Formulary Forum

Infliximab Treatment of Rheumatoid Arthritis and Crohn’s

Disease

Ibrahim K Nahar, Kam Shojania, Carlo A Marra, Abul H Alamgir, and Aslam H Anis

OBJECTIVE: To review the pharmacology, pharmacokinetics, efficacy, safety, and pharmacoeconomic impact of infliximab in the
treatment of Crohn's disease (CD) and rheumatoid arthritis (RA).
DATA SOURCES: MEDLINE and Pre-MEDLINE (1966–June 2002) and manufacturer prescribing literature were employed to find
English-language articles on infliximab. Additional studies and abstracts were identified from the bibliographies of reviewed literature
and conference proceedings.
STUDY SELECTION/DATA EXTRACTION: All articles identified from data sources were evaluated, and all information deemed relevant
was included in this review. Information regarding basic pharmacology was collected from studies in animals. Pharmacokinetic data
were collected from human trials. Safety data were extracted from clinical trials and postmarketing surveillance. Priority was given to
randomized, double-blind, placebo-controlled studies for the assessment of efficacy. All available economic evaluations were
included.
DATA SYNTHESIS: Infliximab is a new monoclonal antibody that appears to work by a unique mechanism: inhibiting the action of
tumor necrosis factor-α (TNF-α). Infliximab is administered by intravenous infusion. In clinical trials in CD, infliximab significantly
decreased the CD activity index compared with placebo in treatment-resistant disease and significantly reduced the number of
draining fistulas in fistulizing disease. In RA, when infliximab was added to methotrexate (MTX), it resulted in a significant
improvement in most disease outcome measures when compared with MTX plus placebo. Few major adverse effects were
reported in the clinical trials; however, serious adverse events, including malignancy and demyelination, have been reported in
postmarketing surveillance. Also, increased susceptibility to infections (including tuberculosis) has been reported.
CONCLUSIONS: Infliximab is an effective new agent for the treatment of CD and RA. Its apparent unique mechanism of action makes
infliximab an important addition to therapy. Caution should be exercised when considering infliximab for individuals who have
chronic or recurrent infections, mild congestive heart failure (New York Heart Association [NYHA] class I/II), nervous system
disorders, or live or have lived in an area endemic for histoplasmosis. Infliximab is contraindicated for patients with a clinically
important, active infection, moderate to severe congestive heart failure (NYHA class III/IV), or an allergy to mouse proteins or any of
the ingredients in infliximab. Further long-term efficacy, safety, and economic data on infliximab are required. Also, for the treatment
of RA, the burden of administering infliximab (as a 2-hour supervised infusion) has to be considered when choosing among anti-
TNF-α medication (as the other 2 approved agents, etanercept and adalimumab, can be self-administered by subcutaneous
injection).
KEY WORDS: Crohn's disease, infliximab, rheumatoid arthritis, tumor necrosis factor-α.

Ann Pharmacother 2003;37:1256-65.

Published Online, 10 Jul 2003, www.theannals.com, DOI 10.1345/aph.1C039
THIS ARTICLE IS APPROVED FOR CONTINUING EDUCATION CREDIT ACPE UNIVERSAL PROGRAM NUMBER: 407-000-03-024-H01

T he recent development of anti–tumor necrosis factor-α

(TNF-α) treatment for rheumatoid arthritis (RA) and
Crohn’s disease (CD) has changed the management of se-
Author information provided at the end of the text.
Infliximab (Remicade, Centocor)
vere or resistant disease. The current anti–TNF-α therapies
approved for use in the US and Canada are infliximab for
RA and CD, etanercept for RA only, and adalimumab for
RA only (currently approved only in the US). There are
several other anti–TNF-α agents in current clinical trials,
and there are newer genetically engineered biological
agents that are also directed against specific proinflamma-

1256 ■ The Annals of Pharmacotherapy ■ 2003 September, Volume 37 www.theannals.com


tory targets. Balancing the effectiveness and safety of these
agents with their high costs will determine their place in
the therapy for these disease states.
Data Sources
Data reported in this review were compiled from pub-
lished literature and from presentations at both national
and international scientific meetings. A MEDLINE and
Pre-MEDLINE search of English-language articles pub-
lished from 1966 to June 2002 was completed using inflix-
imab, rheumatoid arthritis, Crohn’s disease, and combina-
tions of these terms to identify relevant research. Bibli-
ographies and conference proceedings from relevant
articles/meetings were reviewed for additional references.
The pharmaceutical company that markets infliximab in
Canada (Schering Canada) was contacted for additional in-
formation. All trials were critiqued thoroughly for appro-
priate study methodology.
Chemistry
Infliximab is a chimeric anti–TNF-α monoclonal anti-
body. Its approximate molecular weight is 149 100 daltons.1
This immunoglobulin (Ig) molecule has several parts:
murine antigen-binding variable regions, constant human
IgG1 nonantigen-binding Fc heavy chains, and constant
human antigen-binding partial κ light chains and heavy
chains.2,3 The infliximab molecule is approximately 25%
murine and 75% human in origin.3 The molecular structure
of infliximab is shown in Figure 1.
Pharmacology
Cytokines are synthesized by many types of cells and
exert their physiologic or pathologic effects after binding
to cell-surface receptors. TNF-α, one of the key proinflam-
matory cytokines, has the following proposed functions:
apotosis of immune cells, stimulating the release of other
Figure 1. Structure of infliximab. The gray areas represent the 25% murine
portion of the antibody and the TNF-α binding variable-sequence regions. The
black areas represent the 75% human immunoglobulin G1 at the constant-
sequence regions. The κ signifies the kappa light chain. Courtesy of Scher-
ing, Canada.
