Cost-effectiveness Analysis of Golimumab in the Treatment of Non-Radiographic Axial Spondyloarthritis in Scotland
Cost-effectiveness Analysis of Golimumab in the Treatment of Non-Radiographic Axial Spondyloarthritis in Scotland
Rebekah H. Borse . Sumesh Kachroo . Chloe Brown . 0 1
Eilish McCann . Ralph P. Insinga 0 1
0 C. Brown E. McCann Merck Sharp & Dohme , Hoddesdon , UK
1 R. H. Borse (&) S. Kachroo R. P. Insinga Merck & Co., Inc. , Kenilworth, NJ , USA
Introduction: The aim of this study is to assess the cost-effectiveness of golimumab for the treatment of non-radiographic axial spondyloarthritis (nr-axSpA) vs. conventional therapy and other tumor necrosis factor inhibitors from the Scottish payer perspective. Methods: A model comprising a short-term decision tree and a long-term Markov model was developed to compare cost-effectiveness (incremental costs per quality-adjusted life-year [QALY]) for patients in Scotland with nr-axSpA treated by conventional therapy, adalimumab, certolizumab pegol, etanercept, or golimumab for a lifetime period. A network meta-analysis (NMA) was conducted to identify clinical and safety data for treatments and synthesize the available evidence into relative treatment effects between comparators. The probability of patients achieving an Assessment of SpondyloArthritis International Society 20/40% response criteria (ASAS20/ASAS40) or a 50% improvement in Bath Ankylosing Spondylitis Disease Activity Index score (BASDAI50) at week 12 was obtained from the NMA for each of the comparators. Baseline health state utilities were based on the EQ-5D questionnaire collected in the golimumab GO-AHEAD study. The cost of treatment was calculated based on drug acquisition, drug administration, and initiation/monitoring costs. Results: Golimumab resulted in an increase of 2.06 QALYs and additional cost of £39,770 compared with conventional therapy. Incremental cost per QALY gained was £19,280 for golimumab, which was lower than adalimumab (£19,737), etanercept (£20,089), and higher than certolizumab pegol (£18,710). Golimumab remained cost-effective throughout a range of sensitivity analyses where key assumptions were tested. Conclusions: From a Scottish perspective, golimumab was a cost-effective treatment for nraxSpA compared with conventional therapy at a willingness-to-pay threshold of £30,000 per QALY. Funding: Merck & Co., Inc.
Ankylosing spondylitis; Costeffectiveness; Decision tree; Golimumab; Markov model; Non-radiographic axial spondyloarthritis; Scotland; Tumor necrosis factor inhibitors
Axial spondyloarthritis (axSpA) is a group of
chronic, inflammatory diseases, primarily
characterized by inflammation of the spine and
sacroiliac joints [
]. The most commonly
occurring form of axSpA is ankylosing
spondylitis (AS), with radiographic structural
changes in sacroiliac joints being the most
important criterion for a clinical diagnosis [
In 2009, the Assessment of Spondyloarthritis
International Society (ASAS) developed new
classification criteria in order to better
characterize the group of patients with typical features
of axSpA, such as the presence of inflammatory
back pain and positive human leukocyte
antigen B27 (HLA-B27), but the absence of any
definitive radiographic evidence of sacroiliitis
]. This subpopulation is classified as having
non-radiographic axial spondyloarthritis
]. Both European data and
Scotlandspecific data on the prevalence of nr-axSpA are
very limited because of the different diagnostic
criteria adopted in identifying patients with
nraxSpA based on symptom duration, and varying
availability of diagnostic tools. In Europe, the
proportion of nr-axSpA among axSpA patients is
estimated to be 23–80% [
]. The use of the ASAS
classification criteria in identifying nr-axSpA
patients in clinical practice was reported to be
approximately 52% (ranging from 24% in
Germany to 75% in Spain) by a recent European
cross-sectional study [
Some nr-axSpA patients will progress to AS
later in their disease course while approximately
30% will never develop radiographic sacroiliitis
despite persistent inflammatory back pain [
Studies report that the factors associated with
disease progression include male sex, high level
of inflammation (as demonstrated by C-reactive
protein level), and longer symptom duration
]. Patients treated with a tumor necrosis
factor inhibitor (TNFi) also have slower rate of
disease progression, compared with patients
who have never been treated with a TNFi .
Regardless of whether progression to AS
occurs, nr-axSpA can have substantial negative
impacts on patients’ daily activities and quality
of life due to disease-related symptoms and
treatment-related adverse events, as well as the
functional effects of living with the disease. A
number of studies have shown that physical
function is considerably impaired among
patients with nr-axSpA, as assessed with the
Bath Ankylosing Spondylitis Disease Activity
Index (BASDAI) and the Bath Ankylosing
Spondylitis Functional Index (BASFI), with the
Bath Ankylosing Spondylitis Metrology Index
(BASMI) being used to assess spinal mobility
7, 8, 10, 11
]. Studies have shown that,
compared with axSpA, nr-axSpA has a greater
impact on productivity, both at home and in
the workplace [
]. As would be expected,
these effects translate to an increased economic
burden, with healthcare-resource utilization
and lost productivity resulting in approximate
mean 3-year costs of between €5000 and
€38,000 in a mixed cohort of SpA patients, the
majority of whom had nr-axSpA [
Non-steroidal anti-inflammatory drugs
(NSAIDs) are recommended as first-line
treatment for nr-axSpA by ASAS and the European
League Against Rheumatism (EULAR) [
Some patients respond well to initial treatment
with NSAIDs, but a considerable proportion of
patients have an inadequate response and will
need subsequent treatment such as TNFi
therapy to control persistently high disease activity.
