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Rheumatoid arthritis

ORIGINAL RESEARCH

Long-­term safety and efficacy of

upadacitinib versus adalimumab in
patients with rheumatoid arthritis:
5-­year data from the phase 3,
randomised SELECT-­COMPARE study
Roy Fleischmann ‍ ‍,1 Jerzy Swierkot,2 Sara K Penn,3 Patrick Durez ‍ ‍,4
Louis Bessette,5 Xianwei Bu,3 Nasser Khan,3 Yihan Li,3 Charles G Peterfy,6
Yoshiya Tanaka,7 Eduardo Mysler8

To cite: Fleischmann R, ABSTRACT

Swierkot J, Penn SK, et al. WHAT IS ALREADY KNOWN ON THIS TOPIC
Objectives To assess the safety and efficacy of
Long-­term safety and efficacy of upadacitinib versus adalimumab from SELECT-­COMPARE ⇒ Upadacitinib has demonstrated efficacy with an ac-
upadacitinib versus adalimumab ceptable safety profile in the phase 3 SELECT clinical
over 5 years.
in patients with rheumatoid trial programme of patients with rheumatoid arthritis
arthritis:
Methods Patients with rheumatoid arthritis and
inadequate response to methotrexate were randomised (RA), including in the SELECT-­COMPARE long-­term
5-­year data from the phase
3, randomised SELECT-­ to receive upadacitinib 15 mg once daily, placebo or extension (LTE) through 3 years.
COMPARE study. RMD Open adalimumab 40 mg every other week, all with concomitant

by copyright.
WHAT THIS STUDY ADDS
2024;10:e004007. doi:10.1136/ methotrexate. By week 26, patients with insufficient
rmdopen-2023-004007 ⇒ The SELECT-­COMPARE LTE is the first open-­label
response to randomised treatment were rescued; patients
remaining on placebo switched to upadacitinib. Patients study of upadacitinib in RA to assess the safety and
► Additional supplemental efficacy of upadacitinib compared with an active
completing the 48-­week double-­blind period could enter
material is published online only. a long-­term extension. Safety and efficacy were assessed comparator (adalimumab) for >1 year. The safety
To view, please visit the journal profile of upadacitinib through 5 years was consis-
through week 264, with radiographic progression analysed
online (https://​doi.​org/​10.1​ 136/​ tent with the 3-­year safety profile, with no new safe-
rmdopen-​2023-​004007). through week 192. Safety was assessed by treatment-­
ty signals observed and no evidence of an increase
emergent adverse events (TEAEs). Efficacy was analysed
in the risk of adverse events with longer exposure
by randomised group (non-­responder imputation (NRI)) or
to upadacitinib. Upadacitinib also continued to
Received 14 December 2023 treatment sequence (as observed).
Accepted 4 May 2024 show greater efficacy compared with adalimumab
Results Rates of TEAEs were generally similar with through 5 years.
upadacitinib versus adalimumab, although numerically
higher rates of herpes zoster, lymphopenia, creatine HOW THIS STUDY MIGHT AFFECT RESEARCH,
phosphokinase elevation, hepatic disorder and non-­ PRACTICE OR POLICY
melanoma skin cancer were reported with upadacitinib. ⇒ These results support a favourable benefit–risk pro-
Numerically greater proportions of patients randomised file for upadacitinib in the long-­term treatment of RA,
to upadacitinib versus adalimumab achieved clinical up to at least 5 years.
responses (NRI); Clinical Disease Activity Index remission
(≤2.8) and Disease Activity Score based on C reactive
protein <2.6 were achieved by 24.6% vs 18.7% (nominal
p=0.042) and 31.8% vs 23.2% (nominal p=0.006), INTRODUCTION
respectively. Radiographic progression was numerically Rheumatoid arthritis (RA) is a chronic,
© Author(s) (or their lower with continuous upadacitinib versus adalimumab at systemic, inflammatory disease that primarily
employer(s)) 2024. Re-­use week 192. affects the joints, with the development of
permitted under CC BY-­NC. No
Conclusion The safety profile of upadacitinib through significant disability and pain, and reduced
commercial re-­use. See rights
and permissions. Published 5 years was consistent with the known safety profile of quality of life, in most patients.1 A considerable
by BMJ. upadacitinib, with no new safety risks. Clinical responses number of patients with RA have an inadequate
For numbered affiliations see were numerically higher with upadacitinib versus response or intolerance to the initial recom-
end of article. adalimumab at 5 years. Upadacitinib demonstrates a mended treatment of conventional synthetic
favourable benefit–risk profile for long-­term rheumatoid disease-­
modifying antirheumatic drugs
Correspondence to arthritis treatment.
Dr Roy Fleischmann; (csDMARDs).2 3 For these patients, advanced
Trial registration number NCT02629159.
​rfleischmann@​arthdocs.​com therapies, including biological DMARDs

Fleischmann R, et al. RMD Open 2024;10:e004007. doi:10.1136/rmdopen-2023-004007    1

 RMD Open: first published as 10.1136/rmdopen-2023-004007 on 28 May 2024. Downloaded from http://rmdopen.bmj.com/ on November 26, 2024 at Pakistan:BMJ-PG Sponsored. Protected
RMD Open

(bDMARDs) and targeted synthetic DMARDs (tsDMARDs), Briefly, SELECT-­COMPARE is a phase 3 randomised study
are usually initiated as per the treat-­to-­target strategy. comprising a 26-­week double-­blind, placebo-­controlled
Upadacitinib, an oral, reversible Janus kinase (JAK) period that was part of a 48-­week double-­blind active
inhibitor (tsDMARD),4 has demonstrated efficacy in the comparator-­controlled period and an ongoing open-­label
phase 3 SELECT clinical trial programme of patients with LTE for a total of up to 10 years (online supplemental
RA, with an acceptable and generally well-­characterised figure 1). Patients were eligible if they were ≥18 years of
safety profile.5–9 age with a diagnosis of RA (meeting the 2010 ACR/Euro-
SELECT-­COMPARE is an ongoing double-­blind, phase pean Alliance of Associations for Rheumatology classifica-
3 study evaluating upadacitinib 15 mg once daily versus tion criteria)14 and had been on MTX for ≥3 months and
adalimumab 40 mg every other week (EOW), both in at a stable dose of 15–25 mg/week for ≥4 weeks prior to
combination with methotrexate (MTX), in patients with the first dose of study drug (or ≥10 mg/week if intolerant
an inadequate response to MTX alone; the first 26 weeks to ≥12.5 mg/week). Patients had active disease, defined
of the study were placebo controlled. The study met both as ≥6 swollen joints (of 66 examined), ≥6 tender joints (of
primary endpoints of achievement of ≥20% improvement 68 examined), high-­sensitivity CRP (hsCRP)≥5 mg/L and
in American College of Rheumatology response criteria ≥1 of the following at screening: ≥3 erosions on X-­rays
(ACR20; for US/Food and Drug Administration regula- of hands and feet, or ≥1 erosion and seropositivity for
tory purposes) and 28-­joint Disease Activity Score based rheumatoid factor or anti-­ cyclic citrullinated peptide
on C reactive protein (DAS28 (CRP)) <2.6 (for EU/ antibody, and an inadequate response or intolerance to
European Medicines Agency regulatory purposes) in the MTX. Exclusion criteria included inadequate response
upadacitinib group compared with the placebo group at to a prior bDMARD or prior exposure to a JAK inhibitor
week 12.6 In addition, the study met the ranked key or adalimumab. Patients were randomised in a 2:2:1 ratio
secondary endpoint of radiographic progression (change to upadacitinib 15 mg once daily, placebo or adalimumab
from baseline in modified Total Sharp Score (mTSS)) 40 mg EOW, in combination with MTX. Patients could
inhibition in the upadacitinib group compared with the be rescued from placebo to upadacitinib, upadacitinib to
placebo group at week 26. ACR20 and DAS28 (CRP) <2.6 adalimumab or adalimumab to upadacitinib within the
were achieved by a significantly greater proportion of first 26 weeks of the study by predefined criteria. Patients
patients, and radiographic progression was inhibited in a who did not achieve ≥20% improvement in tender joint
significantly greater proportion of patients, in the upad- count (TJC) and swollen joint count (SJC) were rescued

