Download Low-dose infliximab treatment for ankylosing

Rheumatology 2006;45:1566–1569
Advance Access publication 16 May 2006
doi:10.1093/rheumatology/kel156
Concise Report
Low-dose infliximab treatment for ankylosing
spondylitis—clinically- and cost-effective
R. N. Jois, J. Leeder, A. Gibb, K. Gaffney, A. Macgregor, M. Somerville and
D. G. I. Scott
Ojectives. Infliximab has been shown to be effective in the treatment of ankylosing spondylitis (AS) when treated in a dose
of 5 mg/kg at 6 weekly intervals. This dose of infliximab has not been determined by any structured randomized trials and has
significant cost implications. We describe our experience of treating AS with low-dose infliximab (3mg/kg at 8 weekly
intervals). The efficacy and cost implications are discussed.
Methods. Patients who had active AS [Bath AS Disease Activity Index (BASDAI) 4] were treated with infliximab 3 mg/kg at
0, 2, 6 weeks and thereafter at 8 weekly intervals. Response to treatment was defined as 50% improvement in BASDAI. Other
response criteria such as ASAS 20, 40 and five of the six criteria were also assessed. Direct drug costs for infliximab were determined.
Results. Twenty-two consecutive AS patients received infliximab. All 22 completed treatment for 3 months, 15 patients for
6 months and 14 for 12 months. Mean age was 45 years (range 21–62) and mean disease duration 14.5 years (range 2–43).
Of the patients, 54% achieved a 50% BASDAI response at 3 months and the benefit was sustained at 12 months in 63%.
Similar response rate was seen with the other assessment criteria. Direct drug costs were significantly lower when low-dose
infliximab regimen was used.
Conclusions. Low-dose infliximab (3 mg/kg at 8 weekly infusions) is effective in the treatment of AS. Higher doses are required
in a small proportion of patients when treatment is only partially effective. Titrating the dose and frequency of infusions may be
required in individual patients to achieve optimal response. Using low-dose infliximab has significant economic implications.
KEY
WORDS:
Ankylosing spondylitis, Infliximab, Anti-TNF therapy.
Ankylosing spondylitis (AS) is a chronic inflammatory disease
characterized by sacroiliitis, spinal inflammation and
progressive spinal fusion. It may lead to significant disability
and reduced quality of life [1] comparable with that of rheumatoid
arthritis [2].
Non-steroidal anti-inflammatory drugs (NSAIDs) and
physiotherapy were the main stay of treatment for axial disease
until recently. NSAIDs were thought to have little or no effect in
modifying spinal disease [3], and conventional disease-modifying
drugs like methotrexate, which are effective in inflammatory
arthritis, have been proved to be ineffective in spinal disease [4].
Although, more recently, continuous use of NSAIDs has been
shown to reduce radiographic progression in AS [5], the only
treatments to show a significant effect on spinal inflammation
and quality of life have been the biological drugs—anti-TNF
inhibitors. Randomized trials have shown that both infliximab
[6, 7] and etanercept [8–10] are effective in suppressing inflammation in active AS, resulting in improvement in the symptoms and
signs of axial as well as peripheral joint disease, accompanied
by a reduction in magnetic resonance imaging evidence of
inflammation in the spine [11, 12].
Infliximab has recently been shown to maintain persistent
clinical response in patients with AS over 3 yrs [13]. The licensed
and recommended dose of infliximab to treat AS is 5 mg/kg at
6–8 weekly intervals. This dose of infliximab has not been
determined by any structured randomized trials. Infliximab at
5 mg/kg every 6 weeks was shown to be better than 3 mg/kg every
6 weeks in a small study of patients with undifferentiated
spondyloarthropathy. Three patients in each group received
treatment for a period of 12 weeks [14]. This observation and
the fact that the higher dose was found to be effective in
inflammatory bowel disease resulted in subsequent trials being
undertaken at this dose. However, this high dose of infliximab has
considerable cost implications.
In this study, we describe our clinical experience of treating 22
consecutive AS patients attending our rheumatology clinic, using
low-dose infliximab at 3 mg/kg every 8 weeks. The clinical efficacy
and direct drug costs are discussed.
Patients and methods
Patients with AS (defined by the modified New York criteria [15]),
who were symptomatic despite maximum dose of two different
NSAIDs, were considered for biologicals. Eligibility criteria were
defined as the presence of active disease with a Bath Ankylosing
Spondylitis Disease Activity Index (BASDAI) [16] 4.
