New Drugs for Rheumatoid Arthritis

n engl j med

350;21

www.nejm.org may

20, 2004

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 greater

understanding of the underlying mechanisms has facilitated the development of newdrugs 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 endogenousantigen. Consequently, recruited monocytes, macrophages, and fibroblasts producecytokines such as tumor necrosis factor

a

(TNF-

a

) and interleukin-1 within the synovialcavity. 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, whichmediates 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 arthritisare 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 of50 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 placeboand 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 hasantiproliferative effects. In vitro, relatively high concentrations of leflunomide (5

¡

10

M)

r

measuring response to drugs in rheumatoid arthritis

leflunomide

The New England Journal of Medicine Downloaded from nejm.org at Arizona Health Sciences Center and UMC on May 12, 2013. For personal use only. No other uses without permission.

Copyright © 2004 Massachusetts Medical Society. All rights reserved.

n engl j med

350;21

www.nejm.org may

20

,

2004

The

new england journal

of

medicine

2168

modulate nuclear factor-

k

B,

11

tyrosine kinases inthe signaling pathway made up of Janus kinasesand signal transducers and activators of transcrip-tion (the JAK–STAT pathway) and growth-factorreceptors,

12,13

interleukin-6, matrix metallopro-teinases, and prostaglandin E

2

.

14

Because of thetheoretically additive effects of leflunomide andmethotrexate in inhibiting pyrimidine synthesis andpurine synthesis, respectively, these drugs have beenproposed as potentially complementary therapies.

10

clinical pharmacology

Leflunomide is a prodrug that, after oral adminis-tration, undergoes rapid chemical conversion to itsprimary 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 18days.

15,16

Therefore, without a loading dose, it maytake as long as two months to achieve steady-stateconcentrations. In addition, the active metaboliteundergoes extensive enterohepatic recirculation,and it may take up to two years for the amount ofdrug in plasma to decrease to an undetectable level.Renal excretion appears to be limited, and the dosegenerally 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 resulting 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 this article are shown. C denotes serum complement protein, and C* activated serum complement protein.



n engl j med

350;21

www.nejm.org may

20, 2004

drug therapy

2169

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 orother 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 renalurate 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 (Table2). As compared with placebo, leflunomide slowedprogression, as measured radiographically, over aperiod 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 upperlimit 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

Morerecently, 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 incidenceof hepatocellular necrosis was far lower, at approx-imately 0.02 percent to 0.04 percent. The risk ofsevere 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 betreated with leflunomide.

Combination therapy with leflunomide andmethotrexate 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, 41of 130 patients who received leflunomide withmethotrexate (31.5 percent) had an elevation of thealanine 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 thiscombination 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 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


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


100 mg daily 6 Hr



n engl j med

350;21

www.nejm.org may

20

,

2004

The

new england journal

of

medicine

2170

leflunomide, and loss of 20 percent of body weighthas been observed in clinical practice, although themechanisms are unknown.

30

However, weight lossseldom necessitates the discontinuation of therapy.Although diarrhea was reported in 32 percent of thepatients who were treated with leflunomide in theULTRA trial,

21

weight loss can occur in the absenceof gastrointestinal symptoms.

Hypertension of unclear cause was reported in18 percent of the patients in the same trial and wasa new finding in 5 percent.

21

Elevations in bloodpressure can occur within the first two months oftreatment; therefore, regular monitoring of bloodpressure is advisable.

31

Reversible alopecia occurredin approximately 10.5 percent of patients in theULTRA trial,

21

and pancytopenia,

32,33

peripheralneuropathy,

24

and interstitial pneumonitis

34

havealso been reported with this agent.

pregnancy and fertility

Preclinical studies indicated that leflunomide causesfetal death or is teratogenic

35

; thus, women of child-bearing potential must have a negative pregnancytest before beginning treatment and must use reli-able contraception. Because of the drug’s long half-life, discontinuing treatment before conception isinadequate. The manufacturer suggests an elimina-tion protocol of oral cholestyramine, 8 g three timesdaily for 11 days, and verification that the plasmalevel of the drug is below 0.02 mg per liter on twoseparate 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 ofdecreased 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 quicklybut 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 mgcan 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 responserates 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 monitoredclosely.

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 type1 TNF receptor (p55) and the type 2 TNF receptor(p75), that are expressed on many types of cells.

40,41

tumor necrosis factor

antagonists

* 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 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(7.5–15 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



n engl j med

350;21

www.nejm.org may

20, 2004

drug therapy

2171

The biologic activity of TNF-

a

can be attenuated bysoluble 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 haveprovided key evidence that antagonizing TNF-

a

isa viable therapeutic strategy. Inflammatory arthritisdeveloped 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 blockingTNF improved symptoms.

48,49

Currently, threeTNF-blocking drugs — etanercept, infliximab, andadalimumab — are available for clinical use. Theirusual doses and pharmacokinetic characteristics arelisted 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 bothTNF-

a

and TNF-

b

, thereby preventing each frominteracting with its respective receptors.

Clinical Pharmacology

After subcutaneous administration, etanercept isabsorbed slowly, with concentrations peaking at ap-proximately 50 hours. Its half-life is generally fourdays (Table 1).

50,51

In healthy volunteers, systemicexposure to the drug, measured as the area underthe concentration–time curve, varied by a factor ofeight.

