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Pattern of infliximab utilization in rheumatoid arthritis patients at an academic medical center.

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Arthritis & Rheumatism (Arthritis Care & Research)
Vol. 53, No. 6, December 15, 2005, pp 872– 878
DOI 10.1002/art.21582
© 2005, American College of Rheumatology
ORIGINAL ARTICLE
Pattern of Infliximab Utilization in Rheumatoid
Arthritis Patients at an Academic Medical Center
SANDEEP K. AGARWAL,1 AGNES L. MAIER,1 LORI B. CHIBNIK,1 JONATHAN S. COBLYN,1
ANNE FOSSEL,1 RYAN LEE,1 JOHN FANIKOS,2 KAREN FIUMARA,2 COLLEEN LOWRY,2 AND
MICHAEL E. WEINBLATT1
Objective. To investigate the pattern of use of infliximab with an emphasis on treatment escalation and the durability of
infliximab use in the management of rheumatoid arthritis (RA) in an academic setting.
Methods. We conducted a retrospective review of pharmacy and medical records of 183 patients with RA who received
at least 1 infliximab infusion at the infusion centers of the Brigham and Women’s Hospital. Treatment escalation was
defined as an increase in the dosage of infliximab to >3 mg/kg and/or a decrease in the dosing interval to <7 weeks
between infusions.
Results. A total of 183 patients with RA received infliximab infusions for a mean ⴞ SD duration of 58.2 ⴞ 56.6 weeks.
Infliximab was discontinued in 48% of the patients during the first year of therapy and in 67% of the patients overall. A
total of 126 patients had a treatment escalation, including 25 patients with a dose increase, 35 patients with a decrease
in the interval, and 66 patients with both. Infliximab treatment was associated with a decrease in corticosteroid and
methotrexate doses. Patients who had a treatment escalation were more likely to continue infliximab infusions compared
with patients without a treatment escalation (odds ratio 2.0, 95% confidence interval 1.0 – 4.1).
Conclusion. The use of infliximab may be an effective treatment for RA; however, a substantial number of patients will
discontinue its use. Treatment escalation is commonly used in the management of RA with infliximab and is associated
with longer duration of infliximab use.
KEY WORDS. Rheumatoid arthritis; Infliximab; Dose; Interval.
INTRODUCTION
Biologic response modifiers targeting tumor necrosis factor
␣ (TNF␣) have profoundly transformed the management of
rheumatoid arthritis (RA) and dramatically improved the
outlook for patients with RA. Clinical trials with infliximab, a chimeric (mouse-human) monoclonal antibody
targeting human TNF␣, in combination with methotrexate
Supported by an unrestricted grant from Bristol Myers
Squibb. Dr. Agarwal is recipient of the Abbott Scholar
Award in Rheumatology Research.
1
Sandeep K. Agarwal, MD, Agnes L. Maier, MD, Lori B.
Chibnik, MD, Jonathan S. Coblyn, MD, Anne Fossel, MD,
Ryan Lee, MD, Michael E. Weinblatt, MD: Brigham and
Women’s Hospital, Harvard Medical School, Boston, Massachusetts; 2John Fanikos, MD, Karen Fiumara, MD, Colleen
Lowry, MD: Brigham and Women’s Hospital, Boston, Massachusetts.
Address correspondence to Michael E. Weinblatt, MD,
Brigham and Women’s Hospital, Division of Rheumatology,
Immunology, and Allergy, 75 Francis Street, Boston, MA
02115. E-mail: mweinblatt@partners.org.
Submitted for publication March 1, 2005; accepted in
revised form June 16, 2005.
872
have demonstrated an impressive improvement in clinical
signs and symptoms, functional and general health status,
and the prevention of radiographic progression in patients
with established and early RA (1–3). Accordingly, infliximab was approved in 1999 for the treatment of RA, in
combination with methotrexate, at a starting dosage of 3
mg/kg administered by intravenous infusion at 0, 2, and 6
weeks followed by every 8 weeks thereafter.
Despite the impressive clinical response to infliximab in
RA clinical trials, many in the rheumatology community
perceive that a substantial number of patients do not respond adequately when infliximab is administered using
the standard dosing protocol. Pharmacokinetic modeling
suggests that treatment escalation, a decrease in the interval between infusions and/or an increase in the dose at
each infusion, may result in better clinical outcomes (4).