Currently, there are four TNFis (adalimumab,
certolizumab pegol, etanercept, and
golimumab) with marketing authorization for the
treatment of nr-axSpA in Europe, when patients
have high disease severity despite adequate
NSAID treatment (a minimum of two NSAIDs
for a minimum of 4 weeks) [
]. In addition,
golimumab, adalimumab, etanercept, and
certolizumab pegol are recommended by the
Scottish Medicines Consortium (SMC) for the
treatment of patients with nr-axSpA [
Golimumab is a once-a-month,
subcutaneously injected treatment for nr-axSpA that
has been approved for previously treated
nraxSpA in Europe. GO-AHEAD, a 16-week, phase
3, placebo-controlled randomized trial,
demonstrated the efficacy and tolerability of
golimumab in patients with nr-axSpA who were
not responding to NSAIDs [
more patients in the golimumab group
achieved ASAS 20% response criteria (ASAS20),
compared with the placebo group at week 16
(71.1 vs. 40.0%, P \ 0.0001), when looking at
the full analysis set. In part 2 of GO-AHEAD,
where patients in the golimumab group
continued to receive golimumab, and patients in
the placebo group crossed over to receive
golimumab, the proportion of ASAS20 responders
in the golimumab/golimumab group continued
to increase from week 16 to week 32, and in the
placebo/golimumab group, there was a
notable increase in patients achieving ASAS20
after switching to golimumab [
The objective of this analysis was to assess
the cost-effectiveness of golimumab for
treatment of nr-axSpA vs. conventional therapy
(including NSAIDs, cyclooxygenase-2
inhibitors, steroids, gastro-protectants,
bisphosphonates, and physiotherapy) and other TNFis,
namely adalimumab, certolizumab pegol, and
etanercept, from the perspective of payer in
A static decision model comprising an initial,
short-term decision tree and a Markov model
was developed for Scotland to compare
cost-effectiveness outcomes for patients with nr-axSpA
treated with conventional therapy, or TNFis.
The decision tree modeled the potential for
continuation or discontinuation of patients
from TNFis based on response to treatment at
12 weeks. The first cycle of the Markov model
then started, with the first transitions between
Markov health states being applied at 24 weeks.
The model incorporated the BASDAI,
BASDAI50, ASAS20, and ASAS40 scores. BASDAI is a
validated instrument completed by patients,
consisting of six 10-cm horizontal visual
analogue scales (VAS) to measure severity of fatigue,
spinal and peripheral joint pain, localized
tenderness, and morning stiffness, with the final
BASDAI score ranging from 0 to 10 [
BASDAI50 has been recommended by the ASAS as
the response criterion used to determine
treatment success. The ASAS score is a composite
measure, comprising a 10-cm horizontal VAS
for pain, inflammation, well-being, and
function. Improvement in three modalities by 20%
or more, without deterioration in the fourth
modality, constitutes an ASAS20 response, and
40% or more an ASAS40 response [
This study is a modeling study using data
derived from previously conducted studies, and
does not contain any new studies with human
or animal subjects performed by any of the
The decision tree provided estimates of
expected costs and outcomes over the short term
(Fig. 1a). Patients were initially managed with
either a TNFi or conventional therapy. The
model assumed that no patient discontinued
conventional therapy and that no switching
between different types of conventional therapy
occurred. For patients who started treatment
with a TNFi, a probability of remaining on TNFi
treatment was assigned based on response to
treatment (achieving ASAS20, ASAS40, or
BASDAI50) informed by data from the GO-AHEAD
study. Very few patients (\ 5%) discontinued
golimumab treatment prior to week 12 of
GOAHEAD. It was therefore assumed that
discontinuation of TNFis did not occur prior to week
12. Discontinuation at week 12 occurred if the
patient did not have a treatment response
according to the efficacy results. As there are no
published data on long-term persistence with
the modeled TNFis in a large Scottish or UK
population of patients with nr-axSpA, following
week 12 an annual rate of discontinuation of
5% was assumed in the model base case.
Responders were assumed to stay on the same
TNFi treatment and not switch to a second
TNFi. Non-responders to TNFis who switched to
conventional therapy remained in that state for
the remainder of the model.
The Markov model provided estimates of
expected costs and outcomes over the long term
(Fig. 1b). Patients entered the Markov model
following the initial decision tree. The Markov
Fig. 1 Short-term decision tree (a) and long-term Markov
model (b). a Short-term decision treea. a The decision tree
model represents the clinical decision that can be taken at
12 weeks (informed by treatment response) to either
continue or discontinue treatment with TNFis.
Responders were assumed to stay on the same TNFi treatment.
