Identification of two tofacitinib subpopulations with different relative risk versus TNF inhibitors: an analysis of the open label, randomised controlled study ORAL Surveillance

Abstract

Objectives:
Based on primary results from ORAL Surveillance, an event-driven clinical trial of risk-enriched patients, identify subpopulations with different relative risk (ie, 'high-risk' and 'low-risk') with tofacitinib versus tumour necrosis factor inhibitors (TNFi).

Methods:
Patients with rheumatoid arthritis aged ≥50 years with ≥1 additional cardiovascular risk factor received tofacitinib 5 or 10 mg two times a day or TNFi. Prior analyses had identified age and smoking as risk factors of particular interest across safety outcomes. Hazard ratios (HRs) and incidence rates were evaluated by age and smoking individually and in combination. Results were validated across tofacitinib development programmes.

Results:
'Age ≥65 years or ever smoker' defined a group ('high-risk') with increased risk of malignancies (excluding non-melanoma skin cancer), major adverse cardiovascular events, myocardial infarction, venous thromboembolism and all-cause death with tofacitinib (combined doses) versus TNFi (HRs 1.41-5.19). In patients 'aged <65 years and never smokers' ('low-risk'), there was no detectable risk increase with tofacitinib versus TNFi (HRs ≈1.0) up to 6 years of follow-up, and absolute risk remained low and was corroborated across tofacitinib rheumatoid arthritis, psoriatic arthritis and ulcerative colitis programmes with up to 10 years of observation.

Conclusions:
This posthoc analysis of ORAL Surveillance identified two tofacitinib subpopulations with different relative risk versus TNFi. High risk was confined to patients defined by distinct risk factors age ≥65 years or smoking, and these differentiating risk factors accounted for the excess risk observed with tofacitinib versus TNFi. These findings can guide individualised benefit/risk assessment and clinical decision-making on treatment with tofacitinib.

Trial registration numbers:
NCT02092467, NCT01262118, NCT01484561, NCT00147498, NCT00413660, NCT00550446, NCT00603512, NCT00687193, NCT01164579, NCT00976599, NCT01059864, NCT01359150, NCT02147587, NCT00960440, NCT00847613, NCT00814307, NCT00856544, NCT00853385, NCT01039688, NCT02281552, NCT02187055, NCT02831855, NCT00413699, NCT00661661, NCT00787202, NCT01465763, NCT01458951, NCT01458574, NCT01470612, NCT01877668, NCT01882439, NCT01976364.

Full text

901
Kristensen LE, etal. Ann Rheum Dis 2023;82:901–910. doi:10.1136/ard-2022-223715
Rheumatoid arthritis
CLINICAL SCIENCE
Identification of two tofacitinib subpopulations with
different relative risk versus TNF inhibitors: an analysis of
the open label, randomised controlled study ORAL
Surveillance
Lars Erik Kristensen,1 Silvio Danese,2 Arne Yndestad,3 Cunshan Wang,4 Edward Nagy,5
Irene Modesto,6 Jose Rivas,6 Birgitta Benda7
To cite: KristensenLE,
DaneseS, YndestadA,
etal. Ann Rheum Dis
2023;82:901–910.
Handling editor Josef S
Smolen
►Additional supplemental
material is published online
only. To view, please visit
the journal online (http:// dx.
doi. org/ 10. 1136/ ard- 2022-
223715).
1The Parker Institute, Bispebjerg
and Frederiksberg Hospital,
University of Copenhagen,
Copenhagen, Denmark
2Gastroenterology and
Endoscopy, IRCCS San Raffaele
Hospital and Vita-Salute San
Raffaele University, Milan, Italy
3Pfizer Inc, Oslo, Norway
4Pfizer Inc, Groton, Connecticut,
USA
5Pfizer Ltd, Tadworth, UK
6Pfizer SLU, Madrid, Spain
7Pfizer Inc, New York, New
York, USA
Correspondence to
Dr Jose Rivas, Pfizer SLU, Madrid
28108, Spain;
joseluis. rivas@ pfizer. com
Received 2 December 2022
Accepted 8 March 2023
Published Online First
17March2023
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and permissions. Published
by BMJ.
ABSTRACT
Objectives Based on primary results from ORAL
Surveillance, an event- driven clinical trial of risk- enriched
patients, identify subpopulations with different relative
risk (ie, ’high- risk’ and ’low- risk’) with tofacitinib versus
tumour necrosis factor inhibitors (TNFi).
Methods Patients with rheumatoid arthritis aged
≥50 years with ≥1 additional cardiovascular risk factor
received tofacitinib 5 or 10 mg two times a day or TNFi.
Prior analyses had identified age and smoking as risk
factors of particular interest across safety outcomes.
Hazard ratios (HRs) and incidence rates were evaluated
by age and smoking individually and in combination.
Results were validated across tofacitinib development
programmes.
Results ’Age ≥65 years or ever smoker’ defined a
group (’high- risk’) with increased risk of malignancies
(excluding non- melanoma skin cancer), major adverse
cardiovascular events, myocardial infarction, venous
thromboembolism and all- cause death with tofacitinib
(combined doses) versus TNFi (HRs 1.41–5.19). In
patients ’aged <65 years and never smokers’ (’low- risk’),
there was no detectable risk increase with tofacitinib
versus TNFi (HRs ≈1.0) up to 6 years of follow- up, and
absolute risk remained low and was corroborated across
tofacitinib rheumatoid arthritis, psoriatic arthritis and
ulcerative colitis programmes with up to 10 years of
observation.