Indeed, data from the Anti–Tumor Necrosis Factor Trial
in Rheumatoid Arthritis with Concomitant Therapy
(ATTRACT) and Active Controlled Study of Patients Receiving Infliximab for Treatment of Rheumatoid Arthritis
of Early Onset (ASPIRE) studies have demonstrated that
higher dosages (6 mg/kg and 10 mg/kg) were more effective
than 3 mg/kg in treating both the clinical signs and symp-
Infliximab Use in Patients With Rheumatoid Arthritis
toms of RA and reducing radiographic progression (1,3).
Accordingly, the US Food and Drug Administration (FDA)
approved an expanded label for infliximab in combination
with methotrexate for the management of moderate to
severe RA at dosages up to 10 mg/kg and intervals as
frequent as every 4 weeks.
Randomized clinical trials are the gold standard to determine the clinical efficacy of emerging therapies. However, these trials may not reflect actual clinical practice
due to differences in patient selection and monitoring and
are often brief compared with the duration of treatment
required for chronic illnesses such as RA. Furthermore,
clinical practice is influenced by patient and physician
perceptions of effectiveness and adverse events. The extent to which the benefits of infliximab observed in the
clinical trials have translated into sustained clinical benefits for patients with RA in routine clinical care remains
unclear.
A recent observational study using 2 large rheumatology
practices in Dallas, Texas and the National Data Bank for
Rheumatic Diseases demonstrated that dose escalations
were common and that patients had a durable efficacious
response to infliximab consistent with data from clinical
trials (5). These patients are from a variety of clinical
settings and largely reflect the practices of community
rheumatologists, which may differ from the practices in
the academic setting. Fitzcharles et al (6) also reported that
infliximab dose escalations were common in a small cohort from a Canadian academic center. However, this
study only had short-term followup, and infliximab was
used in patients with RA as well as other rheumatic diseases.
The pattern of infliximab use in the management of RA
has not been reported using large cohorts of patients with
RA with long duration of followup in the academic setting.
A better understanding of infliximab use in these patients
would be an important complement to the published randomized clinical trials and would be useful for physicians
who use infliximab in the management of RA. Therefore,
we conducted a retrospective analysis of patients with RA
treated with infliximab at the Brigham and Women’s Center for Arthritis and Joint Diseases. The objective of the
current study was to investigate the pattern of use of infliximab with an emphasis on treatment escalation and the
durability of infliximab use in the management of RA.
PATIENTS AND METHODS
Patients. Patients receiving at least 1 infusion of infliximab were initially identified by reviewing the pharmacy
records at Brigham and Women’s Hospital and Faulkner
Hospitals from September 1999 to September 2003. The
Brigham and Women’s Center for Arthritis and Joint Diseases is a large academic rheumatology practice with ⬎30
practicing board certified rheumatologists engaged in clinical care with ⬎31,000 patient visits per year. Patients who
are prescribed infliximab receive their infusions at either
an infusion center at Brigham and Women’s Hospital or
the Faulkner Hospital, an off-campus affiliated site. Neither infusion center is directly affiliated with the rheuma-
873
tologists, and revenues generated from infusion therapies
are credited solely to the hospital pharmacy departments.
Pharmacy and medical records of 387 patients who were
given infliximab between 1999 and 2003 were reviewed.
Of these 387 patients, 202 patients diagnosed with RA
were identified using the International Classification of
Diseases, Ninth Revision (ICD-9) code for RA (714.00) to
screen the pharmacy records. Using the 1987 American
College of Rheumatology (ACR; formerly the American
Rheumatism Association) criteria for RA (7), the diagnosis
of RA was confirmed in 183 patients. The dates of infusion
and dose administered were obtained from the pharmacy
records. Medical records were reviewed to obtain clinical,
laboratory, and radiographic data. The laboratory data and
radiographic data were gathered at Brigham and Women’s
Hospital per usual clinical practice. The Institutional Review Board at Brigham and Women’s Hospital approved
this study.
