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Januskinase Inhibitors to Treat Rheumatoid Arthritis: Real World Data Match
Clinical Trial Results. An Evaluation by BioReg, the Austrian Registry for
Biologicals, Biosimilars, and Targeted Synthetic DMARDS in the Treatment of
Inflammatory Rheumatic Diseases
Burkhard F. Leeb1,2,3*, Peter Spellitz3,4, Gabriele Eichbauer-Sturm3,5, Manfred Herold3,6, Miriam
Stetter3,7, Rudolf Puchner3,8, Franz St. Singer3, Ruth Fritsch-Stork3,9,10
1Department of Internal Medicine-Rheumatology, Karl Landsteiner Private University for Health Sciences, Krems, Austria;
2Department of Rheumatology, Office and Karl Landsteiner Institute for Clinical Rheumatology, Hollabrunn, Austria; 3BioReg
(Austrian Registry for Biologicals, Biosimilars and tsDMARDs in Rheumatology); Vienna, Austria; 4Department of Out-Patient,
Rheumazentrum Wien Oberlaa Center, Vienna, Austria; 5Department of Rheumatology and Nephrology, Office, Linz, Austria;
6Department of Rheumatology, Autoimmune Laboratory Medical University-Innsbruck, Innsbruck, Austria; 7Department of
Rheumatology, Office, Amstetten, Austria; 8Department of Rheumatology and Gastroenterology, Office, Wels, Austria; 9Department
of Rheumatology, Sigmund Freud Private University, Vienna, Austria; 10Department of Medical Hanusch Hospital, Rheumatology
and Ludwig Boltzmann Institute for Osteology, Vienna, Austria
ABSTRACT
Background: Whether the safety and efficacy of Januskinase Inhibitors (JAKis) in daily routine treatment of
Rheumatoid Arthritis (RA) match the respective clinical trial results is of crucial clinical interest, however, growing,
but still limited corresponding evidence is available.
Patients and methods: Data, including adverse events, disease activity scores, patient-related outcomes, and response
as well as persistence rates, of all RA patients receiving JAKi treatment registered in the BioReg database were
retrieved. The results were described according to those of pivotal clinical trials of JAKis. Analyses were performed using
descriptive statistics, such as mean value comparisons, and by drawing patient trajectories.
Results: One-hundred-and twenty-two patients (mean age 64 years; 83.9% female, 60.5% Rheumatoid Factor (RF)
positive; n=74 receiving Baricitinib and n=48 receiving Tofacitinib) were included from 2017 on. Significant
differences occurred in the initial disease activity (mean Disease Activity Score including 28-joint-count (DAS28) 6.5
versus 3.8) between the trials and real-world data. In the registry, an insufficient response was observed in 24 (32.4%)
and 21 (43.8%) patients, adverse events occurred in 16 (21.6%), and 12 (25.0%); the mean duration of treatment was
1.34 yrs. and 1.5 years. in patients receiving Baricitinib and Tofacitinib, respectively. The response rates were like
those of the clinical trials, whereas adverse events were less frequently reported in the registry and no safety signals
occurred. All scores applied showed a positive course and the results of mean value analysis and patient trajectories
demonstrated the benefits of JAKis; the health assessment questionnaire values remained relatively stable, in contrast
to the trial results.
Conclusion: Real World data for JAKis comply to a high extent with clinical trial results. This may contribute to an
increased confidence in the therapeutic status of these drugs.
Rheumatology: Current Research Research Article
Correspondence to: Burkhard F. Leeb, Department of Internal Medicine-Rheumatology, Karl Landsteiner Private University for Health Sciences,
Krems, Austria, Tel: +436644165686; E-mail: burkhard.leeb@stpoelten.lknoe.at/leeb.rheuma@aon.at
Received: June 02, 2021; Accepted: June 16, 2021; Published: June 23, 2021
Citation: Leeb BF, Spellitz F, Sturmc GE, Herold M, Stetter M, Puchner R, et al. (2021) Januskinase Inhibitors to Treat Rheumatoid Arthritis: Real
World Data Match Clinical Trial Results an Evaluation by BioReg, the Austrian Registry for Biologicals, Biosimilars, and Targeted Synthetic
DMARDS in the Treatment of Inflammatory Rheumatic Diseases. Rheumatology (Sunnyvale). 11.288.
