Download New Drugs for Rheumatoid Arthritis

The
new england journal
of
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review article
drug therapy
Alastair J.J. Wood, M.D., Editor
New Drugs for Rheumatoid Arthritis
Nancy J. Olsen, M.D., and C. Michael Stein, M.B., Ch.B.
r
heumatoid arthritis affects approximately 1 percent of the
U.S. population and can cause irreversible joint deformities and functional impairment. The cause of this autoimmune disease remains obscure, but greater
understanding of the underlying mechanisms has facilitated the development of new
drugs and revolutionized treatment.1
Specific CD4+ T cells are involved in the induction of the immune response in rheumatoid arthritis, most likely as a response to an unknown exogenous or endogenous
antigen. Consequently, recruited monocytes, macrophages, and fibroblasts produce
cytokines such as tumor necrosis factor a (TNF-a) and interleukin-1 within the synovial
cavity. These cytokines are central to a damaging cascade, ultimately triggering the production of matrix metalloproteinases and osteoclasts, which results in irreversible damage to soft tissues and bones. The occurrence of B-lymphocyte dysregulation is suggested by the association of erosive disease with the presence of rheumatoid factor, which
mediates further damage through complement fixation (Fig. 1).2 Several new drugs have
become available for the treatment of rheumatoid arthritis (Table 1), and in this article,
we review their properties.
From the Divisions of Rheumatology
(N.J.O., C.M.S.) and Clinical Pharmacology
(C.M.S.), Departments of Medicine (N.J.O.,
C.M.S.), Pharmacology (C.M.S.), and Microbiology and Immunology (N.J.O.),
Vanderbilt University School of Medicine,
Nashville.
N Engl J Med 2004;350:2167-79.
Copyright © 2004 Massachusetts Medical Society.
measuring response to drugs in rheumatoid arthritis
Both the short-term efficacy and the toxic effects of new drugs for rheumatoid arthritis
are usually evaluated in clinical trials of 6 to 12 months’ duration. Improvement is most
often defined by an outcome measure of the American College of Rheumatology (ACR)
called the ACR 20.3 The ACR 20 is defined as a reduction by 20 percent or more in the
number of tender and swollen joints plus similar improvement in at least three of the
following five measures: pain, global assessments by the patient and the physician,
self-assessed physical disability, and levels of acute-phase reactant. Two other outcome
measures that are deemed to be more clinically relevant, the ACR 50 (improvement of
50 percent or more) and the ACR 70 (improvement of 70 percent or more), are also often
reported.4,5 All the drugs we discuss below appear to be more effective than placebo
and to slow the progression of disease as measured radiologically.6-9 These medications
are thus classified as disease-modifying antirheumatic drugs.
leflunomide
The immunomodulatory drug leflunomide, an isoxazole derivative, is a competitive inhibitor of dihydroorotate dehydrogenase, the rate-limiting intracellular enzyme required for the de novo synthesis of pyrimidines.10 Resting lymphocytes can derive pyrimidines from salvage pathways, but activated lymphocytes are dependent on the de novo
synthesis of pyrimidines. Therefore, blockade of the pyrimidine-synthesis pathway has
antiproliferative effects. In vitro, relatively high concentrations of leflunomide (5¡10 M)
n engl j med 350;21
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Figure 1. Inflammation in the Rheumatoid Joint.
The identity of the inciting antigen is not known, but it most likely drives lymphocyte proliferation, which contributes
to the production of the rheumatoid-factor autoantibody. The fixation of complement amplifies the destructive cascade,
attracting additional inflammatory cells and resulting in the production of cytokines and enzymes. These, in turn, mediate tissue damage, including cartilage loss and bone erosion. Likely sites of action of the major drugs described in this
article are shown. C denotes serum complement protein, and C* activated serum complement protein.
modulate nuclear factor-kB,11 tyrosine kinases in
the signaling pathway made up of Janus kinases
and signal transducers and activators of transcription (the JAK–STAT pathway) and growth-factor
receptors,12,13 interleukin-6, matrix metalloproteinases, and prostaglandin E2.14 Because of the
theoretically additive effects of leflunomide and
methotrexate in inhibiting pyrimidine synthesis and
purine synthesis, respectively, these drugs have been
proposed as potentially complementary therapies.10
clinical pharmacology
drug in the circulation. This metabolite is highly
protein-bound and has a long half-life of 15 to 18
days.15,16 Therefore, without a loading dose, it may
take as long as two months to achieve steady-state
concentrations. In addition, the active metabolite
undergoes extensive enterohepatic recirculation,
and it may take up to two years for the amount of
drug in plasma to decrease to an undetectable level.