50

A regimen of 50 mg once weekly appears tobe 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. The25-mg dose resulted in a more rapid response andmore frequent ACR 50 responses (40 percent) thanthe 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 patientswith early rheumatoid arthritis compared 10 or 25mg of etanercept twice weekly with methotrexatein a dose escalated over the course of eight weeks toa 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 percentin 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 receivebenefit when etanercept is added to their regimenrather than placebo (Table 4).

55

infliximab

Infliximab, first approved for the treatment ofCrohn’s disease, is a chimeric IgG1 anti–TNF-

a

antibody containing the antigen-binding region ofthe mouse antibody and the constant region of thehuman antibody. It binds to soluble and mem-brane-bound TNF-

a

with high affinity, impairingthe 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 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.

Table 3. Monitoring Recommendations.*

Drug Monitoring Recommendation

Leflunomide Obtain a complete blood count and alanine aminotransfer-ase 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.



n engl j med

350;21

www.nejm.org may

20

,

2004

The

new england journal

of

medicine

2172

Clinical Pharmacology

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 variedby 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 by100 mg.

62

Efficacy in Rheumatoid Arthritis

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

Subsequentstudies 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 developmentof anti-infliximab antibodies led to its use in com-bination with methotrexate rather than as mono-therapy. Efficacy and the dose–response relationwere defined in a study involving 428 patients whohad active rheumatoid arthritis despite methotrex-ate therapy.

8,56

Four regimens — infliximab at adose of 3 or 10 mg per kilogram every four or eightweeks 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 mgper kilogram every 4 weeks).

8

All regimens of in-fliximab plus methotrexate were more effective thanmethotrexate 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 every8 weeks (21 percent) was significantly lower thanthose in the two groups receiving 10 mg per kilo-gram (39 percent among those given a dose every8 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 isdecreased to every four to six weeks or if the dose isincreased.

62

adalimumabAdalimumab is a recombinant human IgG1 mono-clonal antibody that binds to human TNF-a withhigh affinity, both impairing cytokine binding to itsreceptors and lysing cells that express TNF-a ontheir surface.

Clinical PharmacologyAfter subcutaneous administration, adalimumab isabsorbed 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 used in 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


Moreland et al.54 Placebo Etanercept

8078

1159

540

115

Weinblatt et al.55 Placebo plus methotrexate Etanercept 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



n engl j med 350;21 www.nejm.org may 20, 2004

drug therapy

2173

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

Efficacy in Rheumatoid ArthritisIn a randomized, double-blind study, the ACR 20 re-sponse rate for 40 mg of adalimumab administeredweekly was similar to the rate for the same dose ad-ministered every other week (53 percent and 46percent, respectively), and both were significantlyhigher than the rate with placebo (19 percent) (Ta-ble 4).67,68 Adalimumab appears to have additiveeffects when used with methotrexate. For example,an ACR 20 response was achieved in a significantlygreater proportion of patients who received metho-trexate plus 20, 40, or 80 mg of adalimumab everytwo 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 widerange of adverse events, including infections, can-cer, vasculitis, lupus-like autoimmune disease, mul-tiple sclerosis–like 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 thetranscript of a meeting of the FDA Arthritis Adviso-ry Committee.79

infectionSerious 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 associationwith 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 thatalthough a similar number of patients had been ex-posed, 70 cases of tuberculosis had been reportedafter treatment with infliximab and 9 after etaner-cept treatment.87 The rate of tuberculosis amongpatients with rheumatoid arthritis who had beentreated with infliximab was 24.4 cases per 100,000,as compared with the background rate of 6.2 casesper 100,000 patients with this illness.87 In earlystudies of adalimumab therapy, tuberculosis devel-oped in 8 of 542 patients.79 The introduction ofscreening procedures and the use of lower doses ofadalimumab reduced the frequency to 5 of the next1900 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 diseaseLymphoma has been reported in association withall three TNF antagonists,77 but whether or notthere 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 timesthat 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-

adverse effects

of tnf antagonists




The new england journal of medicine

2174

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 relationshipis 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 significantlyaltered.79

injection-site and infusion reactionsMinor 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 hypersensitivityresponse, such as urticaria, occur in 2 percent of pa-tients.56 Serious anaphylaxis is uncommon and oc-curred in 2 of 500 patients with Crohn’s disease whowere treated with infliximab.90

immune and autoimmune responsesAntibodies 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 frequencyof 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 associatedwith increased infusion reactions and shorter re-sponses in patients with Crohn’s 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 receivinginfliximab and methotrexate, as compared with 26percent of those who were treated with methotrex-ate alone.8 Antibodies to double-stranded DNAdeveloped after etanercept treatment (in 4 percentof patients),54 after treatment with infliximab plusmethotrexate (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 useof etanercept.94

demyelinating syndromesExacerbation of previously quiescent multiple scle-rosis and new-onset demyelinating neurologic dis-ease have been reported.76 The number of patientsaffected 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 multiplesclerosis95 renders the association plausible.