Non-responders who switched onto conventional therapy
remained on conventional therapy for the remainder of the
model time horizon. Patients who started on conventional
therapy remained on conventional therapy throughout the
model, irrespective of the probability of response at Week
12. b Long-term Markov modela. aPatients entered the
Markov model, following the initial decision tree, after
week 12. Patients treated with a TNFi either stayed on
(the same) treatment or discontinued treatment. For
patients who discontinued treatment, the transition from
the ‘TNFi Treatment’ state to the ‘Discontinued
Treatment’ state was assumed to take 24 weeks (two cycles).
Discontinuing patients first moved to the ‘Just
Discontinued’ tunnel state and remained in that state for one cycle
and then moved to the ‘Discontinued’ tunnel state and
remained in that state for one cycle. Patients in the
‘Discontinued Treatment’ state were thereafter assumed to
receive conventional therapy alone. Patients could die
while in any of the health states. nr-axSpA
Nonradiographic axial spondyloarthritis; TNFi Tumor necrosis
model comprised defined, mutually exclusive
health states through which patients
transitioned at a rate, which was dependent on the
rate of disease progression and the
age-/sexspecific standardized mortality rate (SMR)
(patients could die while in any of the health
states) for people with nr-axSpA, which was
assumed to be the same as for patients with AS
]. A 12-week model cycle was used. Cost and
utility data were summed by treatment arm as
the model progressed cycle by cycle, allowing
for the calculation of incremental costs and
effectiveness per treatment.
Patients treated with a TNFi either stayed on
treatment or discontinued. The proportions of
patients discontinuing treatment were assumed
to be the same for all TNFis. An annual
discontinuation rate of 5% was applied for the
remainder of the model time horizon, informed
by the golimumab arm in the GO-AHEAD
If discontinuing treatment, patients first
moved to the ‘Just Discontinued’ tunnel state
and remained in that state for one cycle and
then moved to the ‘Discontinued’ tunnel state
and remained in that state for one cycle. Tunnel
states are modeled to assist with modeling a
linear resolution of treatment effect following
treatment discontinuation over a 24-week
period. Patients then moved to the ‘Discontinued
Treatment’ state. It was assumed once entering
the ‘Discontinued treatment’ state patients’
disease progression rebounded to the level as if
they had been treated with conventional care
alone. Patients in the ‘Discontinued Treatment’
state were thereafter assumed to receive
conventional therapy alone. Patients could die
while in any of the health states.
There are no head-to-head trials investigating
the efficacy and safety of golimumab compared
to other TNFis, and data informing comparative
efficacy between treatment options of nr-axSpA
are very limited. Therefore, a systematic
literature review (SLR) and a network meta-analysis
(NMA) were conducted to identify all relevant
treatments and synthesize the available
evidence into relative treatment effects between
comparators. Conventional therapy,
adalimumab, certolizumab pegol, and etanercept
were included as comparators in the model
based on their relevance to current clinical
practice in managing nr-axSpA.
GO-AHEAD compared golimumab to
conventional therapy, providing direct evidence on
the comparative efficacy of these two treatments.
As well as GO-AHEAD, the SLR identified
published data from the comparator trials, including
two phase 3 trials investigating adalimumab
], one phase 3 trial on certolizumab pegol
, and two phase 3 trials on etanercept [
In each trial, the TNFi was compared to
conventional therapy. The relative treatment effects
were established by the NMA based on the
identified data in a fixed effects model (as due to
multiple treatment comparators only having
data from a single trial available, there were
insufficient trials to estimate the heterogeneity
parameter for a random effects model).
The probability of patients achieving an
ASAS20, ASAS40, or BASDAI50 response at week
12 was obtained from the NMA for each of the
TNFis and for conventional therapy. BASDAI50
was used as the efficacy measure in the model
base case because this represents the measure
for treatment response most commonly used in
Scottish clinical practice as informed through
seeking expert input.
Disease progression was demonstrated by
change in BASDAI and BASFI scores. Baseline
BASDAI and BASFI scores were based on baseline
scores from the GO-AHEAD study, for both
conventional therapy and TNFis, and were assumed
to be identical for all TNFis. The magnitude of
response to conventional therapy was informed
by the change in BASDAI and BASFI scores at
week 12 in GO-AHEAD, and the magnitude of
response to TNFis was derived from the NMA.
The NMA demonstrated that there were no
statistically significant differences in any
adverse events, any serious adverse events, or
infections (clinically significant opportunistic
infections) between TNFis or with respect to
Baseline health state utility values were based
on the EQ-5D health questionnaire collected in
the GO-AHEAD study alongside the BASDAI
and BASFI scores. A regression equation [
using those baseline EQ-5D scores observed in
the GO-AHEAD study was constructed to
estimate the average change in EQ-5D score per 1
unit change in BASDAI and BASFI scores. In
order to estimate the EQ-5D score at each cycle,
the following equation that accounted for age
and sex was used to elicit the change in EQ-5D.
The average baseline utility score of the cohort
5D ¼ 0:43 þ ð0:10034 0:05735
BASDAI 0:03120 BASFI
The cost of treatment was calculated based on
drug acquisition, drug administration, and
initiation/monitoring costs. All treatment
strategies included conventional therapy and thus
the costs associated with conventional therapy
were not included in the model.
