EMA
recommends that JAK inhibitors should only be used
when no suitable alternatives are available in patients at
higher risk of MACE or malignancy, patients aged
65 years or older, and current or former long-term
smokers, and should be used cautiously in patients
with known risk factors for VTE. Clinicians prescribing
JAK inhibitors to patients with these risk factors are
advised to assess the suitability of alternative treatments
and make individual benefit–risk assessments for their
patients. Regarding the posology of upadacitinib, it is
recommended to use upadacitinib 15 mg once daily for
patients at high risk of MACE, VTE, or malignancy
whenever possible, and to use the lowest effective dose
to maintain response.
No dose-dependent risk for MACE, VTE, or malignancy
excluding non-melanoma skin cancer has been observed
in the indications for which upadacitinib is approved,14
including for patients with ulcerative colitis in the
current analysis. In this study, despite a substantial
proportion of the population sharing characteristics with
patients in ORAL Surveillance (ie, aged ≥50 years with
one or more known baseline risk factor for cardiovascular
events), there were few cases of adjudicated MACE, VTE,
or malignancy (excluding non-melanoma skin cancer).
Furthermore, all upadacitinib-treated patients with
an adjudicated MACE or VTE had more than one known
risk factor. No malignancies were considered by the
investigator as having a reasonable possibility of being
related to upadacitinib treatment and, given the long
latency time in the development of solid tumours
(≥4 years),17,18 the relatively short times between receipt
of first upadacitinib dose and time to onset of the
event (within approximately 1 year) suggests temporal
implausibility for upadacitinib in the oncogenesis of the
malignancies reported. The long-term safety of
upadacitinib will continue to be evaluated by means
of data from the ongoing U-ACTIVATE long-term
extension study (NCT03006068), as well as from other
postmarketing safety commitments by the sponsor.
Although patients were eligible for enrolment in the
U-ACHIEVE Maintenance trial with treatment failure in
at least one type of conventional or biological therapy,
almost half of patients (49%) in the intention-to-treat
population had an inadequate response to biologic therapy
(primarily anti-TNFs). Inadequate response or intolerance
to at least one anti-TNF agent is a label-specified
prerequisite for treatment in some countries where
987
 Articles
upadacitinib is approved; therefore, it is likely that many
patients initiating upadacitinib in real-world practice have
had an inadequate response or intolerance to biologics
(including anti-TNFs), meaning that understanding the
efficacy and safety of upadacitinib in these patients is
important. In this analysis, the efficacy and safety profile
of upadacitinib in patients who had had an inadequate
response, loss of response or intolerance to biologics
(including anti-TNFs) and those who had not had an
inadequate response, loss of response or intolerance to
biologics generally reflected the overall population.
The main limitation of this analysis is that some
analyses were post hoc; results from these should be
interpreted with respect to the study design. In addition,
further data on upadacitinib beyond 52 weeks’ treatment
are warranted.
In conclusion, in patients with moderately to severely
active ulcerative colitis who responded to 8 weeks’
upadacitinib 45 mg once daily induction therapy, both
upadacitinib maintenance doses were significantly
more efficacious than placebo for achieving important
clinical, endoscopic, and histological outcomes, while
maintaining an acceptable safety profile with no new
safety risks in the full trial population over 52 weeks.
The favourable benefit–risk profile of both maintenance
doses in this analysis was consistent with that observed
in the primary analysis of a smaller patient population.
Overall, these findings support the use of upadacitinib as
a therapeutic option for treating patients with moderately
to severely active ulcerative colitis, for whom a large
unmet need persists.
Contributors
SV, SD, XH, JOL, PDRH, QC, HN, J-FC, EVL, and RP participated in
data acquisition. SV, SD, WZ, YSG, PDRH, J-FC, and RP participated in
study design. WZ, DI, JK, GL, XY, SC, YSG, and RP assessed and verified
the data. XY, SC, and RP participated in statistical analysis. All authors
had access to relevant data and participated in data interpretation,
critically reviewed the manuscript, and provided final approval for
publication. No honoraria or payments were made for authorship.
