Artritis Reumatoidea

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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.
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 (510 M)
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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 JAKSTAT 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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Table 1. New Drugs for the Treatment of Rheumatoid Arthritis. Drug Leflunomide Etanercept Adalimumab Infliximab Primary Action Inhibits pyrimidine synthesis Binds TNF-a and TNF-b Human antiTNF-a antibody Chimeric antiTNF-a antibody Route of Administration Oral Subcutaneous injection Subcutaneous injection Intravenous infusion Usual Dose Loading dose of 100 mg daily for 3 days, then 20 mg daily 25 mg twice/wk or 50 mg once/wk 40 mg every second wk 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 100 mg daily Half-Life 2 Wk 4 Days 2 Wk 9 Days
Anakinra
Interleukin-1receptor antagonist
Subcutaneous injection
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
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 Placebo 12 mo Leflunomide (20 mg/day) Methotrexate (7.515 mg/wk) Placebo 6 mo Leflunomide (20 mg/day) Sulfasalazine (2 g/day)
percentage of patients ACR 20 ACR 50 ACR 70 26 8 4 52 34 20 46 23 9 29 14 NS 55 33 NS 56 30 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
clinical use in rheumatoid arthritis
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 drugs 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.
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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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
Table 3. Monitoring Recommendations.* Drug Leflunomide Monitoring Recommendation 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. Be clinically alert for tuberculosis, histoplasmosis, and other infections. Same as for etanercept. Same as for etanercept. Obtain a complete blood count at baseline, monthly for 3 mo, and every 3 mo thereafter.
Etanercept Adalimumab Infliximab Anakinra
* 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.
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 concentrationtime 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
Efficacy in Rheumatoid Arthritis
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
infliximab
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
Infliximab, first approved for the treatment of Crohns disease, is a chimeric IgG1 antiTNF-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 Weinblatt et al.55 Maini et al.56 Abbott Laboratories57 Weinblatt et al.58 Placebo Etanercept Placebo plus methotrexate Etanercept plus methotrexate Placebo plus methotrexate Infliximab plus methotrexate Placebo Adalimumab Placebo plus methotrexate Adalimumab plus methotrexate 80 78 30 59 84 83 110 113 62 67 11 59 27 71 20 50 19 46 15 67 5 40 3 39 5 27 8 22 8 55 1 15 0 15 0 8 2 12 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.
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
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 doseresponse 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
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.
After subcutaneous administration, adalimumab is absorbed slowly, with peak concentrations reached after approximately 130 hours. There is substantial
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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
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 sclerosislike 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
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
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
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
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
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 Crohns 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 Crohns 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
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.
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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-1receptor 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-1receptor 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-
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
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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-intermediateterm 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 Crohns disease,91 and TNF antagonists are finding a place in the treatment of many conditions, including psoriasis,113 ankylosing spondylitis,114 juvenile arthritis,113 Stills
refer enc es
1. Choy EH, Panayi GS. Cytokine pathways
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-lymphocyteassociated antigen 4-IgG1 (CTLA-4Ig) 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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percentage of patients ACR 20 ACR 50 ACR 70 26 8 4 52 34 20 46 23 9 29 14 NS 55 33 NS 56 30 NS

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