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The

new england journal of

medicine

2167

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.

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 Mi-crobiology and Immunology (N.J.O.),Vanderbilt University School of Medicine,Nashville.

N Engl J Med 2004;350:2167-79.

Copyright 2004 Massachusetts Medical Society.

heumatoid arthritis affects approximately 1 percent of the

U.S. population and can cause irreversible joint deformities and functional im-

pairment. The cause of this autoimmune disease remains obscure, but greaterunderstanding 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 rheu-

matoid arthritis, most likely as a response to an unknown exogenous or endogenous

antigen. Consequently, recruited monocytes, macrophages, and fibroblasts producecytokines such as tumor necrosis factora

(TNF-

a

) and interleukin-1 within the synovial

cavity. These cytokines are central to a damaging cascade, ultimately triggering the pro-duction of matrix metalloproteinases and osteoclasts, which results in irreversible dam-

age to soft tissues and bones. The occurrence of B-lymphocyte dysregulation is suggest-ed 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 havebecome available for the treatment of rheumatoid arthritis (Table 1), and in this article,

we review their properties.

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 mostoften 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 thenumber of tender and swollen joints plus similar improvement in at least three of thefollowing five measures: pain, global assessments by the patient and the physician,

self-assessed physical disability, and levels of acute-phase reactant. Two other outcomemeasures 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 oftenreported.

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 medicationsare thus classified as disease-modifying antirheumatic drugs.

The immunomodulatory drug leflunomide, an isoxazole derivative, is a competitive in-hibitor of dihydroorotate dehydrogenase, the rate-limiting intracellular enzyme re-

quired for the de novo synthesis of pyrimidines.

10

Resting lymphocytes can derive pyri-midines from salvage pathways, but activated lymphocytes are dependent on the de novosynthesis of pyrimidines. Therefore, blockade of the pyrimidine-synthesis pathway has

antiproliferative effects. In vitro, relatively high concentrations of leflunomide (5

10

M)

r

measuring response to drugs in rheumatoid arthritis

leflunomide

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Copyright 2004 Massachusetts Medical Society. All rights reserved.

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modulate nuclear factor-

k

B,

11

tyrosine kinases inthe signaling pathway made up of Janus kinases

and signal transducers and activators of transcrip-tion (the JAKSTAT pathway) and growth-factorreceptors,

12,13

interleukin-6, matrix metallopro-

teinases, and prostaglandin E

2

.

14

Because of thetheoretically additive effects of leflunomide and

methotrexate in inhibiting pyrimidine synthesis andpurine synthesis, respectively, these drugs have been

proposed as potentially complementary therapies.

10

clinical pharmacology

Leflunomide is a prodrug that, after oral adminis-tration, undergoes rapid chemical conversion to its

primary active metabolite, A77 1726, which ac-counts for more than 95 percent of the levels of the

drug in the circulation. This metabolite is highlyprotein-bound and has a long half-life of 15 to 18

days.

15,16

Therefore, without a loading dose, it maytake as long as two months to achieve steady-stateconcentrations. 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 de-creased renal function, although caution is advisedbecause information is limited.

17

interactions with other drugs

Leflunomide inhibits cytochrome P-450 2C9(CYP2C9) in vitro and, according to a case report,

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 result ing in the production of cytokines and enzymes. These, in turn, medi-

ate tissue damage, including cartilage loss and bone erosion. Likely sites of action of the major drugs described in thisarticle are shown. C denotes serum complement protein, and C* activated serum complement protein.



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may increase the anticoagulant activity of warfarin,

a substrate of this enzyme.

18

However, there havebeen no specific studies assessing the potential forinteractions between leflunomide and warfarin or

other CYP2C9-substrate drugs. Rifampin raises theconcentration of the active metabolite of lefluno-

mide by 40 percent, and the dose may have to be ad-justed. Leflunomide reduces serum uric acid con-centrations in treated patients

19

by increasing renal

urate excretion, perhaps through effects on theproximal renal tubule.