by copyright.
acitinib group versus the placebo group at weeks 12 and at weeks 14, 18 or 22 while patients who did not achieve
26, respectively. Upadacitinib was also superior to adali- low disease activity (LDA) as defined by Clinical Disease
mumab based on achievement of ≥50% improvement in Activity Index (CDAI) criteria (CDAI≤10) were rescued
ACR response criteria (ACR50), change from baseline in at week 26. All patients receiving placebo who were not
patient’s assessment of pain and change from baseline rescued by week 26 were switched to upadacitinib from
in the Health Assessment Questionnaire-­Disability Index that time point.
(HAQ-­DI) at week 12 and achievement of DAS28 (CRP) From week 26, initiation of, or change in, gluco-
≤3.2 at week 12.6 corticoids, non-­ steroidal anti-­
inflammatory drugs and
Through 26 weeks, the safety profile of upadacitinib was acetaminophen/paracetamol were allowed at the inves-
similar to that of adalimumab, except for higher rates of tigator’s discretion. From week 48, modification or initi-
herpes zoster and creatine phosphokinase (CPK) elevation ation of csDMARDs was allowed at the investigator’s
in the upadacitinib group. All patients either remained on, discretion. csDMARDs were restricted to up to two of the
or were rescued or switched to, upadacitinib or adalimumab following: MTX, sulfasalazine, hydroxychloroquine, chlo-
before or at week 26. Through 3 years in the ongoing open-­ roquine and leflunomide, except for the combination of
label long-­term extension (LTE) of SELECT-­COMPARE, MTX and leflunomide, which was not permitted. Patients
upadacitinib consistently showed better clinical and func- who completed the 48-­week double-­blind period could
tional responses across all efficacy endpoints compared enter the LTE study to continue receiving upadacitinib
with adalimumab, and the safety profile of upadacitinib was 15 mg once daily or adalimumab 40 mg EOW (open-­label
consistent with previous reports in RA and the known safety after the last patient completed their week 48 visit).
profile of upadacitinib in other indications.6 10–13
Here, we report 5-­year data on the safety and efficacy of Safety
upadacitinib 15 mg once daily versus adalimumab 40 mg Safety was assessed up to week 264, through the cut-­off
EOW, both in combination with MTX, from the SELECT-­ date of 5 October 2022. Treatment-­emergent adverse
COMPARE LTE study. events (TEAEs), serious TEAEs, TEAEs leading to
discontinuation, TEAEs of special interest and propor-
tions of patients experiencing grade 3 or grade 4 labo-
METHODS ratory abnormalities were summarised up to 5 years
Study design in all patients who received ≥1 dose of upadacitinib
The study design and eligibility of SELECT-­COMPARE, or adalimumab. TEAEs of special interest included
including the LTE, has been described previously.6 12 13 serious infection, opportunistic infection (excluding

2 Fleischmann R, et al. RMD Open 2024;10:e004007. doi:10.1136/rmdopen-2023-004007

 RMD Open: first published as 10.1136/rmdopen-2023-004007 on 28 May 2024. Downloaded from http://rmdopen.bmj.com/ on November 26, 2024 at Pakistan:BMJ-PG Sponsored. Protected
Rheumatoid arthritis

herpes zoster and tuberculosis), herpes zoster, active Statistical analysis

tuberculosis, malignancy (excluding non-­ melanoma Safety data were assessed in all patients who received
skin cancer (NMSC)), NMSC, lymphoma, adjudicated at least one dose of upadacitinib or adalimumab and
major adverse cardiovascular events (MACEs), adjudi- summarised under two drug exposure groups (any upad-
cated venous thromboembolic events (VTEs), adjudi- acitinib and any adalimumab); assignment of TEAEs was
cated gastrointestinal perforation, renal dysfunction, based on the drug being received at the time of the event.
anaemia, lymphopenia, neutropenia, CPK elevation and Any upadacitinib group included patients who received
hepatic disorder. In addition, malignancies (excluding continuous upadacitinib from randomisation through
NMSC), MACE and VTE were summarised in the subset 5 years as well as upadacitinib exposure from patients who
of patients receiving continuous upadacitinib or contin- were rescued/switched from placebo or adalimumab to
uous adalimumab from randomisation. TEAEs are upadacitinib; any adalimumab group included patients
presented as exposure-­ adjusted event rates (EAERs; who received continuous adalimumab from randomi-
events per 100 patient-­years (E/100 PY)). sation through 5 years as well as adalimumab exposure
Safety assessments were performed as have been from patients who were rescued from upadacitinib to
described previously.6 12 13 TEAEs were coded according adalimumab. Event rates for adjudicated MACE, adjudi-
to the Medical Dictionary for Regulatory Activities, V.25.0. cated VTE and malignancy (excluding NMSC), were also
TEAEs and laboratory changes (other than CPK and assessed in continuous upadacitinib and continuous adal-
creatinine levels) were graded using the Rheumatology imumab subgroups.
Common Toxicity Criteria, V.2.0.15 Changes in CPK Efficacy analyses were conducted in all randomised
and creatinine levels were graded using the Common patients who received ≥1 dose of study drug. Efficacy data
Toxicity Criteria of the National Cancer Institute (NCI up to week 264 were analysed by treatment sequence
CTC).16 MACE and VTE were adjudicated in a blinded (ie, placebo to upadacitinib; continuous upadacitinib;
manner by an independent Cardiovascular Adjudication continuous adalimumab; adalimumab to upadaci-
Committee. Assessment of TEAE severity was made at tinib; and upadacitinib to adalimumab), as well as by
the investigator’s discretion (mild (grade 1), moderate randomised treatment group (intention-­ to-­
treat anal-
(grade 2) or severe (grade 3 or 4)). TEAEs were catego- ysis). For binary endpoints and continuous endpoints
rised as transient based on the availability of an end date analysed by treatment sequence, as well as radiographic