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Infliximab in Rheumatoid Arthritis and Crohn’s Disease
proinflammatory cytokines, stimulating the release of ma-
trix metalloproteinases, assisting in the expression of en-
dothelial adhesion molecules, and blocking the action of
lipoprotein lipase.4 It also plays a central mediator role in
chronic inflammatory disorders such as CD and RA. Stud-
ies showed elevated levels of TNF-α in the mucosa and fe-
ces of patients with CD.5,6 TNF-α and its 2 receptors are
present at many sites within the synovial membrane and,
during the inflammatory process in RA, elevated levels of
TNF-α and its receptors are expressed in the synovial flu-
id.7,8 These studies demonstrated the importance of TNF-α
in CD and RA and provided the hypothesis that a specific
TNF-α–blocking agent may treat these diseases.
Infliximab neutralizes the biological activity of TNF-α
by binding with high affinity and specificity to the soluble
and trans membrane forms of TNF-α and inhibits binding
of TNF-α with its receptors. It down-regulates other proin-
flammatory cytokines (interleukin [IL]-1 and -6) and in-
hibits the production of vascular endothelial growth factor.
Murine monoclonal antibodies have limited use in humans
due to their immunogenicity, but a partially human anti-
body, such as infliximab, results in a longer half-life and
reduced immunogenicity, leading to superior efficacy.3,5
Pharmacokinetics
Three studies with pharmacokinetic data from CD pa-
tients: an open-label study (n = 20) and 2 double-blind,
placebo-controlled trials (n = 108 and 94) were published.9
A direct, linear relationship was found between dose and
the maximum serum concentration (Cmax). Infliximab had a
long half-life such that, after a single infusion of 5 mg/kg,
the terminal half-life was 9.5 days. Other pharmacokinetic
parameters included a median Cmax of 118 µg/mL and clear-
ance of 9.8 mL/h with the 5-mg/kg dose. The AUC ap-
peared to be related to dose. Additional information from
the manufacturer states that the volume of distribution at
steady-state (Vd) was independent of doses up to 20 mg/kg
in RA and CD patients.1 Differences in age and weight in
patient groups have no major effects on clearance and Vd.
The effects of impairment of hepatic and renal function on
pharmacokinetic parameters are unknown.1
A recent study analyzed treatment outcomes from a
large randomized trial in RA as a function of serum inflix-
imab concentrations.10 Through pharmacokinetic model-
ing, serum trough infliximab concentrations were estimat-
ed. From the data, it appeared that the serum concentration
was related to the therapeutic benefit of infliximab and that
the shortening of the dosage interval increased the trough
serum concentrations more than by increasing the dose.
Infliximab in Crohn’s Disease
CLINICAL EFFICACY
Infliximab was found to be effective in a 12-week mul-
ticenter, double-blind study in 108 patients with moderate
to severe CD resistant to conventional treatment.11 En-
The Annals of Pharmacotherapy ■ 2003 September, Volume 37 ■ 1257
IK Nahar et al.
rolled patients had a history of CD for at least 6 months
and a CD activity index (CDAI) between 220 and 400
(range 0–600 with score <150 indicates remission; >450
indicates severe illness). Patients were randomly assigned
to receive a single 2-hour intravenous infusion of placebo
or infliximab 5, 10, or 20 mg/kg. The primary outcome,
clinical response, was examined by pooling all infliximab
groups and comparing them with placebo. At 4 weeks,
clinical response was found in 81% (n = 22) of patients
who received 5 mg/kg, 50% (n = 14) of those who re-
ceived 10 mg/kg, and 64% (n = 18) of those given 20
mg/kg compared with 17% (n = 4) of patients who re-
ceived placebo (p < 0.001 for pooled infliximab groups vs.
placebo). There was no dose–response relationship among
the 3 infliximab treatment groups.
Thirty-three percent of the patients in the combined in-
fliximab groups went into remission compared with 4% of
patients in the placebo group (p = 0.005). At 12 weeks,
41% (n = 34) of those treated with infliximab achieved the
primary endpoint compared with 12% (n = 3) in the place-
bo group (p = 0.008).11
Efficacy of maintenance therapy with infliximab over a
single infusion for the treatment of moderate to severe CD
was assessed in a recent large, randomized, placebo-con-
trolled multicenter study ACCENT I (A Crohn’s Disease
Clinical Trial Evaluating Infliximab in a New Long-Term
Treatment Regimen).12 Patients with CD (n = 573; CDAI
220 – 400) and receiving stable doses of aspirin, antibi-
otics, mercaptopurine, azathioprine, methotrexate, and cor-
ticosteroids (≤40 mg/d) were given an initial single dose of
infliximab 5 mg/kg. A response (defined as a decrease in
CDAI of ≥70 from baseline and at least 25% reduction in
the total score) to the initial dose was evaluated 2 weeks
later. Patients with a response to the initial dose of inflix-
imab (n = 335) were randomized to receive 1 of 3 mainte-
nance regimens (placebo, infliximab 5- and 10-mg/kg dos-
es) given at weeks 2, 6, and every 8 weeks thereafter. Pa-
tients were followed for 54 weeks. The 2 primary
outcomes assessed were clinical remission rate at week 30
and the time to loss of response until week 54. A clinical
remission was defined by a CDAI <150, and time to loss
of response was defined by a CDAI ≥175 or an increase of
CDAI of at least 35% and a CDAI ≥70 points more than
the week 2 CDAI for at least 2 consecutive visits (≥21 d).
Patients who improved with treatment were allowed to ta-
per corticosteroids according to a predefined protocol.