heart failureTNF-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 failurewere stopped early because of lack of evidence ofbenefit and, in the case of infliximab, increasedmortality.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 havea response. There is little information regardinghead-to-head comparisons between various TNFantagonists or between TNF antagonists and otherdisease-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 antagonists

in rheumatoid arthritis




drug therapy

2175

patients should be screened for latent tuberculosisbefore anti-TNF therapy is begun, and should betreated before starting such therapy if they test pos-itive.100 Physicians should be alert to the increasedrisk 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-1–receptor antagonist, a natural inhibitorthat competes for binding to interleukin-1 recep-tors. In mice that are deficient in interleukin-1–receptor antagonist, a chronic inflammatory ar-thritis develops, with features similar to those ofrheumatoid arthritis.102

Anakinra is a recombinant form of human inter-leukin-1–receptor 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 arelower than would be required for the inhibition ofthe amount of interleukin-1 present, and this im-balance is thought to contribute to the persistenceof joint inflammation.103,104

clinical pharmacologyAnakinra is identical to the nonglycosylated formof the endogenous protein except for the additionof one N-terminal methionine.105 Because it has ashort half-life (Table 1),106 daily administration ismore effective than injections given weekly or threetimes a week.107 Renal clearance eliminates 80 per-cent of infused anakinra in rats,104 and 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 hassuggested 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 arthritisAnakinra, 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 anACR 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 effectsThe most common adverse event is dose-dependentskin irritation at the injection site, occurring in 50to 80 percent of patients in trials. Most reactionsappeared to be mild, and resolved within a fewweeks.105 A small number of patients reportedmore severe allergic-type reactions involving itch-ing, swelling, and pain.107

The risk of infection, primarily bacterial, appearsto be increased. Serious infections occurred in 2.1percent of patients receiving anakinra, as comparedwith 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 combination therapy 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


ACR 20 27 43 23 42 35

ACR 50 8 23 4 24 17

ACR 70 4 9 0 10 7





2176

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 chronicor recurrent infection. Because reversible neutrope-nia and thrombocytopenia have occurred in a smallnumber of patients, monitoring the complete bloodcount is recommended (Table 3).

The combination of anakinra and methotrexateappears to be well tolerated.109 However, both drugscan lower the white-cell count; thus, regular labora-tory monitoring is required. Concomitant use ofanakinra and a TNF antagonist may increase therisk of infections and should be avoided.112

The drugs discussed above appear to be relativelysafe and effective in the short-to-intermediate–termtreatment 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 Crohn’s disease,91 andTNF antagonists are finding a place in the treatmentof many conditions, including psoriasis,113 anky-losing spondylitis,114 juvenile arthritis,113 Still’s

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, willbe important for rational clinical use.

Treatments for rheumatoid arthritis continue toadvance rapidly, and many new drugs are under in-vestigation; some have shown promise in clinicaltrials that have been published. These include tac-rolimus,118 rituximab,119 an interleukin-6 antago-nist,120 and a fusion protein — cytotoxic T-lympho-cyte–associated antigen 4-IgG1 (CTLA-4–Ig) —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 effectivetherapies for rheumatoid arthritis will improve theoutlook for patients, since even with the range oftherapies currently available, some patients stillhave poorly or incompletely controlled disease.

Supported by a grant (HS1-0384) from the Center for Educationand 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 twoyears.

limitations

and future directions

references

1. Choy EH, Panayi GS. Cytokine pathwaysand joint inflammation in rheumatoid ar-thritis. N Engl J Med 2001;344:907-16.2. Bukhari M, Lunt M, Harrison BJ, ScottDG, Symmons DP, Silman AJ. Rheumatoidfactor is the major predictor of increasingseverity of radiographic erosions in rheuma-toid arthritis: results from the Norfolk Ar-thritis Register Study, a large inception co-hort. Arthritis Rheum 2002;46:906-12.3. Felson DT, Anderson JJ, Boers M, et al.Preliminary definition of improvement inrheumatoid arthritis. Arthritis Rheum 1995;38:727-35.4. Pincus T, Stein CM. ACR 20: clinical orstatistical significance? Arthritis Rheum1999;42:1572-6.5. Felson DT, Anderson JJ, Lange ML,Wells G, LaValley MP. Should improvementin rheumatoid arthritis clinical trials be de-fined as fifty percent or seventy percent im-provement in core set measures, rather thantwenty percent? Arthritis Rheum 1998;41:1564-70.6. Sharp JT, Strand V, Leung H, Hurley F,Loew-Friedrich I. Treatment with lefluno-mide slows radiographic progression ofrheumatoid arthritis: results from three ran-domized controlled trials of leflunomide inpatients with active rheumatoid arthritis.

Arthritis Rheum 2000;43:495-505. [Erra-tum, Arthritis Rheum 2000;43:1345.]7. Jiang Y, Genant HK, Watt I, et al. A mul-ticenter, double-blind, dose-ranging, ran-domized, placebo-controlled study of re-combinant human interleukin-1 receptorantagonist in patients with rheumatoid ar-thritis: radiologic progression and correla-tion of Genant and Larsen scores. ArthritisRheum 2000;43:1001-9.8. Lipsky PE, van der Heijde DMFM, StClair EW, et al. Infliximab and methotrexatein the treatment of rheumatoid arthritis.N Engl J Med 2000;343:1594-602.9. Bathon JM, Martin RW, FleischmannRM, et al. A comparison of etanercept andmethotrexate in patients with early rheuma-toid arthritis. N Engl J Med 2000;343:1586-93. [Errata, N Engl J Med 2001;344:76, 240.]10. Kremer JM. Methotrexate and lefluno-mide: biochemical basis for combinationtherapy in the treatment of rheumatoid ar-thritis. Semin Arthritis Rheum 1999;29:14-26.11. Manna SK, Mukhopadhyay A, AggarwalBB. Leflunomide suppresses TNF-inducedcellular responses: effects on NF-kappa B,activator protein-1, c-Jun N-terminal proteinkinase, and apoptosis. J Immunol 2000;165:5962-9.