Renal excretion appears to be limited, and the dose
generally does not have to be reduced because of decreased renal function, although caution is advised
because information is limited.17
Leflunomide is a prodrug that, after oral administration, undergoes rapid chemical conversion to its interactions with other drugs
primary active metabolite, A77 1726, which ac- Leflunomide inhibits cytochrome P-450 2C9
counts for more than 95 percent of the levels of the (CYP2C9) in vitro and, according to a case report,
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drug therapy
Table 1. New Drugs for the Treatment of Rheumatoid Arthritis.
Drug
Route of
Administration
Primary Action
Usual Dose
Half-Life
Leflunomide
Inhibits pyrimidine
synthesis
Oral
Loading dose of 100 mg daily for 3 days, then
20 mg daily
2 Wk
Etanercept
Binds TNF-a and TNF-b
Subcutaneous
injection
25 mg twice/wk or 50 mg once/wk
4 Days
Adalimumab
Human anti–TNF-a
antibody
Subcutaneous
injection
40 mg every second wk
2 Wk
Infliximab
Chimeric anti–TNF-a
antibody
Intravenous
infusion
3 mg/kg of body weight at 0, 2, and 6 wk, then
every 8 wk
For incomplete response, maintenance dose
may be gradually increased to a maximum
of 10 mg/kg
9 Days
Anakinra
Interleukin-1–receptor
antagonist
Subcutaneous
injection
100 mg daily
6 Hr
may increase the anticoagulant activity of warfarin,
a substrate of this enzyme.18 However, there have
been no specific studies assessing the potential for
interactions between leflunomide and warfarin or
other CYP2C9-substrate drugs. Rifampin raises the
concentration of the active metabolite of leflunomide by 40 percent, and the dose may have to be adjusted. Leflunomide reduces serum uric acid concentrations in treated patients19 by increasing renal
urate excretion, perhaps through effects on the
proximal renal tubule.20
efficacy in rheumatoid arthritis
Large placebo-controlled studies comparing leflunomide with sulfasalazine19 or methotrexate21,22
suggest that the drugs have similar efficacy (Table
2). As compared with placebo, leflunomide slowed
progression, as measured radiographically, over a
period of 6 to 12 months.19,21 After two years, more
than 80 percent of the patients who received methotrexate or leflunomide in a blinded, randomized,
controlled trial (the Utilization of Leflunomide in
the Treatment of Rheumatoid Arthritis [ULTRA] trial) had no new erosions.21
adverse effects
The most important serious reactions to leflunomide are hepatic. In clinical trials, approximately
5 percent of patients had elevated transaminase levels23 that were generally less than twice the upper
limit of normal and were reversible after the discontinuation of treatment with the drug. In May 2001,
the manufacturer issued a letter to clinicians detailing reports of hepatotoxicity in the postmarketing
n engl j med 350;21
period. During 104,000 patient-years of exposure,
liver-function abnormalities were identified in 296
patients. Fifteen of these patients died from either
liver failure or concomitant illness; hepatic dysfunction was considered to be possibly related to leflunomide treatment in 10 of these 15 patients.24 More
recently, the Arthritis Advisory Committee of the
Food and Drug Administration (FDA) reviewed the
clinical trials and postmarketing studies.25,26 Elevated transaminase concentrations affected 2 percent to 4 percent of patients, although the incidence
of hepatocellular necrosis was far lower, at approximately 0.02 percent to 0.04 percent. The risk of
severe liver injury was deemed to be small and, given the benefits of treatment, acceptable. On the basis of the surveillance data, patients with preexisting liver abnormalities or a history of heavy alcohol
intake or hepatitis virus infections should not be
treated with leflunomide.