The unit costs of TNFis were sourced from
the British National Formulary [
]. Doses were
in accordance with product licences
16, 17, 29, 30
]. TNFis were assumed to be
selfadministered following instruction from a
nurse. The cost of the instruction was £50.00,
based on 1 h of patient-related nurse time .
This cost was only applied in the decision-tree
component of the model (i.e., the first
12 weeks). Initiation and monitoring costs for
TNFis were sourced from the National Institute
for Health and Care Excellence (NICE) Multiple
Technology Appraisal (MTA) for nr-axSpA and
were inflated to 2013/14 prices using the
Hospital & Community Health Services Pay &
Prices Index [
]. Annual disease
management costs for nr-axSpA, beyond the treatment
costs associated with TNFis, were applied based
on a costing equation (NHS cost = 1284.186 *
EXP [0.213 9 BASFI]) derived from the
Outcomes in Ankylosing Spondylitis
International Study (OASIS) . This approach was
validated by clinical experts in Scotland.
For adverse event costs, we included a
weighted cost of infections and the weights
were based on previous Health Technology
Assessment submissions [
]. The cost of an
infection was counted as a one-time cost and
applied for one cycle in the model. The
probabilities of infections for each TNFi were derived
from the NMA. For simplicity, other adverse
events were not modeled, as they would not be
expected to have a substantive impact on model
results and, even in the case of infection, there
was little change in the incremental
cost-effectiveness ratio (ICER) in one-way deterministic
sensitivity analysis, as described in the Results
The base-case analyses evaluated a lifetime time
horizon and applied an annual discount rate of
3.5% to both costs and health benefits based on
SMC’s recommendations. Clinical outcomes
were expressed as gains in quality-adjusted
lifeyears (QALYs). Cost-effectiveness was measured
in terms of incremental costs per QALY gained,
comparing the incremental clinical benefit from
golimumab versus other TNFis or conventional
A one-way deterministic sensitivity analysis
(DSA) was used to identify the key drivers of
uncertainty in the estimation of the
incremental cost-effectiveness of golimumab. The key
parameters varied in the DSA included time
horizon, age at baseline, proportion of males,
12-week treatment response measure, annual
discontinuation rate with TNFis, annual disease
progression (conventional therapy), annual
disease progression post-week 260 (to account
for the uncertainty of the long-term disease
progression), data source for infections,
longterm disease management costs, and utility
decrement per one unit change in BASDAI/
BASFI. For continuous variables, where
available, the standard deviation (SD) or standard
error (SE) of each parameter was used to define
the upper and lower values for the sensitivity
analysis. Where the SD or SE was not available,
the upper and lower limits of the range were
defined either as 100 and 0% or ± 30% of the
parameter. All other variables in the model were
varied by ± 30% of the parameter.
A probabilistic sensitivity analysis (PSA) was
also conducted for 10,000 replications to
account for multivariate and stochastic
uncertainty in the model from which the
probabilistic ICER was calculated. The PSA was based on
the base case. Distributions for parameters were
based on recommendations by Briggs et al. [
The model was based on the approach used
in the previous submission for the NICE MTA
(for AS), which was informed by McLeod et al.
]. Following review of the submission,
amendments to that model were made to adapt
it to nr-axSpA where required and to address
uncertainties raised by the NICE MTA
Assessment Group. The model has since been
revalidated by an independent health economist.
The results are discussed in relation to the
SMC and a Scottish population, with discussion
based around a willingness-to-pay (WTP)
threshold of £30,000, as well as £20,000 WTP
for comparative purposes.
The baseline characteristics of patients used in
the base case of the model were informed by the
GO-AHEAD trial and are summarized in Table 1.
The mean age of the trial population was
31.2 years (SE = 0.51 years) and 57.1% were
male. As expected, disease activity was high for
this group of patients (mean BASDAI = 6.5) [
Golimumab was associated with better clinical
outcomes than conventional therapy, as
demonstrated by significantly higher
proportions of patients in the golimumab group
achieving BASDAI50, ASAS20, and ASAS40
responses (median OR = 3.2, 3.6, and 6.0,
respectively). Specifically, 45.8, 64.6, and 51.7%
of the golimumab arm achieved a BASDAI50,
ASAS20, and ASAS40 response, respectively,
compared with 20.7, 33.8, and 15.2% of patients
receiving conventional therapy, respectively.
When comparing the efficacy outcomes of
golimumab with that of other TNFis, results from the
NMA show that there is no significant difference
(the confidence intervals crossed 1 for
head-tohead comparisons with adalimumab, etanercept,
and certolizumab pegol).
The total cost of administering golimumab is
estimated to be £2667.72 for the first cycle of
12 weeks, and £2195.22 for subsequent cycles,
and includes drug acquisition, drug
administration, and monitoring costs. Golimumab
resulted in an increase of 2.06 QALYs when
compared with use of conventional therapy.
Incremental costs per QALY gained were
£19,280 for golimumab, and £19,737, £18,710,
and £20,089 for adalimumab, certolizumab
pegol, and etanercept, respectively. Base case
results are shown in Table 2.
Results from the one-way DSA comparing
golimumab vs. conventional therapy
demonstrated that no variable, when altered, produced
an ICER greater than £30,000 (except when the
time horizon was limited to 1 year) (Table 3).