Infliximab 5 and 10 mg/kg produced clinical remission
in 39% and 45% of the patients, respectively, at week 30
compared with 21% of patients in the placebo group (OR
2.7; 95% CI 1.6 to 4.6). Remission rates were not different
between the 5- and 10-mg/kg doses at week 30 (OR 1.3;
95% CI 0.74 to 2.2). The median time to loss of response
was significantly longer among the 5- and 10-mg/kg
groups (38 wk, p = 0.002; >54 wk, p = 0.0002, respective-
ly) compared with the placebo group (19 wk). Twenty-
nine percent of subjects in the combined infliximab groups
were able to discontinue corticosteroids compared with 9%
of those receiving placebo by week 54 (p = 0.004).12
1258 ■ The Annals of Pharmacotherapy ■ 2003 September, Volume 37
A 4-week, randomized, double-blind, placebo-controlled
study with infliximab demonstrated both endoscopic and
histologic healing and clinical response in 30 patients with
active CD.13 Infliximab has also been shown to be effective
for the treatment of abdominal and perianal fistulas, a fre-
quent and severe complication of CD.14 A multicenter, ran-
domized, placebo-controlled trial of 94 patients with CD
complicated by enterocutaneous fistulas defined the prima-
ry endpoint as a reduction in ≥50% of the number of fistu-
las draining upon gentle compression, on at least 2 consecu-
tive visits, without an increase in medication or surgery for
CD. This goal was reached by 68% of patients who were
given infliximab 5 mg/kg at weeks 0, 2, and 6 compared
with 26% of the patients in the placebo arm (p = 0.002). In
addition, 56% of patients who were given 10 mg/kg at
weeks 0, 2, and 6 achieved the primary endpoint. No signif-
icant difference between the 2 doses was found (p = 0.35).
The median duration of response was 12 weeks. Clinical
experience with infliximab in the treatment of active CD
and fistulizing disease has also been consistent with the ef-
ficacy results of the above controlled trials.15-17
ECONOMIC EVALUATION
CD exerts an enormous economic burden on the health-
care system. In a 1990 cost-of-illness study, the direct med-
ical costs necessary to manage CD from the US healthcare
perspective were estimated to be $6561 per patient per
year.18 Another analysis used prospective data collection
and Markov modeling to estimate lifetime direct medical
costs of $125 404 (1995 US $) per patient.19 Since with CD
both mortality20,21 and quality of life22 are affected by the
disease, economic evaluations should attempt to assess
both aspects through the use of quality-adjusted life years
(QALYs) as an outcome.
In treatment-resistant CD, Wong et al.23 modeled the in-
cremental cost per QALY of infliximab over usual therapy
from a US healthcare provider’s perspective based on the
results of a clinical trial11 and a previously published
Markov model.19 The incremental cost-effectiveness ratios
for infliximab generated by this analysis by each of the 3
outcomes were cost-saving if the effects of infliximab
were equivalent to those of surgically induced remission,
$22 200 per QALY if the effects of the drug were equiva-
lent to those of medically induced remission, and $38 400
per QALY if the effects of the drug were equivalent to
symptoms of mild disease. Due to numerous assumptions
used in the model, independent evaluations are still neces-
sary to confirm these results.
The cost utility of infliximab for initial medical manage-
ment of CD perianal fistulas was evaluated.24 A Markov
model was used to simulate a 1-year treatment period with
the following strategies: mercaptopurine and metronida-
zole (MP/MET), 3 infliximab infusions plus MP/MET as
second-line therapy, infliximab with episodic reinfusion,
and MP/MET plus infliximab as second-line therapy.
Based on the parameters in the model, all strategies had
similar effectiveness. Interventions that included inflix-
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imab were slightly more effective, but also more costly,
than MP/MET ($355 450/QALY, $360 900/QALY, and
$377 000/QALY, respectively). Thus, the authors conclud-
ed that the incremental benefit of infliximab for treating
CD perianal fistulas over a 1-year period may not justify
the higher cost.
ROLE IN TREATMENT
While there is evidence of the effectiveness of inflix-
imab in the treatment of CD, the use of infliximab must be
considered in the context of other agents. Corticosteroid
therapy is of proven benefit in acute exacerbations of CD,
but long-term treatment is limited by significant adverse
effects. Immunosuppressive agents such as azathioprine,
methothrexate, cyclosporine, and mycophenalate mofetil
have evidence for efficacy in the long-term treatment of
CD. While there is no generally accepted consensus for the
role of infliximab in the treatment of CD, reasonable use
has been outlined in Table 1.
Infliximab in Rheumatoid Arthritis
CLINICAL EFFICACY
In randomized trials, infliximab used as a single agent
for treatment of RA has demonstrated efficacy with im-
provement of clinical symptoms.25 However, with repeated
infusions of infliximab, a reduction in the clinical benefit
was observed, which has been attributed to the generation
of human antichimeric antibodies (HACA).26 A study of
infliximab with and without methotrexate has shown that
the clinical benefit of infliximab treatment was sustained
only with coadministration of methotrexate. This combina-
tion also reduces the generation of HACA.27
In late 1999, a large double-blind, placebo-controlled
trial (ATTRACT, Anti-Tumor Necrosis Factor Trial in
Rheumatoid Arthritis with Concomitant Therapy) was
conducted in 428 patients with active RA not responding
to methotrexate therapy.28 Patients were randomized to re-
ceive placebo or infliximab infusions (3 or 10 mg/kg) giv-
en over 2 hours at 0-, 2-, or 6-week intervals. Following
that, 2 infliximab arms (3 or 10 mg/kg) continued to receive
Table 1. An Approach to Rational Treatment with
Infliximab in CD
Patients who have moderate to severe CD that cannot be controlled
with conventional therapy including those who have failed acute
treatment with corticosteroids
Patients who are steroid dependent and have failed adequate doses
or have not tolerated azathioprine
Patients with fistulizing CD to reduce the number of draining entero-
cutaneous fistulas
As a bridging therapy in CD for patients also started on mercapto-
purine or azathioprinea
CD = Crohn’s disease.
a
The safety and efficacy of this approach has not been established.
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Infliximab in Rheumatoid Arthritis and Crohn’s Disease
their infusions every 4 weeks, while patients in the other 2
infliximab arms (3 or 10 mg/kg) received their infusions
every 8 weeks. All patients were on a stable methotrexate
regimen of at least 12.5 mg/wk for at least 3 months.
The primary outcome measure was a 20% improvement
in the American College of Rheumatology (ACR) response
rate, defined as a decrease of at least 20% in the number of
tender joints, a decrease of at least 20% in the number of
swollen joints, and a 20% improvement in 3 of the follow-
ing: patients’ global assessment of disease status, patients’
assessment of pain, health assessment questionnaire esti-
mate of disability, physician’s global assessment of disease
status, and erythrocyte sedimentation rate or serum C-reac-
tive protein concentration. The ACR 50% and 70% im-
provement response rates are assessed in a similar manner.