Conclusions This posthoc analysis of ORAL Surveillance
identified two tofacitinib subpopulations with different
relative risk versus TNFi. High risk was confined to
patients defined by distinct risk factors age ≥65 years or
smoking, and these differentiating risk factors accounted
for the excess risk observed with tofacitinib versus TNFi.
These findings can guide individualised benefit/risk
assessment and clinical decision- making on treatment
with tofacitinib.
Trial registration numbers NCT02092467,
NCT01262118, NCT01484561, NCT00147498,
NCT00413660, NCT00550446, NCT00603512,
NCT00687193, NCT01164579, NCT00976599,
NCT01059864, NCT01359150, NCT02147587,
NCT00960440, NCT00847613, NCT00814307,
NCT00856544, NCT00853385, NCT01039688,
NCT02281552, NCT02187055, NCT02831855,
NCT00413699, NCT00661661, NCT00787202,
NCT01465763, NCT01458951, NCT01458574,
NCT01470612, NCT01877668, NCT01882439,
NCT01976364.
INTRODUCTION
ORAL Surveillance was a large, randomised,
open- label, event- driven clinical trial in patients
WHAT IS ALREADY KNOWN ON THIS TOPIC
⇒Primary findings from ORAL Surveillance
indicated that patients with rheumatoid
arthritis aged ≥50 years with ≥1 additional
cardiovascular risk factor have an increased risk
of major adverse cardiovascular events (MACE)
and malignancies (excluding non- melanoma
skin cancer) with tofacitinib compared with
tumour necrosis factor inhibitors (TNFi).
⇒Increased risk of MACE with tofacitinib versus
TNFi was primarily observed in patients with a
history of atherosclerotic cardiovascular disease.
⇒Previous analyses from ORAL Surveillance
identified age and smoking as independent (ie,
across treatment groups) risk factors of interest
across safety outcomes.
WHAT THIS STUDY ADDS
⇒This posthoc analysis of ORAL Surveillance
identified high- risk and low- risk populations
with different relative risk with tofacitinib
versus TNFi.
⇒Higher risk versus TNFi was confined to a
subgroup of patients defined by distinct, readily
identifiable risk factors, age 65 years or older
and long- time smoking (current or past).
⇒In ‘low- risk’ patients who were younger than
65 years and had never smoked, there was no
detectable risk increase versus TNFi with up
to 6 years of follow- up in ORAL Surveillance,
and absolute risk remained low and was
corroborated across tofacitinib rheumatoid
arthritis, psoriatic arthritis and ulcerative colitis
development programmes with up to 10 years
of observations.
HOW THIS STUDY MIGHT AFFECT RESEARCH,
PRACTICE OR POLICY
⇒These easily identifiable and clinically practical
subpopulations with different relative risk
versus TNFi (ie, ‘high- risk’ and ‘low- risk’)
can better guide individualised benefit/risk
assessment and clinical decision- making on
treatment with tofacitinib.
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902 Kristensen LE, etal. Ann Rheum Dis 2023;82:901–910. doi:10.1136/ard-2022-223715
Rheumatoid arthritis
with rheumatoid arthritis (RA) designed to demonstrate non-
inferiority of tofacitinib versus TNF inhibitors (TNFi) for the
coprimary endpoints of adjudicated major adverse cardiovas-
cular events (MACE) and adjudicated malignancies (excluding
non- melanoma skin cancer (NMSC)).1 The U.S. FDA required
the study to be of sufficient size and duration to evaluate long-
latency and rare events.2 For the study to be declared complete,
≥1500 patients had to be followed for ≥3 years, and ≥103
MACE, and ≥138 malignancies (excluding NMSC), had to
accrue.1 The study started in 2014, enrolled 4362 patients and
completed 6 years later.
To ensure enough cardiovascular (CV) and malignancy events
accrued in a reasonable timeframe, ORAL Surveillance enrolled
patients with RA with higher- than- average risk; patients had to
be at least 50 years old and have at least one additional CV risk
factor.1 Previous studies have shown a relationship and shared
risk factors between CV disease and malignancy, for example,
data from Dutch and US cohorts found an association between
the 10- year atherosclerotic cardiovascular disease (ASCVD) risk
scores and risk of future cancer.3 4 Importantly, a wide range of
CV risk factors were applied as eligibility criteria, therefore, a
52- year- old with mild hypertension and a 71- year- old with prior
myocardial infarction (MI) would both have been eligible despite
very different risk levels. Indeed, enrolled patients were found to
be distributed across a continuum of risk.5 For example, close to
one- third of the overall ORAL Surveillance study population had
only low- to- borderline predicted 10- year risk of ASCVD.5
Guided by initial thematic analyses of clinically meaningful
factors in ORAL Surveillance, in which age and smoking were
consistently identified as independent (ie, across treatment
groups) risk factors of particular interest across safety outcomes,
we aimed to find easily identifiable and clinically practical
subpopulations with different relative risk vs TNFi (ie, ‘high- risk’
and ‘low- risk’) to better guide individualised benefit/risk assess-
ment and clinical decision- making. For risk minimisation and
product labelling purposes, it was important to identify the risk
factors (individual or combinations thereof) accounting for the
increased risk observed with tofacitinib versus TNFi (ie, differ-
entiating risk factors) and, equally important, where the reverse
was true, that is, the absence of these risk factors produced risk
estimates with no apparent risk difference between treatments
(ie, HR at or below 1). Analyses were repeated in the larger and
longer tofacitinib RA development programme, and tofacitinib
psoriatic arthritis (PsA) and ulcerative colitis (UC) development
programmes to assess consistency and validate results.