12. Siemasko K, Chong AS, Jack HM, GongH, Williams JW, Finnegan A. Inhibition ofJAK3 and STAT6 tyrosine phosphorylationby the immunosuppressive drug lefluno-mide leads to a block in IgG1 production.J Immunol 1998;160:1581-8.13. Xu X, Shen J, Mall JW, et al. In vitro andin vivo antitumor activity of a novel immu-nomodulatory drug, leflunomide: mecha-nisms of action. Biochem Pharmacol 1999;58:1405-13.14. Burger D, Begue-Pastor N, Benavent S,et al. The active metabolite of leflunomide,A77 1726, inhibits the production of prosta-glandin E(2), matrix metalloproteinase 1 andinterleukin 6 in human fibroblast-like syn-oviocytes. Rheumatology (Oxford) 2003;42:89-96.15. Breedveld FC, Dayer JM. Leflunomide:mode of action in the treatment of rheuma-toid arthritis. Ann Rheum Dis 2000;59:841-9.16. Rozman B. Clinical pharmacokineticsof leflunomide. Clin Pharmacokinet 2002;41:421-30.17. Beaman JM, Hackett LP, Luxton G, IllettKF. Effect of hemodialysis on leflunomideplasma concentrations. Ann Pharmacother2002;36:75-7.18. Lim V, Pande I. Leflunomide can poten-




drug therapy

2177

tiate the anticoagulant effect of warfarin.BMJ 2002;325:1333.19. Smolen JS, Kalden JR, Scott DL, et al. Ef-ficacy and safety of leflunomide comparedwith placebo and sulphasalazine in activerheumatoid arthritis: a double-blind, ran-domised, multicentre trial. Lancet 1999;353:259-66.20. Perez-Ruiz F, Nolla JM. Influence ofleflunomide on renal handling of urate andphosphate in patients with rheumatoid ar-thritis. J Clin Rheumatol 2003;9:215-8.21. Cohen S, Cannon GW, Schiff M, et al.Two-year, blinded, randomized, controlledtrial of treatment of active rheumatoid ar-thritis with leflunomide compared withmethotrexate. Arthritis Rheum 2001;44:1984-92.22. Strand V, Cohen S, Schiff M, et al. Treat-ment of active rheumatoid arthritis withleflunomide compared with placebo andmethotrexate. Arch Intern Med 1999;159:2542-50.23. Schuna AA, Megeff C. New drugs for thetreatment of rheumatoid arthritis. Am JHealth Syst Pharm 2000;57:225-34.24. American College of Rheumatology. Re-ports of leflunomide hepatotoxicity in pa-tients with rheumatoid arthritis. Hotline.(Accessed April 26, 2004, at http://www.rheumatology.org/publications/hotline/0801leflunomide.asp?aud=mem.)25. Idem. Hotline. FDA meeting March2003: update on the safety of new drugs forrheumatoid arthritis. Part III: safety and effi-cacy update on leflunomide (Arava) (Ac-cessed April 26, 2004, at http://www.rheumatology.org/publications/hotline/0503leffda.asp?aud=mem.)26. Food and Drug Administration, Centerfor Drug Evaluation and Research, ArthritisAdvisory Committee meeting, WednesdayMarch 5, 2003. (Accessed April 26, 2004, athttp://www.fda.gov/ohrms/dockets/ac/03/transcripts/3930T2.htm.)27. Weinblatt ME, Kremer JM, Coblyn JS, etal. Pharmacokinetics, safety, and efficacy ofcombination treatment with methotrexateand leflunomide in patients with activerheumatoid arthritis. Arthritis Rheum 1999;42:1322-8.28. Kremer JM, Genovese MC, Cannon GW,et al. Concomitant leflunomide therapy inpatients with active rheumatoid arthritis de-spite stable doses of methotrexate: a ran-domized, double-blind, placebo-controlledtrial. Ann Intern Med 2002;137:726-33.29. Weinblatt ME, Dixon JA, Falchuk KR.Serious liver disease in a patient receivingmethotrexate and leflunomide. ArthritisRheum 2000;43:2609-11.30. Coblyn JS, Shadick N, Helfgott S.Leflunomide-associated weight loss in rheu-matoid arthritis. Arthritis Rheum 2001;44:1048-51.31. Rozman B, Praprotnik S, Logar D, et al.Leflunomide and hypertension. Ann RheumDis 2002;61:567-9.