20

efficacy in rheumatoid arthritis

Large placebo-controlled studies comparing leflu-

nomide with sulfasalazine

19

or methotrexate

21,22

suggest that the drugs have similar efficacy (Table

2). As compared with placebo, leflunomide slowedprogression, as measured radiographically, over a

period of 6 to 12 months.

19,21

After two years, morethan 80 percent of the patients who received meth-

otrexate or leflunomide in a blinded, randomized,controlled trial (the Utilization of Leflunomide inthe Treatment of Rheumatoid Arthritis [ULTRA] tri-

al) had no new erosions.

21

adverse effects

The most important serious reactions to lefluno-

mide are hepatic. In clinical trials, approximately5 percent of patients had elevated transaminase lev-els

23

that were generally less than twice the upper

limit of normal and were reversible after the discon-tinuation of treatment with the drug. In May 2001,

the manufacturer issued a letter to clinicians detail-ing reports of hepatotoxicity in the postmarketing

period. During 104,000 patient-years of exposure,

liver-function abnormalities were identified in 296patients. Fifteen of these patients died from eitherliver failure or concomitant illness; hepatic dysfunc-

tion was considered to be possibly related to lefluno-mide treatment in 10 of these 15 patients.

24

More

recently, the Arthritis Advisory Committee of theFood and Drug Administration (FDA) reviewed theclinical trials and postmarketing studies.

25,26

Ele-

vated transaminase concentrations affected 2 per-cent to 4 percent of patients, although the incidence

of hepatocellular necrosis was far lower, at approx-imately 0.02 percent to 0.04 percent. The risk of

severe liver injury was deemed to be small and, giv-

en the benefits of treatment, acceptable. On the ba-sis of the surveillance data, patients with preexist-

ing liver abnormalities or a history of heavy alcoholintake or hepatitis virus infections should not be

treated with leflunomide.Combination therapy with leflunomide and

methotrexate may be associated with a higher riskof hepatotoxic effects than treatment with lefluno-mide alone. In one trial including 30 patients, 3 pa-

tients (10 percent) were withdrawn because of ele-vated levels of liver enzymes.

27

In a larger study, 41

of 130 patients who received leflunomide withmethotrexate (31.5 percent) had an elevation of the

alanine aminotransferase level to more than 1.2times the upper limit of normal, but only 2.3 percentwere withdrawn from the study because of abnor-

mal results on liver-function tests.

28

However, se-vere hepatotoxic effects have been reported with this

combination in a case report.

29

Weight loss was reported in the earliest trials of

Table 1. New Drugs for the Treatment of Rheumatoid Arthritis.

Drug Primary ActionRoute of

Administration Usual Dose Half-Life

Leflunomide Inhibits pyrimidinesynthesis

Oral Loading dose of 100 mg daily for 3 days, then20 mg daily

2 Wk

Etanercept Binds TNF-

a

and TNF-

b

Subcutaneousinjection

25 mg twice/wk or 50 mg once/wk 4 Days

Adalimumab Human antiTNF-

a

antibodySubcutaneous

injection40 mg every second wk 2 Wk

Infliximab Chimeric antiTNF-

a

antibodyIntravenous

infusion3 mg/kg of body weight at 0, 2, and 6 wk, then

every 8 wkFor incomplete response, maintenance dose

may be gradually increased to a maximumof 10 mg/kg

9 Days

Anakinra Interleukin-1receptorantagonist

Subcutaneousinjection

100 mg daily 6 Hr



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leflunomide, and loss of 20 percent of body weighthas been observed in clinical practice, although the

mechanisms are unknown.

30

However, weight lossseldom necessitates the discontinuation of therapy.Although diarrhea was reported in 32 percent of the

patients who were treated with leflunomide in theULTRA 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 bloodpressure can occur within the first two months of

treatment; therefore, regular monitoring of bloodpressure is advisable.

