Clinical Rheumatology

https://doi.org/10.1007/s10067-020-05021-7

ORIGINAL ARTICLE

Real-world evaluation of effectiveness, persistence, and usage

patterns of tofacitinib in treatment of rheumatoid arthritis
in Australia
Paul Bird 1,2 & Geoffrey Littlejohn 1,3 & Belinda Butcher 2,4 & Tegan Smith 1 & Candida da Fonseca Pereira 5 &
David Witcombe 5 & Hedley Griffiths 1,6

Received: 15 December 2019 / Revised: 20 February 2020 / Accepted: 28 February 2020

# International League of Associations for Rheumatology (ILAR) 2020

Abstract
Introduction The aim of this study was to describe the real-world evidence for effectiveness, treatment persistence, and treatment
patterns among patients in the community with rheumatoid arthritis treated with the JAK inhibitor tofacitinib.
Methods This was a retrospective, non-interventional cohort study that extracted data for new users of tofacitinib or
biologic disease-modifying antirheumatic drugs (bDMARDs) from the Australian Optimizing Patient outcomes in
Australian RheumatoLogy (OPAL) dataset between March 2015 and September 2018. Patients were propensity score
matched at a 1:2 tofacitinib to bDMARD ratio based on age, sex, and selected baseline treatment combinations.
Treatment effectiveness was evaluated using disease status measures. Treatment persistence was calculated and the
percentage of patients receiving monotherapy or combination therapy at treatment initiation was evaluated.
Results Data from 2810 patients were extracted and 1950 patients were included in the matched population (1300
bDMARD initiators and 650 tofacitinib initiators). Patients were predominantly aged 55 to 74 years (57.8%) and
female (81.2%). After 18 months of treatment, 52.4% and 57.8% of patients had achieved disease activity score
(DAS) remission in the bDMARD and tofacitinib groups, respectively. The median treatment persistence for tofacitinib
was similar to that for bDMARDs: 34.2 months (95% CI 32.2 to not reached) and 33.8 months (95% CI 28.8 to 40.4),
respectively. In the overall population, more patients were prescribed tofacitinib as monotherapy (43.4%) compared
with bDMARD monotherapy (33.4%).
Conclusions Tofacitinib demonstrated treatment effectiveness and persistence similar to bDMARDs. Overall, there was a trend
for more use of tofacitinib as monotherapy than bDMARDs.

Key Points
• This study provides real-world evidence regarding effectiveness, treatment persistence, and treatment patterns, among patients with rheumatoid
arthritis (RA) in the community being treated with tofacitinib.
• The study suggests that tofacitinib is an effective and enduring intervention in RA with tofacitinib persistence and effectiveness comparable to
bDMARDs.

Keywords Medication persistence . Real-world . Rheumatoid arthritis . Targeted synthetic disease-modifying antirheumatic
drug . TNF-inhibitors . Tofacitinib

* Belinda Butcher 3
Monash University, Clayton, Victoria, Australia
bbutcher@writesourcemedical.com.au 4
WriteSource Medical Pty Ltd, Lane Cove, New South Wales,
Australia
1 5
OPAL Rheumatology Ltd, Sydney, New South Wales, Australia Pfizer Australia, Sydney, New South Wales, Australia
2 6
University of New South Wales, Kensington, New South Wales, Barwon Rheumatology Service, Geelong, Victoria, Australia
Australia