The effect of an increase in the cost of
golimumab after week 12 (from £2195.22 to
£2853.79) increased the incremental cost vs.
conventional therapy and produced a higher
ICER (from £19,280 to £26,290); this estimated
ICER was still lower than a £30,000 WTP
threshold. Uncertainty surrounding all other
variables had a minimal impact on the
estimated ICERs. The one-way DSA performed for
all other variables showed that the ICER of
golimumab versus conventional therapy was
most sensitive to the drivers shown in Fig. 2.
The 10,000 samples run in the PSA produced
an average ICER of £18,291 for golimumab
versus conventional therapy. The
cost-effectiveness acceptability curve estimating the
probability of golimumab being cost-effective
vs. conventional therapy is displayed in Fig. 3.
At a WTP threshold of £20,000, there was a
57.5% probability that golimumab was
cost-effective. At a WTP threshold of £30,000, there
was an 86.5% probability that golimumab was
This economic model was designed to evaluate
the cost-effectiveness of golimumab in treating
Probability of infections
Conventional therapy 0.2096
Certolizumab pegol 0.24945
Probability of SAEs
Conventional therapy 0.01641
Certolizumab pegol 0.046
12-week cycle costs (drug acquisition, drug administration, initiation/monitoring)
Golimumab First 12 weeks 2667.72
Subsequent cycles 2195.22
Adalimumab First 12 weeks 2667.72
Subsequent cycles 2195.22
Certolizumab pegol First 12 weeks 554.88
Subsequent cycles 2227.38
Etanercept First 12 weeks 2699.88
Subsequent cycles 2227.38
Annual disease progression (conventional therapy)
Annual disease progression post-Week 260 (TNFis)
Annual discontinuation rate (TNFis)
Intercept for utility score
Coefficient BASFI score
BASDAI bath ankylosing spondylitis disease activity index, BASFI bath ankylosing spondylitis functional index, SAE serious
adverse event, SD standard deviation, SE standard error, TNFi tumor necrosis factor inhibitor
a According to a BASDAI50 response (this efficacy measure was used in the model base case to reflect Scottish clinical
b Assumed to occur at 50% of the rate of progression on conventional therapy
patients with active nr-axSpA who had
inadequate response to NSAID treatment, from the
SMC perspective. The base case results indicated
approximately 2.06 QALYs gained for
golimumab patients and an ICER of £19,280
relative to patients treated with conventional
The robustness of the base case analysis was
supported by extensive sensitivity analyses,
where the cost-effectiveness of golimumab was
relatively stable across different scenarios.
Golimumab remained a cost-effective treatment
regardless of whether BASDAI50, ASAS20, or
ASAS40 were used to define treatment. The
oneway DSA of golimumab vs. conventional
therapy demonstrated that no variable, when
altered, produced an ICER greater than £30,000,
which is the WTP threshold typically applied by
This analysis has several strengths. The
short-term decision tree and Markov model
were designed to capture the unique aspects of
nr-axSpA and the treatment pathway in
question. The short-term decision tree represents the
clinical decision that can be taken at 12 weeks
to either continue or discontinue treatment
with TNFis. This is in line with the Summary of
Product Characteristics of the TNFis
16, 17, 28, 29
], which states that clinical
response is usually achieved within 12 weeks.
The Markov model then depicts the
transitioning of patients from one health state to another
based on disease progression and
age-/sexspecific mortality rates.
Secondly, a key data source for our model
was the GO-AHEAD trial, a phase 3,
randomized controlled trial comparing the efficacy and
safety of golimumab with conventional
ICER for golimumab vs.
conventional therapy (£)
ASAS20 assessment of Spondyloarthritis International Society 20% Response Criteria, ASAS40 assessment of
Spondyloarthritis International Society 40% Response Criteria, BASDAI bath Ankylosing Spondylitis Disease Activity Index,
BASDAI50 improvement in BASDAI score of 50%, BASFI Bath Ankylosing Spondylitis Functional Index, DSA
deterministic sensitivity analysis, ICER incremental cost-effectiveness ratio, NMA network meta-analysis, nr-axSpA
non-radiographic axial spondyloarthritis, TNFi tumor necrosis factor inhibitor
a Assumed to occur at 50% of the rate of progression on conventional therapy
therapy in a broad patient population with
active nr-axSpA and an inadequate response to
at least one NSAID treatment. In the absence of
head-to-head trial data, for all the currently
available treatment options, namely
conventional therapy, golimumab, etanercept,
adalimumab, certolizumab pegol 200 mg and
certolizumab pegol 400 mg, an SLR was
Golimumab drug costs,
60 week BASDAI score
Change in QALY equation,
Change in BASDAI
60 week BASFI score
Change in QALY equation,
Change in BASFI
Conventional therapy 12 week
Conventional therapy 12 week
Infection costs for TNF-α
Infection costs for conventional
ICER (£/QALY gained)
Fig. 2 Tornado diagram showing drivers affecting ICER
of golimumab versus conventional therapy most. BASDAI
Bath Ankylosing Spondylitis Disease Activity Index,
BASFI Bath Ankylosing Spondylitis Functional Index,
ICER incremental cost-effectiveness ratio, QALY
qualityadjusted life year
performed to identify and include eligible
studies and the indirect comparison was
informed by the NMA.