by copyright.
for that TEAE. endpoints, as observed (AO) analyses were conducted
without imputation for missing data; AO analyses were
based on the number of patients continuing in the LTE.
Efficacy endpoints
For binary endpoints analysed by randomised treatment
Efficacy endpoints assessed through week 264 included
group, non-­responder imputation (NRI) was used for
the proportions of patients achieving CDAI LDA visits after rescue, premature discontinuation of the study
(CDAI≤10) or remission (CDAI≤2.8), DAS28 (CRP) drug and missing data. Treatments were compared using
≤3.2 or <2.6 and ≥20/50/70% improvement in ACR the Cochran-­Mantel-­Haenszel test, adjusting for the strat-
criteria (ACR20/50/70 responses). Changes from ification factor of prior bDMARD use (yes, no). Nominal
baseline in ACR components (TJC based on 68 joints p values are presented.
(TJC68), SJC based on 66 joints (SJC66), patient’s global
assessment of disease activity, physician’s global assess-
ment of disease activity, patient’s assessment of pain RESULTS
(0–100 mm scale), (HAQ-­DI; on a 0–3 scale) and hsCRP Patient disposition and demographics
(mg/L)), as well as change from baseline in severity of Overall, 1629 patients were randomised and received
morning stiffness (0–10 Numerical Rating Scale; 0=no ≥1 dose of study drug (upadacitinib: 651, adalimumab:
morning stiffness, 10=worst possible morning stiffness) 327 and placebo: 651) (online supplemental figure 2). Of
and duration of morning stiffness (minutes), were also the 651 patients randomised to upadacitinib, 252 (38.7%)
assessed. were rescued to adalimumab by week 26 while a greater
Radiographic progression was assessed up to 192 weeks proportion of patients (159/327; 48.6%) randomised to
(latest available collected time point) based on X-­rays of adalimumab were rescued to upadacitinib. Over half of
hands and feet at weeks 0, 26, 96 and 192. X-­rays were patients (342/651; 52.5%) randomised to upadacitinib
assessed by two independent readers who were blinded completed week 48 on randomised therapy and entered
to treatment and visit, with an additional adjudicator if the LTE study compared with 126/327 (38.5%) of those
there was a discrepancy of ≥8 between the two readers’ randomised to adalimumab. A greater proportion of
change in mTSS scores. Radiographic endpoints included patients randomised to upadacitinib also completed
the proportion of patients who showed no radiographic 5 years on continuous therapy (261/651; 40.1%)
progression (patients with a change from baseline in compared with those randomised to adalimumab
mTSS≤0), change from baseline in mTSS,17 18 change (96/327; 29.4%) (online supplemental figure 2).
from baseline in joint erosion scores and change from Between weeks 48 and 264, the proportions of patients
baseline in joint space narrowing. receiving continuous upadacitinib and continuous

Fleischmann R, et al. RMD Open 2024;10:e004007. doi:10.1136/rmdopen-2023-004007 3

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RMD Open

adalimumab who discontinued due to AEs were 9.6% Safety

and 7.9%, respectively, and due to lack of efficacy were Through 5 years, 1417 patients received any upadacitinib
0.9% and 0.8%, respectively. and 579 received any adalimumab. Overall exposure to
Patient demographics and baseline disease characteris- any upadacitinib and any adalimumab through 5 years
tics have been reported previously6; they were generally was 4496.6 PY and 1472.4 PY, respectively. The overall
well balanced across treatment arms (online supple- EAERs of any TEAE in patients receiving any upadac-
mental table 1). Of the proportion of patients receiving itinib were similar to any adalimumab (187.2 E/100 PY
glucocorticoids at baseline, 22.2% and 25.3% had discon- and 202.3 E/100 PY, respectively). Similar rates were also
tinued glucocorticoid use at week 156 in the contin- seen in patients receiving any upadacitinib compared with
uous upadacitinib and continuous adalimumab groups, any adalimumab for serious TEAEs (11.5 E/100 PY and
respectively, and this increased to 28.8% and 35.9%, 13.3 E/100 PY, respectively). TEAEs leading to discontinua-
respectively, at week 264. tion of the study drug, any COVID-­19-­related AEs and deaths

Table 1 TEAEs through 264 weeks

Any UPA 15 mg QD (n=1417; Any ADA 40 mg EOW (n=579;
PY=4496.6) PY=1472.4)
EAER E (E/100 PY) E (E/100 PY)
Any TEAE 8419 (187.2) 2978 (202.3)
Serious TEAE 517 (11.5) 196 (13.3)
TEAE leading to discontinuation of study drug 195 (4.3) 81 (5.5)
Any COVID-­19-­related adverse event 239 (5.3) 62 (4.2)
Any death* 41 (0.9) 14 (1.0)
TEAEs of special interest    
 Serious infection 167 (3.7) 49 (3.3)

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 Opportunistic infection† 13 (0.3) 2 (0.1)
 Herpes zoster 127 (2.8) 17 (1.2)
 Active tuberculosis 3 (<0.1) 3 (0.2)
 Malignancy (excluding NMSC) 26 (0.6) 12 (0.8)
 NMSC 24 (0.5) 2 (0.1)
 Lymphoma 0 3 (0.2)
 Adjudicated MACE‡ 12 (0.3) 4 (0.3)
 Adjudicated VTE§ 12 (0.3) 6 (0.4)
 Adjudicated gastrointestinal perforation 1 (<0.1) 0
 Renal dysfunction 12 (0.3) 6 (0.4)
 Anaemia 113 (2.5) 49 (3.3)
 Lymphopenia 115 (2.6) 13 (0.9)
 Neutropenia 95 (2.1) 34 (2.3)
 CPK elevation 179 (4.0) 26 (1.8)
 Hepatic disorder 476 (10.6) 101 (6.9)
Safety was assessed up to week 264, through the cut-­off date of 5 October 2022. TEAEs included any adverse event with an onset date on
or after the first dose of study drug and up to 30 days after the last dose of placebo or UPA and 70 days for ADA, if patients discontinued
prematurely. Data through 264 weeks include all patients receiving UPA or ADA, including rescue groups, with assignment based on drug
exposure at the time of the event.
*Includes treatment emergent (occurring ≤30 days after the last dose of UPA or ≤70 days after the last dose of ADA) and non-­treatment-­
emergent (occurring >30 days after the last dose of UPA or >70 days after the last dose of ADA) deaths.
†Excluding herpes zoster and tuberculosis.
‡MACE defined as cardiovascular death (includes acute myocardial infarction, sudden cardiac death, heart failure, cardiovascular procedure-­
related death, death due to cardiovascular haemorrhage, fatal stroke, pulmonary embolism and other cardiovascular causes), non-­fatal
myocardial infarction and non-­fatal stroke.
§VTE included deep vein thrombosis and pulmonary embolism (fatal and non-­fatal).
ADA, adalimumab; CPK, creatine phosphokinase; E, Event; EAER, exposure-­adjusted event rate; EOW, every other week; MACE, major
adverse cardiovascular event; NMSC, non-­melanoma skin cancer; PY, patient-­years; QD, once daily; TEAE, treatment-­emergent adverse
event; UPA, upadacitinib; VTE, venous thromboembolic event.