31

Reversible alopecia occurred

in approximately 10.5 percent of patients in the

ULTRA trial,

21

and pancytopenia,

32,33 peripheralneuropathy,

24

and interstitial pneumonitis

34

have

also been reported with this agent.

pregnancy and fertility

Preclinical studies indicated that leflunomide causes

fetal death or is teratogenic

35

; thus, women of child-bearing potential must have a negative pregnancy

test before beginning treatment and must use reli-able contraception. Because of the drugs long half-life, discontinuing treatment before conception is

inadequate. The manufacturer suggests an elimina-tion protocol of oral cholestyramine, 8 g three times

daily for 11 days, and verification that the plasmalevel of the drug is below 0.02 mg per liter on two

separate tests performed at least 2 weeks apart. Thisprotocol should also be followed by men who wishto father a child.

35

There are no reported effects of

decreased fertility in patients who have takenleflunomide.

clinical use in rheumatoid arthritis

Methotrexate remains the most commonly used dis-

ease-modifying antirheumatic drug,

36

but lefluno-mide is a useful alternative in the face of intoleranceto methotrexate. As mentioned above, given its po-

tential for hepatotoxic effects, leflunomide is con-traindicated in patients with any type of liver impair-

ment, and regular monitoring is required (Table 3).A loading dose of 100 mg daily for three days can beused to achieve therapeutic concentrations quickly

but may cause gastrointestinal intolerance. In clin-ical practice, the loading dose is often omitted or re-

duced. The usual daily dose (20 mg) is tolerated wellby most patients. If minor adverse effects such as di-

arrhea or abdominal cramps occur, a dose of 10 mg

can be effective and may be better tolerated.

37

The combination of leflunomide and metho-

trexate appears to be more effective than metho-trexate and placebo, resulting in ACR 20 response

rates of 46.2 and 19.5 percent, respectively.

28

Theprimary drawback of this combination is its poten-

tial for hepatotoxic effects

28,29

; thus, patients whoare treated with both agents should be monitored

closely.

TNF-

a

, an inflammatory cytokine that is released byactivated monocytes, macrophages, and T lympho-

cytes, promotes inflammatory responses that areimportant in the pathogenesis of rheumatoid ar-thritis.

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

tumor necrosis factor

ant agonist s

* 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 oftender and swollen joints plus similar improvement in at least three of five measures specified by the ACR (see text fordetails). Data for 6 months are from Smolen et al.,

19

and data for 12 months are from Strand et al.

22

The rates of re-

sponse to all drugs were significantly higher than those in the corresponding placebo group. NS denotes not stated.

Table 2. Rates of Response to Leflunomide as Compared with Other Disease-Modifying Agents and Placebo.*

Level ofResponse 12 mo 6 mo

PlaceboLeflunomide(20 mg/day)

Methotrexate(7.515 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



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The biologic activity of TNF-

a

can be attenuated by

soluble TNF receptors.

42

Patients with rheumatoid arthritis have highconcentrations of TNF-

a

in the synovial fluid.

43,44

TNF-

a

is localized to the junction of the inflamma-tory pannus and healthy cartilage,

44

and high sy-

novial fluid TNF-

a

concentrations are associatedwith the erosion of bone.

45

Studies in animals have

provided key evidence that antagonizing TNF-

a

isa viable therapeutic strategy. Inflammatory arthritis

developed in transgenic mice that expressed humanTNF-

a

,

46

and in another animal model, treatmentwith anti-TNF antibodies ameliorated arthritis.

47

Subsequent proof-of-concept studies in patientswith rheumatoid arthritis indicated that blocking

TNF improved symptoms.

48,49

Currently, threeTNF-blocking drugs etanercept, infliximab, and

adalimumab are available for clinical use. Theirusual 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 extracel-

lular, ligand-binding portion of the higher-affinitytype 2 TNF receptor (p75) linked to the Fc portionof human IgG1. This fusion protein binds to both

TNF-

a

and TNF-

b

, thereby preventing each frominteracting with its respective receptors.

Clinical Pharmacology

After subcutaneous administration, etanercept is

absorbed slowly, with concentrations peaking at ap-proximately 50 hours. Its half-life is generally four

days (Table 1).

