Download Low dose of infliximab is inadequate in most patients with

Clinical and Experimental Rheumatology 2005; 23: 513-516.
Low dose of infliximab is
inadequate in most patients
with spondylarthropathies
P. Sidiropoulos, H.D. Kritikos,
P. Siakka, M. Mamoulaki,
H. Kouroumali, K. Voudouris1,
D.T. Boumpas
University Hospital, Medical School,
University of Crete, Heraklion; 1First
General Hospital of Thessaloniki
“Agios Pavlos”, Thessaloniki, Greece.
Prodromos Sidiropoulos, MD; Herakles
D. Kritikos, MD; Panagiota Siakka, MD;
Marilena Mamoulaki, MD; Heleni Kouroumali, MD; Kostantinos Voudouris,
MD (deceased); and Dimitrios T.
Boumpas, MD.
This work was supported in part by an
unrestricted grant from Shering Plough
Greece.
Please address correspondence to:
Dimitrios T. Boumpas, MD, FACP,
Department of Internal Medicine,
Division of Rheumatology, Clinical
Immunology and Allergy, University of
Crete, Medical School, Voutes 71500
Heraklion, Greece.
E-mail: [email protected]
Received on September 10, 2004; accepted
in revised form on February 3, 2005.
© Copyright CLINICALAND EXPERIMENTAL RHEUMATOLOGY 2005.
Key words: Spondylarthropathy,
infliximab, BASDAI.
BRIEFPAPER
ABSTRACT
Objectives. The recommended starting
dose for infliximab for ankylosing spon dylitis 5mg/kg is higher than that for
rheumatoid arthritis. Because of the high
expense of the drug lower doses may be
considered. We report our experience
with lower initial doses.
Methods. Thirty patients with active
SpA (16 psoriatic arthritis, 12 ankylos ing spondylitis and 2 undifferentiated)
received 6 infliximab infusions. Pa tients had substantial axial disease
(mean BASDAI at baseline 5.5). Con comitant therapy (methotrexate or pred nisolone) remained stable throughout
treatment period. The mean initial dose
of infliximab was 3.5 mg/kg/infusion.
Clinical efficacy was assessed by BAS DAI. The criterion for dose adjustment
was a BASDAI improvement of less
than 50%. The primary end-points were
the proportion of patients requiring a
dose adjustment and the percentage of
patients achieving 50% improvement in
BASDAI after 6 infusions.
Results. In this cohort, 2 patients dis continued therapy, 1 for pulmonary in fection and 1 for allergic reaction.
Twelve patients (40%) showed 50% im provement in BASDAI between base line and prior to the 7th infusion, while
15 patients (50%) had an improvement
>2 points. To achieve clinical response
the frequency and/or the dose of inflix imab infusions were increased in 63%
of patients. The mean infliximab dose
increased from 3.5 mg/kg at the first
infusion to 4.3 mg/kg (p < 0.001) at the
7th infusion, resulting in a cumulative
dose at the end of the study period com parable to the recommended one.
Conclusions. In the majority of our
SpA patients low starting doses of in fliximab required subsequent adjust ment. In these patients infliximab should
be administered at the recommended
dose of 5mg/kg/infusion.
Introduction
The spondylarthropathies (SpA) are a
heterogeneous group of inflammatory
arthropathies that share common genetic, clinical and radiologic features.
These include ankylosing spondylitis
(AS), psoriatic arthritis (PsA), reactive
arthritis, arthritis associated with in-
513
flammatory bowel disease and undifferentiated spondylarthropathies (uSpA)
(1). For patients with AS, inflammatory
pain as well as progressive impairment
of the spine or peripheral joints results
in decreased health-related quality of
life and increased morbidity (2).Treatment options are limited especially for
patients with axial disease. Non-steroidal anti-inflammatory drugs (NSAIDs)
and physiotherapy are usually used for
AS patients with axial disease, while
sulfasalazine could be efficacious in peripheral arthritis (3). Recent data suggest that methotrexate could be effective in AS patients in the short-term (4).