Combination therapy with leflunomide and
methotrexate may be associated with a higher risk
of hepatotoxic effects than treatment with leflunomide alone. In one trial including 30 patients, 3 patients (10 percent) were withdrawn because of elevated levels of liver enzymes.27 In a larger study, 41
of 130 patients who received leflunomide with
methotrexate (31.5 percent) had an elevation of the
alanine aminotransferase level to more than 1.2
times the upper limit of normal, but only 2.3 percent
were withdrawn from the study because of abnormal results on liver-function tests.28 However, severe hepatotoxic effects have been reported with this
combination in a case report.29
Weight loss was reported in the earliest trials of
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Table 2. Rates of Response to Leflunomide as Compared with Other Disease-Modifying Agents and Placebo.*
Level of
Response
12 mo
Placebo
Leflunomide
(20 mg/day)
6 mo
Methotrexate
(7.5–15 mg/wk)
Placebo
Leflunomide
(20 mg/day)
Sulfasalazine
(2 g/day)
percentage of patients
ACR 20
26
52
46
29
55
56
ACR 50
8
34
23
14
33
30
ACR 70
4
20
9
NS
NS
NS
* The American College of Rheumatology (ACR) response is defined as an improvement of at least 20 percent (ACR 20),
an improvement of at least 50 percent (ACR 50), and an improvement of at least 70 percent (ACR 70) in the number of
tender and swollen joints plus similar improvement in at least three of five measures specified by the ACR (see text for
details). Data for 6 months are from Smolen et al.,19 and data for 12 months are from Strand et al.22 The rates of response to all drugs were significantly higher than those in the corresponding placebo group. NS denotes not stated.
leflunomide, and loss of 20 percent of body weight
has been observed in clinical practice, although the
mechanisms are unknown.30 However, weight loss
seldom necessitates the discontinuation of therapy.
Although diarrhea was reported in 32 percent of the
patients who were treated with leflunomide in the
ULTRA trial,21 weight loss can occur in the absence
of gastrointestinal symptoms.
Hypertension of unclear cause was reported in
18 percent of the patients in the same trial and was
a new finding in 5 percent.21 Elevations in blood
pressure can occur within the first two months of
treatment; therefore, regular monitoring of blood
pressure is advisable.31 Reversible alopecia occurred
in approximately 10.5 percent of patients in the
ULTRA trial,21 and pancytopenia,32,33 peripheral
neuropathy,24 and interstitial pneumonitis34 have
also been reported with this agent.
pregnancy and fertility
Preclinical studies indicated that leflunomide causes
fetal death or is teratogenic35; thus, women of childbearing potential must have a negative pregnancy
test before beginning treatment and must use reliable contraception. Because of the drug’s long halflife, discontinuing treatment before conception is
inadequate. The manufacturer suggests an elimination protocol of oral cholestyramine, 8 g three times
daily for 11 days, and verification that the plasma
level of the drug is below 0.02 mg per liter on two
separate tests performed at least 2 weeks apart. This
protocol should also be followed by men who wish
to father a child.35 There are no reported effects of
decreased fertility in patients who have taken
leflunomide.
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clinical use in rheumatoid arthritis
Methotrexate remains the most commonly used disease-modifying antirheumatic drug,36 but leflunomide is a useful alternative in the face of intolerance
to methotrexate. As mentioned above, given its potential for hepatotoxic effects, leflunomide is contraindicated in patients with any type of liver impairment, and regular monitoring is required (Table 3).
A loading dose of 100 mg daily for three days can be
used to achieve therapeutic concentrations quickly
but may cause gastrointestinal intolerance. In clinical practice, the loading dose is often omitted or reduced. The usual daily dose (20 mg) is tolerated well
by most patients. If minor adverse effects such as diarrhea or abdominal cramps occur, a dose of 10 mg
can be effective and may be better tolerated.37
The combination of leflunomide and methotrexate appears to be more effective than methotrexate and placebo, resulting in ACR 20 response
rates of 46.2 and 19.5 percent, respectively.28 The
primary drawback of this combination is its potential for hepatotoxic effects28,29; thus, patients who
are treated with both agents should be monitored
closely.
tumor necrosis factor
antagonists
TNF-a, an inflammatory cytokine that is released by
activated monocytes, macrophages, and T lymphocytes, promotes inflammatory responses that are
important in the pathogenesis of rheumatoid arthritis.1,38,39 TNF-a binds to two receptors, the type
1 TNF receptor (p55) and the type 2 TNF receptor
(p75), that are expressed on many types of cells.40,41
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drug therapy
The biologic activity of TNF-a can be attenuated by
soluble TNF receptors.42
Patients with rheumatoid arthritis have high
concentrations of TNF-a in the synovial fluid.43,44
TNF-a is localized to the junction of the inflammatory pannus and healthy cartilage,44 and high synovial fluid TNF-a concentrations are associated
with the erosion of bone.45 Studies in animals have
provided key evidence that antagonizing TNF-a is
a viable therapeutic strategy. Inflammatory arthritis
developed in transgenic mice that expressed human
TNF-a,46 and in another animal model, treatment
with anti-TNF antibodies ameliorated arthritis.47
Subsequent proof-of-concept studies in patients
with rheumatoid arthritis indicated that blocking
TNF improved symptoms.48,49 Currently, three
TNF-blocking drugs — etanercept, infliximab, and
adalimumab — are available for clinical use. Their
usual doses and pharmacokinetic characteristics are
listed in Table 1.