METHODS
Study design and patients
ORAL Surveillance
ORAL Surveillance (NCT02092467) was a phase IIIb/IV
randomised, open- label, non- inferiority, safety endpoint study
conducted from March 2014 to July 2020 in patients with active
moderate- to- severe RA despite methotrexate treatment who
were aged ≥50 years with ≥1 additional CV risk factor (current
smoking, hypertension, high- density lipoprotein cholesterol
<40 mg/dL, diabetes mellitus, family history of premature coro-
nary heart disease, RA- associated extra- articular disease and/or
history of coronary artery disease).1
Patients were randomised 1:1:1 to receive oral tofacitinib 5
or 10 mg two times a day or subcutaneous TNFi (adalimumab
40 mg every 2 weeks (North America) or etanercept 50 mg
once a week (rest of the world)). All patients continued their
pre- study stable dose of methotrexate unless modification was
clinically indicated. In February 2019, the tofacitinib 10 mg two
times a day dose was reduced to 5 mg two times a day after the
Data Safety Monitoring Board noted an increased frequency of
pulmonary embolism in patients receiving tofacitinib 10 mg two
times a day versus TNFi and an increase in overall mortality with
tofacitinib 10 vs 5 mg two times a day and TNFi.
RA, PsA and UC development programmes
This exploratory analysis includes data for patients who
received ≥1 dose of tofacitinib in clinical trials and open- label
LTE studies across RA (excluding ORAL Surveillance), PsA and
UC. Full details of the individual studies can be found in online
supplemental table S3.
All cohorts included patients aged ≥18 years who received
tofacitinib as monotherapy (RA and UC) or with background
conventional synthetic disease- modifying antirheumatic drugs
(RA, PsA). All studies have been completed. Final data for the
RA, PsA and UC cohorts are from 18 January 2019, 31 July
2019 and 24 August 2020, respectively.
Patient and public involvement
Patients and/or the public were not involved in the design,
conduct, reporting or dissemination plans of this research.
Outcomes
This analysis focused on events of malignancies (excluding
NMSC), MACE, MI (fatal and non- fatal), venous thromboem-
bolism (VTE) and all- cause death. In ORAL Surveillance, these
events were adjudicated by an external, independent adjudi-
cation committee. MACE was defined as the composite of CV
death, non- fatal MI and non- fatal stroke. Similarly, events of
malignancies (excluding NMSC), MACE and MI were adjudi-
cated in the tofacitinib development programmes. See online
supplemental table S1) for definition of outcomes.
Statistical analyses
ORAL Surveillance was powered to assess non- inferiority for risk
of MACE and malignancies (excluding NMSC) with combined
tofacitinib doses versus TNFi. To maximise statistical precision
and power in these posthoc analyses, data for the combined
doses of tofacitinib were prioritised. HRs and two- sided 95%
CIs comparing tofacitinib and TNFi were estimated using Cox
proportional hazard regression models. Incidence rates (IRs) and
two- sided 95% CIs for malignancies (excluding NMSC), MACE,
MI, VTE and all- cause death were reported as the number of
unique patients with events per 100 patient- years. See online
supplemental table S1 for definition of censoring times for the
different analyses. Exact Poisson, adjusted for exposure, was
used to calculate 95% CIs for the crude IR.
Prior analyses had consistently identified age and smoking
as independent risk factors of particular interest across safety
outcomes and were therefore assessed here, individually and
in combination.1 6 7 Informed by the definition of the geriatric
population from the ICH Topic E7 (Studies in Support of Special
Populations: Geriatrics), a cut- off of 65 years of age was a pre-
specified analysis in ORAL Surveillance and also applied in these
analyses.1 8 IRs and HRs with tofacitinib versus TNFi were also
determined by 5- year intervals of age.
Further analyses were conducted to identify risk factors
accounting for the increased risk observed with tofacitinib
versus TNFi (ie, differentiating risk factors) while when absent
produced tofacitinib risk estimates with no difference versus
TNFi (ie, HR≈1.0). HRs (95% CIs) comparing tofacitinib and
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Rheumatoid arthritis
TNFi (ORAL Surveillance) and IRs (95% CIs) for each treatment
group were calculated for subgroups of patients defined by age
(≥ or <65 years of age), or by smoking status (current, past or
never smoking), or by composites thereof.
For the subgroups defined by ‘age ≥65 years or ever smoker’
(‘high- risk’) and ‘age <65 years and never smoker’ (‘low- risk’),
number needed to harm (NNH) was calculated as the reciprocal
of the difference in IRs between tofacitinib and TNFi. Positive
NNH was defined as patient- years of tofacitinib exposure needed
for one more patient to report an additional event versus TNFi.
Negative NNH was defined as the reverse. The differential or
interaction effect of treatment group (tofacitinib vs TNFi) and
high- risk versus low- risk was assessed using the difference of the
incidence rate difference (IRD, comparing tofacitinib and TNFi)
between high- risk and low- risk and its SE. The two- sided inter-
action p value was calculated assuming normal approximation to
the difference of IRD. In published criteria for how to evaluate
the credibility of subgroup analyses, it is advised to not use a
specified p value threshold, but p<0.1 are generally supportive
of the hypothesis.9 Cumulative probability plots using Kaplan-
Meier estimates were generated for analysis of time to events.