4 Fleischmann R, et al. RMD Open 2024;10:e004007. doi:10.1136/rmdopen-2023-004007

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Rheumatoid arthritis

are summarised in table 1 (further details of COVID-­19 Hunt syndrome); 10 events had ophthalmic involvement
adverse events are described in online supplemental table (2 in any adalimumab group and 8 in any upadacitinib
2). The most common TEAEs (>5 E/100 PY) reported in group). Rates of lymphopenia were 2.6 E/100 PY and
both groups were urinary tract infection, upper respiratory 0.9 E/100 PY in any upadacitinib and any adalimumab
tract infection and nasopharyngitis (online supplemental groups, respectively. The majority of lymphopenia events
table 3). were mild or moderate, with severe events accounting
Overall rates of TEAEs of special interest were gener- for 37.4% (grade 3 or 4 (as assessed by the investigator))
ally similar between groups, except for numerically and 15.4% (grade 3) in any upadacitinib and any adali-
higher rates of herpes zoster, lymphopenia, CPK eleva- mumab groups, respectively. Of 45 severe (grade 3 or 4)
tion, hepatic disorder (mostly transaminase elevations) events of lymphopenia, 3 events (pharyngitis, varicella
and NMSC in patients receiving any upadacitinib and post-­ procedural infection; all in any upadacitinib
compared with any adalimumab (table 1). In any upad- group) were associated with infection, and 1 additional
acitinib and adalimumab groups, similar rates of serious event had a questionable association because COVID-­19
infections (3.7 E/100 PY and 3.3 E/100 PY, respec- infection was reported 1 month prior to lymphopenia in
tively) and opportunistic infections (excluding herpes the patient involved. Higher proportions of patients with
zoster and tuberculosis) (0.3 E/100 PY and 0.1/100 PY, grade 3/4 reductions (as assessed by Outcome Measures
respectively) were observed. Rates of anaemia were also in Rheumatology (OMERACT) criteria) in lymphocytes
similar in any upadacitinib and any adalimumab groups. (grade 3: 0.5 to <1.0×109/L; grade 4: <0.5×109/L) were
Herpes zoster infection rates were 2.8 E/100 PY and reported in any upadacitinib group compared with any
1.2 E/100 PY in any upadacitinib and any adalimumab adalimumab group (table 2). Higher proportions of
groups, respectively. Most herpes zoster infections were patients with grade 3 reductions in neutrophils (8.5%
non-­serious, involved one dermatome and were non-­ and 5.9%) and haemoglobin (1.8% and 0.9%) were
disseminated; rates of serious herpes zoster events were reported in any upadacitinib group compared with any
0.3 E/100 PY and 0 in any upadacitinib and any adali- adalimumab group, respectively. No pattern or trend in
mumab groups, respectively. In any upadacitinib group, types of infection occurring within 30 days of a grade 3 or
17.6% of patients had unilateral presentation involving 4 event of neutropenia was observed.
multiple dermatomes. One event had central nervous Rates of CPK elevations were 4.0 E/100 PY and
system involvement in any upadacitinib group (Ramsay 1.8 E/100 PY in any upadacitinib and any adalimumab

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Table 2 Grade 3 or 4 laboratory abnormalities through 264 weeks
Any UPA 15 mg QD Any ADA 40 mg EOW
(n=1417) (n=579)
Parameter % of patients % of patients
Haemoglobin (g/L) Grade 3 (decrease 21–29* or Hb ≥70 to <80) 8.5 5.9
Grade 4 (decrease ≥30* or Hb <70) 3.7 4.0
Lymphocytes (×109/L) Grade 3 (0.5 to <1.0) 33.3 11.3
Grade 4 (<0.5) 4.7 1.0
Neutrophils (×109/L) Grade 3 (0.5 to <1.0) 1.8 0.9
Grade 4 (<0.5) 0.4 0.3
ALT (U/L) Grade 3 (3.0–8.0×ULN) 6.9 2.8
Grade 4 (>8.0×ULN) 0.9 0.7
AST (U/L) Grade 3 (3.0–8.0×ULN) 4.0 1.9
Grade 4 (>8.0×ULN) 0.8 0.9
CPK (U/L) Grade 3 (>5.0–10.0×ULN) 2.5 0.9
Grade 4 (>10.0×ULN) 1.1 0.5
Creatinine (µmol/L) Grade 3 (>3.0–6.0×ULN) 0.1 0.3
Grade 4 (>6.0×ULN) 0.1 0
Safety was assessed up to week 264, through the cut-­off date of 5 October 2022. Data are for patients with worsening in grade severity for
laboratory parameters. Grading is based on Outcome Measures in Rheumatology criteria, except for CPK and creatinine, for which National
Cancer Institute Common Terminology Criteria were used.
*Decrease from baseline. Baseline is defined as the last observation on or before the date of the first dose of study drug in the corresponding
treatment group.
ADA, adalimumab; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CPK, creatine phosphokinase; EOW, every other week;
Hb, Haemoglobin; QD, once daily; ULN, upper limit of normal; UPA, upadacitinib.

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RMD Open

groups, respectively (table 1). The majority of CPK eleva-

Table 3 EAERs of malignancy (excluding NMSC),
tions were mild or moderate, with severe events (grade adjudicated MACE and VTE through 264 weeks
3 (as assessed by the investigator)) accounting for 5.0%
Continuous UPA Continuous ADA
and 3.8% in any upadacitinib and any adalimumab 15 mg QD 40 mg EOW (n=168;
groups, respectively. The majority of CPK elevations (n=398; PY=1573.0) PY=582.4)
were also transient (79.9% and 96.2% in any upadac- E (E/100 PY) E (E/100 PY)
itinib and any adalimumab groups, respectively) and EAER (95% CI) (95% CI)
did not lead to discontinuation of study drug. Higher Malignancy 12 (0.8) (0.4 to 1.3) 5 (0.9) (0.3 to 2.0)
proportions of patients with grade 3 and grade 4 eleva- (excluding NMSC)
tions (as assessed by NCI CTC criteria) in CPK (>5.0 Adjudicated MACE* 2 (0.1) (0.0 to 0.5) 2 (0.3) (0.0 to 1.2)
to 10.0×upper limit of normal (ULN) and >10.0×ULN) Adjudicated VTE† 3 (0.2) (0.0 to 0.6) 3 (0.5) (0.1 to 1.5)
were reported in any upadacitinib group compared with
any adalimumab group. One case of rhabdomyolysis, Safety was assessed up to week 264, through the cut-­off date
of 5 October 2022.
related to alcohol withdrawal and seizure, was reported
*MACE defined as cardiovascular death (includes acute MI,
in any upadacitinib group and was deemed by the inves- sudden cardiac death, heart failure, cardiovascular procedure-­
tigator to have no reasonable possibility of being related related death, death due to cardiovascular haemorrhage, fatal
to the study drug. Rates of hepatic disorder were 10.6 stroke, pulmonary embolism and other cardiovascular causes),
E/100 PY and 6.9 E/100 PY in any upadacitinib and any non-­fatal MI and non-­fatal stroke.
†VTE included fatal and non-­fatal deep vein thrombosis and
adalimumab groups, respectively (table 1). The majority
pulmonary embolism.
of hepatic disorder events involved alanine aminotrans- ADA, adalimumab; E, events; EAER, exposure-­adjusted
ferase (ALT) or aspartate aminotransferase (AST) eleva- event rate; EOW, every other week; MACE, major adverse
tions, with no cases of Hy’s law identified and were mild cardiovascular event; MI, myocardial infarction; NMSC, non-­
or moderate, with severe events accounting for 9.5% melanoma skin cancer; PY, patient-­years; QD, once daily; UPA,
upadacitinib; VTE, venous thromboembolic event.
(grade 3 or 4 (as assessed by the investigator)) and
8.9% (grade 3) of hepatic disorders and 8.9% (grade
3 or 4) and 12.3% (grade 3) of ALT/AST elevations in had ≥1 risk factor including hypertension, diabetes
any upadacitinib and any adalimumab groups, respec- mellitus, smoking and obesity (online supplemental
tively. The majority of hepatic disorder events were also