etanercept
Etanercept, a soluble TNF-receptor fusion protein,
is composed of two dimers, each with an extracellular, ligand-binding portion of the higher-affinity
type 2 TNF receptor (p75) linked to the Fc portion
of human IgG1. This fusion protein binds to both
TNF-a and TNF-b, thereby preventing each from
interacting with its respective receptors.
Clinical Pharmacology
After subcutaneous administration, etanercept is
absorbed slowly, with concentrations peaking at approximately 50 hours. Its half-life is generally four
days (Table 1).50,51 In healthy volunteers, systemic
exposure to the drug, measured as the area under
the concentration–time curve, varied by a factor of
eight.50 A regimen of 50 mg once weekly appears to
be as effective as a regimen of 25 mg twice weekly.52
Table 3. Monitoring Recommendations.*
Drug
Monitoring Recommendation
Leflunomide
Obtain a complete blood count and alanine aminotransferase measurements at baseline and then monthly until
stable. Usual clinical practice is to repeat these tests
at intervals of 2 to 3 mo.
Etanercept
Be clinically alert for tuberculosis, histoplasmosis, and other
infections.
Adalimumab
Same as for etanercept.
Infliximab
Same as for etanercept.
Anakinra
Obtain a complete blood count at baseline, monthly for
3 mo, and every 3 mo thereafter.
* Patients who are to receive etanercept, adalimumab, or infliximab should be
screened for previous exposure to tuberculosis before treatment is started.
Patients who are also receiving another disease-modifying antirheumatic
drug such as methotrexate require additional monitoring as appropriate
for that drug.
Methotrexate has been considered the standard
against which newer disease-modifying antirheumatic drugs should be evaluated.59 For example, a
double-blind, randomized study in 632 patients
with early rheumatoid arthritis compared 10 or 25
mg of etanercept twice weekly with methotrexate
in a dose escalated over the course of eight weeks to
a final weekly dose of 20 mg.9 Patients who received
the higher dose of etanercept had a more rapid response within the first 2 weeks, but after 12 months,
the ACR 20 response rates were similar — 72 percent in the 25-mg etanercept group and 65 percent
in the methotrexate group (P=0.16).9 The average
increases in radiologic score with 25 mg of etanercept and methotrexate — 1.00 and 1.59 units, respectively — were not significantly different (P=
0.11).9 Another study indicated that patients with
an inadequate response to methotrexate receive
benefit when etanercept is added to their regimen
rather than placebo (Table 4).55
Efficacy in Rheumatoid Arthritis
After dose-finding studies,53 a 10-mg dose of
etanercept, a 25-mg dose of etanercept, and placebo were compared in 234 patients in a six-month
randomized study.54 Both doses of etanercept appeared to be effective, resulting in ACR 20 response
rates of 51 percent and 59 percent, respectively, as
compared with 11 percent in the placebo group. The
25-mg dose resulted in a more rapid response and
more frequent ACR 50 responses (40 percent) than
the 10-mg dose (24 percent) or placebo (5 percent)
(Table 4).54
n engl j med 350;21
infliximab
Infliximab, first approved for the treatment of
Crohn’s disease, is a chimeric IgG1 anti–TNF-a
antibody containing the antigen-binding region of
the mouse antibody and the constant region of the
human antibody. It binds to soluble and membrane-bound TNF-a with high affinity, impairing
the binding of TNF-a to its receptor. Infliximab
also kills cells that express TNF-a through antibody-dependent and complement-dependent cytotoxicity.60,61
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Table 4. Rates of Response to TNF Antagonists Alone and in Combination with Methotrexate.*
Study
Treatment
No. of Patients
ACR 20
ACR 50
ACR 70
percentage of patients
Moreland et al.54
Placebo
Etanercept
80
78
11
59
5
40
1
15
Weinblatt et al.55
Placebo plus methotrexate
Etanercept plus methotrexate
30
59
27
71
3
39
0
15
Maini et al.56
Placebo plus methotrexate
Infliximab plus methotrexate
84
83
20
50
5
27
0
8
Abbott Laboratories57
Placebo
Adalimumab
110
113
19
46
8
22
2
12
Weinblatt et al.58
Placebo plus methotrexate
Adalimumab plus methotrexate
62
67
15
67
8
55
5
27
* Infliximab is approved only for use in combination with methotrexate. The data presented are for the doses that are used
in clinical practice (infliximab, 3 mg per kilogram of body weight every 8 weeks; etanercept, 25 mg by subcutaneous injection twice a week; and adalimumab, 40 mg by subcutaneous injection every other week), as studied in double-blind,
controlled studies lasting 24 to 30 weeks. The studies demonstrating efficacy for the various drugs had different designs;
thus, the response rates cannot be compared directly. Response rates for all drugs at all levels of ACR response were significantly higher than those in the corresponding placebo group.