In addition, the model and the results
derived from it are relevant and generalizable to
Scotland, as the model was based upon a clinical
analysis conducted in a population which
reflects that of Scotland and all relevant
comparator treatments from a Scottish perspective
were included; moreover, the model
incorporates variables that are relevant to Scottish
clinical practice, such as using the BASDAI50
response to determine treatment response in
the base case scenario.
Our analysis is nevertheless subject to
limitations due to a lack of available data and the
model assumptions. There are no head-to-head
trial comparisons for the other TNFis with
golimumab, and the relative treatment effects
were obtained from the NMA, which may have
introduced some uncertainty around the
clinical benefits of the TNFis in the model. Given the
overlapping confidence intervals for efficacy
between the TNFis, comparisons of
cost-effectiveness are unstable and may not reflect real
differences in cost-effectiveness between TNFis.
This is caused by the methodological
limitations associated with combining data from
different trials within an NMA and a relatively
small network. However, since the main
comparator in this analysis was conventional
therapy, this is less likely to have an impact on the
main outcomes. And we have examined the
potential effect of such uncertainty on the ICER
in the sensitivity analyses. In addition, our
model assumed that patients receiving different
TNFis had the same baseline BASDAI and BASFI
scores at the time of TNFi initiation. It is
possible that in clinical practice, disease severity of
patients choosing to initiate one TNFi differ
from that of patients initiating another TNFi.
However, current clinical guidelines for
management of nr-axSpA do not recommend one
TNFi over another based on patient’s BASDAI or
BASFI score, therefore, we consider such an
assumption reasonable in the context of this
cost-effectiveness model. Our analysis also did
not consider the wider benefits of patients
receiving golimumab. As the only
once-amonth self-injecting TNFi, golimumab may
reduce productivity loss in patients with
nraxSpA, as all other comparators require visits to
a medical facility for IV infusions. In addition,
in the UK, patients who receive golimumab
treatment are also provided additional patient
support programs, i.e., homecare services, and
consequently reducing health system resources.
These productivity and societal costs associated
with nr-axSpA can cause a significant economic
burden. Thus, inclusion of those wider costs
may substantially further reduce ICERs
compared with conventional therapy. Furthermore,
mortality rates used in the Markov model were
assumed to be the same as for AS and these data
were taken from a single study [
]. This was the
most current data available during model
design. Newer data from a larger cohort
suggested that SMR for AS were very close to our
original assumptions, but the estimate of SMR
for women was slightly higher than assumed in
our study [
]. However, the results from DSA
were not found to be remarkably sensitive to
variation in mortality rates.
In conclusion, golimumab was demonstrated to
be a cost-effective treatment for nr-axSpA
compared with conventional therapy from a
Scottish perspective, with an ICER of £19,280.
Golimumab remained cost-effective throughout
a range of sensitivity analyses where key
assumptions were tested.
Funding. This work and the article
processing charges was supported by Merck & Co., Inc.,
Kenilworth, NJ USA. The sponsor was involved
in the design of the study and writing of this
manuscript but had no involvement in the data
management, data analysis, or interpretation of
the results. All authors had full access to all of
the data in this study and take complete
responsibility for the integrity of the data and
accuracy of the data analysis.
Authorship. Rebekah H. Borse, Ralph P.
Insinga, and Chloe Brown contributed to the
study design. All authors contributed to data
analysis, data interpretation, and planning and
critical review of the manuscript content. All
named authors meet the International
Committee of Medical Journal Editors (ICMJE)
criteria for authorship for this manuscript, take
responsibility for the integrity of the work as a
whole, and have given final approval to the
version to be published.
Medical Writing, Editorial, and Other
Assistance. The authors are
grateful to Christopher Hoyle and Ahmed Sowdani,
previous employees of MSD UK, for
programming support, and to Oonagh McGill (MSD
UK), for guidance and leadership in planning
the approach to this analysis. The authors
received writing/editorial support in the
preparation of this manuscript from Yunyu Huang,
PhD, of Excerpta Medica, funded by Merck &
Co., Inc., Kenilworth, NJ, USA.
Disclosures. Rebekah H. Borse is an
employee of Merck & Co., Inc., Kenilworth, NJ,
USA. Sumesh Kachroo is an employee of Merck
& Co., Inc., Kenilworth, NJ, USA. Ralph P.
Insinga is an employee of Merck & Co., Inc.,
Kenilworth, NJ, USA. Chloe Brown is an
employee of Merck Sharp & Dohme,
Hoddesdon, UK. Eilish McCann is an employee of
Merck Sharp & Dohme, Hoddesdon, UK.
Compliance with Ethics Guidelines. This
article is a modeling study using data derived
from previously conducted studies, and does
not contain any new studies with human or
animal subjects performed by any of the
Data Availability. The datasets generated
during and/or analyzed during the current
study are available from the corresponding
author on reasonable request.
Open Access. This article is distributed
under the terms of the Creative Commons
Attribution-NonCommercial 4.0 International
by-nc/4.0/), which permits any
noncommercial use, distribution, and reproduction in any
medium, provided you give appropriate credit
to the original author(s) and the source, provide
a link to the Creative Commons license, and
indicate if changes were made.