Introduction
Rheumatoid diseases such as rheumatoid arthritis (RA)
have a significant negative impact on patients’ health-
related quality of life (HQoL) and impose a significant
economic burden on society. Maximization of HQoL is
the primary goal of treatment. This is achieved through
symptom and inflammation control, prevention of pro-
gressive structural damage, preservation or normalization
of function and social participation, and targeting remis-
sion [1, 2]. Treatment of RA usually involves a multi-
faceted approach that includes pharmacologic and non-
pharmacologic strategies. Non-pharmacologic therapy
may include physical, occupational, and psychological
therapy, and surgery, while pharmacological therapy usu-
ally consists of various combinations of non-steroidal
antiinflammatory drugs (NSAIDs), analgesics, corticoste-
roids, and synthetic or biologic disease-modifying anti-
rheumatic drugs (DMARDs).
Recently, oral targeted synthetic DMARDs (tsDMARD),
including tofacitinib, have become available. Tofacitinib is a
potent, selective inhibitor of the Janus kinase (JAK) family of
kinases [3]. Tofacitinib was approved for use in Australia in
February 2015 and included in the Pharmaceutical Benefits
Scheme (PBS) for reimbursement in October 2015 for the
treatment of patients with RA.
The efficacy, safety, and impacts on HQoL of tofacitinib
have been assessed in randomized controlled trials (RCTs)
[4–11]. A review of patient reported outcomes from clinical
studies found that overall tofacitinib was associated with an
increase in quality of life and functionality and with improve-
ments in patient reported assessment of pain and global as-
sessment of disease [12]. However, real-world evidence com-
pliments the knowledge gained from clinical trials and pro-
vides information as to how factors such as the clinical setting
and health system influence treatment effects and outcomes.
Observational studies evaluating the effects of treatment in a
routine clinical environment are a key source of real-world
data [13].
Real-world treatment of RA with tofacitinib has only just
begun to emerge as tofacitinib was only approved in the USA
in 2012 and in Europe in 2017. A review of the real-world
evidence from countries including the USA, Japan, Taiwan,
Switzerland, Latin America, and Russia concerning the use of
tofacitinib in the management of patients with RA has been
reported [14]. The review found that patients initiating
tofacitinib usually had longer disease duration; tofacitinib ap-
peared to be more frequently used as a monotherapy than
biological DMARDS (bDMARDs) and was effective without
background use of methotrexate. The real-world data also
showed that persistence of treatment with tofacitinib and ad-
herence to treatment were good overall and similar to that seen
for bDMARDs [14].
Clin Rheumatol
There is limited data from large real-world populations to
describe the characteristics and outcomes of patients who re-
ceive tofacitinib for the management of RA in Australia. This
study aims to use the Optimizing Patient outcome in
Australian rheumatoLogy (OPAL) dataset to provide real-
world evidence regarding clinical effectiveness, treatment per-
sistence, and treatment patterns, among patients with RA be-
ing treated with tofacitinib in the post-approval setting.
Similar data was collected for patients treated with
bDMARDs to provide context in a large real-world clinical
practice setting.
Materials and methods
Study design and setting
This was a retrospective, non-interventional cohort study of
clinical effectiveness, treatment persistence, and treatment pat-
terns in patients prescribed tofacitinib or bDMARDs. Data was
extracted from real-world patient data from the Australian
OPAL dataset derived from 42 rheumatology clinics around
Australia. The OPAL dataset collects information from individ-
ual clinicians’ servers during routine clinical consultations.
Clinicians contributing data to OPAL use purpose-built
worksheets in Audit4 software (Software4Specialists,
Australia), and this software serves as the patient’s medical
record [15]. Diagnoses were made by individual rheumatolo-
gists rather than being criteria based. Data de-identified for
patient, clinic, and clinician were exported from each of the
OPAL member’s local server, aggregated across all sites, and
analyzed based on a predefined protocol.
The activities of OPAL Rheumatology Ltd. have received
overarching ethics approval from the University of New South
Wales (UNSW) Human Research Ethics Committee (HREC),
based on a patient opt-out arrangement (HC17799). This re-
search protocol was approved by the UNSW HREC
(HC17221).
Patient population and eligibility criteria
Patients were included if they were registered in the OPAL
dataset with a clinical diagnosis of RA and were aged between
18 and 94 years of age. Patients had initiated treatment with
tofacitinib or a bDMARD and had at least 1 year of follow-up
within the sample selection window between March 2015 and
September 2018. The bDMARDs that were approved for use
in Australia and included in this study were abatacept,
adalimumab, anakinra, certolizumab pegol, etanercept,
golimumab, infliximab, rituximab, and tocilizumab.
Tofacitinib was the only tsDMARD included in the study as
no other tsDMARDs were approved in Australia at the com-
