O RIGINAL R EVIEW A RTICLE

Pharmacoeconomics 2004; 22 Suppl. 1: 39-53 1170-7690/04/0001-0039/$30.00/0 © Adis Data Information BV 2004. All rights reserved.

Drugs That Block Tumour Necrosis Factor: Experience in Patients with Rheumatoid Arthritis Larry W. Moreland University of Alabama at Birmingham, Department of Medicine, Division of Clinical Immunology and Rheumatology, Birmingham, Alabama, USA

Abstract

Three biological response modifiers that inhibit tumour necrosis factor-␣ (TNF-␣) are approved for treating rheumatoid arthritis (RA). Etanercept is a fusion protein comprising two soluble human TNF-␣ receptors linked to the Fc fragment of human immunoglobulin G1. Infliximab is a chimeric (human/mouse) monoclonal antibody and adalimumab is a humanised monoclonal antibody. In placebo-controlled trials in established disease-modifying antirheumatic drug (DMARD)-refractory RA, the anti-TNF-␣ agents have reduced disease activity, as monotherapy or in combination with methotrexate. In long-term, open-label studies with etanercept or adalimumab, clinical response was sustained for up to 5 years. In early RA, etanercept has similar efficacy to methotrexate. However, etanercept was more effective than methotrexate in preventing radiographic progression. Preventing or delaying disease progression and disability with etanercept therapy in early RA may reduce costs associated with long-term disease outcomes. Data also suggest a benefit of infliximab plus methotrexate or adalimumab plus methotrexate in early RA. All three agents have been shown to improve functionality as assessed by health assessment questionnaire (HAQ) disability scores. Health-related quality of life is also improved in terms of physical and mental health and vitality. Furthermore, etanercept and adalimumab are associated with a reduction in fatigue. Long-term etanercept or infliximab therapy is associated with increased job employment and etanercept also reduces healthcare utilisation. Mild, transient injection-site reactions occur in about 33% of patients treated with etanercept and 20% of patients treated with adalimumab. In patients treated with infliximab, 16–20% have infusion reactions. The incidence of serious infection associated with etanercept and infliximab was low, about 2–3% in etanercept studies of up to 5 years duration, and 5% in a survey of more than 10 infliximab trials. This paper reviews the evidence for efficacy, safety and effectiveness of anti-TNF-␣ agents in RA.

1. Anti-Tumour Necrosis Factor-␣ (TNF␣) Agents TNF-␣ is a normal component of the immune system that appears to be important in keeping in-

fection localised. However, when present systemically, it exerts proinflammatory effects, and plays a pivotal role in inflammatory and joint damage processes in rheumatoid arthritis (RA).[1–4] The

40

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proinflammatory action of TNF-␣ is receptor-mediated. Recombinant anti-TNF-␣ agents such as etanercept, infliximab and adalimumab are able to suppress inflammation by providing an alternative, high-affinity site that binds TNF-␣ before it reaches its membrane-bound receptor. Etanercept is a fusion protein comprising the extracellular domains of two soluble human TNF␣ p75 receptors, linked to the Fc fragment of human immunoglobulin (Ig) G1 to provide an extended half-life (table I).[1–6] Etanercept, administered subcutaneously, is approved for use in the US in disease-modifying antirheumatic drug (DMARD)refractory and DMARD-naïve patients, as a monotherapy or in combination with methotrexate, for reducing the signs and symptoms of active arthritis and inhibiting the progression of structural damage. Etanercept is also approved in Europe as monotherapy or in combination with methotrexate in DMARD-refractory patients and in adult patients with severe, active and progressive RA not previously treated with methotrexate. In methotrexatenaïve patients, etanercept has been shown to slow progression of disease-associated structural damage as measured by radiography.[7,8] Infliximab is a chimeric mouse/human IgG1 anti-TNF-␣ monoclonal antibody (table I).[9,10] It is approved for use as an intravenous infusion in combination with methotrexate for the treatment of RA in several markets, including the US and Europe. Unlike etanercept, infliximab is not approved for use

in DMARD-naïve patients and must be given in combination with methotrexate. In the US, infliximab is specifically approved to reduce the signs and symptoms of active arthritis, inhibit the progression of structural damage and improve physical function. Adalimumab is a human anti-TNF-␣ monoclonal antibody indicated in the US to reduce signs and symptoms and inhibit the progression of structural damage in adult patients with moderately to severely active RA who have had an inadequate response to one or more DMARDs (table I). It can be used alone or in combination with methotrexate or other DMARDs. The aim of this paper is to review the evidence for efficacy, safety and effectiveness of anti-TNF␣ agents in RA. A literature search was completed with Medline, Pre-Medline and Embase, using the drug names and synonyms and rheumatoid arthritis. Manual searches of the annual meeting abstracts from the European League Against Rheumatism (EULAR) and the American College of Rheumatology (ACR) were also conducted. 2. Efficacy 2.1 Established Rheumatoid Arthritis (DMARD Failure) 2.1.1 Etanercept Randomised Trials

A number of randomised, double-blind, placebocontrolled studies have shown that etanercept reduces disease activity in patients with active RA who have

Table I. Anti-tumour necrosis factor-alpha (TNF-␣) agents for rheumatoid arthritis (RA) Agent

Description

RA indications

Etanercept (Enbrel)

Fusion protein comprising the extracellular domains of two soluble human TNF-␣ p75 receptors linked to the Fc fragment of human IgG1

Monotherapy or in combination with methotrexate in DMARD-refractory or DMARD-naïve patients in US and Europe

Infliximab (Remicade)

Chimeric mouse/human IgG1 anti-TNF-␣ monoclonal antibody

Combination with methotrexate in DMARD-refractory patients in US and Europe

Adalimumab (Humira)

Human anti-TNF-␣ monoclonal antibody

Monotherapy or in combination with DMARDs in DMARDrefractory patients in US Filed for this indication in Europe

DMARD = disease-modifying antirheumatic drug; IgG1 = immunoglobulin G1.

© Adis Data Information BV 2004. All rights reserved.