For PsA patients, disease modifying
antirheumatic drugs (DMARDs) like
sulfasalazine, methotrexate and cyclosporine are used with documented efficacy only for peripheral disease (5).
In several pilot and randomized controlled trials, anti-TNFα agents (etanercept and infliximab) have shown clinical efficacy in patients with AS, as
well as in other subgroups of SpA like
psoriatic arthritis and uSpA(6-8). Treatment with infliximab at 5mg/kg every
8 weeks has been approved for the
treatment of selected patients with AS
and active disease. This dose is higher
than the recommended starting dose for
patients with rheumatoid arthritis (3
mg/kg). Because of the considerable
expense of the drug and the potential
side effects of higher cumulative doses
after long lasting treatment, lower doses may be considered. We report our
experience with initial doses lower
than those recommended.
Materials and methods
Patients
This was an uncontrolled, open-label,
study with patients from two rheumatology clinics, one in northern and the
other in southern Greece. Patients with
a diagnosis of AS fulfilled the modified
New York classification criteria whereas patients in the other subgroups fulfilled the European Spondylarthropathy Study Group criteria for SpA (9,
10). Thirty consecutive patients were
selected because of active SpA (mean
BASDAI at baseline 5.5), despite current or previous treatment with NSAIDs
and DMARDs.
Infliximab dose in spondylarthropathies / P. Sidiropoulos et al.
BRIEFPAPER
Treatment
Methotrexate was continued in 18 patients at a mean dose of 12.8 mg/wk
(range 7.5-20) (Table I), while concomitant prednisolone was used in 3 (mean
dose 6.7 mg/d, range 5-7.5). Patients
received infliximab at a mean initial
dose of 3.5 mg/kg/infusion (range 3-5
mg/kg). Twenty of them were initially
treated with 3mg/kg. Changes in dosage and/or infusion intervals of infliximab were made following the third
infusion (6th week) and were dictated
by the clinical response as assessed by
BASDAI. The criterion for dose adjustment was BASDAI improvement of <
50%.
Patient evaluation: Assessment of
disease activity
Routine laboratory tests such as complete blood count, erythrocyte sedimentation rate (ESR), C-reactive protein
(CRP), blood urea nitrogen, creatinine,
liver function tests and urinalysis were
performed. A chest radiograph and a
skin test with purified protein derivative
(PPD) were performed on study enrollment. Patients were evaluated clinically
at baseline and prior to each infusion by
visual analogue scales (VAS 0-100) for
axial pain, level of morning stiffness
and the patient’s global assessment. The
BASDAI was used for assessment of
axial disease activity.
Primary and secondary end-points
The primary end-points were 50% improvement in BASDAI after 6 infliximab infusions or the requirement of a
dose adjustment. Secondary end-points
were a 2 point absolute improvement
(on a 0-10 scale) in the BASDAI score
and a reduction of spinal pain greater or
equal to 2 units.
Statistical analysis
Statistical evaluation within groups
was done by the use of paired Student’s
t-test. A p value less than 0.05 (twotailed) was considered as statistically
significant.
Results
Patients’demographics and disease
characteristics
Thirty patients, 22 males 8 females,
Table I. Baseline characteristics of the patients (n = 30).
Age (yrs.)
41.3 ± 12*
Male sex (%)
73.3
Disease duration (yrs.)
13.4 ± 8.6
Subgroups (no.)
Psoriatic arthritis
Ankylosing spondylitis
Undifferentiated spondylarthropathy
16
12
2
DMARD history (no. of drugs)
Infliximab starting dose (mg/kg/infusion)
Concomitant methotrexate (%)
Methotrexate dose (mg/wk)
Concomitant prednisolone (%)
Prednisolone dose (mg/d)
2.1 (1-4)
3.5
60
12.8 ± 5.1*
10
6.7 ± 2.9*
* Mean ± SD.
Table II. Clinical improvement after 6 infusions (mean ±SD).