Copyright: © 2021 Leeb BF, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which
permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Rheumatology (Sunnyvale), Vol.11 Iss.5 No:1000288 1
Keywords: Rheumatoid Arthritis (RA); Januskinase Inhibitors (JAKis); Baricitinib; Clinical trial results
INTRODUCTION
Rheumatoid Arthritis (RA), the most common chronic
inflammatory disease, is a progressive, systemic autoimmune
disease characterized by inflammation of the synovial
membrane. This inf lammation, aside from pain, stiffness,
swelling, and loss of function, may also cause bone erosion,
ultimately leading to irreversible joint destruction and disability
[1]. Other systemic symptoms of RA include fatigue, anemia,
and osteoporosis, and RA patient’s the overall risk to develop,
example, cardiovascular diseases and infection is considerably
increased [2,3]. Over the last decades, major advances in RA
treatment have been achieved [4], due to the development of
new biologic Disease-Modifying Drugs
Factor-alpha (TNF- α
Meeting the obvious medical need for further effective
treatments, a different therapeutic approach, targeting
intracellular activation pathways, particularly Janus Kinases
(JAKs), has been applied. JAK-Inhibitors (JAKis) have been
shown to be more efficacious than methotrexate (MTX) and/or
anti-TNF-a agents in clinical trials; providing an alternative for
patients with an inadequate clinical response to biologic or non-
biologic Disease Modifying Anti Rheumatic Drugs (DMARDs)
[8]. Studies with the first two JAKis, Tofacitinib (Tofa) and
Baricitinib (Bari) reimbursed in Austria since October 2017, and
Baricitinib (Bari), reimbursed in Austria since August 2018, have
demonstrated efficacy in several RA patient groups either as
monotherapy or in combination with MTX and Adalimumab,
as a comparator [9]. Those studies lead to a licensing of Bari and
Tofa as monotherapy or in combination with MTX in patients
with moderate-to-severe RA not adequately responding to one or
more DMARDs [10,11].
At the time point this evaluation was carried out, almost no
Real-World Evidence (RWE) for the application of both drugs
was available, which could allow a better understanding of the
JAKis treatment impact in more diverse patient populations.
Meanwhile, a feast of papers from different countries and
cultures dealing with this topic have been published, providing
evidence important for the clinically working rheumatologist,
whether the risk/benefit ration of Januskinase Inhibitors (JAKis)
in daily routine treatment of Rheumatoid Arthritis (RA) can be
regarded reasonable, and which patient groups could expect
benefits from JAKI treatment. However, most of the papers deal
with different questions, in part comparing JAKis with
biological, or giving information about treatment strategies;
similarly to our investigations, the sample sizes are relatively
small, even from big countries like Germany and Italy [12-16].
The objectives of the present evaluation of these registry data
were to evaluate the safety and efficacy of JAKis in routine
treatment of RA in real-life as well as to investigate whether real-
life data match the respective clinical trial results to increase the
knowledge about the position of JAKis in routine therapy of RA
and possibly create a hypothesis for future studies. This paper
presents the respective results from Austria, a relatively small
country with a highly developed health care system, practically
providing access to the drug to all patients who need.
PATIENTS AND METHODS
Real-life data of Austrian RA patients treated with biologicals,
Biosimilars, and Targeted Synthetic DMARDs (tsDMARDs)
including JAKis have been collected in the BioReg Project
database. BioReg, the Austrian registry for patients with chronic
rheumatic diseases treated with these agents, was established in
2010. Meanwhile, more than 3100 patients from 28 centers have
been enrolled into this database. The RA data core set
encompasses joint counts, the Disease Activity score including an
28-joint count (DAS28-ESR), the Clinical Disease Activity Index
(CDAI), and the Health Assessment Questionnaire (HAQ-DI),
additionally, the Rheumatoid Arthritis Disease Activity Index-5
(RADAI-5) [17-21]. Moreover, CRP, ESR, RF, and anti-CCP are
recorded, as well as comorbidities and adverse events. Female or
male patients, treated with Biologicals, Biosimilars or
tsDMARDs, older than 18 years, personally independent with
inflammatory rheumatic diseases, such as RA, Psoriatic
Arthritis, Ankylosing Spondylitis, and other diseases treated
with Biologicals, Biosimilars and tsDMARDs, according to the
licensed indications or generally accepted "off label” use can be
included in BioReg. Personal dependence and withdrawal of
informed consent are the only exclusion criteria. The ethics
committee of Lower Austria has approved the study design of
BioReg (reference number GS4-EK-085-2009) in 2009, and this
approval is renewed annually [6]. All patients gave their written
informed consent before inclusion into the registry. Data
collection in BioReg started in 2010. For this study with a
deadline of May 31st, 2019, the data of all RA patients receiving
Bari or Tofa in the BioReg database were retrieved. Patient
characteristics, including the most prevalent comorbidities, are
given in detail in Tables 1 and 2. According to the primary goal
of the registry, all safety issues and adverse events are
documented, collected, and evaluated, not limited to treatment
withdrawal. These are listed in Tables 3 and 4.