Pharmacoeconomics 2004; 22 Suppl. 1

Drugs That Block Tumour Necrosis Factor

had an inadequate response to DMARDs, as monotherapy (table II)[11–13] or in combination with methotrexate.[14] The standard dosage of etanercept 25 mg twice weekly as monotherapy resulted in ACR20 criteria being achieved in 70% of patients.[12] Combination therapy with methotrexate plus etanercept was more effective than methotrexate plus placebo in a double-blind trial.[14] At 6 months, ACR20 criteria were achieved in 71% of patients receiving etanercept in combination vs 27% of those treated with methotrexate plus placebo (p < 0.001). Patients entered the trial on background methotrexate therapy and were randomized to receive either placebo or etanercept. 2.1.2 Etanercept Nonrandomised Trials

In long-term, open-label extension studies, clinical response to etanercept therapy was sustained in the majority of patients for up to 5 years.[15–25] Among patients treated with methotrexate at baseline, methotrexate dosage was reduced by 26–63% as the trial proceeded, and the drug was discontinued in 26–29% of patients.[14,16,17,19] Similarly, 55–69% of those receiving prednisone or equivalent steroids at the outset of the trial underwent steroid dose reductions of 32–78% during the course of the trial, with 29–42% of initially steroidtreated patients discontinuing therapy.[15–17,19,21,22] C-reactive protein levels are usually elevated with active disease, and median levels were reduced by 70% after 6 months of treatment with etanercept in the study reporting this parameter.[23] 2.1.3 Infliximab Randomised Trials

In large-scale, controlled trials of up to 54 weeks’ duration,[26–31] infliximab has been shown to be effective with regard to clinical response and radiographic progression in patients with DMARDrefractory RA also receiving methotrexate. The largest of these, the Anti-TNF Trial in Rheumatoid Arthritis with Concomitant Therapy (ATTRACT), randomised 428 patients receiving methotrexate to concomitant therapy with infliximab or placebo (table III). Four infliximab dosage groups were stud© Adis Data Information BV 2004. All rights reserved.

41

ied: infliximab 3 mg/kg every 4 weeks or every 8 weeks, or 10 mg/kg every 4 weeks or every 8 weeks. All 4 infliximab doses were significantly more effective than placebo in achieving ACR20 improvements at 30 weeks,[27] and ACR20, ACR50 and ACR70 improvements at 54 weeks.[29] Patients receiving placebo had an increase in radiographic evidence of joint damage, whereas no increase of damage was seen in the infliximab group (p < 0.001).[29] Quality of life was also significantly better in the infliximab group than in the placebo group.[29] 2.1.4 Infliximab Nonrandomised Trials

The efficacy of infliximab in patients receiving methotrexate has also been demonstrated in openlabel noncomparative studies.[32–35] 2.1.5 Adalimumab Randomised Trials

Adalimumab is also effective in patients with RA who have not responded to DMARDs, either as monotherapy[36] or in combination with methotrexate[37–39] (table IV). Combination with methotrexate resulted in ACR20 responses being attained in around 70% of patients.[38,39] Data from a 52-week period revealed that patients who received adalimumab in combination with methotrexate had significantly less radiographic progression than patients who received placebo plus methotrexate.[37] A meta-analysis of four randomised, placebocontrolled trials showed that adalimumab 40 mg every other week, either alone or in combination with methotrexate, provided substantial, sustained improvement in Disease Activity Score (DAS) 28 and EULAR responses in RA patients with active disease.[40] At 24 weeks, DAS28 improvement ranged from 33% to 53% and a moderate EULAR response was seen in 69% of patients. 2.1.6 Adalimumab Nonrandomised Trials

Nonrandomised trials have also shown the effectiveness of adalimumab in patients with RA who have not responded to DMARD therapy, either as monotherapy[41–47] or in combination with methotrexate.[48–50] EULAR response criteria were fulPharmacoeconomics 2004; 22 Suppl. 1

Design ACR20, 50,70

Clinical efficacy Morning stiffness (h or % improvement)

© Adis Data Information BV 2004. All rights reserved.

ND

ND

ND

ND

ND

39%

ND

ND

ND

33%

78%**

ND

ND

ND

ND

ND

ND

2%c

39%c**

34%c**

123 104 141**

137

HAQ (% improvement)a

ND

ND

ND

1.6

0.5**

–207%

31%*

–18%

2.0 0.9 2.6**

2.4

CRP (mg/dL or % improvement)

Bathon et al. (2000)[7]

Weinblatt et al. (1999)[14]

Wajdula et al. (2000)[12]

Moreland et al. (1999)[13]

Moreland et al. (1997)[11]

Reference

* p < 0.05; ** p < 0.001; § p = 0.004 a Scale of 45 (best) to 245 (worst). b Percent normalisation. c Disability index. ACR = American College of Rheumatology scale; CRP = C-reactive protein; ESR = erythrocyte sedimentation rate; HAQ = Health Assessment Questionnaire; ND = no data.

Weekly

65, ND, ND

ND

ND

ND

72, ND, ND

Twice weekly Methotrexate (217)

30

15§

25 mg (207)

1.25

0.17**

ND

27%, 3%, 0%

Double blind, 24- 71%**, 39%**, week evaluation 15%*

Versus methotrexate monotherapy in early rheumatoid arthritis 12-month evaluation 10 mg (208) ND, ND, ND ND

Twice weekly

Placebo (30)

25 mg (59)

Combination therapy with methotrexate in methotrexate-refractory patients 75%**

ND

57%*

12%, ND, ND

53%*

ND

70%*, ND, ND

37% ND

ND

–7%

25 mg weekly 25 mg twice weekly Placebo

6%

34%b*

47%*

43% ND

56%**

67%b

45%*

47%, ND, ND ND

44%**

53%b

10 mg weekly 10 mg twice weekly

–13%**

32%

32%

46% 64% 28%**

25%

11%, 5%, 1%

Double blind, 6- 51%**, 24%**, month evaluation 9%* 59%**, 40%**, 15%*

32% 58% 24%**

27 21 40**

39

Swollen joint count (% improvement)

Placebo Twice weekly

25 mg

5.3

46%, 22%, ND 2.6 75%, 57%, ND 1.1 14%**, 7%**, ND 4.1§

Multicentre, double blind, 3(180) month evaluation 33%, 9%, ND

Placebo Twice weekly 10 mg

2 mg/m2 16 mg/m2

0.25

mg/m2 16%

ESR (mm/h or Tender joint % improvement) count (% improvement)

Monotherapy in disease-modifying antirheumatic drug (DMARD)-refractory patients

Dosage (number of patients)

Table II. Randomised, placebo-controlled trials of etanercept in rheumatoid arthritis (RA)

42 Moreland

Pharmacoeconomics 2004; 22 Suppl. 1

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43

Table III. Randomised, placebo-controlled trials of infliximab in patients with disease-modifying antirheumatic drug-refractory rheumatoid arthritis receiving methotrexate Dosage (number of patients)