IRs (95% CI) of all outcomes were determined by high- risk
and low- risk in the tofacitinib RA, PsA and UC development
programmes.
All analyses were posthoc. Across these exploratory analyses,
no multiplicity adjustments were applied.
RESULTS
Patients
In ORAL Surveillance, 4362 patients were randomised and
treated (tofacitinib 5 mg two times a day, n=1455; tofacitinib
10 mg two times a day, n=1456; TNFi, n=1451).1 In addi-
tion, this analysis includes 9904 tofacitinib- exposed patients
from completed studies in the development programmes:
7964 with RA (excluding ORAL Surveillance), 783 with PsA
and 1157 with UC.10 Table 1 (online supplemental table S2
by low- risk/high- risk) summarises demographics and base-
line characteristics for patients in ORAL Surveillance and
in all patients who received ≥1 dose of tofacitinib in the
RA, PsA and UC development programmes. Compared with
the tofacitinib development programmes, patients included
in ORAL Surveillance represented a risk- enriched popu-
lation as reflected in a higher proportion of patients aged
≥65 years, current smokers and patients with a history of
diabetes, hypertension and ASCVD (table 1).
Tofacitinib relative risk versus TNFi and role of age and
smoking as individual risk factors
Age ≥65 years (figure 1A) and ever (ie, current or past)
smoking (figure 1B) were both independent overall risk
factors with associations with absolute (IRs) and relative
(HRs) risk with tofacitinib versus TNFi of malignancies
(excluding NMSC), MACE, MI, VTE and all- cause death
in ORAL Surveillance.1 6 7 Even though less pronounced,
an increased risk versus TNFi (HRs >1) was observed in
patients who were <65 years as well as in never smokers for
certain outcomes.
Analyses of risk with tofacitinib by 5- year age intervals indi-
cated a risk continuum with increasing age where the inflection
point seemed to appear at or around ≥65 years of age (online
supplemental figure S1).
An analysis of smoking duration showed that the majority
of current and past smokers in ORAL Surveillance were
long- time smokers. More than 90% of patients treated with
tofacitinib in ORAL Surveillance that had ever smoked (ie,
current or past smokers) had a smoking duration of more
Table 1 Demographic and baseline disease characteristics of patients in ORAL Surveillance and the tofacitinib RA, PsA and UC development
programmes
ORAL Surveillance Tofacitinib development programme
N=4362
RA*
N=7964
PsA
N=783
UC
N=1157
Female, % (n) 78.2% (3410) 81.9% (6522) 54.7% (428) 41.3% (478)
Duration of disease (years), mean/median 10.4/8.0 8.1/5.6 7.7/5.5 8.2/6.3
Age, mean (SD) 61.2 (7.1) 52.6 (12.1) 48.7 (12.0) 41.3 (13.9)
≥65 years of age, % (n) 31.0% (1353) 15.9% (1270) 9.2% (72) 6.7% (77)
Smoking status†, % (n)
Current 26.7% (1166) 17.2% (1366) 17.9% (140) 5.1% (59)
Past 21.5% (937) 17.4% (1388) 20.2% (158) 30.9% (357)
Never 51.8% (2259) 62.7% (4996) 61.9% (485) 64.0% (740)
History of other CV risk factors, % (n)
Diabetes mellitus 17.4% (759) 8.2% (651) 13.7% (107) 4.1% (48)‡
Hyperlipidaemia 35.2% (1534) 19.3% (1534) 21.3% (107) NA
Hypertension 66.0% (2878) 35.4% (2818) 39.1% (306) 13.9% (161)‡
Coronary artery disease 11.4% (497) 1.6% (126) 5.6% (44) 1.6% (18)
ASCVD 14.7% (640) 3.4% (274) 6.5% (51) 3.9% (45)
Treatment history, % (n)
Prior TNFi 7.6% (330) 15.6% (1245) 48.1% (377) 54.4% (1124)
Statin at baseline‡ 23.4% (1020) 7.8% (620) 12.8% (100) 6.4% (74)
Aspirin at baseline‡ 15.3% (667) 6.9% (551) 6.4% (50) NA
*Excluding ORAL Surveillance.
†In the tofacitinib RA development programme, 2.7% (N=214) of patients had unknown smoking status. Patients <65 years old with unknown smoking status were not included in the low- risk
group. 25 patients in the high- risk group had unknown smoking status.
‡Based on day 1 of treatment.
ASCVD, atherosclerotic cardiovascular disease; CV, cardiovascular; n, number of patients with characteristic; NA, not available; RA, rheumatoid arthritis; TNFi, tumour necrosis factor inhibitor; UC,
ulcerative colitis.
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904 Kristensen LE, etal. Ann Rheum Dis 2023;82:901–910. doi:10.1136/ard-2022-223715
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Figure 1 Risk of malignancies (excluding NMSC), MACE, MI, VTE and all- cause death with tofacitinib versus TNFi in ORAL Surveillance by (A) age
(≥ or <65 years) or (B) history of smoking (current, past or never) or (C) composite of age and smoking (‘Age ≥65 years and Ever smoked’ or ‘Age <65
years or Never smoked’). HRs (95% CIs), shown on a logarithmic scale, are based on a simple Cox proportional hazard model comparing combined
tofacitinib doses versus TNFi. Arrow heads indicate that CI extends beyond the graph axis. IRs express the number of patients with first events per 100
PY. IRs, n and PY are for combined tofacitinib doses. *Results previously reported in Ytterberg et al.1 †Results reported in Curtis et al.7 IR, incidence
rate; MACE, major adverse cardiovascular events; n, number of evaluable patients; N, number of patients with events; NMSC, non- melanoma skin
cancer; PY, patient- years; TNFi, tumour necrosis factor inhibitor; VTE, venous thromboembolism.