Personal data Baricitinib (n=74) Tofacitinib (n=48)
Age (years; min-max) 64 (26-84) 64 (35-89)
Female sex 80.30% 87.50%
RF pos 60.50% 60.40%
Leeb BF, et al.
Rheumatology (Sunnyvale), Vol.11 Iss.5 No:1000288 2
efficacy in an additional number of
(bDMARDS) with impro-
ved patients compared to
conventional treatments, Conventional Synthetic DMARDs
(csDMARDs), resulting in the change of
However, despite all advances, a
[5].
patients fail to achieve an acceptable
treatment recommend-
ations considerable propor-
tion of clinical response or
drug tolerance to the available treatments [6], including biologic
compounds targeting Tumor Necrosis ),
Interleukin-6 receptor (IL-6r), Interleukin1 (IL-1), the co-stimul-
ation pathway, or B-cells [6,7].
ACPA pos. 52,8% 57,6%
Initial DAS28-ESR
(mean ± SD)
3.83 ( ± 1.2) 3.80 ( ± 1.4)
Height (cm, min-max) 166 (150-182) 167 (153-183)
Weight (kg, min-max) 74,7 (45-130) 71.4 (43-119)
Duration (years;
mean ± SD)
14.1 ( ± 9.7) 12.9 ( ± 9.39)
Biologic naive (n, %) 14 (19%) 8 (17%)
≤ 2 biologics (n, %) 32 (43%) 34 (71%)
>2 biologics (n, %) 28 (38%) 6 (12%)
Co-morbidities (n, %) 48 (65%) 34 (71%)
Table 1: Demographic data of the JAKI treated patients in
BioReg.
Co-morbidities Baricitinib (n=48, multiple answers possible)
No co-morbidity recorded 26
Vascular diseases 15
Endocrine diseases 14
Heart diseases 12
Bone diseases 8
Psychiatric diseases 6
Pulmonary diseases 6
Gastrointestinal diseases 1
Co-morbidities Tofacitinib (n=34, multiple answers possible)
No co-morbidity recorded 14
Heart diseases 12
Endocrine diseases 12
Vascular diseases 11
Bone diseases 5
Psychiatric diseases 4
Pulmonary diseases 1
Gastrointestinal diseases 1
Table 2: Patients’ comorbidities.
BioReg patients Baricitinib (n=74) Tofacitinib (n=48)
Duration of therapy
(median, min-max)
1.25 yrs. (0.25-2.5) 1.25 yrs. (0.25-2.5)
Discontinuation of
therapy (n, %)
13 (17.6%) 14 (29.2%)
Insufficient response*
(n, %)
24 (32.4%) 21 (43.8%)
Adverse events* (n,
%)
16 (21.6%) 12 (25.0%)
*Not all leading to discontinuation of treatment
Table 3: Therapy characteristics of patients in BioReg.
AEs Baricitinib (n=16)
Infections and parasitic diseases 6
Hematological diseases 2
Ear and labyrinthic diseases 2
Endocrine diseases 1
Genitourinary and breast diseases 1
Gastrointestinal diseases 1
Neurological disorders 1
Vascular diseases 1
Heart diseases 1
AEs Tofacitinib (n=12)
Infections and parasitic diseases 5
Gastrointestinal diseases 2
Ear and labyrinthic diseases 1
Skin diseases 1
Neurological disorders 1
Vascular diseases 1
Neoplasms 1
Table 4: Adverse events in JAKi treated patients (MedRA-SOC
terms).
In Austria, LAKIs are licensed for RA patients with moderate
disease activity as expressed by an accepted disease activity scale
(example, DAS28>3.2) after failure of at least one biological.
Bari and Tofa are reimbursed in Austria since October 2017 and
August 2018, respectively, in case of failure to one bDMARD. For
this study, the following scores were retrieved from the registry:
Disease Activity score including a 28-joint count (DAS28-ESR),
Leeb BF, et al.