Design

3 mg/kg q8w (86) 3 mg/kg q4w (86) 10 mg/kg q8w (87) 10 mg/kg q4w (81) Placebo

Double blind, 30-week

3 mg/kg q8w (86) 3 mg/kg q4w (86) 10 mg/kg q8w (87) 10 mg/kg q4w (81) Placebo

Double blind, 54-week

Clinical efficacy

Reference

ACR20, 50, 70

Tender joint count (% improvement)

Swollen joint count (% improvement)

HAQ (% improvement)a

CRP (mg/dL or % improvement)

ND, 27%**, 8%* ND, 29%**, 11%† ND, 31%**, 18%** ND, 26%**, 11%† ND, 5%, 0%

59§

52**

13

60%**

65‡

50**

29**

61%**

58**

60**

27**

68%**

65**

64**

24**

76%**

26

20

3

9%

42**, 21*, 10*

49**

37**

ND

1.6§

48**, 34**, 17** 55**

50**

ND

1.5**

59**, 39**, 25** 56**

60**

ND

1.2**

59**, 38**, 19** 65**

63**

ND

1.1**

17, 8, 2

13

ND

2.8

23

**

p < 0.001; § p = 0.006; † p = 0.002; ‡ p = 0.003

a

Scale of 45 (best) to 245 (worst).

Maini et al. (1999)[27]

Lipsky et al. (2000)[29]

ACR = American College of Rheumatology scale; CRP = C-reactive protein; HAQ = Health Assessment Questionnaire; ND = no data.

filled in 83% of patient visits with adalimumab monotherapy, compared with 40% in a group treated with methotrexate in a 48-week trial.[43] Efficacy of adalimumab monotherapy was sustained in an open-label extension study involving 794 patients, with ACR20 responses of 67% at 5 years.[46] Ratingen radiographic scores were reduced by adalimumab monotherapy in 66 patients treated for 12 months.[44] An open-label extension of this study in 163 patients demonstrated that radiographic progression was still significantly inhibited by adalimumab at 2 years.[47] 2.1.7 Comparisons of Anti-TNF Agents

There are currently no data from prospective trials directly comparing etanercept with infliximab © Adis Data Information BV 2004. All rights reserved.

or adalimumab. In retrospective studies, etanercept and infliximab had similar efficacy in patients who had failed DMARDs.[51,52] No head-to-head comparative studies of etanercept and adalimumab, or infliximab and adalimumab, have been conducted. A recent meta-analysis evaluated the comparative efficacy of anti-TNF agents in patients with established RA who had failed one or more DMARDs.[53] Based on ACR20 response rates, etanercept monoand combination therapy had similar efficacy and significantly higher ACR20 response rates than other anti-TNF agents. There were no significant differences among infliximab-adalimumab combination therapy, adalimumab monotherapy and leflunomide therapy in terms of ACR20 response rates. Pharmacoeconomics 2004; 22 Suppl. 1

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Table IV. Randomised, placebo-controlled trials of adalimumab in patients with active rheumatoid arthritis receiving methotrexate Dosage (number of patients)

20 mg

Design

Double blind, 3-month (283)

40 mg 80 mg Placebo Once weekly 20 mg

Double blind, 24-week (271)

40 mg 80 mg Placebo Every 2 weeks *

Clinical efficacy

Reference

ACR20, 50, 70

Tender joint count (% improvement)

Swollen joint count (% improvement)

HAQ (% improvement)

CRP (mg/dL or % improvement)

49%**, 24%**, ND 59%**, 27%**, ND 56%**, 19%**, ND 14, 3, ND

52**

39**

ND

53%**

57**

56**

ND

61%**

53**

54**

ND

64%**

15

ND

1%

47.8*, 31.9†, 10.1 65.7*, 53.7*, 26.9§ 65.8*, 42.5*, 19.2§ 14.5, 8.1, 4.8

50.8†

41.9†

0.5†

ND

49.3†

52.8†

0.6†

ND

58.0†

60.0†

0.6†

ND

18.2

5.0

0.2

ND

8

van de Putte et al. (2000)[36]

Keystone et al. (2001)[38]

p < 0.0001; ** p < 0.001; § p < 0.02; † p < 0.003

ACR = American College of Rheumatology scale; CRP = C-reactive protein; HAQ = Health Assessment Questionnaire; ND = no data.

2.2 Early RA

One of the major unanswered questions in rheumatology is which drug or combination of drugs is best for treating early RA. Studies suggest a possible therapeutic window where administration of disease-modifying agents during the early stage of joint damage in RA may be more effective than later treatment.[54–56] Thus, initiation of early effective therapy may reduce costs associated with the long-term disease outcomes, such as lost productivity, and costs associated with joint replacement surgery. 2.2.1 Etanercept Trials

In the pivotal randomised early rheumatoid arthritis (ERA) trial, where patients with disease ⱕ3 years received monotherapy with methotrexate or etanercept, greater improvements were observed in disease activity and joint erosion scores after 6 months of treatment with etanercept 25 mg twice © Adis Data Information BV 2004. All rights reserved.

weekly than with methotrexate at a mean weekly dosage of 19 mg.[7] Etanercept recipients had a more rapid rate of improvement than methotrexate recipients, with significantly more patients in the etanercept group having 20%, 50% and 70% improvement in disease activity during the first 6 months (p < 0.05). During the first 6 months, the mean increase in erosion score was 0.30 in the etanercept group, compared with 0.68 in the methotrexate group (p = 0.001). The respective increases during the first 12 months were 0.47 and 1.03 (p = 0.002). An open-label extension of the ERA trial showed similar results at 2 years;[57] at 3 years, patients who switched from methotrexate to etanercept 25 mg showed greater clinical benefit on the TNF-␣ blocker.[58] 2.2.2 Infliximab Trials

Preliminary data from the randomised ATTRACT indicate that infliximab in combination with methotrexate also improves response rates and Pharmacoeconomics 2004; 22 Suppl. 1

Drugs That Block Tumour Necrosis Factor

reduces radiographic progression in early active RA.[59] The infliximab ASPIRE (Active Controlled Study of Patients Receiving Infliximab for Treatment of Rheumatoid Arthritis of Early Onset) study compares the efficacy and safety of infliximab plus methotrexate with methotrexate alone in methotrexate-naïve patients with early RA. The trial ended in June 2003 and data are expected soon. It is anticipated that the trial’s findings will affect the treatment of early RA.[60] 2.2.3 Adalimumab Trials