At 30 weeks, 50–58% of patients in each infliximab treat-
ment group achieved the ACR 20% response criteria com-
pared with 20% of those in the placebo group (p < 0.001).
When ACR 50% and 70% response criteria were used
(secondary outcome defined a priori), they were achieved
in 26–31% and 8–18% of patients in the infliximab 4- and
8-week groups compared with 5% and 0%, respectively, in
the placebo group.28
The radiographic progression of structural damage was
studied in the same patients after an extended follow-up of
54 weeks.29 In this article, the authors assessed the effect of
therapy on structural damage by evaluating X-rays of the
hands and feet for both erosions and joint-space narrowing
using the van der Heijde modification of the Sharp scoring
system, a reliable and valid method. This scale is scored
between 0 and 440, with higher scores indicating greater
structural damage. The results showed that infliximab
slowed the progression of structural damage, with a mean
deterioration of joint erosion scores of 0.5 in any inflix-
imab treatment group compared with a mean score of 4 in
the placebo group (p < 0.001) and a mean deterioration of
the joint-space narrowing score of 0.4 compared with 2.9
in the placebo group (p < 0.001).
Results of a recent, open-label study assessing inflix-
imab safety and timing of onset of clinical benefit among
patients with RA were published by the PROMPT (Profil-
ing Remicade Onset With Methotrexate in a Prospective
Trial) investigators.30 Patients (n = 553) with active RA de-
spite receiving methotrexate were treated with infliximab 3
mg/kg at baseline and at weeks 2, 6, and 14 thereafter. By
48 hours following the first infusion, significant (p <
0.001) improvements were observed in duration of morn-
ing stiffness, physician’s global disease assessment scores,
patient’s global disease assessment scores, and patient’s
pain assessment scores. By the end of the study, 10% (n =
54) of patients reported an adverse event associated with at
least 1 of the 4 infusion procedures. Of these, the majority
were mild and transient in nature.
ECONOMIC EVALUATION
Several analyses have examined either the impact of in-
fliximab on resource utilization,31 employment status,32 or
■ 2003 September, Volume 37 ■ 1259
IK Nahar et al.
cost-effectiveness33-35 in the treatment of RA. Some of the
cost-effectiveness analyses were published only in abstract
form at the time of this review; therefore, a comparison of
their strengths and limitations is difficult. However, all used
a Markov model based on health states derived from the
Health Assessment Questionnaire and used the ATTRACT
trial28 as the primary source of clinical data. Wong et al.33
based their analysis on the 54-week follow-up results from
the ATTRACT trial and costs from the ARAMIS (Arthritis,
Rheumatism, and Aging Medical Information System)
database. In the base-case analysis from the perspective of
the US healthcare system, it was found that the incremental
cost-effectiveness ratio of 54 weeks of infliximab versus
methotrexate was $30 500 per QALY. Kobelt et al.34 con-
ducted a similar analysis from the Swedish and UK health-
care perspectives. Both of these analyses included some as-
sumptions (discontinuation of infliximab after 1–2 y) that
may limit the application of the results. Other investigators
assumed that infliximab is continued for a lifetime for pa-
tients who respond to therapy and, thus, found a somewhat
less optimistic incremental cost-effectiveness ratio.35
ROLE IN TREATMENT
The goal of RA therapy is to reduce symptoms, prevent
structural damage, and improve physical function. While
corticosteroids and nonsteroidal antiinflammatory drugs
(NSAIDs) reduce symptoms, there is sparse evidence that
these drugs inhibit structural damage progression. Disease-
modifying antirheumatic drugs (DMARDs) are a heteroge-
neous group of medications that have been shown to inhib-
it structural damage progression and improve function to a
degree, but these agents have significant toxicity and may
lose effectiveness within 5 years.36,37
Many experts believe that infliximab offers an advan-
tage over conventional DMARD therapy in its onset of ac-
tion and the duration and extent of disease control.38 Thus,
based on these consensus findings, it is generally agreed that
the use of infliximab should be limited to patients who have
moderate to severe active RA and have failed to demon-
strate a sufficient response to methotrexate.38,39 A rational
treatment approach with DMARDs in patients with moder-
ate or severe active RA is suggested in Table 2.2 However, it
remains to be seen whether infliximab will prove to be an
economically attractive treatment strategy in this role.
Table 2. Suggested Treatment with DMARDs in Patients with Moderate or Severe Active RA2
Indication
Persistent synovitis and evidence of radiographic erosions
Inadequate response to oral MTX
Inadequate response to parenteral MTX
Inadequate response or toxicity requiring discontinuation of MTX, sulfa-
salazine, and/or hydroxychloroquine
Toxicity or inadequate response
DMARDs = disease-modifying antirheumatic drugs; MTX = methotrexate; RA = rheumatoid arthritis; TNF-α = tumor necrosis factor-α.
1260 ■ The Annals of Pharmacotherapy ■ 2003 September, Volume 37
Other Uses of Infliximab
Potential uses of infliximab include the treatment of ul-
cerative colitis,40 psoriatic arthritis, and spondyloarthro-
pathies,41 such as complicated ankylosing spondylitis. De-
spite encouraging results, treatment of these conditions
with infliximab is still experimental. Other potential uses
identified by the manufacturer include plaque psoriasis and
sarcoidosis.1
Safety
The safety profile can be divided into adverse reactions
reported in clinical trials with infliximab and postmarket-
ing case reports. In clinical trials, 1372 patients were treat-
ed with infliximab (total of 9535 infusions).1 Adverse
events were reported in a higher proportion of RA patients
receiving 10 than 3 mg/kg; however, no differences were
observed in the frequency of adverse events between 5 and
10 mg/kg in patients with CD.