Rheumatology (Sunnyvale), Vol.11 Iss.5 No:1000288 3
Clinical Disease Activity Index (CDAI), and Health Assessment
Questionnaire (HAQ-DI). Additionally, the Rheumatoid
Arthritis Disease Activity Index-5 (RADAI-5) was documented
[12-16]; not all instruments are applied in each patient, as the
instruments used depend on the participant’s routine practice.
Safety data were gathered according to MedDRA definitions and
are depicted in a descriptive manner.
The registry comprised 1,408 patients with rheumatoid arthritis
at the time of data retrieval, of which 74 patients were treated
with Baricitinib and 48 patients with Tofacitinib together
amounting to 8.7% of all RA-patients included in the registry.
For analytic purposes, patient trajectories (“Spaghetti-blots”),
depicting the course of the disease in an individual patient and
mean value comparisons on a group level (as a conservative
approach) were performed [22]. Propensity score matching with
clinical trial data from the RA-BEACON study with Bari and
the ORAL Step trial with Tofa [23-25] would have been a more
stringent analysis, however, as we had no access to the raw data
of the clinical trials, it was not possible to perform such an
analysis. Thus, the results of the analysis of data obtained from
BioReg were described in comparision data obtained from clini-
cal trials with JAKis. Due to the inherent differences of data
stemming from controlled trials versus registry data in terms of,
among others, patient characteristics, timepoints, and frequency
of control visits as well as the stringency of data completion, a
descriptive rather than a statistical comparison was carried out
and should serve to generate a hypothesis.
RESULTS
Seventy-four patients were treated with Bari, their mean age was
64 (26-84) years, 80.3% were female, and 60.5% were positive
for Rheumatoid Factor (RF) and 52.8% for Antibodies against
Citrullinated Protein (ACPA). Forty-eight patients were treated
with Tofa, their mean age was 64 (range: 35-89) years, 87.5%
were female, and 60.4% were RF and 57.6 were ACPA positive.
JAKi treatment was initiated preferentially after one or two
unsuccessful treatment attempts with biologics, namely, in 32
(43%) Bari treated patients, and in 34 (71%) patients treated
with Tofa respectively, which is in line with the Austrian
reimbursement regulations for these drugs. Fourteen pts (19%)
received Baricitinib as their first treatment after csDMARDS
failure, and 8 pts (17%) Tofa, respectively, see in Table 1. Co-
morbidities were evident in 48 pts on Bari (65%) and in 34 pts
on Tofa (73%). The most prevalent comorbidities were vascular,
endocrine, and heart diseases in Table 2.
The median treatment duration was 1.25 (0.25-2.5) years for
both medications, [R] also the withdrawal rates (Bari 17.6%,
Tofa 29.2%) were similar. After one year of treatment,
approximately 80% of the patients were found still on JAKi
therapy in Table 3. Safety data of the BIOREG registry were
recorded according to the MedDRA classification system and
are depicted in Table 4. Most frequent were infectious/parasitic
diseases with a cumulative incidence of 8.1% for Bari and 10.4%
for Tofa. According to the SOC terms, vascular disease occurred
in one patient each on Bari or Tofa, and neoplasms were noted
in one patient on Tofa Table 4. An insufficient response as
assessed by the physician’s personal global evaluation was
observed in 24 (32.4%) and 21 (43.8%) patients and adverse
events occurred in 16 (21.6%) and 12 (25.0%) patients receiving
Bari and Tofa, respectively Table 3 and Table 4. During the
observation period up until the writing of this manuscript, none
of the patients died or developed deep venous thrombosis. The
DAS28-ESR was available for 50 pts. on Bari and 42 on Tofa,
CDAI for 42/33, HAQ-DI for 57/40 pts., and RADAI-5 for
41/44 pts., respectively.
The mean baseline DAS28 was 3.83 ± 1.21 and 3.80 ± 1.41,
respectively, for the Bari- and the Tofa-treated patients, with
corresponding CDAI values of 15.7, and 20.3 ± 14.4. The
respective RADAI-5 values were 4.4 ± 2.2 and 4.2 ± 2.4). All
disease activity score values indicate moderate disease activity at
the time of JAKi initiation, with mean HAQ values of 1.1 ± 0.7
and 1.2 ± 0.8 for the Bari- resp. Tofa-treated patients in Figures
1a and 1b. During the treatment period, all parameters showed
improvement, which is demonstrated by the course of DAS28
for both drugs as, shown in Figures 2a and 2b. Mean analyses
and patient trajectories, which outline the individual courses,
showed the beneficial effects of JAKis on the disease course up
to 24 weeks for Bari and 18 weeks for tofa. The analysis of the
CDAI and RADAI-5 courses was similar, apart from some
individual fluctuations as shown in Figure 3a and 3b.