1. Sieper J , Rudwaleit M , Baraliakos X , et al. The Assessment of SpondyloArthritis international Society (ASAS) handbook: a guide to assess spondyloarthritis . Ann Rheum Dis . 2009 ; 68 ( Suppl 2 ): ii1 - 44 .
2. Rudwaleit M , van der Heijde D , Khan MA , Braun J , Sieper J . How to diagnose axial spondyloarthritis early . Ann Rheum Dis . 2004 ; 63 ( 5 ): 535 - 43 .
3. Rudwaleit M , van der Heijde D , Landewe R , Listing J , Akkoc N , Brandt J , et al. The development of Assessment of Spondyloarthritis International Society classification criteria for axial spondyloarthritis (part II): validation and final selection . Ann Rheum Dis . 2009 ; 68 ( 6 ): 777 - 83 .
4. Sieper J , van der Heijde D. Review : nonradiographic axial spondyloarthritis: new definition of an old disease? Arthritis Rheum . 2013 ; 65 : 543 - 51 .
5. Sieper J , Hu X , Black CM , et al. Systematic review of clinical, humanistic, and economic outcome comparisons between radiographic and non-radiographic axial spondyloarthritis . Semin Arthritis Rheum . 2017 ; 46 : 746 - 53 .
6. Deodhar A , Strand V , Kay J , et al. The term 'nonradiographic axial spondyloarthritis' is much more important to classify than to diagnose patients with axial spondyloarthritis . Ann Rheum Dis . 2016 ; 75 : 791 - 4 .
7. Rudwaleit M , Haibel H , Baraliakos X , et al. The early disease stage in axial spondylarthritis: results from the German Spondyloarthritis Inception Cohort . Arth Rheum . 2009 ; 60 : 717 - 27 .
8. Poddubnyy D , Haibel H , Braun J , et al. Patients with non-radiographic axial spondyloarthritis and ankylosing spondylitis demonstrate the same clinical disease course over two years: results from the GESPIC cohort . Ann Rheum Dis . 2014 ; 73 ( Suppl 2 ) :THU0071 (abstract).
9. Poddubnyy D , Brandt H , Vahldiek J , et al. The frequency of non-radiographic axial spondyloarthritis in relation to symptom duration in patients referred because of chronic back pain: results from the Berlin early spondyloarthritis clinic . Ann Rheum Dis . 2012 ; 71 : 1998 - 2001 .
10. Kiltz U , Baraliakos X , Karakostas P , et al. Do patients with non-radiographic axial spondylarthritis differ from patients with ankylosing spondylitis? Arthritis Care Res . 2012 ; 64 : 1415 - 22 .
11. Akgol G , Kamanli A , Ozgocmen S . Evidence for inflammation-induced bone loss in nonradiographic axial spondyloarthritis . Rheumatology . 2014 ; 53 : 497 - 501 .
12. Osterhaus JT , Purcaru O . Discriminant validity, responsiveness and reliability of the arthritis-specific Work Productivity Survey assessing workplace and household productivity within and outside the home in patients with axial spondyloarthritis, including nonradiographic axial spondyloarthritis and ankylosing spondylitis . Arthritis Res Ther . 2014 ; 16 : R164 - 79 .
13. Van der Heijde D , Purcaru O , Kavanaugh A . High economic burden of axial spondyloarthritis related to paid work and household productivity at baseline in the rapid-axspa study: differences and similarities between ankylosing spondylitis and nonradiographic axial spondyloarthritis (FRI0439) . Ann Rheum Dis . 2013 ; 72 ( Suppl 3 ): 523 .
14. Harvard S , Guh G , Bansback N , Richette P , Dougados M , Anis A , Fautrel B . Costs of early spondyloarthritis: estimates from the first 3 years of the DESIR cohort . RMD Open . 2016 ; 2 : e000230 .
15. Braun J , van den Berg R , Baraliakos X , et al. 2010 update of the ASAS-EULAR recommendations for the management of ankylosing spondylitis . Ann Rheum Dis . 2011 ; 70 : 896 - 904 .
16. Humira Pre-filled Pen , Pre-filled Syringe and Vial . Summary of Product Characteristics. Available at: http://www.medicines.org.uk/emc/medicine/ 21201.
17. Cimzia 200 mg solution for injection . Summary of Product Characteristics . Available at: http://www. medicines.org.uk/emc/medicine/22323.
18. Sieper J , Van der Heijde D , Dougados M , et al. A randomized, double-blind, placebo-controlled, sixteen-week study of subcutaneous golimumab in patients with active nonradiographic axial spondyloarthritis . Arthritis Rheumatol . 2015 ; 67 : 2702 - 12 .
19. Garrett S , Jenkinson T , Kennedy LG , Whitelock H , Gaisford P , Calin A. A new approach to defining disease status in ankylosing spondylitis: the Bath Ankylosing Spondylitis Disease Activity Index . J Rheumatol . 1994 ; 21 : 2286 - 91 .
20. Anderson JJ , Baron G , van der Heijde D , Felson DT , Dougados M. Ankylosing spondylitis assessment group preliminary definition of short-term improvement in ankylosing spondylitis . Arthritis Rheum . 2001 ; 44 : 1876 - 86 .