Baseline
7th infusion
p
BASDAI
5.5 ± 2.1
3.6 ± 2.1
0.002
VAS axial pain
5.8 ± 2.7
3.6 ± 2.5
0.002
Morning stiffness (level)
5.8 ± 3
3.2 ± 2.5
0.001
Patients’global assessment
6.3 ± 1.8
4.3 ± 2.6
0.001
DAS
3.2 ± 1.4
1.7 ± 0.8
0.002
VAS: Visual analogue scale; DAS: Disease activity index.
with a mean age of 41.3 (±12) years, a
mean disease duration, of 13.4 (± 8.6)
years, and active axial disease (mean
BASDAI at baseline 5.5) were selected
(Table I). Sixteen patients had psoriatic
arthritis, 12 ankylosing spondylitis and
2 undifferentiated spondylarthropathy.
All patients had considerable axial disease. Thus, the mean BASDAI at baseline was 5.5 with 83% of the patients
fulfilling the BASDAI cut-off value of
moderate to severe disease (≥ 4). All
patients had BASDAI > 3. Twentyeight had concomitant peripheral arthritis. Among 16 patients with evaluable
information on peripheral arthritis, the
mean baseline DAS index was 3.2;
4/16 had high level disease activity
(DAS >3.7) while 8/16 had moderate
disease activity (DAS > 2.4). The majority of the patients had failed other
therapies. The mean number of
DMARDs that had been used was 2.1
(1-4), and were usually methotrexate
and sulfasalazine (Table I). Methotrexate (MTX) was continued in 18 patients while concomitant prednisolone
was used in 3 (Table I). The mean initial dose of infliximab was 3.5 mg/kg/
514
infusion. Patients were followed up to
the 7th infusion (mean treatment period
36.8 weeks).
Side effects
In this cohort, 2 patients discontinued
therapy because of side effects. The
first was due to a serious allergic reaction during the second infliximab infusion, while the second was a pulmonary infection with pleural effusion of
unknown etiology.
Efficacy
Just prior to the 7th infliximab infusion
40% of the patients (12/30) were responders (≥50% improvement in BASDAI), while 60% had ≥ 20% improvement in BASDAI. When applying as a
criterion of improvement a > 2-point
decrease in the BASDAI score, 50% of
the patients were responders. Moreover, 78% of our patients showed a reduction in spinal pain of at least 2
points on a 0-10 scale. The mean BASDAI of the cohort on the 7th infusion
was 3.6, being significantly improved
compared to the baseline value (baseline 5.5, p<0.002). Statistically signifi-
Infliximab dose in spondylarthropathies /P. Sidiropoulos et al.
cant improvements were noticed in the
patients’ global assessment, in the
assessment of axial pain on a visual
analog scale (VAS) and in the level of
morning stiffness (Table II). For 16 of
the patients with evaluable information
on peripheral arthritis, the DAS was
also significantly improved between
baseline and the 7th infusion (mean
DAS 3.2 and 1.7 respectively, p <
0.002). 12/16 patients (75%) with peripheral arthritis were responders (7
good and 5 moderate) according to the
EULAR response criteria.
Dose adjustments
To achieve the clinical response described above, the frequency and/or dose
of infliximab infusions were increased
in 63% of patients. The dose was increased in 11 patients, both a dose increase and shortening of the infusion
interval were introduced in 6 patients,
and in 2 patients the infusion intervals
were shortened. The mean infliximab
dose increased from 3.5 mg/kg at the
first infusion to 4.3 mg/kg (p< 0.001)
after 6 infusions. Only 5 of the 20 patients who were started on 3 mg/kg
continued on a stable infliximab dose.
The cumulative dose of infliximab per
patient was increased and was comparable to that had the recommended dose
of 5 mg/kg been initiated from the beginning of the study (25.7/mg/kg/patient was administered in a period of
36.8 weeks, compared to 30mg/kg/ patient administered in 38 weeks if the
recommended dosing was followed).
Discussion
Treatment of AS and other inflammatory diseases with axial involvement requires a multidisciplinary approach
consisting of physical therapy, NSAIDs,
sulfasalazine and often methotrexate,
to control pain and prevent ankylosis.
None of the aforementioned modalities
have a significant impact on disease
progression. Based on data showing
evidence of TNFα involvement in the
pathogenesis of AS, biologic agents
that block this proinflammatory cytokine were tested in clinical trials of patients with AS and in other subgroups
of SpApatients (7, 8, 11).