Treatment escalation. Based on data from the ATTRACT
trial, infliximab is usually started at a dosage of 3 mg/kg
administered by intravenous infusion at 0, 2, and 6 weeks
followed by every 8 weeks thereafter. An interval decrease
was defined as a decrease in the weekly interval to less
than the prior interval. If patients were receiving infliximab every 8 weeks, the interval was only considered
decreased if it was changed to 7 weeks or less. This was
done to capture intentional interval decreases due to medical reasons and to minimize the effect of logistical variables encountered in real-life situations such as slight variations in scheduling of infusions. A dose increase was
defined as an increase in the dose of infliximab from the
previous dose administered. Treatment escalation of infliximab was defined as a dose increase and/or a decrease
in the interval between infusions.
Statistical analyses. All analyses were performed using
the SAS system version 9.1 (SAS Institute, Cary, NC).
Doses were recorded as either milligrams or mg/kg. In
cases where doses were recorded as milligrams, mg/kg
were calculated based on the patient’s weight. All continuous variables were tested for normality using the
D’Agostino-Pearson test. We used t-tests (if normally distributed), Wilcoxon’s rank sum tests (if non-normal), and
chi-square tests to assess differences in baseline characteristics and risk factors between subgroups (dose escalation
versus no dose escalation, and discontinuation versus no
discontinuation). All statistical tests were performed at a
significance level of 5%.
RESULTS
Patient characteristics. A total of 387 patients received
at least 1 infliximab dose at the infusion centers at Brigham
and Women’s Hospital and the Faulkner Hospital between
1999 and 2003. Using the ICD-9 code for RA (714.00) to
screen the pharmacy records, 202 patients diagnosed with
RA were initially identified. Using the 1987 ACR criteria
for RA (7), the diagnosis of RA was confirmed in 183 of 202
874
Agarwal et al
Table 1. Diagnosis of all patients who received
infliximab
Diagnosis
Rheumatoid arthritis
Rheumatoid arthritis (not confirmed
by authors)
Crohn’s disease
Psoriatic arthritis
Juvenile rheumatoid arthritis
Ankylosing spondylitis/spondylarthropathy
Reactive arthritis
Adult Still’s disease
Sjögren’s syndrome
Vasculitis
Undifferentiated polyarthritis
Raynaud’s phenomenon
Unclear diagnosis
Systemic lupus erythematosis,
sarcoidosis, Behçet’s disease,
dermatomyositis, mixed connective
tissue disease
No. of
patients
183
19
99
33
20
7
4
2
3
3
3
2
4
1 of each
patients. The 19 patients initially coded as having RA who
did not meet the ACR criteria for RA were excluded from
the study. The coded diagnoses for the remaining patients,
including psoriatic arthritis, Crohn’s disease, and other
rheumatic diseases, are presented in Table 1.
Our cohort of patients with RA was 87% female with a
mean ⫾ SD age of 59.3 ⫾ 14.4 years (Table 2). The majority
Table 2. Baseline demographics and disease
characteristics*
Characteristic
Value
Total number of patients
Sex
Female
Male
Age, mean ⫾ SD years
Weight, mean ⫾ SD kg
Disease duration, years
⬍2
2–10
⬎10
RF status
Negative
Positive
Unknown
Erosive disease
No
Yes
Unknown
Prior joint arthroplasty
No
Yes
Unknown
ESR, mean ⫾ SD mm/hour (n ⫽ 63)
CRP, mean ⫾ SD mg/liter (n ⫽ 26)
183
159 (87)
24 (13)
59.3 ⫾ 14.4
60.8 ⫾ 27.0
19 (11)
68 (38)
92 (51)
42 (23)
111 (61)
29 (16)
43 (23)
113 (62)
27 (15)
126 (70)
51 (28)
3 (2)
50.5 ⫾ 29.4
10.3 ⫾ 17.5
* Unless otherwise indicated, values are the number (percentage).
RF ⫽ rheumatoid factor; ESR ⫽ erythrocyte sedimentation rate;
CRP ⫽ C-reactive protein level.
of patients in our cohort had long-standing RA (51% ⬎10
years, 38% 2–10 years). Consistent with the long duration
of disease, patients had received multiple disease-modifying antirheumatic drugs (DMARDs) prior to initiating infliximab treatment (Table 3). The most common reason for
discontinuation of DMARD therapy was lack of efficacy,
although a substantial number of patients discontinued
DMARD therapy due to toxicity. Methotrexate was confirmed to be part of the past therapeutic regimen in 87
patients. Of those patients who had previously taken
methotrexate, 47 patients discontinued methotrexate due
to lack of sustained clinical benefit and 41 stopped due to
toxicity or intolerance. Etanercept was used in 42 patients
and adalimumab was used in 1 patient prior to receiving
infliximab.