mencement of the study. Patients who had no visit data
Clin Rheumatol
recorded and patients who had missing start dates for
tofacitinib/bDMARD treatment were not included. Patients
with a diagnosis of any autoimmune rheumatic disease or
inflammatory bowel disease except for RA were excluded.
Statistical and analytical assessment
The primary exposure of interest was an initial prescription for
tofacitinib or a bDMARD identified during the sample selec-
tion window. The date of the first prescription after the start of
the sample selection window served as the study index date
and the beginning of the post-index period. Patients that had
received a prescription of tofacitinib during the sample selec-
tion window were considered part of the “tofacitinib group”
even if they had also been prescribed a DMARD. All other
patients were considered to be in the bDMARD group.
Patients who discontinued treatment were followed up for a
minimum period of 1 year from their date on index. Data was
evaluated for missing data and to identify implausible values.
Implausible values were adjudicated by two rheumatologists,
who were members of OPAL but independent of the sponsor.
Treatment effectiveness was evaluated from baseline (in-
dex date) to 18 months using Disease Activity Score-28 with
erythrocyte sedimentation rate (DAS28-ESR) and Clinical
Disease Activity Index (CDAI) and Simplified Disease
Activity Index (SDAI) measures. An exploratory and descrip-
tive analysis of the most common adverse events was per-
formed. Treatment persistence with the index DMARD, in
part a surrogate for efficacy, was defined as the time (in con-
secutive days) from treatment initiation until treatment discon-
tinuation. Duration of treatment of the index DMARD was
summarized using Kaplan-Meier estimates of treatment per-
sistence. Treatment pattern evaluation included percentage of
patients receiving monotherapy or conventional synthetic
DMARD (csDMARD) combination therapy at treatment ini-
tiation and at 19- to 26-month follow-up. No formal compar-
isons were made between patients treated with tofacitinib and
bDMARDs. Any numerical differences or trends were de-
scriptive only.
Propensity score matching
In order to address the observational nature of the data,
propensity score matching was planned between the
tofacitinib and bDMARD groups. Propensity score
matching increases the comparability of the observed
baseline characteristics in patients treated with tofacitinib
and bDMARDs. The propensity score was the condition-
al probability of receiving treatment (e.g., tofacitinib ver-
sus other biologic agent), which was estimated using
logistic regression. Covariates included age, sex, and se-
lected baseline (where baseline is the index date) treat-
ment combinations. The baseline treatment combination
covariates were methotrexate monotherapy, methotrexate
in combination with other csDMARD(s), csDMARD(s)
other than methotrexate and neither methotrexate nor
other csDMARD(s) (bDMARD monotherapy). Disease
severity based on DAS28-ESR was not included as a
covariate as it led to the exclusion of too many patients.
Propensity score matching was determined on a ratio of
one tofacitinib user to two bDMARD users (1:2) using a cal-
iper width of 0.20. The success of the matching was deter-
mined by examining the propensity score distribution (density
plot) in both the original sample and the matched sample and
comparing the standardized differences (in means and propor-
tions) between the groups in the matched cohort. A difference
above 0.1 was considered indicative of a substantial difference
in that covariate [16].
Study size
A planned sample size of 500 and 2500 patients, in the
tofacitinib and bDMARD groups respectively, would ensure
acceptably precise estimates of treatment patterns and clinical
effectiveness. Data was extracted for 652 patients adminis-
tered tofacitinib and 2158 patients administered bDMARDs.
Though the bDMARD sample size was smaller than planned,
this sample size still ensured clinically acceptable precision in
the estimates of treatment patterns and clinical effectiveness;
for example, for a proportion of 30%, the confidence interval
is 28 to 32% for samples of 2500 or 2158.
Results
From March 2015 to September 2018, 2810 patients initiated
tofacitinib or bDMARDs and met the initial study selection
criteria. Overall, 2158 (77%) patients received index treatment
with bDMARDs and 652 (23%) patients received index treat-
ment with tofacitinib. The matched population included 1950
patients (1300 bDMARD initiators and 650 tofacitinib initia-
tors). Participant demographics for the matched population are
reported in Table 1. Patients were predominantly aged 55 to
74 years (57.8%), and female (81.2%). Baseline comorbidities
(not shown) were well matched across bDMARD and
tofacitinib groups. The disease status was similar between
the two groups and the treatment combinations were also well
matched at index between the two groups. At index, in the
matched population, median disease duration was 107 months
and 120 months (p = 0.037), for the bDMARD and tofacitinib
groups, respectively. In the overall population, median disease
duration was 100 months and 120 months (p = 0.002) for the
bDMARD and tofacitinib groups, respectively (data not
shown).
 Clin Rheumatol