50,51

In healthy volunteers, systemicexposure to the drug, measured as the area under

the concentrationtime curve, varied by a factor ofeight.

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

After dose-finding studies,

53

a 10-mg dose ofetanercept, a 25-mg dose of etanercept, and place-

bo were compared in 234 patients in a six-monthrandomized study.

54

Both doses of etanercept ap-

peared to be effective, resulting in ACR 20 responserates of 51 percent and 59 percent, respectively, ascompared with 11 percent in the placebo group. The

25-mg dose resulted in a more rapid response andmore frequent ACR 50 responses (40 percent) than

the 10-mg dose (24 percent) or placebo (5 percent)(Table 4).

54

Methotrexate has been considered the standardagainst which newer disease-modifying antirheu-

matic drugs should be evaluated.

59

For example, adouble-blind, randomized study in 632 patients

with early rheumatoid arthritis compared 10 or 25mg of etanercept twice weekly with methotrexatein a dose escalated over the course of eight weeks to

a final weekly dose of 20 mg.

9

Patients who receivedthe higher dose of etanercept had a more rapid re-

sponse within the first 2 weeks, but after 12 months,the ACR 20 response rates were similar 72 per-

cent in the 25-mg etanercept group and 65 percent

in the methotrexate group (P=0.16).

9

The averageincreases in radiologic score with 25 mg of etaner-

cept and methotrexate 1.00 and 1.59 units, re-spectively were not significantly different (P=

0.11).

9

Another study indicated that patients withan inadequate response to methotrexate receive

benefit when etanercept is added to their regimenrather than placebo (Table 4).

55

infliximab

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 thehuman antibody. It binds to soluble and mem-brane-bound TNF-

a

with high affinity, impairing

the binding of TNF-

a

to its receptor. Infliximabalso kills cells that express TNF-

a

through anti-

body-dependent and complement-dependent cy-totoxicity.

60,61

* Patients who are to receive etanercept, adalimumab, or infliximab should bescreened for previous exposure to tuberculosis before treatment is started.Patients who are also receiving another disease-modifying antirheumaticdrug such as methotrexate require additional monitoring as appropriatefor that drug.

Table 3. Monitoring Recommendations.*

Drug Monitoring Recommendation

Leflunomide Obtain a complete blood count and alanine aminotransfer-ase measurements at baseline and then monthly untilstable. Usual clinical practice is to repeat these testsat intervals of 2 to 3 mo.

Etanercept Be clinically alert for tuberculosis, histoplasmosis, and otherinfections.

Adalimumab Same as for etanercept.

Infliximab Same as for etanercept.

Anakinra Obtain a complete blood count at baseline, monthly for3 mo, and every 3 mo thereafter.



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There are marked differences among patients in thepharmacokinetics of infliximab. In one study in-

volving 428 subjects, trough concentrations eightweeks after the intravenous administration of 3 mgof infliximab per kilogram of body weight varied

by a factor of more than 100.

62

Pharmacokineticmodeling indicated that shortening the interval be-

tween doses to six weeks would increase the troughlevels more effectively than increasing the dose by

100 mg.

62


A single infusion of infliximab (1 or 10 mg per kilo-gram) was reported to improve symptoms of rheu-

matoid arthritis rapidly, providing early evidence ofthe effectiveness of TNF antagonism.

63

Subsequent

studies demonstrated that monotherapy with inflix-imab (at a dose of 3 or 10 mg per kilogram) was su-perior to placebo,

64

but the frequent development

of anti-infliximab antibodies led to its use in com-bination with methotrexate rather than as mono-

therapy. Efficacy and the doseresponse relationwere defined in a study involving 428 patients who

had active rheumatoid arthritis despite methotrex-ate therapy.8,56 Four regimens infliximab at adose of 3 or 10 mg per kilogram every four or eight

weeks combined with methotrexate were all sim-ilarly and significantly more effective than metho-

trexate plus placebo. After 54 weeks, the ACR 20 re-sponse 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 in-fliximab plus methotrexate were more effective than

methotrexate plus placebo in preventing progres-sion as measured radiologically.8 The ACR 50 re-sponse rates in all the infliximab groups were simi-

lar after 24 weeks,56 but after 54 weeks, the responserate in the group receiving 3 mg per kilogram every