At the time of initiation of infliximab, 143 patients were
taking concomitant DMARDs and continued their use during the infliximab treatment (Table 3). Of note, only 101
patients were taking methotrexate at the time of infliximab
initiation, despite recommendations for use of concomitant methotrexate with infliximab. The mean ⫾ SD dosage
of methotrexate at the time of infliximab initiation was
16.2 ⫾ 5.9 mg (range 7.5–25 mg) per week. Corticosteroids
were part of the therapeutic regimen in 112 of 183 patients,
with a mean daily prednisone equivalent dosage of 7.9 ⫾
5.2 mg (range 2–50 mg).
Duration of infliximab therapy and adverse events. In
total, 183 patients with RA received at least 1 infliximab
infusion. The mean ⫾ SD duration of infliximab use for the
entire cohort was 58.2 ⫾ 56.6 weeks (range 0 –246 weeks).
The loading doses at weeks 0, 2, and 6 were completed in
147 patients. During the study period, 123 (67%) of 183
patients discontinued infliximab infusions at our center.
As seen in Table 4, patients were more likely to discontinue infliximab in the first year of use (48%) compared
with patients receiving infliximab infusions for a longer
duration. The mean ⫾ SD duration of infliximab therapy in
patients who remained on treatment was 97.7 ⫾ 63.1
weeks (range 2–246 weeks) compared with a mean of
41.0 ⫾ 41.5 weeks (range 0 –182 weeks) for patients who
discontinued infliximab infusions (P ⬍ 0.0001). The reasons for discontinuation of infliximab are listed in Table 5.
Forty-five (25%) of 123 patients stopped infliximab infusions due to lack of efficacy, and 40 patients stopped
infliximab infusions due to toxicity. Furthermore, 8 patients stopped infliximab infusions due to lack of remaining clinical activity as determined by the treating physician. Patients who discontinued infliximab within the first
3 doses (i.e., during the loading protocol) were more likely
to stop due to toxicity (odds ratio [OR] 6.8, 95% confidence interval [95% CI] 2.3–19.8; P ⬍ 0.001) and were less
likely to stop due to continued disease activity (OR 0.2,
95% CI 0.1– 0.4; P ⬍ 0.001) than patients who continued to
receive infliximab after the loading doses.
There were 31 patients (17%) who reported a nonserious
adverse event, including 25 mild infusion reactions. Infliximab was discontinued in 24 patients as a result of these
mild adverse events. Serious adverse events, defined as
adverse events requiring hospitalization, intravenous an-
Infliximab Use in Patients With Rheumatoid Arthritis
875
Table 3. Prior disease-modifying antirheumatic drug (DMARD) exposure and
concomitant DMARD therapy
Prior exposure
Concomitant
therapy
Discontinuation reason
Drug
No.
Toxicity
Ineffective
Other
No.
Hydroxychloroquine
Sulfasalazine
Methotrexate
Leflunomide
Etanercept
Adalimumab
Anakinra
Azathioprine
Gold
Cyclosporine
116
67
87
60
42
1
2
15
56
12
6
17
41
29
9
0
0
4
6
0
102
48
47
33
26
1
0
9
42
10
8
2
0
0
7
0
2
2
8
2
10
6
101
22
0
0
0
3
0
1
tibiotics, new medical diagnosis, or resulting in death,
were observed in 23 (13%) patients. These included 3
serious infusion reactions and 7 infections (4 pneumonia,
1 cellulitis, 1 osteomyelitis, and 1 aspergillus infection).
Infliximab was discontinued in 16 patients due to these
serious adverse events. Two of the 7 patients with infections died as a result of pneumonia complicated by sepsis
and disseminated aspergillus infection. No cases of demyelination, lupus-like syndrome, lymphoma, or tuberculosis were observed. Confirmation of tuberculin skin testing
was documented in 145 (79%) of the 183 medical records
prior to starting infliximab therapy. Ten of these patients
had a positive tuberculin skin test result, and confirmation
of isoniazid therapy was observed in the medical records
of 5 of these patients.