While adalimumab plus methotrexate is effective in patients with both early and late RA, there is a trend toward higher efficacy in patients with early onset disease.[61] A study of 618 patients who were previously enrolled in a randomised, controlled trial of adalimumab plus methotrexate were divided into those with early disease (n = 74) or late disease (n = 544).[61] At six months, ACR20, ACR50 and ACR70 responses were 70%, 59% and 41%, respectively, in patients with early disease, and 63%, 36% and 18%, respectively, in those with late disease. This trial was not designed to address the efficacy of adalimumab in patients with early RA specifically. Patients were not randomised and the control was not prospectively identified. 3. Safety Upper Respiratory Tract Infections

Upper respiratory tract infections (URIs) are one of the most common adverse events seen in controlled trials of etanercept.[7,11,13,22] In a randomised trial, the incidence of URI in patients with early RA treated with etanercept was similar to that of patients treated with methotrexate (35% vs 39%).[7] In the randomised ATTRACT trial, the 30week incidence of URI with methotrexate plus infliximab was 20% to 33%, versus 16% with methotrexate plus placebo.[27] At 54 weeks, the incidence was 34% versus 22%, respectively.[29] © Adis Data Information BV 2004. All rights reserved.

45

In a meta-analysis of controlled and open-label trials of patients treated for a median of 25 months, the rate of URI was 0.82/patient year in etanercept recipients, compared with 0.68/patient year in placebo recipients.[21] 3.2 Incidence of Serious Infections

In nonrandomised studies of up to 5 years’ duration, the incidence of serious infection necessitating hospitalisation or intravenous antibiotics associated with etanercept treatment was low, reported as 2–3%, or 0.03–0.05/patient year.[15,16,18,19,21] US labelling for etanercept has a black box warning about postmarketing reports of serious, sometimes fatal, infections during etanercept treatment.[1,62] Rare cases of tuberculosis have also been observed.[62] Patients with an active infection should not receive etanercept and caution is advised on the use of etanercept in patients with recurrent infections or conditions such as diabetes.[62] In a survey of more than ten trials of patients with RA or Crohn’s disease, the incidence of serious infections was similar with infliximab and placebo, at 5% and 8%, respectively.[63] Infliximab’s US labelling contains a boxed warning about the risk of serious infections including tuberculosis, invasive fungal infections, and other opportunistic infections, some of which have been fatal.[64] Postmarketing surveillance has revealed a rate of tuberculosis of 24.4 per 100 000 patients per year,[65] compared with an expected incidence of 6.2 per 100 000 per year in the US general population. Prospective patients must undergo tuberculin skin testing to exclude latent tuberculosis prior to starting anti-TNF-␣ therapy.[64] It is not clear if tuberculosis is a class effect of anti-TNF-␣ agents.[66] Lee and colleagues note that the risks for developing histoplasmosis associated with etanercept or infliximab may differ because the two drugs block TNF-␣ through different mechanisms.[67] Furthermore, infliximab lyses TNFexpressing cells in vitro whereas etanercept does not,[68] and infliximab may induce apoptosis of pePharmacoeconomics 2004; 22 Suppl. 1

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ripheral monocytes in patients with active Crohn’s disease.[69] Thus, it is possible that infliximab may cause lysis of monocytes and macrophages, which would modify cytokine secretion or other functions of these cells. However, in a postmarketing study, the reported incidence in more than 117 000 patients treated with etanercept was 13 cases (0.01%), compared with an expected 11 cases based on the age-adjusted background incidence among the US population.[70] 3.3 Other Issues 3.3.1 Requirement for Concomitant Methotrexate

It is recommended that infliximab be administered with methotrexate to avoid an immune response that can negate clinical efficacy.[26] However, etanercept is recommended as monotherapy, as well as in combination with methotrexate.[11] Adalimumab can also be used effectively as monotherapy. Response to adalimumab monotherapy was rapid with marked improvement seen at 2 weeks and further improvement at 6 months.[40] Efficacy and tolerability of adalimumab monotherapy was also shown to be sustained for four years in DMARD-resistant patients with long-standing RA.[71] 3.3.2 Injection/Infusion-site Reactions

Injection/infusion-site reactions occur in about one-third of patients treated with etanercept, and are usually mild-to-moderate and transient.[1] In the ATTRACT trial, 16–20% of patients receiving infliximab developed infusion reactions, compared with 10% who received placebo.[27] Most of these reactions were mild and transient. In a retrospective comparison of etanercept with infliximab, infusion reactions were more frequent with infliximab (7% of all infusions; 25% of patients), and 13 infliximab-treated patients withdrew from therapy because of severe infusion reactions.[51] In an analysis of four placebo-controlled trials, 20.3% of patients treated with adalimumab developed injection-site reactions, compared with 13.8% of patients who re© Adis Data Information BV 2004. All rights reserved.

ceived placebo.[72] Most cases were mild and transient and rarely led to withdrawal from the study. 3.3.3 Malignancy

In a survey of long-term use in RA and Crohn’s disease, the rate of malignancy occurring with infliximab treatment was similar to placebo.[63] The incidence of malignancy in nonrandomised studies of etanercept of up to 5 years’ duration was similar to the incidence among the general population.[15–18,21,22] A recent Food and Drug Administration Advisory Committee meeting recommends that anti-TNF labeling regarding the risk of lymphoma include a statement that standardized incidence ratios cannot be compared between agents.[73] They indicate that adalimumab’s labeling is being considered as a template for revisions to warnings in the labeling for etenercept and infliximab. 3.3.4 Neurological Disorders

Central nervous system demyelinating disorders have been reported in a limited number of patients treated with etanercept or infliximab.[74] Other central nervous system disorders have been observed in association with etanercept therapy;[62] however, causal relationships remain unclear. Adalimumab therapy has also been associated with rare cases of exacerbation of clinical symptoms or radiographic evidence of demyelinating disease.[75] 3.3.5 Congestive Heart Failure

In the anti-TNF Therapy Against Congestive Heart Failure (ATTACH) trial, a 28-week phase II trial of infliximab in patients with moderate-tosevere congestive heart failure (CHF), 7 of 101 infliximab-treated patients died, compared with no deaths among the 49 patients receiving placebo.[76] Rates of hospitalisation for worsening heart failure were higher with infliximab 10 mg/kg compared with infliximab 5 mg/kg or placebo. The combined risk of death from any cause or hospitalisation for heart failure up to 28 weeks was higher in the patients randomised to infliximab 10 mg/kg (hazard ratio 2.84, Pharmacoeconomics 2004; 22 Suppl. 1