INFUSION REACTIONS
Reactions occurring during an infusion or within 1–2
hours after an infusion occurred in 22% of all infliximab-
treated patients compared with 9% of placebo patients.1
These reactions included nonspecific symptoms such as
headache, nausea, fever or chills (3%), pruritus or urticaria
(<1%), or the combined symptoms of pruritus/urticaria and
cardiopulmonary reactions such as chest pain, hypoten-
sion, hypertension, or dyspnea (1%). Serious reactions (re-
quiring hospitalization or deemed to be life threatening),
occurring in <1% of all infusions, included anaphylaxis,
seizures, erythematous rash, and hypotension. Three per-
cent of 1372 patients discontinued treatment because of in-
fusion reactions. Medications including antihistamines,
corticosteroids, and epinephrine should be available for
immediate use in the case of such events.
ANTIBODIES TO INFLIXIMAB
Approximately 10% of all patients in clinical trials de-
veloped antibodies to infliximab.1 Patients who developed
these antibodies were more likely to experience infusion
reactions. Antibody development was also noted to be
Action
start oral MTX
switch to parenteral MTX
add sulfasalazine and hydroxychloroquine
discontinue sulfasalazine, hydroxychloroquine, and/or MTX; add
leflunomide
discontinue leflunomide, add a TNF-α blocking agent (infliximab,
etanercept, or adalimumab)
www.theannals.com

lower among patients receiving concomitant immunosup-
pressive therapy. Antibodies are not typically measured in
clinical practice.
LUPUS-LIKE REACTIONS
Six cases of drug-induced lupus were noted among
1372 patients in the trials with infliximab.1 Symptoms in-
cluded migratory arthritis, pleuropericarditis, butterfly
rash, and forearm rash. None of these patients had renal or
central nervous system involvements. All patients improved
following discontinuation of therapy and appropriate medi-
cal treatment. Positive antinuclear antibodies (ANAs) devel-
oped in infliximab-treated patients to a greater extent than
placebo patients in the ATTRACT study through week
102.28 Of CD patients treated with infliximab who were
evaluated for ANAs, 44% developed ANAs between
screening and last evaluation.1 Anti– double-stranded DNA
(anti-dsDNA) antibodies developed in 4% of infliximab-
treated patients, but in no placebo-treated patients in the
ATTRACT study. Anti-dsDNA antibodies developed in
approximately 22% of CD patients treated with infliximab.
MALIGNANCY
Eighteen of 1372 patients treated with infliximab devel-
oped 19 new or recurrent malignancies over 1430 patient-
years of follow-up.1 These malignancies were non-Hodgkin’s
B-cell lymphoma, breast cancer, rectal adenocarcinoma,
melanoma, squamous-cell skin cancer, and basal-cell carci-
noma. From the available data, it cannot be determined
whether these malignancies were induced by infliximab
treatment. Thus, further long-term observational studies
are required to examine this issue. It should be remem-
bered that patients with RA and CD are also at increased
risk of certain types of malignancies in the absence of im-
munosuppressive therapy.42,43
INFECTIONS
During the randomized clinical trials with infliximab,
treated infections were reported in 36% of patients receiv-
ing infliximab compared with 26% of those randomized to
receive placebo.1 Most of the patients in the ACCENT I12
and ATTRACT28 studies were on concomitant immuno-
suppressive therapies that may have predisposed them to
an increased risk of infection. The types of infections most
frequently reported were respiratory and urinary tract. Seri-
ous infections, including pneumonia, cellulitis, abscess,
skin ulceration, pyelonephritis, and sepsis have also been
reported. Tuberculosis was diagnosed in 2 patients in the
clinical trials with infliximab, of which 1 died of miliary
tuberculosis. Another infection-related death was attribut-
ed to a disseminated coccidioidomycosis in a patient treat-
ed with infliximab in the ATTRACT study.
With the widespread use of infliximab, case reports of
serious opportunistic infections identified by postmarketing
surveillance have been reported to the Food and Drug Ad-
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Infliximab in Rheumatoid Arthritis and Crohn’s Disease
ministration (FDA). Between August 24, 1998, and June
30, 2001, in approximately 170 000 patients treated with in-
fliximab, there were 84 cases of tuberculosis reported
worldwide (52 cases in Europe).44 Of these cases, 14 result-
ed in death and were mostly extrapulmonary and dissemi-
nated. The majority of these patients were on concomitant
immunosuppressive therapies. This increased risk of tuber-
culosis among infliximab-treated patients may be related to
TNF-α blockade on macrophage activation and granuloma
formation.45 Patients for whom infliximab is being consid-
ered should be assessed for risk of tuberculosis and
screened with a tuberculin skin test and/or a chest X-ray.
Patients should start treatment for latent tuberculosis infec-
tion prior to initiation of therapy with infliximab.44,45
Histoplasmosis is another potentially life-threatening in-
fection that has been reported to the FDA as a complica-
tion of treatment with infliximab. Lee et al.46 reviewed data
on 9 cases of infliximab-associated histoplasmosis in the
US reported through July 2001 to the FDA. All patients
resided in states known to be endemic for histoplasmosis.
These infections occurred from within 1 week to 6 months
after initiating therapy with infliximab. The presenting
signs and symptoms were fever, malaise, cough, dyspnea,
and interstitial pneumonia shown on chest X-rays. All pa-
tients were receiving concomitant immunosuppressive
medication. One patient died and 8 patients recovered with
treatment. Because of this potential complication, a warn-
ing by the manufacturer has indicated that, for patients
who have resided in regions where histoplasmosis is en-
demic, the benefit and risks of infliximab treatment should
be carefully considered before beginning treatment.1 Other
serious opportunistic infections have been reported as well,
including listeriosis, aspergillosis, severe candida infec-
tions, and Pneumocystis carinii pneumonia.
Patients with clinically important active infections should
not receive anti–TNF-α therapy. Infliximab should be used
with caution in patients with chronic infections or a history
of recurrent infections. Recent serious infections are also po-
tential contraindications to infliximab therapy.