8 weeks (21 percent) was significantly lower thanthose in the two groups receiving 10 mg per kilo-

gram (39 percent among those given a dose every

8 weeks and 38 percent among those given a doseevery 4 weeks).8 As a result of these studies, a stan-

dard regimen has evolved (Table 1). Patients who donot have an adequate response or who have an ini-

tial response followed by a relapse may have a betterresponse either if the interval between infusions is

decreased to every four to six weeks or if the dose isincreased.62

adalimumab

Adalimumab is a recombinant human IgG1 mono-

clonal antibody that binds to human TNF-a withhigh affinity, both impairing cytokine binding to its

receptors and lysing cells that express TNF-a ontheir surface.


After subcutaneous administration, adalimumab is

absorbed slowly, with peak concentrations reachedafter approximately 130 hours. There is substantial

* Infliximab is approved only for use in combination with methotrexate. The data presented are for the doses that are usedin clinical practice (infliximab, 3 mg per kilogram of body weight every 8 weeks; etanercept, 25 mg by subcutaneous in-jection 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 sig-nificantly higher than those in the corresponding placebo group.

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 PlaceboEtanercept

8078

1159

540

115

Weinblatt et al.55 Placebo plus methotrexateEtanercept plus methotrexate

3059

2771

339

015

Maini et al.56 Placebo plus methotrexateInfliximab plus methotrexate

8483

2050

527

08

Abbott Laboratories57 PlaceboAdalimumab

110113

1946

822

212

Weinblatt et al.58 Placebo plus methotrexateAdalimumab plus methotrexate

6267

1567

855

527



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interpatient variability in disposition,65 but clear-

ance is similar in men and women and appears to beunaffected by age or body weight.66 The addition ofmethotrexate to the regimen reduced adalimumab

clearance by 20 percent after a single dose and by44 percent after multiple doses.57


In a randomized, double-blind study, the ACR 20 re-sponse rate for 40 mg of adalimumab administered

weekly was similar to the rate for the same dose ad-ministered every other week (53 percent and 46percent, respectively), and both were significantly

higher than the rate with placebo (19 percent) (Ta-ble 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 metho-trexate plus 20, 40, or 80 mg of adalimumab every

two weeks than of those who received methotrexateplus placebo (48 percent, 67 percent, 66 percent,and 15 percent, respectively).58

Initial studies reported substantial efficacy with al-

most no serious adverse effects,9,53,56,58,69 andpostmarketing data were also reassuring.70 How-

ever, wider use of TNF antagonists has resulted inreports largely case reports or small series of pa-

tients that link TNF-antagonist use with a wide

range of adverse events, including infections, can-cer, vasculitis, lupus-like autoimmune disease, mul-

tiple sclerosislike demyelinating disorders, liverdisease, hematologic abnormalities including aplas-

tic anemia and lymphoma, severe allergy, and asep-tic meningitis.71-79 The relationships between anti-

TNF therapy and many of these adverse events areunknown. Much safety information regarding TNFantagonists is unpublished but may be found in the

transcript of a meeting of the FDA Arthritis Adviso-ry Committee.79

infection

Serious bacterial infections, tuberculosis, atypi-cal mycobacterial infection, aspergillosis, histo-plasmosis, coccidioidomycosis, listeriosis, Pneu-

mocystis carinii pneumonia, cryptococcal infections,cytomegalovirus, and other infections have oc-

curred,71,72,75,79-82 and such infections may bemore common among patients 65 years of age or

older than among younger patients.83 The back-

ground risk of serious infection is approximatelytwice as high among patients with rheumatoid ar-thritis as among those without this condition84;

therefore, it is difficult to interpret sporadic reportsof infection in patients receiving anti-TNF thera-