Clinical Pharmacology
There are marked differences among patients in the
pharmacokinetics of infliximab. In one study involving 428 subjects, trough concentrations eight
weeks after the intravenous administration of 3 mg
of infliximab per kilogram of body weight varied
by a factor of more than 100.62 Pharmacokinetic
modeling indicated that shortening the interval between doses to six weeks would increase the trough
levels more effectively than increasing the dose by
100 mg.62
Efficacy in Rheumatoid Arthritis
A single infusion of infliximab (1 or 10 mg per kilogram) was reported to improve symptoms of rheumatoid arthritis rapidly, providing early evidence of
the effectiveness of TNF antagonism.63 Subsequent
studies demonstrated that monotherapy with infliximab (at a dose of 3 or 10 mg per kilogram) was superior to placebo,64 but the frequent development
of anti-infliximab antibodies led to its use in combination with methotrexate rather than as monotherapy. Efficacy and the dose–response relation
were defined in a study involving 428 patients who
had active rheumatoid arthritis despite methotrexate therapy.8,56 Four regimens — infliximab at a
dose of 3 or 10 mg per kilogram every four or eight
weeks combined with methotrexate — were all similarly and significantly more effective than methotrexate plus placebo. After 54 weeks, the ACR 20 response rate ranged from 42 percent (with 3 mg per
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kilogram every 8 weeks) to 59 percent (with 10 mg
per kilogram every 4 weeks).8 All regimens of infliximab plus methotrexate were more effective than
methotrexate plus placebo in preventing progression as measured radiologically.8 The ACR 50 response rates in all the infliximab groups were similar after 24 weeks,56 but after 54 weeks, the response
rate in the group receiving 3 mg per kilogram every
8 weeks (21 percent) was significantly lower than
those in the two groups receiving 10 mg per kilogram (39 percent among those given a dose every
8 weeks and 38 percent among those given a dose
every 4 weeks).8 As a result of these studies, a standard regimen has evolved (Table 1). Patients who do
not have an adequate response or who have an initial response followed by a relapse may have a better
response either if the interval between infusions is
decreased to every four to six weeks or if the dose is
increased.62
adalimumab
Adalimumab is a recombinant human IgG1 monoclonal antibody that binds to human TNF-a with
high affinity, both impairing cytokine binding to its
receptors and lysing cells that express TNF-a on
their surface.