32. Auer J, Hinterreiter M, Allinger S, Kirch-gatterer A, Knoflach P. Severe pancytopeniaafter leflunomide in rheumatoid arthritis.Acta Med Austriaca 2000;27:131-2.33. Marchesoni A, Arreghini M, Panni B,Battafarano N, Uziel L. Life-threatening re-versible bone marrow toxicity in a rheuma-toid arthritis patient switched from lefluno-mide to infliximab. Rheumatology (Oxford)2003;42:193-4.34. Aventis statement in response to report-ed cases of interstitial pneumonitis in Japan.(Accessed April 26, 2004, at http://www.arava.com/docs/Japan_IP_Arava.pdf.) 35. Brent RL. Teratogen update: reproduc-tive risks of leflunomide (Arava): a pyrimi-dine synthesis inhibitor: counseling womentaking leflunomide before or during preg-nancy and men taking leflunomide who arecontemplating fathering a child. Teratology2001;63:106-12.36. Sokka T. Pincus T. Contemporary diseasemodifying antirheumatic drugs (DMARD)in patients with recent onset rheumatoid ar-thritis in a US private practice: methotrexateas the anchor drug in 90% and new DMARDin 30% of patients. J Rheumatol 2002;29:2521-4.37. Mladenovic V, Domljan Z, Rozman B, etal. Safety and effectiveness of leflunomide inthe treatment of patients with active rheu-matoid arthritis: results of a randomized,placebo-controlled, phase II study. ArthritisRheum 1995;38:1595-603.38. Bazzoni F, Beutler B. The tumor necro-sis factor ligand and receptor families.N Engl J Med 1996;334:1717-25.39. Taylor PC, Peters AM, Paleolog E, et al.Reduction of chemokine levels and leuko-cyte traffic to joints by tumor necrosis factoralpha blockade in patients with rheumatoidarthritis. Arthritis Rheum 2000;43:38-47.40. Black RA, Rauch CT, Kozlosky CJ, et al.A metalloproteinase disintegrin that releas-es tumour-necrosis factor-alpha from cells.Nature 1997;385:729-33.41. Newton RC, Solomon KA, CovingtonMB, et al. Biology of TACE inhibition. AnnRheum Dis 2001;60:Suppl 3:iii25-iii32.42. Smith CA, Davis T, Anderson D, et al. Areceptor for tumor necrosis factor definesan unusual family of cellular and viral pro-teins. Science 1990;248:1019-23.43. Saxne T, Palladino MA Jr, Heinegard D,Talal N, Wollheim FA. Detection of tumornecrosis factor alpha but not tumor necrosisfactor beta in rheumatoid arthritis synovialfluid and serum. Arthritis Rheum 1988;31:1041-5.44. Chu CQ, Field M, Feldmann M, MainiRN. Localization of tumor necrosis factor al-pha in synovial tissues and at the cartilage-pannus junction in patients with rheuma-toid arthritis. Arthritis Rheum 1991;34:1125-32.45. Neidel J, Schulze M, Lindschau J. Asso-ciation between degree of bone-erosion andsynovial fluid-levels of tumor necrosis factor

alpha in the knee-joints of patients withrheumatoid arthritis. Inflamm Res 1995;44:217-21.46. Keffer J, Probert L, Cazlaris H, et al.Transgenic mice expressing human tumournecrosis factor: a predictive genetic modelof arthritis. EMBO J 1991;10:4025-31.47. Williams RO, Feldmann M, Maini RN.Anti-tumor necrosis factor ameliorates jointdisease in murine collagen-induced arthri-tis. Proc Natl Acad Sci U S A 1992;89:9784-8.48. Elliott MJ, Maini RN, Feldmann M, et al.Treatment of rheumatoid arthritis with chi-meric monoclonal antibodies to tumor ne-crosis factor alpha. Arthritis Rheum 1993;36:1681-90.49. Elliott MJ, Maini RN, Feldmann M, et al.Repeated therapy with monoclonal antibodyto tumour necrosis factor alpha (cA2) in pa-tients with rheumatoid arthritis. Lancet1994;344:1125-7.50. Korth-Bradley JM, Rubin AS, HannaRK, Simcoe DK, Lebsack ME. The pharma-cokinetics of etanercept in healthy volun-teers. Ann Pharmacother 2000;34:161-4.51. Lee H, Kimko HC, Rogge M, Wang D,Nestorov I, Peck CC. Population pharmaco-kinetics and pharmacodynamics modelingof etanercept using logistic regressionanalysis. Clin Pharmacol Ther 2003;73:348-65.52. Keystone EC, Schiff MH, Kremer JM, etal. Once-weekly administration of 50 mgetanercept in patients with active rheuma-toid arthritis: results of a multicenter, ran-domized, double-blind, placebo-controlledtrial. Arthritis Rheum 2004;50:353-63.53. Moreland LW, Baumgartner SW, SchiffMH, et al. Treatment of rheumatoid arthritiswith a recombinant human tumor necrosisfactor receptor (p75)-Fc fusion protein.N Engl J Med 1997;337:141-7.54. Moreland LW, Schiff MH, BaumgartnerSW, et al. Etanercept therapy in rheumatoidarthritis: a randomized, controlled trial.Ann Intern Med 1999;130:478-86.55. Weinblatt ME, Kremer JM, BankhurstAD, et al. A trial of etanercept, a recombi-nant tumor necrosis factor receptor:Fc fu-sion protein, in patients with rheumatoidarthritis receiving methotrexate. N Engl JMed 1999;340:253-9.56. Maini R, St Clair EW, Breedveld F, et al.Infliximab (chimeric anti-tumour necrosisfactor alpha monoclonal antibody) versusplacebo in rheumatoid arthritis patients re-ceiving concomitant methotrexate: a ran-domised phase III trial. Lancet 1999;354:1932-9.57. Humira (adalimumab). Abbott Labora-tories (package insert). (Accessed April 26,2004, at http://www.fda.gov/cder/foi/label/2002/adalabb123102LB.htm.)58. Weinblatt ME, Keystone EC, Furst DE,et al. Adalimumab, a fully human anti-tumor necrosis factor alpha monoclonalantibody, for the treatment of rheumatoid