Figure 1: DAS28 of the Baricitinib-treated patients. (a)
Trajectories showing the individual courses; (b) Conventional
bar graphs depicting mean values.
Figure 2: DAS28 of the Tofacitinib-treated patients. (a)
Trajectories showing the individual courses; (b) Conventional
bar graphs depicting the mean values.
Figure 3: Patient trajectories for the RADAI-5 (a) in the
Baricitinib (b) in the Tofacitinib treated patients.
Leeb BF, et al.
Rheumatology (Sunnyvale), Vol.11 Iss.5 No:1000288 4
Comparison with Bari in the RA-BEACON trial
The RA-BEACON trial was performed as a 6-month phase 3
clinical trial investigating the efficacy and safety of Bari in
combination with csDMARDS in patients not adequately
responding to prior therapy with a biological. This situation very
much mirrors the characteristics of patients in BioReg treated wi-
th Bari, which was also the case in the Austrian patients included
in the RA-BEACON study. [24]. In BioReg, 81% of the 74
patients treated with Bari had a treatment history of one or
more biologics. Therefore, we compared the registry data with
the patient group (n=177) treated with 4 mg Bari/day from the
RA-BEACON trial [24]. Whereas sex distribution and disease
duration were similar, patients in the BioReg were older (64 ±
12 vs.
BioReg displayed less severe disease activity mean
DAS28-ESR: 3.83 ± 1.2 vs. 6.6 ± 1.1, mean HAQ 1.1 ± 0.7) vs.
1.7 ± 1.6 compared to those in the RA-BEACON trial. The
mean DAS28 and HAQ reductions at month six in the RA-
BEACON trial were 1.7 and 0.4, respectively [24], whereas in
BioReg, the respective reduction of DAS28 was 1.1, and the
mean HAQ was found unchanged after six months. In the RA-
BEACON trial, 88% of the patients completed the 6-month
treatment, whereas in BioReg, 82.4% of the patients remained
on Bari throughout the observation period, which lasted for
1.25 (0.25-2.5) years. The response rate, although difficult to
compare in the clinical trial, was primarily assessed with the
ACR criteria [26], whereas that in BioReg above all was assessed
according to the physician’s discretion; 67.6% of the patients in
BioReg were assessed to have a positive response, whereas in the
RA-BEACON trial, only 30% achieved an ACR response of
50%. For the sake of better comparability, we also compared the
percentage of patients achieving a DAS28ESR<3.2 at week 24.
In BioReg, 48% (15 of 31) patients achieved the low disease
activity threshold, while in the trial this percentage was 26%.
Adverse events were more frequently reported in the clinical
trial than in the registry (77% vs. 21.6%) and no new signals
with respect to AEs were observed.
Comparison with Tofa in the ORAL-step trial
This study was performed as a 6-month phase 3 clinical trial
investigating the efficacy and safety of Tofa in combination with
MTX in patients with insufficient response to TNF inhibitors.
This was also the case in 83% of patients BioReg treated with
Tofa, suggesting similar patient populations in BioReg and the
patient group (n=122) treated with 5 mg Tofa/twice a day in the
ORAL step trial [25]. Gender distribution, RF positivity, and
disease duration were similar in both groups, whereas the
patients in BioReg were older (64 ± 12.2 vs. 55.1 ± 11.3) years
and less active in their disease (DAS28-ESR 3.8 ± 1.4 vs. 6.5 ±
1.1, HAQ: 1.2 ± 0.8 vs. 1.6 ± 0.7) than those in the trial. The
mean DAS28 and HAQ reductions at 6 months in ORAL step
trial were 1.6 and 0.5, respectively [25], in contrast to 1.0 and
0.3 in BioReg. In the ORAL step trial, 80.5% of the patients
completed the 6-month treatment, whereas, in BioReg, 70.8%
of the patients remained on Tofa throughout the median
observation period of 1.25 (0.25-2.5) years. Whereas 51.1% of
the patients achieved an ACR response of 50% in the ORAL
step one, 56.2% of the patients were evaluated by their treating
physicians to have a sufficient response in BioReg. A
DAS28ESR<3.2 at week 24 was achieved by 44% (12 of 27) in
BioReg, in contrast to 25% in the trial. Adverse events were
more frequently reported in the clinical trial than in the registry
(42.9% vs. 25.0%). It is important to note that no new or
unexpected adverse events occurred in the patients in BioReg.