Clinical Pharmacology
After subcutaneous administration, adalimumab is
absorbed slowly, with peak concentrations reached
after approximately 130 hours. There is substantial
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drug therapy
interpatient variability in disposition,65 but clearance is similar in men and women and appears to be
unaffected by age or body weight.66 The addition of
methotrexate to the regimen reduced adalimumab
clearance by 20 percent after a single dose and by
44 percent after multiple doses.57
Efficacy in Rheumatoid Arthritis
In a randomized, double-blind study, the ACR 20 response rate for 40 mg of adalimumab administered
weekly was similar to the rate for the same dose administered every other week (53 percent and 46
percent, respectively), and both were significantly
higher than the rate with placebo (19 percent) (Table 4).67,68 Adalimumab appears to have additive
effects when used with methotrexate. For example,
an ACR 20 response was achieved in a significantly
greater proportion of patients who received methotrexate plus 20, 40, or 80 mg of adalimumab every
two weeks than of those who received methotrexate
plus placebo (48 percent, 67 percent, 66 percent,
and 15 percent, respectively).58
adverse effects
of tnf antagonists
Initial studies reported substantial efficacy with almost no serious adverse effects,9,53,56,58,69 and
postmarketing data were also reassuring.70 However, wider use of TNF antagonists has resulted in
reports — largely case reports or small series of patients — that link TNF-antagonist use with a wide
range of adverse events, including infections, cancer, vasculitis, lupus-like autoimmune disease, multiple sclerosis–like demyelinating disorders, liver
disease, hematologic abnormalities including aplastic anemia and lymphoma, severe allergy, and aseptic meningitis.71-79 The relationships between antiTNF therapy and many of these adverse events are
unknown. Much safety information regarding TNF
antagonists is unpublished but may be found in the
transcript of a meeting of the FDA Arthritis Advisory Committee.79
infection
Serious bacterial infections, tuberculosis, atypical mycobacterial infection, aspergillosis, histoplasmosis, coccidioidomycosis, listeriosis, Pneumocystis carinii pneumonia, cryptococcal infections,
cytomegalovirus, and other infections have occurred,71,72,75,79-82 and such infections may be
more common among patients 65 years of age or
n engl j med 350;21
older than among younger patients.83 The background risk of serious infection is approximately
twice as high among patients with rheumatoid arthritis as among those without this condition84;
therefore, it is difficult to interpret sporadic reports
of infection in patients receiving anti-TNF therapy. However, the risk of opportunistic infections,
including histoplasmosis and tuberculosis, is increased. Such observations are congruent with animal studies showing that TNF is important for granuloma formation85 and preventing the reactivation
of latent tuberculosis.86
Tuberculosis has been reported in association
with all TNF antagonists. Data from the FDA Adverse Event Reporting System, a passive surveillance system that has no reliable denominator and
may underestimate true incidence, indicated that
although a similar number of patients had been exposed, 70 cases of tuberculosis had been reported
after treatment with infliximab and 9 after etanercept treatment.87 The rate of tuberculosis among
patients with rheumatoid arthritis who had been
treated with infliximab was 24.4 cases per 100,000,
as compared with the background rate of 6.2 cases
per 100,000 patients with this illness.87 In early
studies of adalimumab therapy, tuberculosis developed in 8 of 542 patients.79 The introduction of
screening procedures and the use of lower doses of
adalimumab reduced the frequency to 5 of the next
1900 patients.79
Tuberculosis in patients who are receiving antiTNF therapy most often arises from the reactivation of latent infection and usually occurs within
the first two to five months of treatment.87 Extrapulmonary and disseminated disease is common,
and atypical clinical presentations may lead to delayed diagnosis and increased morbidity.87
malignant disease
Lymphoma has been reported in association with
all three TNF antagonists,77 but whether or not
there is a causal relationship is debated. The reason
for the uncertainty is that the incidence of lymphoma is increased among patients with rheumatoid
arthritis and increases with the severity of the condition.88,89 Therefore, the increased incidence of
lymphoma among patients who receive TNF antagonists, which is estimated to be 2.3 to 6.4 times
that in the general population, could be ascribed to
either severe rheumatoid arthritis or its treatment.79
The transcripts of the FDA meeting in which all the
studies were examined together indicate that lym-
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phoma developed in six patients who were receiving TNF antagonists during the controlled portion
of clinical trials, as compared with none of the control patients,79 indicating that a causal relationship
is plausible. The type of lymphoma reported is similar to that occurring in the general population of patients with rheumatoid arthritis.77 Apart from lymphoma, the incidence of cancer is not significantly
altered.79
injection-site and infusion reactions
of
medicine
with adalimumab plus methotrexate (in 4 percent).58 However, drug-induced systemic lupus
erythematosus is rare78,92,93: the FDA Adverse Event
Reporting System identified 16 cases after the use
of etanercept.94
demyelinating syndromes
Exacerbation of previously quiescent multiple sclerosis and new-onset demyelinating neurologic disease have been reported.76 The number of patients
affected is not known, but in the FDA Adverse Event
Reporting System, 18 cases were reported after
etanercept therapy and 2 after infliximab therapy.
The range of symptoms was broad and included
paresthesia (in 65 percent of patients), optic neuritis (in 40 percent), and confusion (in 25 percent).76
Although a causal relationship has not been established, the fact that another TNF antagonist, lenercept, worsened symptoms in patients with multiple
sclerosis95 renders the association plausible.