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Rheumatoid arthritis
than 10 years. Median duration of smoking in current and
past smokers was 35.0 and 39.0 years, respectively. Majority
of past smokers had been smoke- free for 10 years or longer
(table 2).
Tofacitinib relative risk versus TNFi and composites of age
and smoking as differentiating risk factors
Figures 1C and 2 show the relative risk (HRs) for malig-
nancies (excluding NMSC), MACE, MI, VTE and all- cause
death with tofacitinib versus TNFi in subgroups defined by
composites of age and smoking. In patients with both risk
factors, that is, ‘age≥65 years and ever smoker’ (figure 1C),
or one risk factor, that is, ‘age ≥65 years or ever smoker’
(figure 2; online supplemental figure S2 by tofacitinib dose),
the risk was higher with tofacitinib versus TNFi, and for
some endpoints, the 95% CI for the HR excluded 1. It was
only in patients with neither risk factor, that is, ‘age <65
years and never smoker’ group that we could not detect a
higher risk with tofacitinib vs TNFi (ie, HRs≈1.0) for any
of these events (figure 2). Based on IRD, the p values for
the treatment- by- risk high/low interaction for these events
with combined doses of tofacitinib versus TNFi ranged from
0.002 to 0.173 (figure 2), supporting that this composite of
age ≥65 years or ever smoker represents a differentiating
risk factor for these events.9
Table 2 Smoking duration in current and past smokers and time since smoking cessation in past smokers in ORAL Surveillance
Current smokers Past smokers
Tofacitinib
N=811
TNFi
N=352
Tofacitinib
N=605
TNFi
N=322
Smoking Duration (years)
Mean (SD) 32.7 (13.1) 31.9 (13.2) 37.2 (13.0) 39.9 (12.2)
Median (Range) 35.0 (0.02, 67.00) 34.2 (0.02, 69.00) 39.0 (0.00, 69.00) 41.0 (1.00, 70.00)
Smoking duration levels*, % (n)
>10 years 91.4% (741) 91.2% (321) 96.2% (582) 98.4% (317)
>5–10 years 4.4% (36) 3.7% (13) 2.3% (14) 0.9% (3)
>0–5 years 4.2% (34) 5.1% (18) 1.5% (9) 0.6% (2)
Time since smoking cessation levels, % (n)
≥10 years – – 61.5% (372) 71.7% (231)
<10 years – – 38.5% (233) 28.3% (91)
<5 years – – 21.8% (132) 15.2% (49)
<1 year – – 5.6% (34) 3.1% (10)
*Information on smoking duration was missing on eight patients (two current and six past smokers) treated with tofacitinib and five patients (one current and four past smokers) treated with TNFi.
n, number of patients with characteristic; TNFi, tumour necrosis factor inhibitor.
Figure 2 Risk of malignancies (excluding NMSC), MACE, MI, VTE and all- cause death with tofacitinib versus TNFi in ORAL Surveillance by subgroups
of high- risk and low- risk patients. HRs (95% CIs), shown on a logarithmic scale, are based on a simple Cox proportional hazard model comparing
combined tofacitinib doses versus TNFi. Arrow heads indicate that CI extends beyond the graph axis. IRs express the number of patients with first
events per 100 PY. Treatment- by- risk interaction p values were calculated based on IR differences (two- sided, normal approximation of difference in
IR). NNH (PY) should be interpreted as the number of patient- years of exposure to tofacitinib required to have one additional event versus TNFi. All
data are for combined tofacitinib doses. *Results reported in Curtis et al.7 IR, incidence rate; MACE, major adverse cardiovascular events; N, number
of evaluable patients; n, number of patients with events; NMSC, non- melanoma skin cancer; NNH, numbers needed to harm; PY, patient- years; TNFi,
tumour necrosis factor inhibitor; VTE, venous thromboembolism.
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906 Kristensen LE, etal. Ann Rheum Dis 2023;82:901–910. doi:10.1136/ard-2022-223715
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Cumulative probability of events with tofacitinib and TNFi in
high-risk and low-risk subpopulations
‘Age ≥65 years or ever smoker’ and ‘age <65 years and never
smoker’ are hereafter referred to as ‘high- risk’ and ‘low- risk’,
respectively. To further assess absolute and relative risk of malig-
nancies (excluding NMSC), MACE, MI, VTE and all- cause
death with tofacitinib versus TNFi over time in high- risk and
low- risk patients, cumulative probability curves were gener-
ated (figure 3). These curves confirmed that there were two
tofacitinib subpopulations with different relative risk versus
TNFi: one subpopulation (‘high- risk’) of patients which had
higher risk with tofacitinib versus TNFi for all these outcomes
and one subpopulation (‘low- risk’) for which the curves repre-
senting treatment with tofacitinib and TNFi overlapped and/or
Figure 3 Cumulative probability of patients with malignancies (excluding NMSC), MACE, MI, VTE and all- cause death in ORAL Surveillance overall
population and by subgroups of high- risk and low- risk patients. Overall population received tofacitinib 5 mg or 10 mg two times a day (N=2911)
or TNFi (N=1451). High- risk patients were ≥65 years of age or ever smoker (tofacitinib, N=1895; TNFi, N=926). Low- risk patients were <65 years
of age and never smoker (tofacitinib, N=1016; TNFi, N=525). Cumulative probabilities of events were calculated based on Kaplan- Meier estimates.