CONGESTIVE HEART FAILURE
Increased mortality and worsening of heart failure were
noted during a Phase II study evaluating infliximab in pa-
tients with New York Heart Association (NYHA) class
III/IV congestive heart failure (CHF) (left-ventricular ejec-
tion fraction ≤35%).1 A preliminary analysis of data from
150 patients who received 3 infusions of infliximab 5
mg/kg, 10 mg/kg, or placebo over 6 weeks showed wors-
ening of heart failure, at 28 weeks, in 14 of 101 infliximab-
treated patients (3 at 5 mg/kg, 11 at 10 mg/kg) compared
with 5 of 49 placebo patients. At 38 weeks, 9 deaths oc-
curred in infliximab-treated patients (2 at 5 mg/kg, 7 at 10
mg/kg) compared with 1 death among placebo patients.
The manufacturer has recommended that patients with
NYHA class III/IV moderate or severe CHF should not re-
ceive infliximab.1 Caution should be exercised when using
infliximab in patients with mild heart failure (NYHA class
■ 2003 September, Volume 37 ■ 1261
IK Nahar et al.
I/II). Doses >5 mg/kg should not be administered to pa-
tients with CHF. Infliximab must not be continued in pa-
tients who develop new or worsening CHF symptoms.
DELAYED INFUSION REACTIONS
Care should be taken when patients are considered for
retreatment with infliximab after it had been stopped for a
prolonged period of time. There have been reports of de-
layed infusion reactions among 10 of 37 patients with CD
in whom therapy with infliximab was restarted after 2– 4
years without treatment.1 Signs and symptoms included
myalgia and/or arthralgia with fever and/or rash, pruritus,
facial and hand edema, dysphagia, urticaria, sore throat, lip
edema, and headache. Six patients were reported as having
serious reactions. These symptoms developed 3–12 days
following treatment. Patient’s signs and symptoms im-
proved substantially or resolved with discontinuation of in-
fliximab.
DEMYELINATING DISEASE
Infliximab should be used with caution in patients with
preexisting or recent-onset central nervous system demyeli-
nating disorders and seizure disorders or numbness, tingling,
or visual disturbances. Exacerbation of clinical symptoms
and/or radiographic evidence of demyelinating disease have
been reported in rare cases with the use of infliximab. Mo-
han et al.47 identified a case and obtained data from the Ad-
verse Events Reporting System of the FDA on a further 19
patients (17 receiving etanercept, 2 receiving infliximab)
who developed neurologic symptoms suggestive of de-
myelination. In all patients, symptoms improved after dis-
continuation of anti–TNF-α therapy. Upon rechallenge with
etanercept, 1 patient’s symptoms returned. In addition, 4 of
these patients had a prior history of multiple sclerosis (MS)
or MS-like symptoms, prompting the authors to recommend
avoidance of anti–TNF-α therapy in this group.
PREGNANCY AND LACTATION
The manufacturer labels infliximab as a category B drug.1
As of October 2001, there have been 102 pregnancies iden-
tified in women exposed to infliximab.48 In the 54 women
for whom pregnancy outcome information was known, the
incidences of live births, miscarriages, and therapeutic ter-
minations were consistent with those observed in healthy
women. However, the manufacturer recommends that, if a
woman would like to ensure that infliximab is cleared from
her bloodstream prior to conception, a period of at least 6
months without receipt of infliximab is required.1
A single report of excretion of infliximab into breast
milk of a patient with CD showed that concentrations of
infliximab in the milk at 24 hours and 1 week after the first
infusion were undetectable by standard assays.49 However,
because many immunoglobulins are excreted into human
milk and due to the unknown potential for infliximab to
cause adverse effects in newborns, the manufacturer rec-
1262 ■ The Annals of Pharmacotherapy ■ 2003 September, Volume 37
ommends that a decision be made to either discontinue
nursing for at least 6 months after the last infliximab infu-
sion or discontinue treatment.1
VACCINATION AND DRUG INTERACTIONS
No data are available on the safety of vaccination or the
risk of transmission of infection following live vaccines.
However, the manufacturer recommends that live vaccines
not be given during therapy with infliximab.1
There have been no studies examining the issue of drug
interactions with infliximab.1 In clinical trials, infliximab
has been administered concomitantly with immunosup-
pressive therapy (methotrexate, mercaptopurine, azathio-
prine, corticosteroids), folic acid, aspirin, NSAIDs, some
antibiotics, and antivirals.
CONTRAINDICATIONS
Contraindications to infliximab include hypersensitivity
to murine proteins or components of the product, moderate
to severe heart failure (NYHA class III/IV), and the pres-
ence of clinically important active infection.1
PEDIATRIC AND GERIATRIC CONSIDERATIONS
Controlled trials in children have not been conducted. A
small, uncontrolled trial was performed in children with
inflammatory bowel disease with some favorable clinical
responses.50 However, the long-term safety and efficacy of
infliximab has not been determined in children.
The use of infliximab in the older population (≥65 y)
should be undertaken cautiously given this population’s
higher incidence of infection.1 There are insufficient data re-
garding effectiveness of infliximab in patients ≥65 years of
age; however, the results from the small number of patients
treated in the ATTRACT study show no overall difference
in efficacy or safety when compared with younger patients.28
UNRESOLVED ISSUES
Issues that remain to be resolved include the long-term
safety of immunosuppressive biological agents, particular-
ly with respect to infections and malignancies. At what
point should biological agents be used in the treatment al-
gorithms of CD or RA? Are such agents safe and effective
in combination with DMARDs other than methotrexate for
the treatment of RA? What are important drug interactions
with these agents? These questions should be the focus of
further clinical research. In addition, further long-term eco-
nomic evaluations of the proposed strategies need to be
undertaken in order to ensure that infliximab therapy rep-
resents good value in this time of fiscal restraint.