py. However, the risk of opportunistic infections,including histoplasmosis and tuberculosis, is in-

creased. Such observations are congruent with ani-mal studies showing that TNF is important for gran-

uloma formation85 and preventing the reactivationof latent tuberculosis.86

Tuberculosis has been reported in association

with all TNF antagonists. Data from the FDA Ad-verse Event Reporting System, a passive surveil-

lance system that has no reliable denominator andmay underestimate true incidence, indicated that

although a similar number of patients had been ex-posed, 70 cases of tuberculosis had been reported

after treatment with infliximab and 9 after etaner-cept treatment.87 The rate of tuberculosis amongpatients 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 earlystudies of adalimumab therapy, tuberculosis devel-oped in 8 of 542 patients.79 The introduction of

screening procedures and the use of lower doses ofadalimumab reduced the frequency to 5 of the next

1900 patients.79

Tuberculosis in patients who are receiving anti-

TNF therapy most often arises from the reactiva-

tion of latent infection and usually occurs withinthe first two to five months of treatment.87 Extra-

pulmonary and disseminated disease is common,and atypical clinical presentations may lead to de-

layed diagnosis and increased morbidity.87

malignant disease

Lymphoma has been reported in association withall three TNF antagonists,77 but whether or not

there is a causal relationship is debated. The reasonfor the uncertainty is that the incidence of lympho-

ma is increased among patients with rheumatoidarthritis and increases with the severity of the con-

dition.88,89 Therefore, the increased incidence oflymphoma among patients who receive TNF an-tagonists, which is estimated to be 2.3 to 6.4 times

that in the general population, could be ascribed toeither severe rheumatoid arthritis or its treatment.79

The transcripts of the FDA meeting in which all thestudies were examined together indicate that lym-

adver se ef f ect s

of tnf antagonists



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phoma developed in six patients who were receiv-

ing TNF antagonists during the controlled portionof clinical trials, as compared with none of the con-trol patients,79 indicating that a causal relationship

is plausible. The type of lymphoma reported is sim-ilar to that occurring in the general population of pa-

tients with rheumatoid arthritis.

77

Apart from lym-phoma, the incidence of cancer is not significantly

altered.79

injection-site and infusion reactions

Minor redness and itching at the injection site, last-ing a few days, are common among patients who re-

ceive etanercept and adalimumab.54,68 Symptoms,most often headache and nausea, occur in 20 per-

cent of patients during the infusion of infliximaband appear to be controllable with the use of anti-

histamines or by slowing the infusion rate.62 Symp-toms suggestive of an immediate hypersensitivity

response, such as urticaria, occur in 2 percent of pa-tients.56 Serious anaphylaxis is uncommon and oc-curred in 2 of 500 patients with Crohns disease who

were treated with infliximab.90

immune and autoimmune responses

Antibodies to etanercept developed in 3 percent ofpatients,9 but their clinical significance is unknown.

In other reports, human antichimeric antibodies toinfliximab developed in 53, 21, and 7 percent of pa-

tients who were receiving 1, 3, and 10 mg of inflix-imab per kilogram, respectively.64 The frequency

of antichimeric antibodies was lower (8.5 percent)

among patients who were treated with infliximabat a dose of 3 or 10 mg per kilogram plus concomi-

tant methotrexate.62 These antibodies acceleratedthe clearance of infliximab62 and were associated

with increased infusion reactions and shorter re-sponses in patients with Crohns disease.91 Anti-

bodies to adalimumab developed in 12 percent ofpatients; the rate was reduced to 1 percent with con-current methotrexate treatment.92 The ACR 20 re-

sponse rate was lower in patients treated with adal-imumab in whom antibodies developed.92

Antinuclear antibodies were detected in approx-imately 60 percent of patients who were receiving

infliximab and methotrexate, as compared with 26percent of those who were treated with methotrex-ate alone.8 Antibodies to double-stranded DNA

developed after etanercept treatment (in 4 percentof patients),54 after treatment with infliximab plus

methotrexate (in 10 percent),8 and after treatment

with adalimumab plus methotrexate (in 4 per-

cent).58 However, drug-induced systemic lupuserythematosus is rare78,92,93: the FDA Adverse EventReporting System identified 16 cases after the use

of etanercept.94

demyelinating syndromesExacerbation of previously quiescent multiple scle-

rosis and new-onset demyelinating neurologic dis-ease have been reported.76 The number of patients

affected is not known, but in the FDA Adverse EventReporting System, 18 cases were reported afteretanercept therapy and 2 after infliximab therapy.