by copyright.
tables 5 and 6). In the subgroups of patients receiving
transient (78.4% and 76.2% in any upadacitinib and continuous upadacitinib (n=398; 1573.0 PY) or contin-
any adalimumab groups, respectively). Higher propor- uous adalimumab (n=168; 582.4 PY), the rates of
tions of patients with grade 3 elevations (as assessed by malignancies (excluding NMSC) were 0.8 E/100 PY vs
OMERACT criteria) in ALT/AST (3.0–8.0×ULN) were 0.9 E/100 PY, rates of adjudicated MACE were
reported in any upadacitinib group compared with any 0.1 E/100 PY vs 0.3 E/100 PY and rates of adjudicated
adalimumab group; similar proportions of patients with VTE were 0.2 E/100 PY vs 0.5 E/100 PY, respectively
grade 4 elevations (>8×ULN) in ALT/AST were reported (table 3).
in both groups. 14 patients discontinued study drug due 55 deaths (41 of which were treatment emergent)
to ALT/AST elevations (11 in any upadacitinib group occurred in patients receiving any upadacitinib (41
and 3 in any adalimumab group). One event of adjudi- deaths) and any adalimumab (14 deaths). The rate of
cated gastrointestinal perforation occurred in a patient deaths in any upadacitinib and any adalimumab groups
receiving any upadacitinib. were similar (0.9 E/100 PY and 1.0 E/100 PY, respec-
Rates of malignancies (excluding NMSC) were tively; table 1 and online supplemental table 7). The most
similar in any upadacitinib and any adalimumab groups common causes of death reported were COVID-­19 or
(0.6 E/100 PY and 0.8 E/100 PY, respectively) (table 1). pneumonia associated with COVID-­19 (12 events); rates
Rates of NMSC were numerically higher in any upad- of any COVID-­19 infection, serious COVID-­19 infection
acitinib group compared with any adalimumab group and fatal COVID-­19 infection were numerically higher in
(0.5 E/100 PY and 0.1 E/100 PY, respectively), while any upadacitinib group compared with any adalimumab
rates of lymphoma were numerically higher in any group (online supplemental table 2).
adalimumab group compared with any upadacitinib
group (0.2 E/100 PY and 0 E/100 PY, respectively). Efficacy
Rates of melanoma were similar in any upadacitinib Over 5 years, the proportions of patients achieving LDA
and any adalimumab groups (<0.1 E/100 PY for both and remission as defined by CDAI criteria (CDAI≤10 and
groups). A full list of malignancies can be found in CDAI≤2.8), and the proportions of patients achieving
online supplemental table 4. Rates of adjudicated DAS28 (CRP) ≤3.2 and DAS28 (CRP) <2.6, were
MACE and adjudicated VTE were similar in any upad- consistently higher in patients randomised to upadac-
acitinib and any adalimumab groups (0.3 E/100 PY itinib (n=651) compared with adalimumab (n=327) as
and 0.3 E/100 PY for MACE and 0.3 E/100 PY and analysed by NRI (figure 1). At week 264, CDAI≤10 was
0.4 E/100 PY for VTE, respectively; table 1 and online achieved by 36.4% vs 26.9% (NRI; nominal p=0.004) of
supplemental table 4). All patients with MACE or VTE patients randomised to upadacitinib versus adalimumab,

6 Fleischmann R, et al. RMD Open 2024;10:e004007. doi:10.1136/rmdopen-2023-004007

 RMD Open: first published as 10.1136/rmdopen-2023-004007 on 28 May 2024. Downloaded from http://rmdopen.bmj.com/ on November 26, 2024 at Pakistan:BMJ-PG Sponsored. Protected
Rheumatoid arthritis

by copyright.
Figure 1 Proportions of patients achieving CDAI LDA/remission and DAS28 (CRP) ≤3.2/<2.6 through 264 weeks (NRI).
#p<0.05, ##p<0.01, ###p<0.001 for UPA 15 mg once daily vs ADA 40 mg every other week. All p values are nominal. Treatment
groups are by initial randomisation. NRI was used for patients who were rescued or prematurely discontinued study drug, as
well as for missing data. Data points plotted here are shown in online supplemental table 8. ADA, adalimumab; CDAI, Clinical
Disease Activity Index; DAS28 (CRP), 28-­joint Disease Activity Score based on C reactive protein; LDA, low disease activity;
NRI, non-­responder imputation; UPA, upadacitinib.

respectively; CDAI≤2.8 was achieved by 24.6% vs 18.7% (figure 2). DAS28 (CRP) ≤3.2 and DAS28 (CRP) <2.6
(NRI; nominal p=0.042) of patients randomised to upad- were achieved by numerically higher proportions of
acitinib versus adalimumab, respectively. At week 264, patients who switched from adalimumab to upadacitinib
DAS28 (CRP) ≤3.2 was achieved by 34.7% vs 24.8% (NRI; versus upadacitinib to adalimumab.
nominal p=0.002) of patients randomised to upadacitinib Over 5 years, the proportions of patients achieving
versus adalimumab, respectively; DAS28 (CRP) <2.6 was ACR20, ACR50 and ACR70 were consistently higher in
achieved by 31.8% vs 23.2% (NRI; nominal p=0.006) of patients randomised to upadacitinib (n=651) compared
patients randomised to upadacitinib versus adalimumab, with adalimumab (n=327) as analysed by NRI (figure 3).
respectively. At week 264, ACR20 was achieved by 38.4% vs 28.4%
Summarising by treatment sequence (AO), at week (NRI; nominal p=0.002) of patients randomised to upad-
264, similar proportions of patients receiving continuous acitinib versus adalimumab, respectively; ACR50 was
upadacitinib versus continuous adalimumab achieved achieved by 35.3% vs 25.7% (NRI; nominal p=0.003) of
CDAI≤10 and CDAI≤2.8 (figure 2). CDAI≤10 and patients randomised to upadacitinib versus adalimumab,
CDAI≤2.8 were achieved by numerically higher propor- respectively; and ACR70 was achieved by 28.6% vs 22.3%
tions of patients who switched from adalimumab to (NRI; nominal p=0.042) of patients randomised to upad-
upadacitinib versus upadacitinib to adalimumab. At week acitinib versus adalimumab, respectively.
264, similar proportions of patients receiving contin- Summarising by treatment sequence (AO), ACR20
uous upadacitinib versus continuous adalimumab also rates were generally similar in patients receiving contin-
achieved DAS28 (CRP) ≤3.2 and DAS28 (CRP) <2.6 uous upadacitinib versus continuous adalimumab