DISCUSSION
The JAKis Bari and Tofa rapidly and very successfully found their
position in the therapeutic armamentarium for RA [8]. This is
also apparent in Austria with 8.7% of RA patients enrolled in
BioReg two and a half years after licensing. In terms of gender
and disease duration, patients in BioReg correspond to the
patient population of the pivotal RA-BEACON and ORAL
STEP ONE trials, however, BioReg patients are older, suffer
from a higher number of comorbidities, and display a lower
disease activity than the clinical trial cohorts. Altogether, data
from the BioReg registry paint a reassuring picture of safety and
affectivity similar/better to the ones in the pivotal trials. To
translate data from successful clinical trials acquired from a
highly selected patient population into clinical practice, data
from registries, which include patients as comprehensively as
possible, are important [27,28]. Due to the relative recent
approval of Baricitinib and Tofacitinib by the European
Medicines Agency in 2017, registry data pertaining to JAKi from
Europe are limited and have mostly been presented at meetings
[29] However, due to earlier approval in other states, sporadic
real-life data have been published, e.g. from the US, Australia or
Switzerland [22] The main scope of these reports was a
comparison with other bDMARDs, in which the non-inferiority
of JAKi compared to anti TNF known from clinical trials was
underscored [12-14]. Mueller et al., on the other hand,
investigated the safety of Tofa assessed by the reason to stop the
medication and laboratory abnormalities. Again, clinical trial
data were corroborated, and no new relevant safety signals were
described [13]. The present report from the BioReg registry
differs from most publications due to the comprehensive
description of patient characteristics, safety data, and
effectiveness data. Furthermore, the direct reference between
clinical trial data and BioReg data provides additional insight
beyond the data provided from other registries. Here we show
that the efficacy of JAKi not only applies to the clinical trial
population of patients in their mid 50ies with high disease
activity but is used safely and effectively in patients>60 years old
with only moderate disease activity reflected in the lower DAS28
values in BioReg vs. trials with Bari and Tofa [24,25]. In Austria,
in contrast to many other countries, biological and tsDMARDs
are usually initiated at this (rather low) disease activity stage [6].
The role of high DAS28 as a predictor of clinical response has
been acknowledged in several trials of biological therapy [29,
30]. However, also in registry data with lower initial disease
activity values, a significant improvement could generally be
observed [31] a positive contribution of a lower baseline DAS28
to the achievement of low activity has also been observed in a
Japanese report presented at the EULAR 2020 [32].
Altogether, patients in the trials as well as in the registry finally
developed a low moderate disease activity on average, which was
Leeb BF, et al.
Rheumatology (Sunnyvale), Vol.11 Iss.5 No:1000288 5
56 ± 11 years and less likely to be RF positive (60.6%
Patients in
±
72%).
demonstrated in several disease scores. The BioReg data,
also included the RADAI-5, not applied in the trials, which also
mirrored the course of the composite indexes [15]. Additionally,
visualizing the individual disease activity score courses by patient
trajectories using BioReg revealed a beneficial course in most of
the patients, despite some fluctuations. Patient trajectories may
allow better insight into the course of the disease and may offer
the opportunity to better estimate the individual patient’s
chance for success [17]. The improvement of the HAQ values
was less prominent in the registry than in the clinical trials, with
lower baseline HAQ values, comparable disease duration despite
higher mean age in the BioReg patients. Apart from the lower
disease activity, which may have contributed to the lower HAQ
score, the sociocultural variety in the participants of
multinational trials may have played a role. At the end of the
day, the JAKis proved to be effective to a remarkably similar
extent, although without formal statistical comparison, in
clinical trial population and the real world setting of the
Austrian registry.
As expected, adverse events were more frequently reported in
the clinical trial than in the registry (77% vs. 21.6%). Bari and
Tofa were found to be well tolerated by the patients in the
registry with an overall incidence of infection of approximately
10% as the most frequent adverse event. To our knowledge, this
is the first report of any infection derived from registry data, and
it implicates no new safety signals in the use of JAKi in real life.