Escalation of treatment. Treatment escalation was defined as an increase in the dose per kilogram of weight to
⬎3 mg/kg, a decrease in the interval between infusions to
⬍7 weeks, or both. Using these criteria, 126 (69%) of 183
patients had a treatment escalation of infliximab. Of these
patients, 66 patients had a change in both the dose and
interval, 25 patients had only an increase in the dose, and
35 patients had only a decrease in the interval between
infusions. In total, 91 patients (50%) had a dose increase
and 101 patients (55%) had an interval decrease. Of note,
5 patients had a decrease in the dose of infliximab and 25
patients had an increase in the interval between infusions.
In patients who had a dose increase, the infliximab dose
was increased a mean ⫾ SD of 1.6 ⫾ 1.1 times per patient
Table 4. Number of infliximab discontinuations by year
of patient treatment
Year of
treatment
Total no.
patients
No. patients
discontinued (%)
1
2
3
4
5
Total
183
79
32
16
5
183
88 (48)
26 (33)
5 (16)
4 (25)
0 (0)
123 (67)
(median 1.0, range 1– 8). The first dose change usually
occurred in the first 22 weeks of treatment, as seen in
Figure 1 (mean ⫾ SD 33 ⫾ 29, median 25.1 weeks; range
2–126 weeks). The dosage was increased to 5 mg/kg in 91
patients and 10 mg/kg in only 10 patients. The frequency
of specific infliximab doses given to patients as a result of
dose escalation is shown in Figure 2. Evidence for the dose
escalation was apparent in both the entire cohort and the
dose escalation group. In the entire cohort, infliximab was
started at a mean ⫾ SD dosage of 3.15 ⫾ 0.53 mg/kg
(median 3.0 mg/kg, range 3.0 –5.0 mg/kg), and at the end of
the study the mean dosage was 4.39 ⫾ 1.81 mg/kg (median
3.5 mg/kg, range 3.0 –10.0 mg/kg; P ⬍ 0.0001). In patients
with a dose increase, infliximab was started at a mean
dosage of 3.11 ⫾ 0.46 mg/kg (median 3.00 mg/kg, range
3–5 mg/kg), and at the end of the study the mean dosage
was 5.46 ⫾ 1.76 mg/kg (median 5.00 mg/kg, range 3–10
mg/kg; P ⬍ 0.0001).
In patients who had an interval decrease, the interval
between infliximab infusions was decreased a mean of
4.2 ⫾ 4.1 times per patient (median 1, range 0 –19). As seen
in Figure 1, the first interval decrease occurred at a mean ⫾
SD 30.7 ⫾ 27.2 weeks (median 20.0 weeks, range 2–153
weeks). In patients who had an interval decrease, the mean
Table 5. Reasons for withdrawal of infliximab
Reason
No. patients
who withdrew*
% of total
patients
(n ⴝ 183)
Continued disease activity
Toxicity
Health insurance/cost
Other
Positive response
Infusions done elsewhere
Moved or lost to followup
Family issue
Patient request
Planning pregnancy
Unknown
45
40
5
35
8
7
9
1
5
1
4
25
22
3
19
4
4
5
⬍1
3
⬍1
2
* Some patients had more than one reason listed.
876
Agarwal et al
Fifty-four (48%) of 112 patients had a change in their
corticosteroid dose, including 18 discontinuations, 27 decreases, 5 increases, and 4 initiations. The mean ⫾ SD
prednisone dosage in these 54 patients decreased from
7.94 ⫾ 6.91 mg/day (range 0 –50 mg/day) at the time of
infliximab initiation to 3.56 ⫾ 3.57 mg/day (range 0 –15
mg/day; P ⬍ 0.0001) at the end of the study. The reason for
a change in the prednisone dose was a positive clinical
response in 42 patients. In contrast to the trend seen with
methotrexate, patients who had a treatment escalation
were not more likely to have a change in their prednisone
dose.