Drugs That Block Tumour Necrosis Factor

95% CI 1.01 to 7.97; p = 0.043). Based on these data, the manufacturer issued a ‘Dear Doctor’ letter in October 2001, indicating that infliximab treatment should not be initiated in patients with CHF. Two large clinical trials examining the use of etanercept for the treatment of heart failure were halted due to lack of efficacy.[62] There was a suggestion (though not statistically significant) of worse heart failure outcomes in patients treated with etanercept in one of the trials. There have been postmarketing reports of worsening conditions of CHF in patients who receive etanercept, with and without identifiable precipitating factors.[62] Thus, caution should be taken when giving this drug to patients with heart failure. 4. Effectiveness 4.1 Functionality (Health Assessment Questionnaire [HAQ])

Etanercept treatment has been shown to improve functionality as measured by HAQ scores.[11,13,22,77–82] In DMARD-refractory patients, HAQ disability scores improved by a greater extent with etanercept than placebo in a randomised controlled trial.[77] Improvement was sustained for up to 1 year in patients with both early and late disease in an observational study,[81] and for up to three years in patients who had failed DMARD therapy in an open-label extension study.[80] Patients treated with methotrexate plus infliximab have shown significantly greater improvements in HAQ scores, compared with patients who received methotrexate plus placebo, according to results of the randomised ATTRACT study[83] and an open-label study.[33] Patients treated with adalimumab in combination with DMARDs had significantly greater improvements in HAQ scores compared with those receiving placebo plus DMARDs in three 24-week randomised trials.[84] Furthermore, in one of these trials, improvement in HAQ score was not significantly greater in patients with early disease than © Adis Data Information BV 2004. All rights reserved.

47

late disease (0.79 vs 0.57 units), and an HAQ score of 0 was seen in 38% of patients with early disease versus 15% of patients with late disease.[61]

4.2 Vitality and General Well-being

Pain and fatigue are the two most prevalent symptoms of RA. Fatigue may result in significant incapacity and impairment in quality of life. The ACR disease remission criteria include fatigue as one of the six outcome measures, and a comprehensive evaluation of novel biologic therapies for RA should also include a systematic assessment of their effect on fatigue. 4.2.1 Etanercept

Etanercept has been shown to improve physical function, mental health and vitality in patients with RA in randomised[77,79,82,85] and nonrandomised[81,86,87] trials. In patients with either early RA[81,82,85] or more advanced disease,[81] these effects were observed and were greater than seen with methotrexate in early disease.[79,82] In a randomised trial, treatment of 632 patients with early RA with etanercept 10 or 25 mg or methotrexate had its greatest impact on measures of physical health status, specifically the Short Form (SF)-36 Physical Component Summary (PCS).[79] The Mental Component Summary (MCS) was also improved with etanercept in a randomised trial[77] and long-term observational study.[81] In a randomised controlled trial of 234 patients with DMARD-refractory disease, the improvement on the vitality domain of the HAQ after six months of treatment with etanercept 25 mg twice weekly was 26%.[13] The SF-36 Vitality Scale, proposed to measure fatigue, was found to be a reliable and valid instrument in 632 patients with early RA who had not received methotrexate in another randomised trial.[88] It was found to correlate well with both clinical and patient assessments of disease activity. Singh and colleagues randomised patients with early, active RA to etanercept 10 mg (n = 208) or 25 mg (n = 207) twice Pharmacoeconomics 2004; 22 Suppl. 1

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weekly or methotrexate 20 mg weekly (n = 217) for up to 12 months.[89] Based on intent to treat, etanercept produced more rapid changes in SF-36 vitality scale than methotrexate. At 4 weeks, patients receiving etanercept 25 mg had achieved an 18.2% reduction in fatigue versus a 5.5% reduction in the methotrexate group. Patients on etanercept 25 mg experienced a 25% reduction in fatigue by 8 weeks, while patients on methotrexate did not achieve this level of fatigue reduction until 20 weeks. The onset of action of etanercept was rapid, with improvements of more than 10% as early as 2 weeks, compared with a 2% deterioration with methotrexate (p < 0.01). Evidence suggests that the ability to perform valued living activities is the type of function most highly correlated with psychological well being.[90] This is borne out by data from a longitudinal observational study of 301 patients receiving etanercept long-term; these patients reported that the ability to perform complex integrated valued living activities was the aspect of physical function with which they were most satisfied.[91] The RAPOLO (Rheumatoid Arthritis Pharmacoeconomics and Outcomes Longitudinal Observational) study involves long-term follow-up of 647 patients involved in randomised trials of etanercept treatment; both the treatment and control groups received etanercept therapy after trial completion.[87] Initial treatment with etanercept was found to be associated with a reduction in fatigue in patients with either early or advanced RA. Among patients with long-term disease, scores on the single-item fatigue scale (0–10) improved by 8.5% with long-term etanercept treatment. Scores on the single-item fatigue scale improved by 4.7% in these patients, and in patients with early stage disease (mean duration 3.7 years) treated early with etanercept. In the patients with early disease, SF-36 fatigue scores improved by 5.1%. 4.2.2 Infliximab

Compared with methotrexate plus placebo, methotrexate plus infliximab produced signifi© Adis Data Information BV 2004. All rights reserved.

cantly greater improvements in the physical component summary of SF-36 (34% vs 9%), arthritisspecific health index (44% vs 12%), and patient global assessment (50% vs 2%), in the ATTRACT trial.[83] No significant ‘between-group’ difference in the mental component summary score of the SF36 was observed; however, the subscale scores for vitality and social functioning were significantly higher in methotrexate plus infliximab recipients. Benefits in terms of fatigue have not been evaluated for infliximab in RA. 4.2.3 Adalimumab

In three randomised controlled trials, DMARDs plus adalimumab significantly improved healthrelated quality of life at 24 weeks, as measured by SF-36 (including PCS, physical functioning, bodily pain and vitality scores), compared with DMARDs plus placebo, in patients with active RA (p < 0.05).[84] The impact of adalimumab on fatigue was evaluated in two of these trials.[92] Fatigue, as measured by Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) scores, was significantly improved in adalimumab recipients, compared with placebo recipients, after 24 and 52 weeks of treatment (p < 0.01). 4.3 Impact on Employment 4.3.1 Etanercept