Fleischmann R, et al. RMD Open 2024;10:e004007. doi:10.1136/rmdopen-2023-004007 7

 RMD Open: first published as 10.1136/rmdopen-2023-004007 on 28 May 2024. Downloaded from http://rmdopen.bmj.com/ on November 26, 2024 at Pakistan:BMJ-PG Sponsored. Protected
RMD Open

by copyright.
Figure 2 Proportions of patients achieving CDAI LDA/remission and DAS28 (CRP) ≤3.2/<2.6 through 264 weeks (AO).
Groups are by treatment sequence AO, without imputation for missing data. All patients in the PBO group who were not
previously rescued were switched to UPA at week 26. Data points plotted here are shown in online supplemental table 9. ADA,
adalimumab; AO, as observed; CDAI, Clinical Disease Activity Index; DAS28 (CRP), 28-­joint Disease Activity Score based on C
reactive protein; LDA, low disease activity; PBO, placebo; UPA, upadacitinib.

throughout 5 years, including at week 264 (97.0% vs For ACR components over 264 weeks analysed by treat-
96.0%) (figure 4). ACR50 and ACR70 rates were generally ment sequence (AO), patients receiving continuous
numerically higher in patients receiving continuous upad- upadacitinib generally achieved numerically greater
acitinib versus continuous adalimumab until week 216, improvements compared with those receiving contin-
but at week 264, similar proportions of patients receiving uous adalimumab, except for TJC68 in which responses
continuous upadacitinib versus continuous adalimumab were generally similar (online supplemental figure 3).
achieved ACR50 and ACR70. At week 264, ACR20 was Numerically greater improvements in severity and dura-
achieved by similar proportions of patients who switched tion of morning stiffness were also achieved in patients
from adalimumab to upadacitinib compared with those receiving continuous upadacitinib compared with those
who switched from upadacitinib to adalimumab, respec- receiving continuous adalimumab (online supplemental
tively, while ACR50 and ACR70 were achieved by numer- figure 4A,B).
ically higher proportions of patients who switched from At week 192, as analysed by treatment sequence (AO),
adalimumab to upadacitinib compared with those who similar proportions of patients demonstrated no radio-
switched from upadacitinib to adalimumab (figure 4). graphic progression (ΔmTSS≤0 from baseline; 80.9% vs

8 Fleischmann R, et al. RMD Open 2024;10:e004007. doi:10.1136/rmdopen-2023-004007

 RMD Open: first published as 10.1136/rmdopen-2023-004007 on 28 May 2024. Downloaded from http://rmdopen.bmj.com/ on November 26, 2024 at Pakistan:BMJ-PG Sponsored. Protected
Rheumatoid arthritis

by copyright.
Figure 3 Proportions of patients achieving ACR20, ACR50 and ACR70 through 264 weeks (NRI). #p<0.05, ##p<0.01,
###p<0.001 for UPA 15 mg once daily vs ADA 40 mg every other week. All p values are nominal. Treatment groups are by initial
randomisation. NRI was used for patients who were rescued or prematurely discontinued study drug, as well as for missing
data. Data points plotted here are shown in online supplemental table 8. ACR20/50/70, ≥20/50/70% improvement in American
College of Rheumatology response criteria; ADA, adalimumab; NRI, non-­responder imputation; UPA, upadacitinib.

78.0% for continuous upadacitinib vs continuous adali- the published 3-­year data.13 Open-­label LTE studies such
mumab and 77.5% vs 74.0% for adalimumab to upad- as this provide systematic information on long-­term safety
acitinib vs upadacitinib to adalimumab) (figure 5A). profiles, which are of key clinical relevance in chronic
Additionally, at week 192, patients receiving continuous conditions such as RA.13 19 SELECT-­COMPARE is unique
upadacitinib showed numerically lower radiographic in that it assesses the safety and efficacy of upadacitinib
progression compared with the other treatment sequence compared with the active comparator adalimumab for up
groups) (ΔmTSS; 0.53 vs 1.18 for continuous upadaci- to 10 years; other head-­to-­head studies of upadacitinib in
tinib vs continuous adalimumab, respectively, and 0.88 RA only compared upadacitinib to active comparators for
vs 1.72 for adalimumab to upadacitinib vs upadacitinib up to 1 year.20–22
to adalimumab, respectively) (figure 5B and online The safety profile of upadacitinib 15 mg once daily
supplemental figure 5A). In addition, changes from through 5 years was consistent with the 3-­year safety profile
baseline in joint erosion and joint space narrowing were and the integrated safety analysis from the SELECT phase 3
numerically lower in patients receiving continuous upad- programme,11 13 with no new safety signals observed. Rates of
acitinib versus continuous adalimumab and in patients any TEAE, serious TEAEs and TEAEs leading to discontinu-
who switched from adalimumab to upadacitinib versus ation were similar with upadacitinib and adalimumab. Rates
upadacitinib to adalimumab at week 192 (online supple- of any COVID-­ 19 infection, serious COVID-­ 19 infection
mental figure 5B,C). and fatal COVID-­19 infection were numerically higher in
patients receiving upadacitinib compared with adalimumab.
DISCUSSION These results are consistent with the findings of a long-­term
These 5-­
year data from the ongoing, open-­ label LTE safety study of upadacitinib using pooled data across indi-
of the SELECT-­COMPARE study provide a longer-­term cations.10 Overall, rates of TEAEs of special interest were
update on the safety and efficacy of upadacitinib since generally similar between patients receiving upadacitinib

Fleischmann R, et al. RMD Open 2024;10:e004007. doi:10.1136/rmdopen-2023-004007 9

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RMD Open

by copyright.
Figure 4 Proportions of patients achieving ACR20, ACR50 and ACR70 through 264 weeks (AO). Groups are by treatment
sequence AO, without imputation for missing data. All patients in the PBO group who were not previously rescued were
switched to UPA at week 26. Data points plotted here are shown in online supplemental table 9. ACR20/50/70, ≥20/50/70%
improvement in American College of Rheumatology response criteria; ADA, adalimumab; AO, as observed; PBO, placebo;
UPA, upadacitinib.