Figure 1. Time to infliximab dose escalation or interval decrease.
interval throughout the study was 7.0 ⫾ 1.9 weeks (range
2–14 weeks) compared with 8.7 ⫾ 1.8 weeks (range 6 –16
weeks; P ⫽ 0.0001) in patients without an interval decrease. The mean ⫾ SD final interval between the last 2
infusions (either at the end of the study or prior to discontinuation) in patients without an interval decrease was
8.5 ⫾ 1.9 weeks (range 6 –16 weeks). In contrast, the mean
final interval in patients who had an interval decrease was
6.3 ⫾ 2.4 weeks (range 2–14 weeks; P ⬍ 0.0001). Three
patients from the interval decrease group were not included in this particular analysis because they had an
interval ⬎3 SDs above the group mean.
Change in methotrexate and prednisone dose. As noted
above, at the time of infliximab initiation, 101 patients
were taking weekly methotrexate and 112 patients were
taking daily prednisone. Thirty-eight (38%) patients had a
change in their methotrexate dose, including 7 discontinuations, 19 decreases, 9 increases, and 3 initiations. The
mean ⫾ SD methotrexate dosage in these 38 patients decreased from 15.0 ⫾ 7.21 mg/week (range 0 –25 mg/week)
at the time of infliximab initiation to 10.53 ⫾ 6.61 mg/
week (range 0 –22.5 mg/week; P ⫽ 0.009) at the end of the
study. The reason for a change in the methotrexate dose
was a positive clinical response in 21 patients.
Figure 2. Frequency of infliximab doses administered to patients
with rheumatoid arthritis.
Factors associated with treatment escalation and discontinuation. Risk factor analysis was performed to determine factors associated with treatment escalation and discontinuing infliximab. Sex, rheumatoid factor status,
presence of erosions on radiographs, duration of disease,
prior joint arthroplasty, and baseline erythrocyte sedimentation rate or C-reactive protein level were not found to be
associated with a higher risk of dose escalation or rates of
discontinuation. Furthermore, there were no differences in
rates of treatment escalation or infliximab discontinuation
in patients who were taking either methotrexate or corticosteroids compared with those not taking either medication. Interestingly, patients who had a treatment escalation
were more likely to continue receiving infliximab infusions compared with patients who did not have a treatment escalation (OR 2.0, 95% CI 1.0 – 4.1; P ⫽ 0.05).
DISCUSSION
Infliximab, an intravenous biologic response modifier targeting TNF-␣, in combination with methotrexate has been
demonstrated to effectively improve clinical outcomes in
patients with RA. Clinical trials have demonstrated a sustained clinical response with minimal adverse events
(1,2). Pharmacokinetic modeling has suggested that treatment escalation, either decreasing the interval between
infusions or increasing the dose of infliximab, may result
in improved clinical efficacy (4). The extent to which a
durable clinical response to infliximab and the use of
treatment escalation have become part of routine clinical
practice in the management of RA has not been clearly
identified in the literature. Therefore, we conducted a
retrospective analysis to characterize the pattern of infliximab use in the management of RA by rheumatologists in
an academic center.
In our cohort, 183 patients with RA were treated with
infliximab for up to 246 weeks (mean ⫾ SD 58.3 ⫾ 56.6
weeks), but there was a surprisingly high rate of discontinuation within the first year of treatment (48%) and
within the entire study overall (67%). Treatment escalations were very common, occurring in 69% of patients
treated with infliximab. Treatment escalation was associated with a longer duration of infliximab use and a higher
likelihood of continuing infliximab. Lastly, both corticosteroids and methotrexate doses were decreased in patients treated with infliximab.
Stern and Wolfe (5) have recently described patterns of
Infliximab Use in Patients With Rheumatoid Arthritis
infliximab use in 2 separate cohorts largely made up of
patients with RA treated in the community health care
setting. They reported rates of treatment escalation of infliximab in the 2 cohorts (66% and 56%) similar to our
cohort of patients with RA treated at an academic rheumatology center. However, the treatment escalations in these
2 cohorts were almost all dose escalations. In contrast, our
cohort had similar rates of dose escalation and interval
decreases. Based on pharmacokinetic modeling, it has
been suggested that decreasing the interval may be more
effective than increasing the dose at raising serum infliximab trough levels, which correlate with clinical response;
however, this has not been investigated in more formal
clinical settings (4).