Minor redness and itching at the injection site, lasting a few days, are common among patients who receive etanercept and adalimumab.54,68 Symptoms,
most often headache and nausea, occur in 20 percent of patients during the infusion of infliximab
and appear to be controllable with the use of antihistamines or by slowing the infusion rate.62 Symptoms suggestive of an immediate hypersensitivity
response, such as urticaria, occur in 2 percent of patients.56 Serious anaphylaxis is uncommon and occurred in 2 of 500 patients with Crohn’s disease who heart failure
were treated with infliximab.90
TNF-a levels are elevated in patients with heart failure and associated with decreased cardiac contracimmune and autoimmune responses
tility.96 Initial reports on anti-TNF therapy for heart
Antibodies to etanercept developed in 3 percent of failure were encouraging.97,98 However, subsequent
patients,9 but their clinical significance is unknown. studies of etanercept and infliximab in heart failure
In other reports, human antichimeric antibodies to were stopped early because of lack of evidence of
infliximab developed in 53, 21, and 7 percent of pa- benefit and, in the case of infliximab, increased
tients who were receiving 1, 3, and 10 mg of inflix- mortality.79,99
imab per kilogram, respectively.64 The frequency
of antichimeric antibodies was lower (8.5 percent)
c linical use of tnf antagonists
among patients who were treated with infliximab
in rheumatoid arthritis
at a dose of 3 or 10 mg per kilogram plus concomitant methotrexate.62 These antibodies accelerated TNF antagonists appear to be among the most efthe clearance of infliximab62 and were associated fective treatments available for rheumatoid arthritis.
with increased infusion reactions and shorter re- The response is generally rapid, often occurring
sponses in patients with Crohn’s disease.91 Anti- within a few weeks, although not all patients have
bodies to adalimumab developed in 12 percent of a response. There is little information regarding
patients; the rate was reduced to 1 percent with con- head-to-head comparisons between various TNF
current methotrexate treatment.92 The ACR 20 re- antagonists or between TNF antagonists and other
sponse rate was lower in patients treated with adal- disease-modifying antirheumatic drugs. There is
imumab in whom antibodies developed.92
also a need for data that will show whether particuAntinuclear antibodies were detected in approx- lar adverse effects are class effects. Until convincimately 60 percent of patients who were receiving ing data to the contrary are available, similar preinfliximab and methotrexate, as compared with 26 cautions are appropriate with regard to all TNF
percent of those who were treated with methotrex- antagonists.
ate alone.8 Antibodies to double-stranded DNA
Anti-TNF therapy should not be started in padeveloped after etanercept treatment (in 4 percent tients with active infection and should be disconof patients),54 after treatment with infliximab plus tinued if a serious infection occurs. Chronic or remethotrexate (in 10 percent),8 and after treatment current infection is a relative contraindication. All
2174
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drug therapy
patients should be screened for latent tuberculosis
before anti-TNF therapy is begun, and should be
treated before starting such therapy if they test positive.100 Physicians should be alert to the increased
risk of tuberculosis and other opportunistic infections.
TNF antagonists should also be avoided in patients with any demyelinating disorder or heart failure, and therapy should be discontinued if such an
illness develops. Rare cases of pancytopenia, aplastic anemia, and liver failure have been reported,79
but no specific monitoring is recommended.
pairment.106 Hemodialysis and peritoneal dialysis do not appear to remove substantial amounts of
anakinra.106
efficacy in rheumatoid arthritis
Anakinra, alone or in combination with methotrexate, has been more effective than placebo in
randomized, controlled trials involving approximately 900 patients with rheumatoid arthritis (Table 5).108,109 A long-term extension study documented that responses seen in the first 24-week
phase of the study were durable; after 48 weeks, 18
percent of patients treated with anakinra had an
ACR 50 response, and 3 percent had an ACR 70 reanakinra
sponse.110 Treatment with anakinra also signifiInterleukin-1, produced by monocytes, macrophag- cantly slows the rate of damage, as measured on raes, and some specialized cells in the synovial lining, diography.7
has inflammatory effects that include the induction
of interleukin-6 and cyclooxygenase-2.101 The ac- adverse effects
tions of interleukin-1 are down-regulated by inter- The most common adverse event is dose-dependent
leukin-1–receptor antagonist, a natural inhibitor skin irritation at the injection site, occurring in 50
that competes for binding to interleukin-1 recep- to 80 percent of patients in trials. Most reactions
tors. In mice that are deficient in interleukin-1– appeared to be mild, and resolved within a few