Dosage and Administration
Infliximab is supplied in a vial that contains 100 mg of
lyophilized infliximab powder. This is reconstituted with 10
www.theannals.com

mL of sterile water, then diluted with 250 mL of sodium
chloride 0.9% solution. Shaking should be avoided when
mixing the solution. The reconstituted material should not
be stored, as Remicade vials do not contain antibacterial
preservatives. Infliximab should be administered by intra-
venous infusion over a period of not less than 2 hours.1
CROHN’S DISEASE
For the treatment of moderate to severe active CD, in-
cluding fistulizing disease, infliximab is given at a dose of
5 mg/kg at weeks 0, 2, and 6, followed by maintenance
doses of 5 mg/kg every 8 weeks thereafter.1 Increasing the
maintenance dose to 10 mg/kg may be considered, if need-
ed, in patients who fail to maintain their initial response.
The treatment of fistulizing disease is an infliximab infu-
sion at a dose of 5 mg/kg given at weeks 0, 2, and 6. Re-
treatment of fistulizing disease with infliximab has not
been sufficiently studied.
RHEUMATOID ARTHRITIS
Infliximab should be given with methotrexate at a dose
of 3 mg/kg at weeks 0, 2, and 6 and then every 8 weeks
thereafter. The dose may be increased to 10 mg/kg and
given as frequently as every 4 weeks if needed. Doses >5
mg/kg should not be given to patients with CHF.
Summary/Formulary Considerations
Results of economic studies evaluating infliximab for
the treatment of CD and RA range from infliximab being a
dominant strategy (both less costly and more effective) to a
strategy that has the potential to significantly increase
healthcare costs over competing alternatives. Thus, the re-
sults of these analyses are largely inconclusive. However,
since all of these studies rely heavily on modeling tech-
niques to predict long-term outcomes and costs, further in-
vestigations are necessary to determine whether infliximab
is cost effective for these indications.
However, there is little debate about whether infliximab
is an effective strategy for some patients with CD and RA.
In these types of patients, infliximab has been shown to
significantly improve both clinical outcomes and quality of
life. Due to its unique mechanism of action and the dra-
matic response it elicits in some patients with RA and CD,
it offers significant advantage over agents traditionally
used. Thus, it has been or will be necessary for most
healthcare agencies to add this medication (or, for treat-
ment of RA, another anti–TNF-α agent) to their formulary
systems. As such, due to the high acquisition cost of inflix-
imab, there is the potential for significant costs to be in-
curred. In addition, since infliximab must be infused, there
are several requirements for its safe use. Proper equipment
and monitoring must be in place to ensure proper infusion
techniques and the detection of infusion-related adverse
events. Since most drugs that this agent replaces are taken
orally in the ambulatory setting, these factors will result in
www.theannals.com The Annals of Pharmacotherapy
Infliximab in Rheumatoid Arthritis and Crohn’s Disease
an increased workload. Thus, appropriate budgeting and
planning must be in place to facilitate appropriate infusion
sites staffed by experienced healthcare personnel.
These administration requirements may make inflix-
imab less of an attractive option for the treatment of RA
when compared with other anti–TNF-α medications (e.g.,
etanercept, adalimumab), which can be self-administered
subcutaneously. Conversely, patients may appreciate the
freedom of the every-8-week dosage regimen that inflix-
imab affords and may experience improved compliance
over the other agents. Thus, formulary committees will
have to weigh the burden of administering this agent (in
terms of workload and costs) against the convenience of
having 1 anti–TNF-α agent on formulary for the treatment
of both CD and RA (as the other 2 anti–TNF-α medica-
tions are only approved for RA).
Ibrahim K Nahar MBBS FRCP(C) ABIM (Rheum), Rheumatology
Fellow, Division of Rheumatology, Faculty of Medicine, University of
British Columbia, Vancouver, British Columbia, Canada
Kam Shojania MD FRCP(C), Clinical Assistant Professor, Division
of Rheumatology, Faculty of Medicine, University of British Columbia;
Director of Clinical Trials, Arthritis Research Centre of Canada, Van-
couver
Carlo A Marra BSc(Pharm) PharmD FCSHP, Clinical Assistant
Professor, Faculty of Pharmaceutical Sciences, University of British
Columbia; PhD Candidate, Department of Health Care and Epi-
demiology, Faculty of Medicine, University of British Columbia
Abul H Alamgir BPharm MPharm MBA, PhD Candidate, Depart-
ment of Health Care and Epidemiology, Faculty of Medicine, Uni-
versity of British Columbia
Aslam H Anis PhD, Associate Professor, Department of Health
Care and Epidemiology, University of British Columbia
Reprints: Carlo A Marra BSc(Pharm) PharmD FCSHP, Centre for
Health Evaluation and Outcome Sciences, 620B-1081 Burrard St.,
St. Paul’s Hospital, Vancouver, British Columbia V6Z 1Y6, Canada,
FAX 604/806-8778, cmarra@interchange.ubc.ca
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aph.10395
EXTRACTO
OBJETIVO: Revisar la farmacología, farmacocinética, eficacia, seguridad,
e impacto farmacoeconómico del infliximab en el manejo de la
enfermedad de Crohn’s (EC) y la artritis reumatoidea (AR).
FUENTES DE DATOS: Se utilizó el MEDLINE (1966 a junio de 2002) y la
información de prescripción del manufacturero para identificar artículos
escritos en inglés sobre el infliximab. Se identificaron estudios
adicionales y extractos a través de las bibliografías de la literatura
revisada y las publicaciones de convenciones.
www.theannals.com

EXTRACCIÓN DE DATOS Y SELECCIÓN DE ESTUDIOS: Se revisaron todos los
artículos hallados y se incluyó en este análisis toda la información
considerada relevante al estudio. La información sobre la farmacología
básica se obtuvo de estudios en animales. Los datos farmacocinéticos se
obtuvieron de estudios en humanos. Los concernientes a la seguridad
del producto fueron obtenidos de los estudios clínicos y la vigilancia
post mercadeo. Se dio prioridad a los estudios de asignación aleatoria,
doble ciego, y controlados por placebo para evaluar la eficacia del
producto. Todas las evaluaciones económicas disponibles fueron
incluidas en el análisis.