The range of symptoms was broad and includedparesthesia (in 65 percent of patients), optic neuri-

tis (in 40 percent), and confusion (in 25 percent).76

Although a causal relationship has not been estab-

lished, the fact that another TNF antagonist, lener-cept, worsened symptoms in patients with multiple

sclerosis95

renders the association plausible.

heart failure

TNF-a levels are elevated in patients with heart fail-ure and associated with decreased cardiac contrac-

tility.96 Initial reports on anti-TNF therapy for heartfailure were encouraging.97,98 However, subsequentstudies of etanercept and infliximab in heart failure

were stopped early because of lack of evidence ofbenefit and, in the case of infliximab, increased

mortality.79,99

TNF antagonists appear to be among the most ef-fective treatments available for rheumatoid arthritis.

The response is generally rapid, often occurringwithin a few weeks, although not all patients have

a response. There is little information regardinghead-to-head comparisons between various TNFantagonists or between TNF antagonists and other

disease-modifying antirheumatic drugs. There isalso a need for data that will show whether particu-

lar adverse effects are class effects. Until convinc-ing data to the contrary are available, similar pre-

cautions are appropriate with regard to all TNFantagonists.

Anti-TNF therapy should not be started in pa-

tients with active infection and should be discon-tinued if a serious infection occurs. Chronic or re-

current infection is a relative contraindication. All

clinical use of tnf antagonistsin rheumatoid arthritis



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patients should be screened for latent tuberculosis

before anti-TNF therapy is begun, and should betreated before starting such therapy if they test pos-itive.100 Physicians should be alert to the increased

risk of tuberculosis and other opportunistic infec-tions.

TNF antagonists should also be avoided in pa-tients with any demyelinating disorder or heart fail-

ure, and therapy should be discontinued if such anillness develops. Rare cases of pancytopenia, aplas-

tic anemia, and liver failure have been reported,79

but no specific monitoring is recommended.

Interleukin-1, produced by monocytes, macrophag-es, and some specialized cells in the synovial lining,

has inflammatory effects that include the inductionof interleukin-6 and cyclooxygenase-2.101 The ac-

tions of interleukin-1 are down-regulated by inter-leukin-1receptor antagonist, a natural inhibitorthat competes for binding to interleukin-1 recep-

tors. In mice that are deficient in interleukin-1receptor antagonist, a chronic inflammatory ar-

thritis develops, with features similar to those ofrheumatoid arthritis.102

Anakinra is a recombinant form of human inter-

leukin-1receptor antagonist that targets the type Iinterleukin-1 receptor that is expressed in many tis-

sues. In patients with rheumatoid arthritis, levelsof this receptor antagonist in the inflamed joint are

lower than would be required for the inhibition of

the amount of interleukin-1 present, and this im-balance is thought to contribute to the persistence

of joint inflammation.103,104

clinical pharmacology

Anakinra is identical to the nonglycosylated form

of the endogenous protein except for the additionof one N-terminal methionine.105 Because it has ashort half-life (Table 1),106 daily administration is

more effective than injections given weekly or threetimes a week.107 Renal clearance eliminates 80 per-

cent of infused anakinra in rats,104and humans withrenal failure have markedly decreased clearance;

clearance decreases by half in moderate renal dis-ease, by two thirds in severe renal disease, and by 75percent in end-stage renal disease.106 In such pa-

tients, adjustment of the dose or frequency of injec-tion may be indicated; computer simulation has

suggested that a dose of 100 mg every second daymay be appropriate in patients with severe renal im-

pairment.106 Hemodialysis and peritoneal dialy-

sis do not appear to remove substantial amounts ofanakinra.106

efficacy in rheumatoid arthritis

Anakinra, alone or in combination with metho-

trexate, has been more effective than placebo inrandomized, controlled trials involving approxi-

mately 900 patients with rheumatoid arthritis (Ta-ble 5).108,109 A long-term extension study docu-

mented that responses seen in the first 24-weekphase of the study were durable; after 48 weeks, 18percent of patients treated with anakinra had an