Patients were referred to a specialized biologicals clinic for
further assessment to discuss the introduction of infliximab.
Patients with contraindications for biologicals were excluded.
Department of Rheumatology, Norfolk and Norwich University Hospital, Norwich, Norfolk, UK.
Received 18 December 2005; revised version accepted 7 April 2006.
Correspondence to: Ramesh N. Jois, Department of Rheumatology, Norfolk and Norwich University Hospital, Colney Lane, Norwich NR4 7UY, UK.
E-mail: [email protected]
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ß The Author 2006. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: [email protected]
Low-dose infliximab for AS
BASDAI, Bath AS Functional Index (BASFI) [17], Bath AS
Metrology Index (BASMI) [18], patient global assessment [0–100
on visual analogue scale (VAS)], erythrocyte sedimentation
rate (ESR) and C-reactive protein (CRP) were recorded at
baseline and at 3, 6 and 12 months follow-up. Data concerning
infliximab efficacy, concomitant treatment and toxicity were
recorded.
Infliximab was started at 3 mg/kg and given at 0, 2 and 6 weeks
of initiation and at 8-weekly intervals thereafter. Response to
treatment was defined as a >50% reduction in BASDAI
compared with baseline. Treatment response was assessed at
3 months. If there was at least 20% reduction in BASDAI score
at 3 months, the same infliximab regimen was continued until
6 months. If the 50% reduction in BASDAI was not achieved by
6 months or 20% at 3 months, then the dose of infliximab was
increased to 5 mg/kg. If the therapeutic response was short-lived,
such that there appeared to be a flare before the time of the next
infusion (i.e. before 8 weeks) but the initial response was
reasonable, then the frequency of the infusions was increased
to 6- or 7-weekly intervals. Pre-biologicals medications such as
NSAIDs, sulphasalazine and methotrexate were left unchanged
for the first 6 months.
Other assessments of response included ASAS 20 criteria [19]
and the more recently defined short-term improvement criteria:
ASAS 40 and ASAS 5 of 6 [20].
Cost-effectiveness was calculated as direct drug costs among
responders to the low-dose infliximab regimen (3 mg/kg 8-weekly)
and compared with the potential costs involved if these patients
were to be treated with infliximab in the licensed dose (5 mg/kg
6–8 weekly). The cost of each 100 mg of infliximab was taken
as £451 (equivalent to E667.5) (cost as per British National
Formulary, March 2005). The direct drug cost savings after using
the low-dose infliximab regimen was determined.
Statistics
All the values were expressed as median (range). Differences of the
various response criteria at 3, 6 and 12 months when compared
with baseline were tested using the Wilcoxon matched-pairs
signed-ranks test for statistical significance. A P < 0.05 was
considered statistically significant. The percentage of patients
who met the treatment response criteria was determined by
actuarial analysis.
Results
We treated 22 consecutive AS patients with infliximab 3 mg/kg at
8-weekly intervals.
The baseline characteristics of the patients are shown in
Table 1. One patient had previous history of psoriasis and
another had ulcerative colitis, both of which were quiescent.
Twenty-two patients have been treated for 3 months, 15 for
6 months and 14 for 12 months. The median change in BASDAI
along with other assessment parameters over time are shown in
Table 2.
The BASDAI for individual patients at different time points are
illustrated in Fig. 1.
The percentage of patients who attained BASDAI 50 response
at various time points and the other assessment parameters—
ASAS 20, ASAS 40 and ASAS 5 of 6—are shown in Table 3.
Three of the 15 patients (20%) who continued infliximab to
6 months did not show 50% reduction in the BASDAI scores at
3 months but achieved this response criterion at 6 months. They
had, however, shown a 20% reduction in BASDAI at 3 months.
One patient increased the frequency to 7-weekly cycles at
3 months and one patient to 6-weekly cycles at 3 months for
optimal response. Two patients have reduced the frequency of
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TABLE 1. Baseline characteristics
Total number of patients
Male/female
Age, yrs: median (range)
Disease duration, yrs: median (range)
HLA B27 positive: n (%)
Peripheral arthritis: n (%)
Methotrexate users: n (%)
Methotrexate and sulphasalazine combination users: n (%)
NSAID users: n (%)
22
19/3
45 (21–62)
10.5 (2–27)
20 (90.9)
8 (36)
6 (27)
2 (9)
22 (100)
infliximab infusions to 9-weekly cycles on 3 mg/kg after 6 months
of treatment. Two of the non-responders increased the dose
to 5 mg/kg (one after 6 months and the other after 12 months).