Cumulative probability plots for malignancies (excluding NMSC) and MACE in overall population have been reported in Ytterberg et al1 and are
included for reference. MACE, major adverse cardiovascular events; MI, myocardial infarction; NMSC, non- melanoma skin cancer; TNFi, tumour
necrosis factor inhibitor; VTE, venous thromboembolism.
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crossed, and we could not detect a difference between tofacitinib
and TNFi up to 6 years of follow- up in ORAL Surveillance.
Absolute risk in low-risk patients in ORAL Surveillance
Absolute risk of malignancies (excluding NMSC), MACE, MI,
VTE and all- cause death in low- risk patients (figure 2) was low
as reflected in low event rates and IRs. NNH based on the IR
differences with tofacitinib versus TNFi indicated that 1485 and
9898 low- risk patients would need to be treated with tofacitinib
for 1 year to have one additional event of, respectively, malig-
nancies (excluding NMSC) and all- cause mortality versus TNFi.
For MACE, MI and VTE in low- risk patients, IRD and NNH
were negative and in favour of tofacitinib versus TNFi. The
relatively large NNH (positive or negative numbers) principally
reflect similar absolute risk with tofacitinib versus TNFi in low-
risk patients.
Absolute risk in low-risk patients in tofacitinib RA, PsA and
UC clinical development programmes
ORAL Surveillance was a substantial RA study, in terms of
number of patients and exposure time. However, it makes up
only a third of the overall tofacitinib experience in RA. Specifi-
cally, 34.1% (1016/2911) of patients treated with tofacitinib in
ORAL Surveillance were <65 years of age and never smokers,
and this population had low absolute risk and no detectable
excessive risk of malignancies (excluding NMSC), MACE, MI,
VTE and all- cause death versus TNFi. To increase the precision
of absolute low- risk estimates, we conducted additional anal-
yses in the tofacitinib development programmes of RA, PsA and
UC, collectively representing 25 437 patient years of tofacitinib
exposure and safety observations extending up to 10.5 years.10
52.7% (4198/7964) of patients in the tofacitinib RA develop-
ment programme were <65 years of age and never smokers,
representing more than 4000 patients and 13 497 patient years
of tofacitinib exposure in the low- risk group of interest (table 3).
In the tofacitinib PsA and UC development programmes, 56.4%
and 59.6% of patients were <65 years of age and never smokers.
Figure 4 shows absolute risk (ie, IRs (95% CIs)) of malig-
nancies (excluding NMSC), MACE, MI, VTE and all- cause
death in the overall population and in low- risk patients treated
with tofacitinib in the overall RA, PsA and UC development
programmes compared with absolute risk with TNFi and tofac-
itinib in ORAL Surveillance (RA controlled phase and high- risk
patient data in online supplemental figure S3). Consistently, IRs
for malignancies (excluding NMSC), MACE, MI, VTE and all-
cause death in low- risk patients treated with tofacitinib in the
RA development programme were similar to those observed in
low- risk patients in ORAL Surveillance; however, the precision
of the estimate was higher, that is, the 95% CIs were narrower.
Similarly, IRs of malignancies (excluding NMSC), MACE, MI,
VTE and all- cause death in the PsA and UC tofacitinib develop-
ment programmes in overall populations and low- risk patients
were similar to those observed in tofacitinib- treated RA low-
risk patients in ORAL Surveillance and the RA development
programme (figure 4).
DISCUSSION
Primary findings in ORAL Surveillance demonstrated a higher
incidence of MACE and malignancies with tofacitinib versus
TNFi.1 5 In this posthoc analysis, two clinically practical and
easily identifiable subpopulations were found that demarcated
tofacitinib- treated patients with increased risk of these events
from patients with similar risk relative to TNFi- treated patients.
Given the design of ORAL Surveillance, enough events accrued
to allow for posthoc identification of patients at higher risk
with tofacitinib versus TNFi. Initial analyses identified age and
smoking as potential independent risk factors, and more than
80% of tofacitinib- treated patients with MACE, MI, malignan-
cies (excluding NMSC), VTE or all- cause death were accounted
for by the combination of these two risk factors. Of note, ‘having
ever smoked’ was found to largely correspond to substantial
smoking history. Specifically, more than 90% of current or past
smokers in ORAL Surveillance were long- time smokers with
more than 10 years of smoking and a median smoking history
over 30 years on study entry.
We found an exacerbation in risk with the combination of
risk factors age 65 years or older and having ever smoked, and
patients with at least one of these risk factors had a dispropor-
tionately larger risk increase with tofacitinib versus TNFi, while
in patients without these two differentiating risk factors, we
could not detect a risk difference for malignancies (excluding
NMSC), MACE, MI, VTE or all- cause death between tofacitinib
and TNFi.