ACR 50 response, and 3 percent had an ACR 70 re-sponse.110 Treatment with anakinra also signifi-

cantly slows the rate of damage, as measured on ra-diography.7

adverse effects

The most common adverse event is dose-dependentskin irritation at the injection site, occurring in 50to 80 percent of patients in trials. Most reactions

appeared to be mild, and resolved within a fewweeks.105 A small number of patients reported

more severe allergic-type reactions involving itch-ing, swelling, and pain.107

The risk of infection, primarily bacterial, appears

to be increased. Serious infections occurred in 2.1percent of patients receiving anakinra, as compared

with 0.4 percent of those receiving placebo, in onestudy involving 1000 patients (P= 0.07); no oppor-

tunistic infections were observed.111

clinical use in rheumatoid arthritis

Anakinra may be useful in patients who have no re-sponse to or are unable to tolerate methotrexate,

leflunomide, or TNF antagonists. Anakinra therapy

anakinra

* Data on monotherapy are from Bresnihan et al.,108 and data on combinationtherapy are from Cohen et al.109

Table 5. Rates of Response to 24 Weeks of Anakinra Therapy.*

Level ofResponse Monotherapy Combination Therapy with Methotrexate

PlaceboAnakinra,150 mg Placebo

Anakinra,1 mg/kg/day

Anakinra,2 mg/kg/day

percentage of patientsACR 20 27 43 23 42 35

ACR 50 8 23 4 24 17

ACR 70 4 9 0 10 7



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should not be started in patients with active infec-

tion and should be discontinued if a serious infec-tion occurs. Caution should be exercised when con-sidering the use of anakinra in patients with chronic

or recurrent infection. Because reversible neutrope-nia and thrombocytopenia have occurred in a small

number of patients, monitoring the complete bloodcount is recommended (Table 3).

The combination of anakinra and methotrexateappears to be well tolerated.109However, both drugs

can lower the white-cell count; thus, regular labora-tory monitoring is required. Concomitant use ofanakinra and a TNF antagonist may increase the

risk of infections and should be avoided.112

The drugs discussed above appear to be relatively

safe and effective in the short-to-intermediatetermtreatment of rheumatoid arthritis. In addition, therole of these agents in the treatment of illnesses oth-

er than rheumatoid arthritis is evolving. Infliximabis an effective treatment for Crohns disease,91 and

TNF antagonists are finding a place in the treatmentof many conditions, including psoriasis,113 anky-losing spondylitis,114 juvenile arthritis,113 Stills

disease,115 uveitis,116 and vasculitis.117 However,

much remains unknown. Hard data regarding thecomparative long-term efficacy and toxicity of theseagents, 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 in-vestigation; some have shown promise in clinical

trials that have been published. These include tac-rolimus,118 rituximab,119 an interleukin-6 antago-

nist,120 and a fusion protein cytotoxic T-lympho-cyteassociated antigen 4-IgG1 (CTLA-4Ig) that blocks T-cell costimulatory pathways.121 Oth-

er drugs that are now at earlier stages of develop-ment include pegylated, soluble TNF receptor an-

tagonists and agents that trap cytokines, blockinterleukin-15, prevent the cleavage of human com-

plement component C5, or inhibit adhesion mole-cules.122 The introduction of additional effective

therapies for rheumatoid arthritis will improve theoutlook for patients, since even with the range oftherapies 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 Aventisand research support from Bristol-Myers Squibb in the past two

years.

l im it at ions

and future directions

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