One patient switched over to etanercept after 12 months. Overall,
19 of the 22 patients are still receiving infliximab at 3 mg/kg.
No significant side effects from infliximab were observed.
About 40% of the patients were able to stop NSAID use
altogether. Of the eight methotrexate users, three
stopped medication and five reduced the dose by a mean of
11.3 mg/week. Both the patients, who were on sulphasalazine,
discontinued the drug.
Cost evaluation
Direct drug cost calculations were done on the assumption that
the 19 patients who are at present receiving infliximab 3 mg/kg
dose would continue the same treatment for a period of
12 months. The dose of infliximab was calculated after taking
into consideration the actual body weight of these 19 patients.
Three doses of infliximab were required for induction (0, 2 and
6 weeks) and thereafter an additional 6 doses for maintenance
(8-weekly infusions) in the first year of treatment. The resulting
direct drug cost would be £183 507.26 (E272 324.77) for the first
year of treatment.
Assuming that these 19 patients would need to be treated
according to their actual body weight with the recommended
(licensed) dose of infliximab i.e. 5 mg/kg 6-weekly infusions, they
would need three doses for induction (0, 2 and 6 weeks) and nine
doses (6-weekly infusions) or six doses (8-weekly infusions) for
maintenance when treated for the first year. The resulting cost
would then be £407 794.2 (E605 166.59) for the first year of
treatment when treated 6-weekly and £305 845.65 (E453 874.94)
when treated 8-weekly infusions. By using the low-dose infliximab
regimen, the potential savings to our unit for the first year would
therefore be £224 286.94 (E331 944.67) when compared with the
6-weekly regimen and £122 338.39 (E181 060.81) with the 8-weekly
regimens.
Discussion
The efficacy of infliximab in relieving various symptoms in
AS has been clearly demonstrated in randomized trials [6, 7].
The recommended and licensed dose of infliximab for treating AS
is 5 mg/kg 6- to 8-weekly infusions. Infliximab has been found to
very effective in controlling inflammation in rheumatoid arthritis
at a lower dose (3 mg/kg 8-weekly infusions) [21]. There have not
been any dose-finding randomized trials in AS.
Maksymowych et al. [22] were the only group (from published
data) to report efficacy of infliximab at 3 mg/kg every 8 weeks
and noted that the lower dose appeared to be effective for both
axial and peripheral involvement in AS. BASDAI 50 response
was seen in 58% of their patients (n ¼ 17) at 3 months and in 75%
at 12 months (n ¼ 8). The BASDAI 50 response seen in our cohort
(54% at 3 months and 63% at 6 and 12 months) is comparable.
R. N. Jois et al.
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TABLE 2. Median (range) of various parametres with infliximab (3 mg/kg) treatment
Assessment parameter
0 months (n ¼ 22)
BASDAI (0–10)
BASFI (0–10)
BASMI (0–10)
Spinal pain VAS (0–10)
Morning stiffnessa (0–10)
ESR (mm/h)
CRP (mg/dl) (normal<7)
6.6
6.4
4.6
6.7
6.2
22
21
(4.2–8.7)
(4.7–8.2)
(0.9–7.7)
(1.0–9.5)
(1.2–9.7)
(9–119)
(3–108)
3 months (n ¼ 22)
3.2*
3.7y
3.6y
4.4y
3.2y
9*
7*
(0.2–8.5)
(1.0–8.9)
(0.8–7.7)
(0.1–9.9)
(0.3–9.2)
(3–31)
(3–20)
6 months (n ¼ 15)
z
2.1
1.7z
3.8z
2.5**
1.5z
8y
7y
(0.2–6.9)
(0.1–8.6)
(0–7.4)
(0.1–8.6)
(0–9.2)
(3–21)
(3–17)
12 months (n ¼ 14)
1.8z
1.7y
3.2y
2.5z
1.1z
12z
6z
(0.1–9.9)
(0.1–9.2)
(0–6)
(0.1–10)
(0–9.35)
(3–40)
(3–34)
6
4
0
2
BASDAI
8
10
*P < 0.0001 yP < 0.001 zP < 0.01 **P < 0.05.
a
Average of items 5 and 6 on BASDAI.
0
3
6
12
Follow-up (months)
FIG. 1. BASDAI for individual patients at different time points.