Declaration of interests
SV has received grants from AbbVie, Galapagos, Johnson & Johnson,
Pfizer, and Takeda; and consulting or speaking fees from AbbVie, Abivax,
Alimentiv (formerly Robarts Clinical Trials), Arena Pharmaceuticals,
Avaxia, Boehringer Ingelheim, Celgene, Dr Falk Pharma, Ferring,
Galapagos, Genentech-Roche, Gilead, Hospira, Janssen, MSD,
Mundipharma, Pfizer, Prodigest, Progenity, Prometheus, Second
Genome, Shire, Takeda, Theravance, and Tillotts Pharma. SD has received
consultancy fees from Boehringer Ingelheim, Celgene, Celltrion, Eli Lilly,
Enthera, Ferring Pharmaceuticals, Gilead, Hospira, Janssen, Johnson &
Johnson, MSD, Mundipharma, Mylan, Pfizer, Roche, Sandoz, Sublimity
Therapeutics, Takeda, TiGenix, UCB, and Vifor. WZ is a former employee
of AbbVie and may hold AbbVie stock or stock options. DI, JK, GL, XY,
SC, and YSG are full-time employees of AbbVie and may hold AbbVie
stock or stock options. XH reports clinical research funding from AbbVie,
Abivax, Alphasigma, Arena, Gilead, Eli Lilly, Enterome, Fresenius-Kabi,
Janssen, InDex Pharmaceuticals, Pfizer, Prometheus Biosciences,
Sangamo, Takeda, and Theravance; serving on advisory boards for
AbbVie, Abivax, Boehringer Ingelheim, Celltrion, Fresenius-Kabi,
Galapagos, Janssen, Nestlé Health Sciences, Nordic Pharma, and Viatris;
and participating in lectures and educational activities for AbbVie,
Amgen, Celltrion, Fresenius-Kabi, Janssen, MSD, Nordic Pharma, Nestlé
Health Sciences, Nutricia, Pfizer, Tillotts, Takeda, and Viatris. JOL has
served as a consultant and an advisory board participant for AbbVie,
988
Allergan (Warner Chilcott), Atlantic Healthcare, Bristol-Myers Squibb,
Celgene, Celltrion, Eli Lilly, Ferring Pharmaceuticals, Gilead, GSK,
Janssen, MSD, Napp, Pfizer, Shire, Takeda, and Vifor Pharma; has
received speaker fees and sponsorship for academic meetings from
AbbVie, Allergan (Warner Chilcott), Ferring Pharmaceuticals, Janssen,
MSD, Napp, Norgine, Pfizer, Shire, Tillotts Pharma, and Takeda; and has
received investigator-led research grants from AbbVie, Gilead, Pfizer,
Shire, and Takeda. PDRH has received grants from AbbVie, the Crohn’s &
Colitis Foundation, the National Institutes of Health, and Takeda; and has
served as a consultant for Eli Lilly, the Gastrointestinal Health Foundation,
Imedex, Pfizer, Takeda, and Vindico Medical Education. QC declares no
competing interests. HN has received support from AbbVie, Celgene
Corporation, Daiichi Sankyo, EA Pharma, Janssen Pharmaceutical,
JIMRO, Kissei Pharmaceutical, Kyorin Pharmaceutical, Mitsubishi
Tanabe Pharma, Mochida Pharmaceutical, Nippon Kayaku, Pfizer, Takeda,
and Zeria Pharmaceutical; as well as grants for commissioned or joint
research from Boehringer Ingelheim, Bristol Myers Squibb, and Hoya
Group Pentax Medical. J-FC has received personal fees from AbbVie,
Amgen, Boehringer Ingelheim, Celgene, Celltrion, Enterome, Ferring,
Genentech, Janssen–Johnson & Johnson, MedImmune, Merck, Pfizer,
Protagonist, PPM Services, Second Genome, Seres, Shire, Takeda, and
Theradiag; has received grant support from AbbVie, Janssen, Johnson &
Johnson, and Takeda; and holds stock options in Genfit and Intestinal
Biotech Development. EVL has received consulting fees from AbbVie,
Alvotech, Amgen, Arena, Avalo Therapeutics, BMS, Boehringer
Ingelheim, Calibr, Celgene, Celltrion Healthcare, Eli Lilly, Fresenius Kabi,
Genentech, Gilead, GlaxoSmithKline, Gossamer Bio, Iota Biosciences,
Iterative Scopes, Janssen, KLS Diagnostics, Morphic Therapeutics, Ono
Pharma, Pfizer, Protagonist, Scipher Medicine, Sun Pharma, Surrozen,
Takeda, and UCB; has served as an advisory board participant for Eli Lilly
and Morphic; has received research support from AbbVie, BMS,
Celgene/Receptos, Genentech, Gilead, Gossamer Bio, Janssen,
Pfizer, Takeda, Theravance, and UCB; and holds stock in Exact Sciences.
RP has received consulting fees, speaker fees, and research support from
Abbott, AbbVie, Alimentiv (formerly Robarts Clinical Trials), Amgen,
Arena Pharmaceuticals, AstraZeneca, BMS, Boehringer Ingelheim,
Celgene, Celltrion, Cosmos Pharmaceuticals, Eisai, Élan, Eli Lilly, Ferring,
Galapagos, Genentech, Gilead, GlaxoSmithKline, Janssen, Merck, Mylan,
Oppilan Pharma, Pandion Pharma, Pfizer, Progenity, Protagonist
Therapeutics, Roche, Sandoz, Satisfai Health, Schering-Plough, Shire,
Sublimity Therapeutics, Takeda, Theravance, and UCB.
Data sharing
AbbVie is committed to responsible data sharing regarding the clinical
trials that it sponsors. Sharing includes access to anonymised,
individual, and trial-level data (analysis datasets), and other information
(eg, protocols, clinical study reports, and analyses plans), as long as the
trials are not part of an ongoing or planned regulatory submission, and
accepting requests for clinical trial data for unlicensed products and
indications. These clinical trial data can be requested by any qualified
researchers who engage in rigorous independent scientific research and
will be provided following review and approval of a research proposal
and statistical analysis plan and execution of a data sharing statement.
Data requests can be submitted at any time after approval in the USA
and Europe and acceptance for publication, and the data will be
accessible for 12 months, with possible extensions considered. Further
instructions can be provided by the corresponding author, on request.
Acknowledgments
AbbVie and the authors thank the participants, study sites, and
investigators who participated in this clinical trial. AbbVie funded this
study and participated in the study design, research, analysis, data
collection, interpretation of data, and the review and approval of the
publication. Medical writing assistance was provided by Fraser Harris,
on behalf of 2 the Nth (Cheshire, UK), and was funded by AbbVie.
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