2178

arthritis in patients taking concomitantmethotrexate: the ARMADA trial. ArthritisRheum 2003;48:35-45. [Erratum, ArthritisRheum 2003;48:855.]59. American College of Rheumatologysubcommittee on Rheumatoid ArthritisGuidelines. Guidelines for the managementof rheumatoid arthritis: 2002 update. Ar-thritis Rheum 2002;46:328-46.60. Knight DM, Trinh H, Le J, et al. Con-struction and initial characterization of amouse-human chimeric anti-TNF antibody.Mol Immunol 1993;30:1443-53.61. Scallon BJ, Moore MA, Trinh H, KnightDM, Ghrayeb J. Chimeric anti-TNF-alphamonoclonal antibody cA2 binds recombi-nant transmembrane TNF-alpha and acti-vates immune effector functions. Cytokine1995;7:251-9.62. St Clair EW, Wagner CL, Fasanmade AA,et al. The relationship of serum infliximabconcentrations to clinical improvement inrheumatoid arthritis: results from ATTRACT,a multicenter, randomized, double-blind,placebo-controlled trial. Arthritis Rheum2002;46:1451-9.63. Elliott MJ, Maini RN, Feldmann M, et al.Randomised double-blind comparison ofchimeric monoclonal antibody to tumournecrosis factor alpha (cA2) versus placeboin rheumatoid arthritis. Lancet 1994;344:1105-10.64. Maini RN, Breedveld FC, Kalden JR, et al.Therapeutic efficacy of multiple intravenousinfusions of anti-tumor necrosis factor alphamonoclonal antibody combined with low-dose weekly methotrexate in rheumatoid ar-thritis. Arthritis Rheum 1998;41:1552-63.65. den Broeder A, van de Putte LBA, et al. Asingle dose, placebo controlled study of thefully human anti-tumor necrosis factor-aantibody adalimumab (D2E7) in patientswith rheumatoid arthritis. J Rheumatol2002;29:2288-98.66. Velagapudi RB, Noertershauser P, Bank-mann Y, et al. Pharmacokinetics of adali-mumab (D2E7), a fully human anti-TNF-amonoclonal antibody, following a single in-travenous injection in rheumatoid arthritispatients treated with methotrexate. ArthritisRheum 2002;46:Suppl:S133. abstract.67. van de Putte LBA, Atkins C, Malaise M,et al. Adalimumab (D2E7) monotherapy inthe treatment of patients with severely activerheumatoid arthritis. Arthritis Rheum 2002;46:Suppl:S205. abstract.68. Abbott Laboratories. Humira (adalimu-mab). Advisory Committee briefing docu-ment, February 4, 2003. (Accessed April26, 2004, at http://www.fda.gov/ohrms/dockets/ac/03/briefing/3930B1_02_A-Abbott-Humira.doc.)69. Moreland LW, Cohen SB, BaumgartnerSW, et al. Long-term safety and efficacy ofetanercept in patients with rheumatoid ar-thritis. J Rheumatol 2001;28:1238-44.70. Day R. Adverse reactions to TNF-alphainhibitors in rheumatoid arthritis. Lancet2002;359:540-1.