TABLE 3. Responders to various assessment criteria as determined by
actuarial analysis
Variable
BASDAI 50
ASAS 20
ASAS 40
ASAS 5 of 6
Time
(months)
Probability of meeting
response criteria (%)
95% CI
3
6
12
3
6
12
3
6
12
3
6
12
54.6
63.6
63.6
63.6
78.2
78.2
50.0
66.7
66.7
59.1
79.6
79.6
35.7–75.6
41.8–84.9
41.8–84.9
44.3–82.6
56.9–93.7
56.9–93.7
31.6–71.8
44–87.6
44–87.6
39.9–79.2
58.3–94.4
58.3–94.4
and BASMI at 3 months compared with baseline in our cohort
was statistically significant (P < 0.0001 for BASDAI and
P < 0.001 for the others). The absolute change in the mean
value in various indices in our cohort (data not shown) compared
with other studies like Braun et al. [23] were similar; for example,
BASDAI was 3.0 in our cohort and 3.3 in Braun et al., BASFI
2.5 and 2.2, and BASMI 0.8 and 0.9 in the two respective
groups. The absolute change in all these parameters at 6 months
and after 1 yr was also similar in both studies.
The efficacy of infliximab at lower doses has also been shown
in the present study by other response criteria such as ASAS 20,
40 and 5 of 6. ASAS 20 response in our cohort was 63% at
3 months and 78% at 6 and 12 months. The ASAS 20 response
seen when higher dose of infliximab (5 mg/kg 6 weekly) was
used in various other trials were: 75% at 3 months [6], 80% [23]
at 6 months and 60 [23] and 71% [24] at 12 months. The
percentage of patients meeting the ASAS 40 (50% at 3 months
and 66% at 6 and 12 months in our cohort compared with 47% at
6 months [7] and 66% at 12 months in other trials [24]) and ASAS
5 of 6 (59% at 3 months and 79% at 6 and 12 months in our
cohort compared with 49% at 6 months [7] and 51% at 12 months
in other trials [24]) when treated with inflixiamb 3 mg/kg 8 weekly
is very encouraging and the efficacy is sustained over a period of
12 months. However, it is important to note that the percentage
of responders in our study was determined by actuarial analysis,
which was not the case with other studies. About 40% of the
patients were able to completely stop NSAID use, and reduction
in dose or discontinuation of DMARDs such as methotrexate and
sulphasalazine were observed.
The recommended dose of infliximab for AS has significant
cost implications and using the low-dose regimen, as we have
shown, has a lot of potential for cost savings. The cost savings is
not only with the direct drug costs but will also include various
other indirect costs such as hospital attendance, nursing time, etc.
It is important to note that the numbers of patients treated in
our study are small and the results, therefore, need confirmation
in a large cohort, such as a well-structured randomized controlled
trial, where AS patients are treated with either infliximab at the
licensed dose or on low dose.
Conclusions
The BASDAI 50 response seen in our patients is also
comparable with other studies in which patients were treated
with infliximab 5 mg/kg (53% at 3 months [6], 51% at 6 months
[7] and 51% [23], 57% [24] and 60% [25] at 12 months). Even
though direct comparison between studies is not always possible
due to differences in patient demographics, assessment criteria
and strict exclusions in formal clinical trials, the response rate seen
in our patients is very encouraging especially when using lower
doses of infliximab. The median change in BASDAI, BASFI
We have shown that infliximab is effective in suppressing the
signs and symptoms of AS at 3 mg/kg and that higher doses are
required in a small proportion of patients when treatment is
only partially effective. This may be adjusted also by titrating
the dose to individual patients and titrating the frequency of
infusions. Starting at the low dose of infliximab (3 mg/kg
8-weekly infusions) and then increasing the dose when indicated
seems a sensible way in clinical practice, especially in a cashstrapped health service. Using low-dose infliximab has significant
economic implications.
Low-dose infliximab for AS
Rheumatology
Key messages
Low-dose infliximab (3 mg/kg 8 weekly)
is effective in treatment of AS.
Results of efficacy are comparable with
the recommended high-dose regimen
(5 mg/kg 6 weekly).
Low-dose infliximab has significant cost
implications.
11.
12.
13.
Acknowledgements
We would like to thank all our patients without whom this work
would not have been possible. We would also like to thank
Dr P. Merry, consultant rheumatologist, Norfolk and Norwich
University Hospital, for allowing us to include his patients in the
study.
Research grant support to the department received from ScheringPlough, Wyeth and Abbott Pharmaceuticals.
14.
15.
16.
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