Data from randomized clinical trials
BRIEFPAPER
are of paramount importance to determine clinical efficacy of new therapies,
but they have limitations related to
their applicability in a general, unselected population. Observational studies and clinical protocols provide useful additional information about longterm outcomes and side effects. Although the size of this cohort was modest, we believe it represents a "reallife" SpA population of clinical practice. Thus, most patients had long
standing disease (mean disease duration 13.4 years) with multiple DMARD
failure (mean 2.1), considerable axial
(mean baseline BASDAI 5.5) and substantial peripheral disease activity
(mean baseline DAS 3.2).
Patients with AS show comparable disability and reduced health-related quality of life to patients with rheumatoid
arthritis (12). Although there is evidence from short-term clinical trials for
an improvement in the quality of life of
AS patients treated with infliximab,
there are no data for the cost-effectiveness of this treatment. Considering the
high cost of biologic treatment, we
wondered whether we could initiate
therapy with lower than the recommended dose. Following patients up to
the 7th infusion, it was shown that in
the majority of them (63%) the frequency and/or the dose of infliximab
had to be increased in order to achieve
or maintain clinical efficacy. Seventyfive percent (15/20) of the patients who
were started on 3 mg/kg were switched
to a higher dose. The cumulative dose
after dose adjustments was 25.7mg/kg/
patient over 36.8 weeks (or 26.5mg/kg/
patient in 38 weeks), culminating in a
final dose that was close to the recommended level (30mg/kg/patient in 38
weeks). Individualization of infliximab
dosing, an approach that is applied in
patients with rheumatoid arthritis, may
also be helpful for patients with AS.
The trend for higher than 3mg/kg doses
in our study is comparable to published
data from other studies where the dose
usually applied is 5 mg/kg (6,7). On
the contrary, in a small cohort of 21 AS
patients studied by Maksymowych et
al., it was found that after 14 weeks of
treatment the majority of the patients
could be effectively treated with a low
515
(3 mg/kg) infliximab regimen, but longterm data on this group are not available (13). Additional evidence supporting the efficacy of the lower dose
scheme comes from a small group of
Mexican patients, but again long-term
efficacy data are lacking (14).
In this study, dose adjustments were
dictated by clinical efficacy as assessed
by the BASDAI, which represents the
patient’s perception of disease activity.
Although BASDAI has been evaluated
only in patients with AS it was applied
in our study because all patients had
substantial axial disease and this was
the main indication for infliximab
treatment. The mean BASDAI was significantly improved just prior to 7th
infusion compared to the baseline evaluation (3.6 compared to 5.5, p < 0.002).
Forty percent of the patients responded
prior to the 7th infusion. This efficacy
is comparable to that reported by other
groups (15). However, the data on efficacy in this study have to be interpreted
with caution. Because this was an open
label study, we cannot completely rule
out the possibility that a placebo effect
or regression to the mean may have
influenced the response rates.
Anti-TNFα agents are potent immune
modulators that may prove to be the
first disease controlling agents for SpA.
Issues like their considerable cost and
safety profile call for patient selection
criteria as well as guidelines for monitoring clinical efficacy such as those
recently published (16), so as to optimize cost effectiveness and the everyday clinical application of biologic
therapy in patients with SpA. The concomitant use of immunosuppressive
agents like methotrexate or azathioprine in order to reduce immunogenicity and increase the long-term efficacy
of infliximab has to be further investigated (17).
Acknowledgments
The authors thank Maria Kasapaki,
RN, Sofia Sfakianaki, RN and the nursing staff of the rheumatology clinics
(University Hospital – Heraklion and
the First General Hospital of Thessaloniki “Agios Pavlos”) for patient care
and Dr Gabor Illei for critical review of
the manuscript.
Infliximab dose in spondylarthropathies / P. Sidiropoulos et al.
BRIEFPAPER
References
1. BRAUN J, BOLLOW M, REMLINGER G et
al.: Prevalence of spondylarthropathies in
HLA-B27 positive and negative blood donors. Arthritis Rheum 1998; 41: 58-67.