71. Warris A, Bjørneklett A, Gaustad P. In-vasive pulmonary aspergillosis associatedwith infliximab therapy. N Engl J Med 2001;344:1099-100.72. Kamath BM, Mamula P, Baldassano RN,Markowitz JE. Listeria meningitis aftertreatment with infliximab. J Pediatr Gastro-enterol Nutr 2002;34:410-2.73. Kashyap AS, Kashyap S. Infliximab-induced aseptic meningitis. Lancet 2002;359:1252.74. McCain ME, Quinet RJ, Davis WE. Etan-ercept and infliximab associated with cuta-neous vasculitis. Rheumatology (Oxford)2002;41:116-7.75. Nakelchik M, Mangino JE. Reactivationof histoplasmosis after treatment with in-fliximab. Am J Med 2002;112:78.76. Mohan N, Edwards ET, Cupps TR, et al.Demyelination occurring during anti-tumornecrosis factor alpha therapy for inflamma-tory arthritides. Arthritis Rheum 2001;44:2862-9.77. Brown SL, Greene MH, Gershon SK,Edwards ET, Braun MM. Tumor necrosisfactor antagonist therapy and lymphomadevelopment: twenty-six cases reported tothe Food and Drug Administration. ArthritisRheum 2002;46:3151-8.78. Shakoor N, Michalska M, Harris CA,Block JA. Drug-induced systemic lupuserythematosus associated with etanercepttherapy. Lancet 2002;359:579-80.79. Food and Drug Administration, Centerfor Drug Evaluation and Research, ArthritisAdvisory Committee. Safety update meetingon TNF blocking agents. Tuesday, March 4,2003. (Accessed April 26, 2004, at http://www.fda.gov/ohrms/dockets/ac/03/transcripts/ 3930T1.htm.) 80. Kroesen S, Widmer AF, Tyndall A,Hasler P. Serious bacterial infections in pa-tients with rheumatoid arthritis under anti-TNF-alpha therapy. Rheumatology (Oxford)2003;42:617-21.81. Lee JH, Slifman NR, Gershon SK, et al.Life-threatening histoplasmosis complicat-ing immunotherapy with tumor necrosis fac-tor alpha antagonists infliximab and etaner-cept. Arthritis Rheum 2002;46:2565-70.82. Helbling D, Breitbach TH, Krause M.Disseminated cytomegalovirus infection inCrohn’s disease following anti-tumour ne-crosis factor therapy. Eur J GastroenterolHepatol 2002;14:1393-5.83. Fleischmann RM, Baumgartner SW,Tindall EA, et al. Response to etanercept(Enbrel) in elderly patients with rheumatoidarthritis: a retrospective analysis of clinicaltrial results. J Rheumatol 2003;30:691-6.84. Doran MF, Crowson CS, Pond GR,O’Fallon WM, Gabriel SE. Frequency ofinfection in patients with rheumatoid ar-thritis compared with controls: a popula-tion-based study. Arthritis Rheum 2002;46:2287-93.85. Kindler V, Sappino AP, Grau GE, PiguetPF, Vassalli P. The inducing role of tumor ne-crosis factor in the development of bacteri-

cidal granulomas during BCG infection.Cell 1989;56:731-40.86. Mohan VP, Scanga CA, Yu K, et al. Ef-fects of tumor necrosis factor alpha on hostimmune response in chronic persistent tu-berculosis: possible role for limiting pathol-ogy. Infect Immun 2001;69:1847-55.87. Keane J, Gershon S, Wise RP, et al. Tu-berculosis associated with infliximab, a tu-mor necrosis factor a–neutralizing agent.N Engl J Med 2001;345:1098-104.88. Ekstrom K, Hjalgrim H, Brandt L, et al.Risk of malignant lymphomas in patientswith rheumatoid arthritis and in their first-degree relatives. Arthritis Rheum 2003;48:963-70.89. Baecklund E, Ekbom A, Sparen P, Felte-lius N, Klareskog L. Disease activity and riskof lymphoma in patients with rheumatoidarthritis: nested case-control study. BMJ1998;317:180-1.90. Colombel JF, Loftus EV Jr, Tremaine WJ,et al. The safety profile of infliximab in pa-tients with Crohn’s disease: the Mayo Clinicexperience in 500 patients. Gastroenterolo-gy 2004;126:19-31.91. Baert F, Noman M, Vermeire S, et al. In-fluence of immunogenicity on the long-term efficacy of infliximab in Crohn’s dis-ease. N Engl J Med 2003;348:601-8.92. Food and Drug Administration. Adali-mumab — for use in the treatment of rheu-matoid arthritis. Abbott biologic licensingapplication. (Accessed April 26, 2004, athttp://www.fda.gov/cder/biologics/review/adalabb123102r1.htm.)93. Charles PJ, Smeenk RJ, De Jong J, Feld-mann M, Maini RN. Assessment of antibod-ies to double-stranded DNA induced in rheu-matoid arthritis patients following treatmentwith infliximab, a monoclonal antibody totumor necrosis factor alpha: findings inopen-label and randomized placebo-con-trolled trials. Arthritis Rheum 2000;43:2383-90.94. Mohan AK, Edwards ET, Cote TR, SiegelJN, Braun MM. Drug-induced systemic lu-pus erythematosus and TNF-alpha block-ers. Lancet 2002;360:646.95. TNF neutralization in MS: results of arandomized, placebo-controlled multicenterstudy. Neurology 1999;53:457-65.96. Francis GS. TNF-alpha and heart fail-ure: the difference between proof of princi-ple and hypothesis testing. Circulation 1999;99:3213-4.97. Fichtlscherer S, Rossig L, Breuer S, VasaM, Dimmeler S, Zeiher AM. Tumor necrosisfactor antagonism with etanercept improvessystemic endothelial vasoreactivity in pa-tients with advanced heart failure. Circula-tion 2001;104:3023-5.98. Bozkurt B, Torre-Amione G, Warren MS,et al. Results of targeted anti-tumor necro-sis factor therapy with etanercept (ENBREL)in patients with advanced heart failure. Cir-culation 2001;103:1044-7.99. Chung ES, Packer M, Lo KH, Fasan-made AA, Willerson JT. Randomized, dou-