21. Bakland G , Gran JT , Nossent JC . Increased mortality in ankylosing spondylitis is related to disease activity . Ann Rheum Dis . 2011 ; 70 : 1921 - 5 .
22. Haibel H . Efficacy of adalimumab in the treatment of axial spondylarthritis without radiographically defined sacroiliitis: results of a twelve-week randomized, double-blind, placebo-controlled trial followed by an open-label extension up to week fifty-two . Arthritis Rheum . 2008 ;7: 1981 - 91 .
23. Sieper J . Efficacy and safety of adalimumab in patients with non-radiographic axial spondyloarthritis: results of a randomised placebo-controlled trial (ABILITY-1) . Ann Rheum Dis. 2012 ; 6 : 815 - 22 .
24. Landewe R . Efficacy of certolizumab pegol on signs and symptoms of axial spondyloarthritis including ankylosing spondylitis: 24-week results of a doubleblind randomised placebo-controlled phase 3 study . Ann Rheum Dis. 2014 ; 1 : 39 - 47 .
25. Maksymowych WP , Van Der HD , Dougados M , Sieper J , Braun J , Citera G , et al. Clinical and imaging efficacy of etanercept in early non-radiographic axial spondyloarthritis: 48-week treatment data . Ann Rheum Dis . 2014 ; Conference (var .pagings): June.
26. Dougados M , Van Der HD , Sieper J , Braun J , Maksymowych WP , Citera G , et al. Clinical and imaging efficacy of etanercept in early non-radiographic axial spondyloarthritis: a 12-week, randomized, double-blind, placebo-controlled trial . Ann Rheum Dis . 2013 ; Conference(var .pagings):June.
27. McLeod C , Bagust A , Boland A , et al. Adalimumab, etanercept and infliximab for the treatment of ankylosing spondylitis: a systematic review and economic evaluation . Health Technol Assess . 2007 ; 11 : 1 - 158 , iii-iv.
28. British National Formulary August 2015 . Available at: https://www.medicinescomplete.com/mc/bnf/ current/.
29. Simponi 50 mg solution for injection . Summary of Product Characteristics . Available at: http://www. medicines.org.uk/emc/medicine/23766.
30. Enbrel 50 mg solution for injection in pre-filled pen . Summary of Product Characteristics . Available at: http://www.medicines.org.uk/emc/medicine/ 22143.
31. Personal Social Services Research Unit. 2014 . Available at: http://www.pssru.ac.uk/.
32. National Institute for Health and Excellence. Technology Appraisal Guidance . TNF-alpha inhibitors for ankylosing spondylitis and non-radiographic axial spondyloarthritis . https://www.nice. org.uk/guidance/ta383/.
33. Personal Social Services Research Unit. Unit Costs of Health and Social Care 2014 . http://www.pssru. ac.uk/project-pages/unit-costs/ 2014 /.
34. Boonen A , van der Heijde D , Landewe´ R, Guillemin F , Rutten-van Mo ¨ lken M , Dougados M , et al. Direct costs of ankylosing spondylitis and its determinants: an analysis among three European countries . Ann Rheum Dis . 2003 ; 62 : 732 - 40 .
35. National Institute for Health and Excellence. TNFalpha inhibitors for ankylosing spondylitis and axial spondyloarthritis without radiographic evidence of ankylosing spondylitis (including a review of technology appraisal 143 and technology appraisal 233) Assessment Report . https://www. nice.org.uk/guidance/ta383/documents/ ankylosing -spondylitis-and-axial-spondyloarthritisnonradiographic-adalimumab-etanerceptinfliximab-and-golimumab-inc-rev- ta143- andta233 - id694 - appraisal -consultation-document2.
36. Briggs A , Claxton K , Sculpher M. Decision modelling for health economic evaluation . Oxford University Press, 2006 .
37. Exarchou S , Lie E , Lindstro¨m U , Askling J , Forsbladd'Elia H , Turesson C , Kristensen LE , Jacobsson LT . Mortality in ankylosing spondylitis: results from a nationwide population-based study . Ann Rheum Dis . 2016 ; 75 : 1466 - 72 .
38. Bansback N , Maetzel A , Drummond M , et al. Considerations and preliminary proposals for defining a reference case for economic evaluations in ankylosing spondylitis . J Rheumatol . 2007 ; 34 ( 5 ): 1178 - 83 .
39. Ankylosing spondylitis and axial spondyloarthritis (non-radiographic)-adalimumab, etanercept infliximab and golimumab (inc rev TA143 and TA233) ID694 . NICE. http://www.nice.org.uk/ guidance/indevelopment/gid-tag355.
40. Kobelt G , Andlin-Sobocki P , Brophy S , Jo¨nsson L , Calin A , Braun J. The burden of ankylosing spondylitis and the cost-effectiveness of treatment with infliximab (Remicade) . Rheumatology (Oxford) . 2004 ; 43 : 1158 - 66 .
41. Singh JA , Wells GA , Christensen R , Tanjong Ghogomu E , Maxwell L , Macdonald JK et al. Adverse effects of biologics: a network meta-analysis and Cochrane overview . Cochrane Database Syst Rev . 201116 ; 2:CD008794 . https://doi.org/10.1002/ 14651858.cd008794. pub2 .