Perhaps the most impressive difference in the use of
infliximab in our report compared with both clinical trials
as well as other observational studies is the high rate of
infliximab discontinuation (1,5,8). The ATTRACT trial reported a 1-year discontinuation rate of 21%. In clinical
practice, the rate of discontinuation may have been higher
because an additional 18% of patients who received infliximab did not meet ACR20 criteria (9). Stern and Wolfe
(5) reported discontinuation rates of 14% at 1 year and
25% at 2 years, and Sidiropoulos et al (8) reported a
discontinuation rate of 29% after the 12th infusion. Both
of these observational studies likely had patients with
similar disease duration and severity as well as a similar
degree of dose escalation compared with our cohort. However, a critical difference may be that the previous reports
only included patients who had completed the loading
protocol at 0, 2, and 6 weeks. Consistent with this possibility is the higher rate of adverse reactions and the association of early discontinuation with adverse reactions in
our cohort compared with prior studies. However, the high
rate of discontinuation observed in the current study (48%
at 1 year and 67% overall) can only partially be explained
by including all patients with RA who have received at
least 1 infliximab dose. Other factors such as patient and
physician perceptions and physician incentives may also
be involved.
Another possible explanation for the high rate of discontinuation could be the surprisingly low rate of concomitant methotrexate administration. Infliximab has been approved for use in patients with RA with concomitant
methotrexate administration. Despite these recommendations, only 101 of the 183 patients in our cohort were
taking methotrexate. The lack of association between concomitant methotrexate use and either treatment escalation
or discontinuation suggests that the high rate of discontinuation is not due to the low rate of concomitant methotrexate. However, it remains possible that in some patients, concomitant methotrexate use may help prevent the
formation of antichimeric antibodies that potentially contribute to infusion reactions and/or treatment discontinuation.
In May 2002, a consensus statement by 158 rheumatologists stated that physicians may consider either a dose
increase or an interval decrease in patients with an incomplete response to TNF␣ antagonists (10). Also in 2002, the
US FDA issued an expanded label for the use of infliximab
in patients with RA up to 10 mg/kg and as often as every 4
877
weeks. Although dose escalation was common in our cohort, it is rather surprising that most patients with a treatment escalation only reached 5 mg/kg. Only 10 patients
reached the maximum recommended dosage of 10 mg/kg.
A more aggressive approach to dose escalation may be
beneficial in the treatment of patients who may not be
responding optimally to infliximab therapy. However, the
increased cost and potential increased risk of adverse
events relative to an unproven clinical benefit should also
be considered in this medical decision (11).
Although infliximab treatment escalation may be commonly used, it remains to be determined if this practice
has added clinical benefit in the management of RA. The
ATTRACT and ASPIRE studies suggest that the higher
dose may be more efficacious in patients who have not
been previously exposed to infliximab. However, it is unknown if escalating infliximab treatment in a patient with
an initial suboptimal response to infliximab, in contrast to
an infliximab-naı̈ve patient, will have any added clinical
benefit. Two recent reports have addressed this issue and
concluded that treatment escalations were not always sufficient to maintain adequate disease control, and that the
perceived clinical benefit from treatment escalation may
actually represent a regression-like effect as opposed to a
real clinical response (8,12).
Because the current study is a retrospective review of
medical records, it is difficult to accurately determine if
patients received an additional clinical benefit from the
treatment escalation. However, it is intriguing that patients
who had a treatment escalation were more likely to continue to receive infliximab infusions. Furthermore, patients treated with infliximab often had a decreased need
for corticosteroids and methotrexate. This change in methotrexate was also associated with treatment escalation.
Although not conclusive, these data suggest a beneficial
effect of treatment escalation of infliximab. Future prospective studies are needed to address whether treatment
escalation is clinically and cost effective.
Infliximab has been a critical advance in the management of RA, resulting in dramatic clinical improvement
and the prevention of disabling radiographic damage. Despite the use of infliximab with the common practice of
treatment escalation in patients with RA, many patients
continue to have disease activity, emphasizing the need
for prospective studies that address the risks and benefits
of treatment escalation. Furthermore, these observations
also underscore the importance of future research to identify novel therapeutic targets and develop new agents for
the management of RA.
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