Table 1 Patient demographics and disease characteristics at baseline for the propensity score matched population

bDMARD Tofacitinib

N (%) 1300 (66.7) 650 (33.3)

Age at index (years)
Mean (SD) 60.8 (13.1) 61.0 (12.7)
Median (min, max) 62 (21, 92) 63 (23, 89)
Gender, n (% of column)
Female 1056 (81.2%) 528 (81.2%)
Disease duration in months, median 107 [N = 818] 120 [N = 411]
Disease status
DAS28-CRP, n (% of column) N = 542 N = 304
Rem Low Mod High Rem Low Mod High
88 (16.2) 48 (8.9) 185 (34.1) 221 (40.8) 54 (17.8) 26 (8.6) 109 (35.9) 115 (37.8)
CDAI, n (% of column) N = 533 N = 308
Rem Low Mod High Rem Low Mod High
37 (6.9) 82 (15.4) 131 (24.6) 283 (53.1) 20 (6.5) 53 (17.2) 78 (25.3) 157 (51.0)
TJC28, mean (SD) 9.17 (8.65) [N = 783] 8.42 (8.24) [N = 402]
SJC28, mean (SD) 9.03 (8.47) [N = 783] 8.18 (8.09) [N = 402]
RAPID3, mean (SD) 3.58 (2.58) [N = 126] 4.39 (2.25) [N = 54]
Baseline treatment combinationsa
Methotrexate + cDMARD 294 (22.6%) 146 (22.5%)
Methotrexate alone 300 (23.1%) 150 (23.1%)
cDMARD (excluding methotrexate) 142 (10.9%) 72 (11.1%)
bDMARD monotherapy 564 (43.4%) 282 (43.4%)
Missing – –
a
Monotherapy was assigned for patients who were treated with a bDMARD or tsDMARD but had no record of methotrexate or alternative cDMARD at
the time of index. It is not clear, therefore, whether this is the true proportion of patients with monotherapy, or whether it represents missing information.
Missing represents patients with no information in the Medication dataset. These patients received bDMARD or tsDMARD but have no concomitant
medication reported

Treatment effectiveness treatment, 49.1% (n = 157/320) and 49.7% (n = 73/147)

In the matched population, the percentage of patients
achieving DAS28-ESR disease remission and low disease
activity (LDA) are shown in Fig. 1. Only patients with
baseline DAS28-ESR data are represented. At index,
16.1% (n = 87/539) and 17.3% (n = 52/300) of patients
were in DAS28-ESR remission for the bDMARD and
tofacitinib groups, respectively. After 3 months of
had achieved DAS28-ESR remission and after 18 months
of treatment, 52.4% (n = 89/170) and 57.8% (n = 48/83)
of patients had achieved DAS28-ESR remission in the
bDMARD and tofacitinib groups, respectively. There
were no significant differences in remission rates be-
tween the bDMARD and tofacitinib groups at any of
these time points (p = 0.66, p = 0.90, and p = 0.41 at in-
dex, 3 months, and 18 months respectively).