and adalimumab, except for numerically higher rates of group). Herpes zoster vaccination is recommended for all
herpes zoster, lymphopenia, CPK elevation, hepatic disor- patients prior to initiating upadacitinib treatment.29–32 The
ders (mostly transaminase elevations) and NMSC with majority of CPK elevations were transient, and the rates
upadacitinib. The proportions of patients with grade 3/4 at 5 years versus those at 3 years, were numerically lower
laboratory abnormalities were generally higher with upad- in the upadacitinib group and similar in the adalimumab
acitinib compared with adalimumab and were similar to group (4.0 E/100 PY vs 4.7 E/100 PY and 1.8 E/100 PY vs
the results reported at 3 years. Higher rates of herpes zoster 1.7 E/100 PY), respectively. Rates of NMSC were numeri-
and CPK elevation with upadacitinib are expected based on cally higher in patients receiving upadacitinib compared
the known safety profile of JAK inhibitors.11 23–28 However, with adalimumab, as expected based on the known risk
most cases of herpes zoster were non-­serious, involved one of NMSC in patients with inflammatory diseases receiving
dermatome and did not lead to discontinuation of study JAK inhibitors.33–35 Although SELECT-­COMPARE was not
drug; there were three events of ophthalmic herpes zoster designed as a head-­to-­head safety study, the rates of TEAEs
(two in any upadacitinib group and one in any adalimumab of special interest, including MACE, VTE and malignancies

10 Fleischmann R, et al. RMD Open 2024;10:e004007. doi:10.1136/rmdopen-2023-004007

 RMD Open: first published as 10.1136/rmdopen-2023-004007 on 28 May 2024. Downloaded from http://rmdopen.bmj.com/ on November 26, 2024 at Pakistan:BMJ-PG Sponsored. Protected
Rheumatoid arthritis

malignancies (excluding NMSC) between upadacitinib and

adalimumab through 5 years when analysed by treatment
at time of event and in subgroups receiving continuous
upadacitinib or adalimumab treatment from randomisa-
tion. While there appears to be some numerical imbalance
between upadacitinib and adalimumab in malignancies per
organ system (online supplemental table 4), particularly
for basal cell carcinoma, the rates are generally comparable
between the treatment groups. The event rate for malig-
nancies (excluding NMSC) was consistent with RA popu-
lations37–39 and, as expected, most malignancies occurred
in patients ≥50 years of age. Although rates of MACE/VTE
and rates of death were similar between the two groups, the
rate of deaths due to cardiac disorders was higher in the
upadacitinib group. However, all cases of MACE or VTE
(including deaths due to cardiac disorders) occurred in
patients with ≥1 known risk factor. A post hoc analysis of
the SELECT RA clinical programme, which evaluated the
safety of upadacitinib in patients with increased cardiovas-
cular risk, found that while herpes zoster and NMSC were
observed at higher rates in patients receiving upadacitinib
compared with adalimumab or MTX, rates of MACE, VTE
and malignancy (excluding NMSC) were similar across
treatments, although they were numerically higher in
patients at increased cardiovascular risk.40 Further long-­
term studies are required to fully determine whether there
is an association between JAK inhibitors and NMSC,10 and
VTE given that conditions for which JAK inhibitors are indi-

by copyright.
cated carry inherent risks for VTE.
At 264 weeks, upadacitinib continued to show greater
efficacy than adalimumab when analysed by NRI while anal-
ysis by treatment sequence (AO) showed similar responses
between patients receiving continuous upadacitinib and
continuous adalimumab. The AO analysis included all
patients who continued therapy, likely because they experi-
enced clinical benefit without significant toxicity; therefore,
the similar AO results between continuous upadacitinib
and continuous adalimumab are as expected and suggest
that if patients experience clinical benefit and tolerate the
Figure 5 Radiographic outcomes at 26, 96 and
study drug, their benefit is likely to continue. On the other
192 weeks (AO). Groups are by treatment sequence AO,
without imputation for missing data. All patients in the PBO
hand, the NRI analysis comprised all randomised patients,
group who were not previously rescued were switched to including patients who did not experience a significant
UPA at week 26. Data points plotted here are shown inonline response or who discontinued study drug. The NRI results
supplemental tables 9,10. Δ, change from baseline; ADA, in this population suggest that patients are more likely to
adalimumab; AO, as observed; BL, baseline; LS, least benefit from, and tolerate, upadacitinib compared with
squares; PBO, placebo; mTSS, modified Total Sharp Score; adalimumab. Due to rescue handling, in the NRI analysis,
UPA, upadacitinib. patients who did not achieve CDAI LDA and were rescued
at week 26 were considered non-­responders for all binary
(excluding NMSC), which have emerged for the JAK inhib- endpoints at all visits after rescue, therefore; NRI response
itor class of drugs, were prespecified based on findings in rates are very conservative after week 26 for endpoints less
previous studies and other JAK inhibitors.36 The observed stringent than CDAI LDA.
rates of TEAEs of special interest, including MACE, VTE Patients receiving upadacitinib showed greater
and malignancies (excluding NMSC), were consistent with achievement of LDA and remission as defined by CDAI
the SELECT-­ COMPARE 3-­ year results,13 demonstrating criteria, DAS28 (CRP) ≤3.2/<2.6 and ACR20/50/70,
no evidence of an increase in risk with longer exposure to as well as greater improvements in the patient-­
upadacitinib. This is also consistent with results from a long-­ reported outcomes of HAQ-­DI and morning stiffness
term safety analysis of upadacitinib across indications.10 severity and duration at week 264. Inhibition of radio-
No differences were observed in rates of MACE, VTE or graphic progression (change from baseline in mTSS

Fleischmann R, et al. RMD Open 2024;10:e004007. doi:10.1136/rmdopen-2023-004007 11