2. BRAUN J, PINCUS T: Mortality, course of disease and prognosis of patients with ankylosing spondylitis. Clin Exp Rheumatol 2002;
20 (Suppl. 28): S16-S22.
3. BRAUN J, SIEPER J: Therapy of ankylosing
spondylitis and other spondyloarthritides: established medical treatment, anti-TNF-alpha
therapy and other novel approaches. Arthritis
Res 2002; 4: 307-21.
4. GONZALEZ-LOPEZ L, GARCIA-GONZALEZ
A, VAZQUEZ-DEL-MERCADO M, MUNOZVALLE JF, GAMEZ-NAVA JI : Efficacy of
methotrexate in ankylosing spondylitis: a
randomized, double blind, placebo controlled
trial. J Rheumatol 2004; 31: 1568-74.
5. MEASE PJ : Cytokine blockers in psoriatic
arthritis. Ann Rheum Dis 2001; 60 (Suppl. 3):
iii37-40.
6. BRAUN J, BRANDT J, LISTING J et al.:
Treatment of active ankylosing spondylitis
with infliximab: a randomised controlled
multicentre trial. Lancet 2002; 359: 1187193.
7. VAN DEN BF, KRUITHOF E, BAETEN D et al.:
Randomized double-blind comparison of
chimeric monoclonal antibody to tumor necrosis factor alpha (infliximab) versus placebo in active spondylarthropathy. Arthritis
Rheum 2002; 46: 755-65.
8. ANTONI C, DECHANT C, HANNS-MARTIN
LORENZ PD et al.: Open-label study of infliximab treatment for psoriatic arthritis: clinical and magnetic resonance imaging measurements of reduction of inflammation.
Arthritis Rheum 2002; 47: 506-12.
9. DOUGADOS M, VAN DER LS, JUHLIN R et al.:
The European Spondylarthropathy Study
Group preliminary criteria for the classification of spondylarthropathy. Arthritis Rheum
1991; 34: 1218-27.
10. VAN DER LS, VALKENBURG HA, CATS A :
Evaluation of diagnostic criteria for ankylosing spondylitis. A proposal for modification
of the New York criteria. Arthritis Rheum
1984; 27: 361-8.
11. BRAUN J, BOLLOW M, NEURE L et al.: Use
of immunohistologic and in situ hybridization techniques in the examination of sacroiliac joint biopsy specimens from patients with
ankylosing spondylitis. Arthritis Rheum
1995; 38: 499-505.
12. ZINK A, BRAUN J, LISTING J, WOLLENHAUPT J: Disability and handicap in rheu-
516
matoid arthritis and ankylosing spondylitis—
results from the German rheumatological database. German Collaborative Arthritis Centers. J Rheumatol 2000; 27: 613-22.
13. MAKSYMOWYCH WP, JHANGRI GS, LAMBERT RG et al.: Infliximab in ankylosing
spondylitis: a prospective observational inception cohort analysis of efficacy and safety.
J Rheumatol 2002; 29: 959-65.
14. RUSSELL AS, OROZCO JH, MAKSYMOWYCH WP: The dose of infliximab in the
treatment of ankylosing spondylitis: Dollars
and sense. Clin Exp Rheumatol 2002; 20
(Suppl. 28): S135-S136.
15. BRAUN J, BRANDT J, LISTING J et al.:
Long-term efficacy and safety of infliximab
in the treatment of ankylosing spondylitis: an
open, observational, extension study of a
three-month, randomized, placebo-controlled
trial. Arthritis Rheum 2003; 48: 2224-33.
16. BRAUN J, PHAM T, SIEPER J et al.: International ASAS consensus statement for the use
of anti-tumour necrosis factor agents in patients with ankylosing spondylitis. Ann
Rheum Dis 2003; 62: 817-24.
17. BAERT F, NOMAN M, VERMEIRE S et al.:
Influence of immunogenicity on the longterm efficacy of infliximab in Crohn’s disease. N Engl J Med 2003; 348: 601-8.