drug therapy

2179

ble-blind, placebo-controlled, pilot trial ofinfliximab, a chimeric monoclonal antibodyto tumor necrosis factor-alpha, in patientswith moderate-to-severe heart failure: re-sults of the anti-TNF Therapy Against Con-gestive Heart Failure (ATTACH) trial. Circu-lation 2003;107:3133-40.100. Furst DE, Cush J, Kaufmann S, Siegel J,Kurth R. Preliminary guidelines for diag-nosing and treating tuberculosis in patientswith rheumatoid arthritis in immunosup-pressive trials or being treated with biologi-cal agents. Ann Rheum Dis 2002;61:Suppl2:ii62-ii63.101. Dinarello CA. Biologic basis for inter-leukin-1 in disease. Blood 1996;87:2095-147.102. Horai R, Saijo S, Tanioka H, et al. De-velopment of chronic inflammatory arthrop-athy resembling rheumatoid arthritis in in-terleukin 1 receptor antagonist-deficientmice. J Exp Med 2000;191:313-20.103. Firestein GS, Boyle DL, Yu C, et al. Syn-ovial interleukin-1 receptor antagonist andinterleukin-1 balance in rheumatoid arthri-tis. Arthritis Rheum 1994;37:644-52.104. Arend WP, Malyak M, Guthridge CJ,Gabay C. Interleukin-1 receptor antagonist:role in biology. Annu Rev Immunol 1998;16:27-55.105. Bresnihan B, Cunnane G. Interleukin-1receptor antagonist. Rheum Dis Clin NorthAm 1998;24:615-28.106. Yang BB, Baughman S, Sullivan JT.Pharmacokinetics of anakinra in subjectswith different levels of renal function. ClinPharmacol Ther 2003;74:85-94.107. Campion GV, Lebsack ME, LookabaughJ, Gordon G, Catalano M. Dose-range anddose-frequency study of recombinant humaninterleukin-1 receptor antagonist in patientswith rheumatoid arthritis. Arthritis Rheum1996;39:1092-101.

108. Bresnihan B, Alvaro-Gracia JM, CobbyM, et al. Treatment of rheumatoid arthritiswith recombinant human interleukin-1 re-ceptor antagonist. Arthritis Rheum 1998;41:2196-204.109. Cohen S, Hurd E, Cush J, et al. Treat-ment of rheumatoid arthritis with anakinra,a recombinant human interleukin-1 receptorantagonist, in combination with metho-trexate: results of a twenty-four-week, mul-ticenter, randomized, double-blind, placebo-controlled trial. Arthritis Rheum 2002;46:614-24.110. Nuki G, Bresnihan B, Bear MB, Mc-Cabe D. Long-term safety and maintenanceof clinical improvement following treat-ment with anakinra (recombinant humaninterleukin-1 receptor antagonist) in pa-tients with rheumatoid arthritis: extensionphase of a randomized, double-blind, place-bo-controlled trial. Arthritis Rheum 2002;46:2838-46.111. Fleischmann RM, Schechtman J, Ben-nett R, et al. Anakinra, a recombinant hu-man interleukin-1 receptor antagonist (r-metHuIL-1ra), in patients with rheumatoidarthritis: a large, international, multicenter,placebo-controlled trial. Arthritis Rheum2003;48:927-34.112. Schiff MH, Bulpitt K, Weaver AA, et al.Safety of combination therapy with anakinraand etanercept in patients with rheumatoidarthritis. Arthritis Rheum 2001;44:Suppl:S79. abstract.113. Mease PJ, Goffe BS, Metz J, Vander-Stoep A, Finck B, Burge DJ. Etanercept inthe treatment of psoriatic arthritis and pso-riasis: a randomised trial. Lancet 2000;356:385-90.114. Gorman JD, Sack KE, Davis JC Jr.Treatment of ankylosing spondylitis by inhi-bition of tumor necrosis factor a. N Engl JMed 2002;346:1349-56.

115. Husni ME, Maier AL, Mease PJ, et al.Etanercept in the treatment of adult patientswith Still’s disease. Arthritis Rheum 2002;46:1171-6.116. Reiff A, Takei S, Sadeghi S, et al. Etan-ercept therapy in children with treatment-resistant uveitis. Arthritis Rheum 2001;44:1411-5.117. Stone JH, Uhlfelder ML, Hellmann DB,Crook S, Bedocs NM, Hoffman GS. Etaner-cept combined with conventional treatmentin Wegener’s granulomatosis: a six-monthopen-label trial to evaluate safety. ArthritisRheum 2001;44:1149-54.118. Yocum DE, Furst DE, Kaine JL, et al. Ef-ficacy and safety of tacrolimus in patientswith rheumatoid arthritis: a double-blindtrial. Arthritis Rheum 2003;48:3328-37.119. Silverman GJ, Weisman S. Rituximabtherapy and autoimmune disorders: pros-pects for anti-B cell therapy. ArthritisRheum 2003;48:1484-92.120. Choy EH, Isenberg DA, Garrood T, etal. Therapeutic benefit of blocking interleu-kin-6 activity with an anti-interleukin-6 re-ceptor monoclonal antibody in rheumatoidarthritis: a randomized, double-blind, pla-cebo-controlled, dose-escalation trial. Ar-thritis Rheum 2002;46:3143-50.121. Kremer JM, Westhovens R, Leon M, etal. Treatment of rheumatoid arthritis by se-lective inhibition of T-cell activation with fu-sion protein CTLA4Ig. N Engl J Med 2003;349:1907-15.122. Smolen JS, Steiner G. Therapeuticstrategies for rheumatoid arthritis. Nat RevDrug Discov 2003;2:473-88.Copyright © 2004 Massachusetts Medical Society.



Documents

New Drugs for Rheumatoid Arthritis