Long-term etanercept therapy (mean 882 days) was associated with increased employment and reduced healthcare utilisation in patients with early disease (mean disease duration 3.7 years) in the long-term observational RAPOLO study.[93] The 260 patients, of mean age 53 years, who had received etanercept for a mean of 239 days, had undergone a mean of 0.88 fewer visits for RA, 0.03 fewer outpatient surgeries, and 0.04 fewer hospitalisations than controls. Among study participants working outside the home at the time of evaluation, the long-term etanercept group had completed a mean of 237 hours (6 weeks) more work than controls (p < 0.05). Pharmacoeconomics 2004; 22 Suppl. 1

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In a study by Yelin et al. (2003), etanercept use in patients employed at RA diagnosis was associated with a higher employment rate and a greater number of hours worked per week than those not treated with etanercept.[94] In a study carried out by the South Sweden Arthritis Treatment Group in patients with active RA not responding to DMARDs, etanercept was superior to infliximab in improving working capacity.[95] The study population comprised 117 patients (81 receiving etanercept and 36 infliximab). The employment was increased from 22.2 person-years at baseline with etanercept to 25.5 person-years after 1 year of treatment (p < 0.05). The increase from 11.2 to 12.3 person-years with infliximab was not statistically significant. However, the magnitude of the increase was similar with both drugs and the difference likely relates to poor statistical power due to the lower sample size in the infliximab group of only 36 patients. The number of person-years’ sick leave was reduced from 11.1 to 2.4 (p < 0.001) with etanercept, and nonsignificantly from 6.1 to 3.6 with infliximab. Again, this nonsignificant result may well be a function of statistical power. Actual sick leave as a proportion of maximum possible was reduced with etanercept from 33.3% at baseline to 8.6% after one year (p < 0.001). The reduction with infliximab was 35.3% to 22.6%, not statistically significant. The lower reduction in sick leave in the infliximab arm may be due to the fact that infliximab requires in-office infusion and the patient must leave work for treatment. The need for hospital care was also reduced with etanercept.[96] Hospital days per patient were reduced from a mean of 7.4 before treatment to 3.6 after 1 year’s treatment (p < 0.05); with infliximab the reduction from 8.5 to 5.3 days was nonsignificant. Once again, this nonsignificance may be due to poor statistical power. Day care per patient was reduced nonsignificantly from 1.6 to 0.7 days with etanercept. In contrast, infliximab treatment greatly increased the need for day care, from 1.7 to 11.1 days (p < 0.001 vs etanercept; vs pre-treatment), re© Adis Data Information BV 2004. All rights reserved.

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flecting the requirement for administration by intravenous infusion. 4.3.2 Infliximab

In a study of 229 US patients participating in the ATTRACT trial, fewer work days were lost by those treated with infliximab plus methotrexate, than by patients receiving methotrexate alone.[97] Direct cost savings were derived primarily from a 34% reduction in hospitalisations. A subanalysis of the ATTRACT trial found that successful treatment may have a substantial positive impact on the employability of patients with RA.[98] Employability was considered restricted if patients were unemployed and felt unable to work due to their arthritis even if a job was available; employability was considered unrestricted if patients were employed or felt well enough to work if a job was available. At baseline, 60% of patients were unemployed and 89% of unemployed patients felt they could not work even if a job were available. However, at week 54, 22% of clinical responders versus 10% of clinical nonresponders changed employability status from restricted to unrestricted (p < 0.03 vs baseline for responders; p = 0.655 vs baseline for nonresponders). Furthermore, 94% of clinical responders versus 87% of clinical nonresponders retained their unrestricted employability status from baseline to week 54 (p < 0.03 vs baseline for responders; p = 0.655 vs baseline for nonresponders). 5. Conclusions The anti-TNF-␣ agents are effective in reducing disease activity and delaying the progression of structural damage in patients with RA who have failed DMARD therapy. Unlike traditional DMARDs, the onset of action is rapid. While methotrexate is currently the standard of care, etanercept is also effective as first-line therapy in patients with early RA and may be more beneficial early in the disease process. Preventing or delaying disease progression by treating RA early may reduce disability, thereby reducing costs associated with the disease. Etanercept and Pharmacoeconomics 2004; 22 Suppl. 1

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adalimumab are approved as monotherapy and etanercept is the only anti-TNF-␣ agent approved for first-line therapy. Functionality, as measured by HAQ scores, is improved in etanercept, infliximab and adalimumab recipients who have not responded to DMARDs. This is also true for patients with early disease who take etanercept or adalimumab; the extent of improvement was greater for these patients than for those with advanced disease, supporting the implementation of early treatment. Physical function, vitality and physical and mental components of the SF-36 are improved in patients who receive etanercept, infliximab or adalimumab, compared with standard therapies. Etanercept and adalimumab are also associated with a reduction in fatigue. Both etanercept and infliximab increase work capacity, while etanercept therapy is also associated with a reduction in healthcare utilisation; this has the potential to reduce long-term costs of RA therapy. Among the anti-TNF-␣ agents, etanercept has been shown in open-label, long-term safety trials to improve the long-term outcome for patients with RA, and thereby reduces the economic burden imposed by this disease. Acknowledgement

8.

9. 10.

11.

12.

13. 14.

15.

16. 17.

18.

This work was supported by a grant from Wyeth.