SÍNTESIS DE DATOS: El infliximab es un anticuerpo monoclonal con un
mecanismo de acción único. Este anticuerpo actúa mediante inhibición
del factor de necrosis de tumor alfa (TNF-α, por sus siglas en ingles). El
infliximab se administra mediante infusión intravenosa. Estudios
clínicos en EC demostraron que el infliximab redujo significativamente
el índice de actividad de EC al compararse con placebo en el manejo de
enfermedad resistente. Además, redujo significativamente el número de
fístulas con drenaje. En AR, el uso combinado de infliximab con el
metotrexato produjo una mejoría significativa en la mayoría de las
medidas de progresión de la enfermedad al compararse con metotrexato
solo y placebo. Los eventos adversos reportados en los estudios clínicos
fueron pocos. Sin embargo, algunos eventos serios incluyeron el
desarrollo de malignidades y demielinización. Además, se ha reportado
un aumento en la susceptibilidad a infecciones, incluyendo tuberculosis.
CONCLUSIONES: Infliximab es un agente efectivo en el manejo de EC y
AR. Su mecanismo de acción único lo convierte en un agente
importante para la terapia adyuvante. Se debe tener precaución al usar el
infliximab en pacientes con infecciones crónicas o recurrentes, fallo
cardíaco congestivo leve (Clase I/II de la Asociación Cardíaca de Nueva
York), desórdenes del sistema nervioso central, o que vivan o hayan
vivido en áreas endémicas a la histoplasmosis. Se requieren estudios
adicionales sobre la eficacia a largo plazo, la seguridad, y el impacto
económico del infliximab. Además, se debe considerar la
inconveniencia de la administración intravenosa sobre 2 horas en el
manejo de AR cuando otros agentes anti-TNF-α pueden administrarse
mediante inyección subcutánea por el propio paciente.
Mitchell Nazario
RÉSUMÉ
OBJECTIF: Revoir la littérature concernant la pharmacologie, la
pharmacocinétique, l’efficacité, l’innocuité, et l’impact
pharmacoéconomique de l’infliximab lors du traitement de la maladie
de Crohn (MC) et de la polyarthrite rhumatoïde (PAR).
REVUE DE LITTÉRATURE: Une recherche effectuée dans la banque
informatisée MEDLINE et Pre-MEDLINE (1966–juin 2002), ainsi que
de la documentation pertinente à la prescription de ce médicament
fournie par le fabricant, a permis d’identifier des articles de langue
anglaise concernant l’infliximab. Des études additionnelles et des
abrégés ont été identifiés à partir des références bibliographiques de ces
articles et des résumés de congrès ou colloques.
www.theannals.com The Annals of Pharmacotherapy
Infliximab in Rheumatoid Arthritis and Crohn’s Disease
SÉLECTION DES ÉTUDES ET DE L’INFORMATION: Tous les articles identifiés à
partir des sources précitées ont été évalués, et toute l’information jugée
pertinente a été incluse dans cette revue. L’information concernant la
pharmacologie provient d’études chez l’animal. Les données
pharmacocinétiques proviennent elles, d’études chez l’humain. Les
données d’innocuité sont issues d’essais cliniques et d’études de
surveillance après la commercialisation. La priorité a été accordée aux
études randomisées, contrôlées contre placebo, et en double aveugle
pour évaluer l’efficacité de l’infliximab. Toutes les évaluations
économiques ont été incluses.
RÉSUMÉ: L’infliximab est un nouvel anticorps monoclonal chimérique
homme-souris IgG1, obtenu par recombinaison, qui posséde un
mécanisme d’action unique. Cet anticorps se lie de façon spécifique aux
formes soluble et transmembranaire du facteur de nécrose tumorale
alpha (FNTα) et en neutralise l'activité. L’infliximab s’administre par
perfusion intraveineuse. Dans les essais cliniques lors de MC,
l’infliximab a diminué de façon significative l’index d’activité de la
maladie comparativement au placebo lors du traitement d’adultes dont la
maladie est réfractaire à un traitement complet et approprié par un
corticostéroïde ou un immunosuppresseur. L’infliximab a aussi diminué
de façon significative le nombre de fistules avec écoulement lors de MC
avec fistulation. Lors de PAR, lorsque l’infliximab est associé au
méthotrexate, on observe une amélioration significative de la plupart des
mesures de résultats lorsque comparé au méthotrexate plus placebo. Peu
d’effets indésirables majeurs ont été rapportés dans les essais cliniques ;
cependant, des effets majeurs tels des néoplasies et une maladie
démyélinisante ont été observés dans des études de surveillance après la
commercialisation. De plus, une plus grande susceptibilité aux
infections, incluant la tuberculose, peut se produire.
CONCLUSIONS: L’infliximab est un nouvel agent efficace pour le
traitement de la MC et de la PAR. Son mécanisme d’action unique fait
de l’infliximab un ajout important dans l’arsenal thérapeutique. Une
prudence est de mise lorsque l’on considère un traitement par
l’infliximab chez des personnes qui présentent des infections chroniques
ou récurrentes, une insuffisance cardiaque congestive légère (New York
Heart Association, NYHA, classe I/II), des troubles du système nerveux
ou chez ceux qui vivent ou ont vécu dans une région endémique pour
l’histoplasmose. L’infliximab est contre-indiqué chez les patients
présentant une infection active et cliniquement importante, une
insuffisance cardiaque congestive modérée à grave (NYHA, classe
III/IV), ou présentant une allergie aux protéines de souris ou à un des
composés de ce médicament. Des données à long terme d’efficacité,
d’innocuité et des données pharmacocinétiques sont requises. Enfin, lors
du traitement de la PAR, la lourdeur de l’administration de ce
médicament (perfusion supervisée d’une durée de 2 heures) doit être
considérée dans le choix du traitement par un agent anti-TNFα, les 2
autres agents, l’étanercept et l’adalimumab, pouvant être auto-
administrés par la voie sous-cutanée.
Denyse Demers
■ 2003 September, Volume 37 ■ 1265