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RMD Open

≤0) remained high and consistently similar between Acknowledgements AbbVie and the authors thank the participants, study sites
and investigators who are participating in this clinical trial. Medical writing support
patients receiving continuous upadacitinib and contin- was provided by Laura Chalmers, PhD, of 2 the Nth (Cheshire, UK).
uous adalimumab. The mean change from baseline in
Contributors RF, YL and CGP contributed to the study conception and design.
mTSS was numerically lower with continuous upadac- RF, JS, PD, LB, CGP, YT and EM participated in data acquisition. SKP and NK were
itinib than continuous adalimumab from week 96 to involved in the interpretation of the data. XB and YL conducted the statistical
week 192. The rate of radiographic progression was not analyses. All authors analysed and interpreted the data and contributed to the
critical revision of the manuscript. All named authors met the International
clinically significant in patients receiving continuous Committee of Medical Journal Editors criteria for authorship for this article, take
upadacitinib or continuous adalimumab and is, there- responsibility for the integrity of the work as a whole and have given their approval
fore, likely to translate to very little functional decline for this version to be published. RF acts as guarantor and accepts full responsibilty
for the work, had access to the data, and controlled the decision to publish.
in these patients.
Funding This work is supported by AbbVie, who is funding this trial and
In line with improved efficacy, the use of corticosteroids participated in the trial design, research, analysis, data collection, interpretation
continued to decline in the continuous upadacitinib and of data, and the review and approval of the publication. All authors had access
continuous adalimumab groups. to relevant data and participated in the drafting, review and approval of this
publication. No honoraria or payments were made for authorship.
Limitations of this analysis include that SELECT-­
Competing interests RF has received consulting fees and/or grant/research
COMPARE was not designed or powered to detect statis- support from AbbVie, Amgen, BI, Biosplice, BMS, Flexion, Galapagos, Galvani,
tical differences in safety events; nor was it designed Gilead, GSK, Horizon, Janssen, Lilly, Novartis, Pfizer, Sanofi-­Aventis, Selecta, UCB,
with parallel groups in the LTE because of rescue Viela, Vorso and Vyne and has participated on a data safety monitoring board or
advisory board for Kiniksa. JS has received speaking fees, consulting fees and
switching.13 Therefore, these data should be interpreted grant/research support from AbbVie, Accord, BMS, Janssen, MSD, Pfizer, Roche,
with respect to this. The nature of LTE studies means Sandoz and UCB. SKP, XB, NK and YL are employees of AbbVie and may hold
that AO data may be biased by patients who remain in stock or options. PD has received speaker fees from AbbVie, Galapagos, Lilly,
Nordimed and Thermofischer. LB has received speaking fees, consulting fees and
the study being better able to tolerate the drug and show grant/research support from AbbVie, Amgen, BMS, Celgene, Lilly, Fresenius Kabi,
response; however, all binary endpoints were also anal- Gilead, Janssen, Novartis, Organon, Pfizer, Sanofi-­Aventis, Teva and UCB. CGP is
ysed by NRI, which provides insight into an intention-­ an employee and shareholder of Spire Sciences and has served as a consultant
for Aclaris, AstraZeneca, Daiichi-­Sankyo, Five Prime, Genentech, Gilead, GSK,
to-­treat comparison between those randomised to Istesso, Labcorp, Lilly, Pacira, Paradigm, SetPoint, Sorrento, SynOx and UCB. YT has
upadacitinib versus adalimumab. Also, the analysis of received speaker fees and/or honoraria from AbbVie, Asahikasei, AstraZeneca, BI,
treatment response did not take into consideration how BMS, Chugai, Eisai, Gilead, GSK, Lilly, Pfizer, Taiho and Taisho and research grants
from Asahikasei, Chugai, Eisai, Mitsubishi-­Tanabe and Taisho. EM has received
modifications to background RA medications may have speaking fees, consulting fees and grant/research support from AbbVie, Amgen,

by copyright.
contributed to the ability of these patients to achieve AstraZeneca, BMS, Hi-­Bio, Janssen, Lilly, Novartis, Pfizer, Roche, Sandoz and
treatment goals. Specifically, no analysis was conducted Sanofi, and has received payment for expert testimony from AbbVie.
to assess whether a higher proportion of patients who Patient consent for publication Not applicable.
switched to adalimumab also discontinued MTX, which Ethics approval The study is being conducted according to the International
could have affected efficacy in the upadacitinib to adali- Council for Harmonization guidelines, local regulations and guidelines governing
clinical study conduct, and the Declaration of Helsinki. All patients provided written
mumab arm. informed consent, and the study protocol and consent forms were approved by
In summary, the safety profile of upadacitinib 15 mg an institutional review board or independent ethics committee at each study site.
once daily through 5 years in the SELECT-­COMPARE The coordinating investigator (Charles Birbara of the University of Massachusetts,
Worcester, Massachusetts, USA) received approval from the Advarra Institutional
study was consistent with previous reports in RA and the Review Board.
known safety profile of upadacitinib in other indications, Provenance and peer review Not commissioned; externally peer reviewed.
with no new safety risks observed.6 10–13 Upadacitinib Data availability statement Data are available on reasonable request. AbbVie
15 mg once daily continued to show numerically better is committed to responsible data sharing regarding the clinical trials we sponsor.
clinical responses in terms of CDAI LDA and remission, This includes access to anonymised, individual-­level and trial-­level data (analysis
datasets), as well as other information (eg, protocols and clinical study reports),
DAS28 (CRP) ≤3.2/<2.6 and ACR20/50/70 compared provided the trials are not part of an ongoing or planned regulatory submission.
with adalimumab 40 mg EOW at 5 years, and radio- This includes requests for clinical trial data for unlicensed products and indications.
graphic progression remained low with both treatments These clinical trial data can be requested by any qualified researchers who engage
in rigorous, independent scientific research, and will be provided following review
at week 192. These results continue to support a favour- and approval of a research proposal and statistical analysis plan, and execution of
able benefit–risk profile for upadacitinib 15 mg once a Data Sharing Agreement. Data requests can be submitted at any time and the
daily in the long-­term treatment of RA. data will be accessible for 12 months, with possible extensions considered. For
more information on the process or to submit a request, visit https://www.abbvie.​
com/our-science/clinical-trials/clinical-trials-data-and-information-sharing/data-​
Author affiliations
1 and-information-sharing-with-qualified-researchers.html.
Metroplex Clinical Research Center, University of Texas Southwestern Med Center,
Dallas, Texas, USA Supplemental material This content has been supplied by the author(s). It has
2 not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been
Department of Rheumatology and Internal Medicine, Wroclaw Medical University,
peer-­reviewed. Any opinions or recommendations discussed are solely those
Wroclaw, Poland of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and
3
Immunology, AbbVie, North Chicago, Illinois, USA responsibility arising from any reliance placed on the content. Where the content
4
Pôle de Recherche en Rhumatologie, Institut de Recherche Expérimentale et includes any translated material, BMJ does not warrant the accuracy and reliability
Clinique, UCLouvain Saint-­Luc, Brussels, Belgium of the translations (including but not limited to local regulations, clinical guidelines,
5
Rheumatology, Laval University, Quebec, Quebec, Canada terminology, drug names and drug dosages), and is not responsible for any error
6
Spire Sciences Inc, Boca Raton, Florida, USA and/or omissions arising from translation and adaptation or otherwise.
7
The First Department of Internal Medicine, University of Occupational and Open access This is an open access article distributed in accordance with the
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Rheumatology, Organización Medica de Investigación, Buenos Aires, Argentina permits others to distribute, remix, adapt, build upon this work non-­commercially,

12 Fleischmann R, et al. RMD Open 2024;10:e004007. doi:10.1136/rmdopen-2023-004007

 RMD Open: first published as 10.1136/rmdopen-2023-004007 on 28 May 2024. Downloaded from http://rmdopen.bmj.com/ on November 26, 2024 at Pakistan:BMJ-PG Sponsored. Protected
Rheumatoid arthritis

and license their derivative works on different terms, provided the original work is prospective followup of patients with early rheumatoid arthritis.
properly cited, appropriate credit is given, any changes made indicated, and the Arthritis Rheum 1992;35:26–34.
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tofacitinib for up to 9.5 years in the treatment of rheumatoid arthritis:
ORCID iDs final results of a global, open-­label, long-­term extension study.
Roy Fleischmann http://orcid.org/0000-0002-6630-1477 Arthritis Res Ther 2019;21:89.
Patrick Durez http://orcid.org/0000-0002-7156-2356 20 Combe B, Kivitz A, Tanaka Y, et al. Filgotinib versus placebo or
adalimumab in patients with rheumatoid arthritis and inadequate
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21 Fleischmann R, Mysler E, Hall S, et al. Efficacy and safety of
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