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40. Schiff M, Furst D, Kavanaugh A, et al. Efficacy of adalimumab measured by the disease activity score 28 (DAS28) and EULAR response criteria [abstract]. Presented at EULAR 2003, Lisbon, Portugal 41. den Broeder A, Joosten L, Saxne T, Fenner H, van Riel P. Effect of long-term anti-TNF monotherapy on radiologic course and on markers of cartilage breakdown and endothelial activation in RA [abstract]. Arthritis Rheum 2000; 43 Suppl. 9: 227 42. den Broeder AA, Creemers MC, van Gestel AM, van Riel PL. Dose titration using the Disease Activity Score (DAS28) in rheumatoid arthritis patients treated with anti-TNF-alpha. Rheumatology 2002; 41 (6): 638-42 43. Barrera P, van der Maas A, van Ede AE, et al. Drug survival, efficacy and toxicity of monotherapy with a fully human antitumour necrosis factor-alpha antibody compared with methotrexate in long-standing rheumatoid arthritis. Rheumatology 2002; 41 (4): 430-9 44. Rau R, Herborn G, Sander O, van de Putte LBA, van Riel PLC. Long-term treatment with the fully human anti-TNF-antibody D2E7 slows radiographic disease progression in rheumatoid arthritis [abstract]. Arthritis Rheum 1999; 42 Suppl. 9: 400 45. Rau R, Sander O, den Broeder AA, van Riel PLCM, van der Putte L. Long-term efficacy and tolerability of multiple i.v. doses of the fully human anti-TNF-antibody D2E7 in patients with rheumatoid arthritis [abstract]. Arthritis Rheum 1998; 41 Suppl. 9: 55 46. Burmester G, van de Putte LBA, Rau R, Schattenkirchner M, Hartz D, Kupper H. Sustained efficacy of adalimumab monotherapy for more than four years in DMARD-refractory RA [abstract]. Presented at EULAR 2003, Lisbon, Portugal 47. Rau R, Herborn G, van de Putte LBA. Adalimumab inhibits radiographic disease progression in long-standing, rapidly progressive rheumatoid arthritis [abstract]. Presented at EULAR 2003, Lisbon, Portugal 48. Breedveld F, Allaart CF, Rau R, Herborn G, Wassenberg S. The long-term efficacy and safety of adalimumab, the fully human anti-TNF monoclonal antibody, in combination with methotrexate in the treatment of rheumatoid arthritis: results of a 2-year study [abstract]. J Clin Rheum 2002; 8 Suppl. 3: 46 49. Schattenkirchner M, Wastlhuber J, Rau R, Herborn G, Kroot EJ. Long-term use of the fully human anti-TNF antibody D2E7 in combination with methotrexate in active rheumatoid arthritis [abstract]. Arthritis Rheum 2000; 43 Suppl. 9: 228 50. Weisman M, Keystone EC, Paulus H, Weinblatt ME, Furst DE. A dose escalation study designed to demonstrate the safety, tolerability and efficacy of the fully human anti-TNF antibody, D2E7, given in combination with methotrexate in patients with active RA [abstract]. Arthritis Rheum 2000; 43 Suppl. 9: 391 51. van Vollenhoven R, Harju A, Bratt J, Ernestam S, Brannemark S. Etenercept and infliximab treatment in the stockholm TNFalpha antagonist registry: a comparison of two TNF-alpha antagonists [abstract]. Arthritis Rheum 2001; 44 Suppl. 9: 79 52. Yazici Y, Erkan D, Kulman I, Schwartzman S, Harrison MJ. Etanercept vs infliximab: a comparison of efficacy in controlling rheumatoid arthritis flares during the first year of therapy and the year prior to their use [abstract]. Arthritis Rheum 2001; 44 Suppl. 9: 81 53. Singh A and Nab H. A meta-analysis of biological response modifiers in the treatment od rheumatoid arthritis for patients failing one or more disease modifying antirheumatic drugs [abstract]. Ann Rheum Dis 2003; 62 Suppl. 1: 185 54. Egsmose C, Lund B, Borg G, et al. Patients with rheumatoid arthritis benefit from early 2nd line therapy: 5 year followup of a prospective double blind placebo controlled study. J Rheumatol 1995; 22 (12): 2208-13

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55. van der Heide A, Jacobs JW, Bijlsma JW, et al. The effectiveness of early treatment with “second-line” antirheumatic drugs. A randomized, controlled trial. Ann Intern Med 1996; 124 (8): 699-707 56. Albers JM, Paimela L, Kurki P, et al. Treatment strategy, disease activity, and outcome in four cohorts of patients with early rheumatoid arthritis. Ann Rheum Dis 2001; 60 (5): 453-8 57. Spencer-Green G, Genovese MC, Martin R. Enbrel (etanercept) vs. methotrexate in early rheumatoid arthritis (ERA trial): two-year follow-up [abstract]. J Rheumatol 2001; 28 Suppl. 63: 106 58. Genovese M, Martin R, Fleischmann R, Keystone E, J B. Etanercept (ENBREL) in early erosive rheumatoid arthritis (ERA trial): observations at 3 years [abstract]. Arthritis Rheum 2001; 44 Suppl. 9: 78 59. Emery P, Maini RN, Lipsky P. Infliximab plus methotrexate prevents structural damage, reduces signs and symptoms and improves disability in patients with active early rheumatoid arthritis [abstract]. Ann Rheum Dis 2000; 59 Suppl. 1: 48 60. Smolen JS, Emery P, Bathon J, et al. Treatment of early rheumatoid arthritis with infliximab plus methotrexate or methotrexate alone: preliminary results of the ASPIRE trial [abstract]. Presented at EULAR 2003, Lisbon, Portugal 61. Keystone E, Kavanaugh A, Fischkoff S. Response to adalimumab in patients with early versus late rheumatoid arthritis (RA) [abstract]. Presented at EULAR 2003, Lisbon, Portugal 62. Wyeth, Enbrel (etanercept) package insert. 2002, Wyeth Pharmaceuticals 63. Hanauer SB, Schaible TF, DeWoody KL. Long-term follow-up of patients treated with infliximab (anti-TNF alpha antibody) in clinical trials [abstract]. Gastroenterology 2000; 118 Suppl. 2. Pt 1: 566 64. Centocor, Remicade (infliximab) recombinant for IV injection prescribing information. 2002, Centocor 65. Keane J, Gershon SK, Wise RP, et al. Tuberculosis associated with infliximab, a tumor necrosis factor alpha-neutralizing agent. N Engl J Med 2001; 345 (15): 1098-104 66. Emery P, Reginster JY, Appelboom T, et al. WHO Collaborating Centre consensus meeting on anti-cytokine therapy in rheumatoid arthritis. Rheumatology 2001; 40 (6): 699-702 67. Lee J-H, Slifman NR, Gershon SK, et al. Life-threatening histoplasmosis complicating immunotherapy with tumor necrosis factor alpha antagonists infliximab and etanercept. Arthritis Rheum 2002; 46 (10): 2565-70 68. Scallon BJ, Moore MA, Trinh H, Knight DM, Ghrayeb J. Chimeric anti-TNF-alpha monoclonal antibody cA2 binds recombinant transmembrane TNF-alpha and activates immune effector functions. Cytokine 1995; 7 (3): 251-9 69. Lugering A, Schmidt M, Lugering N, Pauels HG, Domschke W, Kucharzik T. Infliximab induces apoptosis in monocytes from patients with chronic active Crohn’s disease by using a caspase-dependent pathway. Gastroenterology 2001; 121 (5): 1145-57 70. Holman J, Wallis WJ, Sabath DF, et al. Tuberculosis reports with etanercept (Enbrel) therapy [abstract]. Ann Rheum Dis 2002; 61 Suppl. 1: 167 71. Burmester GR, Van de Putte LB, Rau R, Schattenkirchner M, Hartz D, Kupper H. Sustained efficacy of adalimumab monotherapy for more than four years in DMARD-refractory RA [abstract]. Presented at EULAR 2003, Lisbon, Portugal 72. Wells A, Kupper H, Fischkoff S, Chartash E. Injection-site reactions in adalimumab rheumatoid arthritis (RA) pivotal clinical trials [abstract]. Presented at EULAR 2003, Lisbon, Portugal