Fig. 1 Percentage of patients in the propensity score matched population achieving DAS28-ESR a disease remission and b low disease activity (LDA)
Clin Rheumatol
Fig. 2 Percentage of patients in the propensity score matched population achieving a CDAI and b SDAI disease remission
At index, 7.4% (n = 40/539) and 8.0% (n = 24/300) of pa-
tients were in DAS28-ESR LDA for the bDMARD and
tofacitinib groups, respectively. After 18 months of treatment
14.1% (n = 24/170) and 10.8% (n = 9/83) of patients were in
DAS28-ESR LDA in the bDMARD and tofacitinib groups,
respectively. There were no significant differences in LDA
rate between the bDMARD and tofacitinib groups at any of
these time points (p = 0.76 and p = 0.47, at index and
18 months respectively).
The percentage of patients in the matched population
achieving CDAI and SDAI disease remission activity is
shown in Fig. 2. At 18 months, the percentage of pa-
tients achieving CDAI and SDAI remission was similar
with 29.0% (n = 51/176) and 29.2% (n = 50/171)
bDMARD patients and 30.5% (n = 25/82) and 30.9%
(n = 25/81) tofacitinib patients reporting CDAI or SDAI
remission, respectively (p = 0.80 and p = 0.79,
respectively).
No adverse events were reported in more than 5% of the
population for bDMARD or tofacitinib treatment for the over-
all or the matched population.
Fig. 3 Treatment persistence in the propensity score matched population
for bDMARD and tofacitinib
Treatment persistence
The median persistence of treatment for the matched popula-
tion was 33.8 months (95% CI 28.8 to 40.4) for patients pre-
scribed bDMARDs and was 34.2 months (95% CI 32.2 to
“not reached”) for patients prescribed tofacitinib (Fig. 3).
The difference in median persistence between groups was
not significant (p = 0.19, log rank test). In the propensity score
matched population, the most common reasons for discontin-
uation were completion of treatment (429/1300 (33%), 135/
650 (25%)), lack of efficacy (281/1300 (22%), 113/650
(17%)), lack of efficacy, secondary failure (213/1300 (16%),
63/650 (10%)), and adverse reaction (211/1300 (16%), 81/650
(12%)), in the bDMARD and tofacitinib arms, respectively.
Note patients could have more than one reason for discontin-
uation recorded.
Treatment patterns
Monotherapy and combination cDMARD therapy treatment
patterns are shown in Table 2 for the overall population. At
index, more patients were prescribed tofacitinib as monother-
apy (43.4%, n = 282/650) compared with bDMARD mono-
therapy (33.4%, n = 719/2154; p < 0.001). For patients re-
maining on index tofacitinib or index bDMARD at 19 to
26 months of follow-up, the percentage of patients on mono-
therapy increased for both groups (tofacitinib 49.1% (n = 208/
424); bDMARD 39.0% (n = 518/1329) (p < 0.001)).
Corticosteroid use was similar at index for both groups
(tofacitinib 35.6% (n = 232/652); bDMARD 34.2% (n = 738/
2158)) and similar at 18 months of treatment (tofacitinib
34.3% (n = 185/540); bDMARD 32.1% (n = 567/1764); p =
0.51 and 0.36). (Data not shown).
Discussion
This study of real-world treatment in Australian patients
with RA found that tofacitinib demonstrated treatment
effectiveness and persistence that was similar to
 Clin Rheumatol