The risk difference for long- latency events between tofaci-
tinib and TNFi observed at the overall study population level
emerged after approximately two years of follow- up in ORAL
Surveillance. Since JAK inhibitors are used chronically, patients
without risk factors could potentially be exposed for prolonged
periods of time during which a small risk increase could become
clinically relevant. Analyses of absolute and relative risk over
time found that the excess risk with tofacitinib versus TNFi
was confined to patients defined by the composite of age ≥65
years or ever smoking (‘high- risk’), and these differentiating risk
factors accounted for the excess risk of malignancies (excluding
NMSC), MACE, MI, VTE or all- cause death observed with
tofacitinib versus TNFi. On the other hand, in patients who were
younger than 65 and had never smoked (‘low- risk’), but who
all had prevalent other CV risk factors per ORAL Surveillance
eligibility criteria, we could not detect a difference between
tofacitinib and TNFi even up to 6 years of follow- up which is
longer than the median drug survival in RA.11 This observa-
tion was consistent across outcomes including malignancies
(excluding NMSC), MACE, MI, VTE and all- cause death, and
Table 3 Tofacitinib treatment exposure in high- risk and low- risk
populations in ORAL Surveillance and RA, PsA, UC development
programmes
ORAL
Surveillance (RA)
Tofacitinib development programme
RA* PsA UC
Overall population
N 2911 7964 783 1157
Exposure (PY) 10 922 23 497 2038 2814
Follow- up; mean, max (years) 3.8, 6.1 3.0, 10.5 2.6, 4.8 2.4, 7.8
High- risk: ≥65 years or ever smoked
N 1895 3577 341 444
% 65.1% 44.9% 43.6% 38.4%
Exposure (PY) 6986 9961 837 1113
Low- risk: <65 years and never smoked
N 1016 4198 442 713
% 34.9% 52.7% 56.4% 61.6%
Exposure (PY) 3937 13 168 1201 1702
PY was calculated from the first dose of tofacitinib to the last contact date in ORAL Surveillance, and
from the first dose of tofacitinib to the last dose of tofacitinib for all other development programmes.
*Excluding ORAL Surveillance.
N, number of patients treated with tofacitinib; PsA, psoriatic arthritis; PY, patient- years; RA, rheumatoid
arthritis; UC, ulcerative colitis.
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908 Kristensen LE, etal. Ann Rheum Dis 2023;82:901–910. doi:10.1136/ard-2022-223715
Rheumatoid arthritis
the magnitude of absolute risk in the low- risk group remained
low over time and was similar to TNFi with large NNH.
The composite of age ≥65 years or ever smoker was strongly
associated with absolute risk of malignancies (excluding NMSC),
MACE, MI, VTE and all- cause death in ORAL Surveillance,
and, as mentioned above, with treatment with tofacitinib, most
events (>82%) occurred in the 65% of patients in this high-
risk subgroup. There were accordingly few events in the low- risk
Figure 4 Risk of malignancies (excluding NMSC), MACE, MI, VTE and all- cause death in low- risk populations in ORAL Surveillance and tofacitinib
clinical development programmes. Low- risk patients were <65 years of age and never smoker. Horizontal dotted line represents IR in low- risk
patients treated with tofacitinib in ORAL Surveillance. IRs express the number of patients with first events per 100 PY. All data are for combined
tofacitinib doses. *Excluding ORAL Surveillance. Data from ORAL Surveillance overall populations have previously been published and are included
for reference; malignancies (excluding NMSC) and MACE (Ytterberg et al1), MI (Charles- Schoeman et al5). Also, previously published are data from
the tofacitinib RA and PsA development programmes on MACE (Burmester et al25) and VTE (Mease et al26). IR, incidence rate; MACE, major adverse
cardiovascular events; MI, myocardial infarction; N, number of evaluable patients; n, number of patients with events; NMSC, non- melanoma skin
cancer; PsA, psoriatic arthritis; PY, patient- years; RA, rheumatoid arthritis; TNFi, tumour necrosis factor inhibitor; UC, ulcerative colitis; VTE, venous
thromboembolism.
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Kristensen LE, etal. Ann Rheum Dis 2023;82:901–910. doi:10.1136/ard-2022-223715
Rheumatoid arthritis
group, patients <65 years of age that had never smoked, which
made up 35% of the overall study population. Consequently, it
can be argued that there is not sufficient precision in the absolute
and relative risk estimates in this low- risk population in ORAL
Surveillance. Even though ORAL Surveillance was a large and
long study, it makes up only a third of the overall tofacitinib
experience (excluding ORAL Surveillance) in RA and therefore,
it was important to validate the absolute risk estimate in ORAL
Surveillance within the larger tofacitinib RA clinical programme
which extended up to 10 years and included more than 4000
patients in the low- risk group of interest. Importantly, we corrob-
orated the absolute risk estimates from ORAL Surveillance and
with higher precision, with data from the overall population
and the low- risk population of the more extensive tofacitinib
RA development programme. Moreover, the magnitude of the
absolute risk in the low- risk group was low also in relation to
published rates in randomised controlled trials and their LTEs in
RA populations treated with TNFi and other biologics,12–18 and
this finding was confirmed also in the other tofacitinib devel-
opment programmes of PsA and UC. A limitation of these anal-
yses is that the average follow- up time in the tofacitinib clinical
development programmes (3.0, 2.6 and 2.4 years in the RA, PsA
and UC programmes, respectively) was shorter than in ORAL
Surveillance (3.8 years).