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73. FDA AC, TNF Inhibitor Labeling On Risk Of Lymphoma Should Caution Against Comparisons Between Agents. 2003 74. Mohan N, Edwards ET, Cupps TR, Oliverio PJ, Sandberg G. Demyelination occurring during anti-tumor necrosis factor alpha therapy for inflammatory arthritides. Arthritis Rheum 2001; 44 (12): 2862-9 75. Abbott, Humira (adalimumab) prescribing information. 2003, Abbott Laboratories 76. Chung ES, Packer M, Lo KH, Fasanmade AA, Willerson JT. Randomized, double-blind, placebo-controlled, pilot trial of infliximab, a chimeric monoclonal antibody to tumor necrosis factor-alpha, in patients with moderate-to-severe heart failure: results of the anti-TNF Therapy Against Congestive Heart Failure (ATTACH) trial. Circulation 2003; 107 (25): 3133-40 77. Mathias SD, Colwell HH, Miller DP, Moreland LW, Buatti MC, Wanke L. Health-related quality of life and functional status of patients with rheumatoid arthritis randomly assigned to receive etanercept or placebo. Clin Ther 2000; 22 (1): 128-39 78. Baumgartner SW, Fleischmann RM, Moreland LW, Schiff MH, Markenson J, Spencer-Green G. Improvement of disability in RA patients with early vs established disease after treatment with Enbrel (etanercept) [abstract]. J Rheumatol 2001; 28 Suppl. 63: 106 79. Bury-Maynard D, Kosinski M, Wanke LA, Buatti MC. Comparing the health related quality of life outcomes of treatment for early rheumatoid arthritis [abstract]. Value in Health 2000; 3: 97 80. Kalden JR, Pedersen R, Yeh P, Etanercept Study 301 Investigator Network. Sustained improvement in physical function after etanercept treatment in patients with rheumatoid arthritis (3-year interim data) [poster]. Arthritis Rheum 2002; 46 Suppl. 9: S32 81. Lubeck D, Katz P, Yelin E, Wanke L, Buatti M. Long-term impact of etanercept (Enbrel) on health-related quality of life and functional status of persons with rheumatoid arthritis [abstract]. Arthritis Rheum 2001; 44 Suppl.: 184 82. Kosinski M, Kujawski SC, Martin R, et al. Health-related quality of life in early rheumatoid arthritis: impact of disease and treatment response. Am J Manag Care 2002; 8 (3): 231-40 83. Kavanaugh A, Lipsky P, Furst DE. Infliximab improves longterm quality of life and functional status in patients with rheumatoid arthritis [abstract]. Arthritis Rheum 2000; 43 Suppl. 9: 147 84. Strand V, Weisman M, Nichol M, Knight T, Chang K, Chartash E. Adalimumab improves health-related quality of life in rheumatoid arthritis patients [abstract]. Presented at EULAR 2003, Lisbon, Portugal 85. Singh A, Wanke L, Parasuraman TV, Lubeck D. Clinically meaningful improvement (CMI) in SF-36 vitality scale for methotrexate (MTX)-naive patients with early, active rheumatoid arthritis (RA) [abstract]. Presented at EULAR 2003, Lisbon, Portugal 86. Hermann J, Aytekin A, Broll J, et al. Open-label evaluation of the quality of life of patients treated with etanercept in common rheumatology usage (ECRU) [abstract]. Presented at EULAR 2001, Prague, Czech Republic 87. Lubeck DP, Katz P, Yelin EH, Rush S, Wanke L, Buatti MC. Fatigue in patients with early stage and long term rheumatoid arthritis: Data from RAPOLO [abstract]. Presented at ACR 2002, New Orleans, Louisiana 88. Singh A, Wanke LA, Parasuraman TV, Lubeck D. Reliability and validity of SF-36 vitality scale in measuring vitality of methotrexate-naive patients with early, active rheumatoid

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89.

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arthritis [abstract]. Presented at ACR 2002, New Orleans, Louisiana Singh G, Singh A, Wanke L, Sato R. Rapid improvement of fatigue in patients on etanercept compared to those on methotrexate: a double-blind randomized trial in 632 methotrexate-naive patients with early, active rheumatoid arthritis [abstract]. Presented at EULAR 2003, Lisbon, Portugal Ditto PH and Druley JA. Fates worse than death: the role of valued life activities in health-state evaluations. Health Psych 1996; 15 (5): 332-43 Katz P, Yelin EH, Lubeck DP, Wanke LA, Buatti MC. Satisfaction with function: what type of function do rheumatoid arthritis patients value most? [abstract]. Presented at EULAR 2002, Stockholm, Sweden Chartash E, Vasey F, Yount S, Cella D, Sengupta N. Adalimumab improves fatigue in patients with active rheumatoid arthritis [abstract]. Presented at EULAR 2003, Lisbon, Portugal Yelin E, Katz P, Lubeck D, Wanke L, Buatti M. Impact of etanercept (Enbrel) on health care utilization and employment among persons with early rheumatoid arthritis [abstract]. Presented at EULAR 2002, Stockholm, Sweden Yelin EH, Trupin L, Katz PP, Lubeck DP, Rush S, Wanke LA.

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Association between etanercept use and employment outcomes among persons with rheumatoid arthritis [abstract]. Ann Rheum Dis 2003; 62 Suppl. 1: 352 Geborek P, Eberhardt KB, Larsson B, Nived K, Saxne T. Etanercept and infliximab treatment improves working capacity in arthritis patients [abstract]. Presented at EULAR 2002, Stockholm, Sweden Geborek P, Eberhardt K, Saxne T. Etanercept and infliximab treatment reduces hospital care in arthritis patients [abstract]. Presented at EULAR 2002, Stockholm, Sweden Kavanaugh A, Patel KK, Bala M. Cost effectiveness of infliximab in rheumatoid arthritis [abstract]. Arthritis Rheum 2000; 43 Suppl. 9: 144 Kavanaugh A, Han C, Bala M, Marsters P, Antoni C. Successful treatment improves employability in patients with rheumatoid arthritis [abstract]. Presented at EULAR 2002.

Correspondence and offprints: Dr Larry W. Moreland, Division of Clinical Immunology and Rheumatology, 1717 6th Avenue South, Room 068, Birmingham, AL 352947201, USA. E-mail: [email protected]

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