receptor antagonist, a chronic inflammatory ar- weeks.105 A small number of patients reported
thritis develops, with features similar to those of more severe allergic-type reactions involving itchrheumatoid arthritis.102
ing, swelling, and pain.107
Anakinra is a recombinant form of human interThe risk of infection, primarily bacterial, appears
leukin-1–receptor antagonist that targets the type I to be increased. Serious infections occurred in 2.1
interleukin-1 receptor that is expressed in many tis- percent of patients receiving anakinra, as compared
sues. In patients with rheumatoid arthritis, levels with 0.4 percent of those receiving placebo, in one
of this receptor antagonist in the inflamed joint are study involving 1000 patients (P=0.07); no opporlower than would be required for the inhibition of tunistic infections were observed.111
the amount of interleukin-1 present, and this imbalance is thought to contribute to the persistence clinical use in rheumatoid arthritis
of joint inflammation.103,104
Anakinra may be useful in patients who have no response to or are unable to tolerate methotrexate,
clinical pharmacology
leflunomide, or TNF antagonists. Anakinra therapy
Anakinra is identical to the nonglycosylated form
of the endogenous protein except for the addition
of one N-terminal methionine.105 Because it has a
Table 5. Rates of Response to 24 Weeks of Anakinra Therapy.*
short half-life (Table 1),106 daily administration is
Level of
more effective than injections given weekly or three
Response
Monotherapy
Combination Therapy with Methotrexate
times a week.107 Renal clearance eliminates 80 perAnakinra,
Anakinra,
Anakinra,
cent of infused anakinra in rats,104 and humans with
Placebo
150 mg
Placebo 1 mg/kg/day 2 mg/kg/day
renal failure have markedly decreased clearance;
percentage of patients
clearance decreases by half in moderate renal disACR 20
27
43
23
42
35
ease, by two thirds in severe renal disease, and by 75
ACR
50
8
23
4
24
17
percent in end-stage renal disease.106 In such paACR 70
4
9
0
10
7
tients, adjustment of the dose or frequency of injection may be indicated; computer simulation has
* Data on monotherapy are from Bresnihan et al.,108 and data on combination
suggested that a dose of 100 mg every second day therapy are from Cohen et al.109
may be appropriate in patients with severe renal im-
n engl j med 350;21
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may 20, 2004
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2175
The
new england journal
should not be started in patients with active infection and should be discontinued if a serious infection occurs. Caution should be exercised when considering the use of anakinra in patients with chronic
or recurrent infection. Because reversible neutropenia and thrombocytopenia have occurred in a small
number of patients, monitoring the complete blood
count is recommended (Table 3).
The combination of anakinra and methotrexate
appears to be well tolerated.109 However, both drugs
can lower the white-cell count; thus, regular laboratory monitoring is required. Concomitant use of
anakinra and a TNF antagonist may increase the
risk of infections and should be avoided.112
limitations
and future directions
The drugs discussed above appear to be relatively
safe and effective in the short-to-intermediate–term
treatment of rheumatoid arthritis. In addition, the
role of these agents in the treatment of illnesses other than rheumatoid arthritis is evolving. Infliximab
is an effective treatment for Crohn’s disease,91 and
TNF antagonists are finding a place in the treatment
of many conditions, including psoriasis,113 ankylosing spondylitis,114 juvenile arthritis,113 Still’s
of
medicine
disease,115 uveitis,116 and vasculitis.117 However,
much remains unknown. Hard data regarding the
comparative long-term efficacy and toxicity of these
agents, as well as the variable rates of response, will
be important for rational clinical use.
Treatments for rheumatoid arthritis continue to
advance rapidly, and many new drugs are under investigation; some have shown promise in clinical
trials that have been published. These include tacrolimus,118 rituximab,119 an interleukin-6 antagonist,120 and a fusion protein — cytotoxic T-lymphocyte–associated antigen 4-IgG1 (CTLA-4–Ig) —
that blocks T-cell costimulatory pathways.121 Other drugs that are now at earlier stages of development include pegylated, soluble TNF receptor antagonists and agents that trap cytokines, block
interleukin-15, prevent the cleavage of human complement component C5, or inhibit adhesion molecules.122 The introduction of additional effective
therapies for rheumatoid arthritis will improve the
outlook for patients, since even with the range of
therapies currently available, some patients still
have poorly or incompletely controlled disease.
Supported by a grant (HS1-0384) from the Center for Education
and Research on Therapeutics and grants (HL 65082 and HL 67964)
from the U.S. Public Health Service.
Dr. Olsen reports having received an honorarium from Aventis
and research support from Bristol-Myers Squibb in the past two
years.
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