Table 2 Monotherapy and

combination therapy treatment Treatment combinations At index 19 to 26 months
patterns at treatment initiation and
at 19- to 26-month follow-up bDMARD Tofacitinib bDMARD Tofacitinib
(overall population) (N = 2154) (N = 650) (N = 1329) (N = 424)
n (%) n (%) n (%) n (%)

Methotrexate + cDMARD 589 (27.3) 146 (22.5) 270 (20.3) 78 (18.4)

Methotrexate alone 556 (25.8) 150 (23.1) 386 (29.0) 86 (20.3)
cDMARD (excluding 290 (13.5) 72 (11.1) 155 (11.7) 52 (12.3)
methotrexate)
bDMARD monotherapy 719 (33.4) 282 (43.4) 518 (39.0) 208 (49.1)

This is limited to patients who remained on their index bDMARD or tofacitinib at the time of follow-up

bDMARDs. Similar persistence between tofacitinib and
bDMARDs has also been observed in other real-world
studies [17, 18]. The criteria for reimbursement in
Australia require that patients demonstrate a response to
treatment within 3 months. The small reduction in per-
sistence observed at 3 months in both treatment arms
may be due to those patients who had not responded
adequately to treatment by 3 months and were no longer
eligible for receiving government-subsided treatment.
Patients that initiated tofacitinib at index had longer disease
duration than patients that initiated bDMARD treatment. This
has also been observed for patients in the US Corrona dataset
where the mean disease duration was significantly longer for
initiators of tofacitinib (13.9 years) compared with initiators of
bDMARDs (9.9 years, p < 0.001) [19]. The longer duration of
disease for patients that initiated tofacitinib may reflect that
tofacitinib has only recently become available compared with
other bDMARD therapy. Patients may have been waiting for a
therapy with a new mode of action because they were not
responsive to other bDMARDs. It may also reflect that some
patients may have been waiting to use orally administered
tofacitinib rather than use an injectable bDMARD.
There was a trend for a greater use of tofacitinib as mono-
therapy compared with bDMARDs. Observational studies in
the USA have also observed that tofacitinib was used more
commonly as monotherapy than bDMARDs [17, 19, 20].
The results from this study suggest that tofacitinib is an
effective and enduring intervention in RA with tofacitinib per-
sistence and effectiveness comparable to bDMARDs. Future
research could focus on trying to identify factors associated
with lack of persistence.
“missing not at random” data occur. We assume, given the
source of this data however, that data are likely to be missing
at random, as important clinical information is likely to have
been recorded within the patient’s notes. In addition, the
Pharmaceutical Benefits Scheme only requires a total joint
count/swollen joint count along with ESR or CRP, and as such
the patient global VAS is often not clinically recorded, so a
DAS-28 score cannot be calculated. Propensity score
matching was not possible using the DAS28-ESR score due
to insufficient numbers.
Acknowledgments The authors acknowledge the members of OPAL
Rheumatology Ltd. and their patients for providing clinical data for this
study, and Software4Specialists Pty Ltd. for providing the Audit4 plat-
form. Medical writing services provided by Theresa Wade from
WriteSource Medical were funded by OPAL in accordance with Good
Publication Practice (GPP3) guidelines (http://ismpp.org/gpp3).
Funding information This study was funded by Pfizer.
Compliance with ethical standards
Conflict of interest PB has attended advisory board meetings for Pfizer,
Celgene, Novartis, Janssen, Gilead, and AbbVie; been a consultant for
Roche; and received speaker financial support from Janssen. BB is an
independent statistical consultant, funded by OPAL. HG has attended
advisory board meetings for Pfizer, Novartis, Janssen, and AbbVie; been
a consultant for Roche; and received speaker financial support from
Janssen and conference financial support from Bristol-Myers Squibb.
GL has attended advisory board meetings for Janssen and AbbVie and
has received speaker financial support from AbbVie and Bristol-Myers
Squibb. TS has no conflicts to report. DW and CdFP are employees of
Pfizer.

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