However, the strikingly higher rate of adverse events in the trials
vs. the registry is evident and can-at least partly-be explained by
the rigorous monitoring procedures of clinical trials, which
cannot be guaranteed in registries.
There are some shortcomings of this study. The differences
between clinical trials and BioReg are evident: In the registry, no
close monitoring is performed; data are collected with differing
frequencies and extent. However, the registries reflect the real-
life setting, considering the above-mentioned shortcomings. The
number of included patients in our Austrian registry is smaller
compared to globally performed clinical trials or some other
registries, but the evidence published in that respect is also
founded on relatively small patient numbers [13,15]. However,
the advantage of our registry data is the homogenous patient
population with little sociocultural differences, a highly
developed social insurance system, the unusual older age, and
low disease activity of the BioReg patients. A caveat is the
inclusion of all patients treated with JAKis, and not only
biological non-responders [33]. However, we believe that
following the new recommendations [34], JAKis will increasingly
be used in biological naïve patients, justifying the inclusion of
these patients.
Large, non-interventional observations, such as registries, seek to
include as many patients as possible irrespective of
comorbidities, age, disease activity, or other confounding
factors, in contrast to the highly selected patient population of
clinical investigations, to reflect daily practice as precisely as
possible. Therefore, it is of particular importance for clinical
practice to undertake efforts to verify or falsify the results of
clinical trials by real-world evidence, which has been just recently
strengthened by the German Institute for Quality and Economy
in Health Care (IQWiG) [35]. Of course, propensity matching
had constituted a method to achieve more robust results.
However, the nature of the registry data and the impossibility to
access the clinical trials’ raw data made it seem appropriate not to
perform other than our primarily descriptive analysis. Registry
data may serve as a possibility to generate hypotheses for future
research. Such studies should comprise as many real-world data
as possible as well as raw data from clinical trials with a
propensity score analysis to validate our observations so that the
efficacy and safety of JAKis is like clinical trial results and real-
world data in RA.
CONCLUSION
In conclusion, for the Austrian patients enrolled in BioReg, the
application of JAKis in clinical practice leads to results
comparable to those of clinical trials, even though the patient
population was older and had lower disease activity. This may
contribute to an increased confidence of the treating physicians
in the therapeutic properties of these drugs.
ETHICS APPROVAL
The ethics committee of Lower Austria has approved the study
design of BioReg (reference number GS4-EK-085-2009) in 2009,
and this approval is renewed annually (most recently
02/14/2020).
DISCLOSURES
BFL Clinical trials: TRB, Roche, Consultancies: AbbVie,
Amgen, Roche, MSD, Pfizer, Celgene, Grünenthal, Kwizda, Eli-
Lilly, Novartis, Sandoz.
Speakers ‘bureau: AbbVie, Roche, MSD, Pfizer, Actiopharm,
Boehringer-Ingelheim, Kwizda, Celgene, Sandoz, Grünenthal,
Eli-Lilly.
RP: Consultancies: AbbVie, Amgen, Pfizer, Celgene,
Grünenthal, Eli-Lilly; Speakers ‘bureau: AbbVie, BMS, Janssen,
Kwizda, MSD, Pfizer, Celgene, Grünenthal, Eli-Lilly, PS, GES,
MS, MH, FStS, RFS declared no conflicts of interest.
FUNDING
BioReg is a non-profit organization supported by ABBVIE
GmbH; AMGEN GmbH, CELGENE GmbH; BIOGEN
GmbH, ELI-LILLY GmbH, FRESENIUS-KABI Austria GmbH;
JANSSEN-CILAG Austria GmbH, MERCK SHARP and
DOHME GmbH; PFIZER CORPORATION AUSTRIA
GmbH, ROCHE AUSTRIA GmbH; SANDOZ Pharma GmbH,
UCB Pharma GmbH through an unrestricted educational grant.
This study was supported by ELI-LILLY GmbH, Austria.
AUTHOR CONTRIBUTIONS
BFL: Contributed to data acquisition, design of the study, data
analysis, manuscript writing.
PS, GES, MH, MS, RP: Data acquisition, data analysis, study
design.
Leeb BF, et al.
Rheumatology (Sunnyvale), Vol.11 Iss.5 No:1000288 6
FSS, RFS: Data analysis, study design, manuscript writing.
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