Recognising limitations associated with the posthoc nature
of these results, multiple aspects were considered to improve
robustness and confirm validity of findings. First, only data for
the combined doses of tofacitinib (with larger number of patients
and events vs per individual dose) were used for increased preci-
sion. In ORAL Surveillance, p values (0.002–0.173 for the
outcomes) for the interactions between treatment groups and
subgroups of high- risk/low- risk patients lent support to the
presence of a differential treatment effect for the two subgroups
of patients. Second, the analyses are based on risk factors (ie,
older age and smoking) already identified as major risk factors
of malignancies, MACE and VTE in the general and RA popula-
tions.3 19–24 Finally, we cannot, based on these posthoc analyses,
rule out that there is an increased relative risk of safety outcomes
with tofacitinib versus TNFi in the low- risk group. However, if
such an increased risk is present, we show that the absolute risk
is low, as indicated by low or no difference in IRs over time and
high NNH. Moreover, we have recently reported on history of
ASCVD as another differentiating risk factor.5 However, whereas
the combination of age and smoking is capable of differentiating
risk across major outcomes, history of ASCVD is specific for
MACE. These are all factors that need to be considered in an
individualised benefit/risk assessment.
The analyses presented herein had a particular focus on the
identification of a high- risk and a low- risk population. Future
investigations should aim at assessing whether the high- risk
population can be further segmented into different relative risk
levels.
In summary, ORAL Surveillance identified a high- risk and
low- risk tofacitinib population with different relative risk vs
TNFi. Higher risk versus TNFi was confined to a subgroup of
patients defined by distinct, readily identifiable risk factors, age
65 years or older and long- time smoking (current or past), and
these differentiating risk factors accounted for the excess risk
observed with tofacitinib versus TNFi. In ‘low- risk’ patients who
were younger than 65 and had never smoked, but who all had
prevalent other CV risk factors per ORAL Surveillance inclusion
criteria, there was no detectable risk increase vs TNFi with up
to 6 years of follow- up in ORAL Surveillance and the magni-
tude of absolute risk remained low and was corroborated across
tofacitinib programmes with up to 10 years of observations. It
is acknowledged that the findings are posthoc, nevertheless, the
results are clinically important and appear generalizable. These
findings can guide individualised benefit/risk assessment and
clinical decision- making on treatment with tofacitinib.
Acknowledgements Select data in this manuscript were previously presented at
ACR Convergence 2021.6 The authors would like to thank the patients, investigators
and study teams involved in the study. The authors would like to thank Hernan
Valdez for invaluable scientific discussions and guidance and Joseph Wu and
Kenneth Kwok, employees and shareholders of Pfizer Inc, for their contribution to
the statistical analyses.
Contributors LEK, SD, AY, CW, EN, IM, JR and BB conceived or designed the study
and data analyses. CW analysed the data. All authors had access to the data, were
involved in interpretation of data and reviewed and approved the manuscript’s
content before submission. LEK accepts final responsibility for this work and
controlled the decision to publish.
Funding This study was sponsored by Pfizer Inc.
Competing interests LEK has received fees for speaking and consultancy from
Pfizer, AbbVie, Amgen, Galapagos, UCB, Gilead, Biogen, BMS, MSD, Novartis, Eli Lilly
and Janssen pharmaceuticals. LEK has received IIT research grants from Novo, UCB,
Eli Lilly, Novartis and AbbVie. SD reports consultancy fees from AbbVie, Alimentiv,
Allergan, Amgen, Applied Molecular Transport, AstraZeneca, Athos Therapeutics,
Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celltrion, Dr Falk
Pharma, Eli Lilly, Enthera, Ferring Pharmaceuticals Inc., Gilead, Hospira, Inotrem,
Janssen, Johnson & Johnson, Morphic, MSD, Mundipharma, Mylan, Pfizer, Roche,
Sandoz, Sublimity Therapeutics, Takeda, Teladoc Health, TiGenix, UCB Inc., Vial,
Vifor. SD reports lecture fees from AbbVie, Amgen, Ferring Pharmaceuticals Inc.,
Gilead, Janssen, Mylan, Pfizer, Takeda. AY, CW, EN, IM, JR and BB are employees and
stockholders of Pfizer Inc.
Patient and public involvement Patients and/or the public were not involved in
the design, or conduct, or reporting, or dissemination plans of this research.
Patient consent for publication Not applicable.
Ethics approval All studies included in this manuscript were conducted in
accordance with the Declaration of Helsinki, International Council on Harmonisation
Guidelines for Good Clinical Practice and local country regulations and were
approved by each centre’s Institutional Review Board or Independent Ethics
Committee. Participants gave informed consent to participate in the study before
taking part.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement Data are available on reasonable request. On
request, and subject to review, Pfizer will provide the data that support the findings
of this study. Subject to certain criteria, conditions and exceptions, Pfizer may also
provide access to the related individual deidentified participant data. See https://
www.pfizer.com/science/clinical-trials/trial-data-and-results for more information.
Supplemental material This content has been supplied by the author(s). It
has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have
been peer- reviewed. Any opinions or recommendations discussed are solely those
of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and
responsibility arising from any reliance placed on the content. Where the content
includes any translated material, BMJ does not warrant the accuracy and reliability
of the translations (including but not limited to local regulations, clinical guidelines,
terminology, drug names and drug dosages), and is not responsible for any error
and/or omissions arising from translation and adaptation or otherwise.
Open access This is an open access article distributed in accordance with the
Creative Commons Attribution Non Commercial (CC BY- NC 4.0) license, which
permits others to distribute, remix, adapt, build upon this work non- commercially,
and license their derivative works on different terms, provided the original work is
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is non- commercial. See:http://creativecommons.org/licenses/by-nc/4.0/.
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