Pharmacoeconomics 2003; 21 (13): 927-940 1170-7690/03/0013-0927/$30.00/0

REVIEW ARTICLE

© Adis Data Information BV 2003. All rights reserved.

Quality of Life in Patients with Rheumatoid Arthritis Which Drugs Might Make a Difference? Barbara Blumenauer,1 Ann Cranney,1 Jennifer Clinch2 and Peter Tugwell1 1 2

Ottawa Hospital, University of Ottawa, Ottawa, Ontario, Canada Clinical Epidemiology Unit, University of Ottawa, Ottawa, Ontario, Canada

Contents Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 927 1. Literature Search . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 929 2. QOL Measures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 929 2.1 Disease-Specific QOL Scales . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 930 2.2 Generic QOL Scales . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 931 3. Disease-Modifying Antirheumatic Drugs (DMARDs): Effect on Health-Related QOL . . . . . . . . . . . . . . 931 3.1 Methotrexate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 931 3.2 Leflunomide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 934 3.3 Cyclosporin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 934 3.4 Gold . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 935 3.5 Glucocorticoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 935 3.6 Etanercept . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 936 3.7 Infliximab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 936 3.8 Minocycline . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 937 3.9 Other DMARDs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 937 4. Non-DMARD Drugs: Effect on Health-Related QOL . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 937 4.1 Epoetin-α . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 937 4.2 NSAIDs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 938 5. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 938

Abstract

Rheumatoid arthritis (RA) is a chronic, disabling, inflammatory polyarthritis that affects patient well-being and QOL. Many disease-modifying antirheumatic drugs (DMARDs) are available for treating RA but patients are often refractory to treatment. The goal of treatment is to improve both general health and health-related QOL. Generic and disease-specific instruments exist to measure QOL. Using these instruments, one can determine if QOL improves with treatment. If the minimal clinically important difference (MCID) for the instrument is known, one can determine if the change is clinically significant. The literature was reviewed in a systematic manner to determine which drugs could affect QOL in patients with refractory RA. Refractory RA is poorly defined but we used the definition of failing at least two DMARDs. Methotrexate, leflunomide, cyclosporin, glucocorticoids, etanercept and infliximab clinically and statistically significantly improved QOL in patients with RA. Gold and

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epoetin-α (erythropoietin) statistically improved QOL in patients with RA but the clinical significance of the improvements could not be determined. These studies were either in non-refractory populations or the refractoriness could not be determined. Further study is required to determine the response of QOL to treatment in patients with refractory RA and instruments with known MCIDs should be used so that the clinical significance of the improvement can be determined.

Rheumatoid arthritis (RA) is a chronic inflammatory polyarthritis affecting 1% of the general population. It is associated with significant morbidity including pain, disability, deformity (resulting from joint erosions and joint destruction) and decreased QOL. It impacts on the patient’s ability to maintain gainful employment and can therefore affect socioeconomic status. RA is also associated with an increase in mortality, as patients die 4–20 years prematurely. A recent study[1] with methotrexate showed that controlling disease activity reduced the excess mortality, so there are many compelling reasons to control RA. Many disease-modifying antirheumatic drugs (DMARDs) are available. The goal of treatment is patient well-being and prevention of joint destruction. Disability in RA is progressive and the rate is variable so long-term follow-up is required to determine if an individual DMARD is effective. Unfortunately, many patients’ disease is refractory to treatment. Refractory RA is not clearly defined. In a recent study,[2] a Medline search was performed for the period 1992–1997 using the MeSH headings ‘arthritis, rheumatoid’ and ‘refractory’, and 37 studies using the term refractory were identified. The investigators found that the definition of refractory RA was quite variable in terms of the number, dose and duration of DMARDs failed and also the activity and duration of RA activity. They recommended a patient fail at least two DMARDs, preferably including methotrexate and sulfasalazine, before being considered refractory. We feel this is reasonable, and have chosen to define refractory RA as having failed at least two DMARDs for this paper. Traditional outcome measures in RA trials have been clinical efficacy variables such as tender or © Adis Data Information BV 2003. All rights reserved.

swollen joint counts. The American College of Rheumatology (ACR) has defined a core set of disease activity measures for RA clinical trials,[3] which includes not only traditional multiple clinical efficacy outcome variables but also functional assessment measured by a validated scale such as the Health Assessment Questionnaire (HAQ). This reflects the importance to the patient of health-related QOL (HR-QOL), which describes “that portion of life that is influenced by a person’s health”.[4] QOL measurements are an attempt to ensure patient concerns are addressed, since clinical efficacy outcomes alone often ignore outcomes important to patients. Although there are several studies that show that QOL improvements correlate well with clinical efficacy outcome variables, it is important to directly demonstrate the magnitude of the QOL benefit. Furthermore, not all patients show consistent effects across the different component measures of the ACR core set. The ACR set of outcome measures combines functional status measures, biological parameters, measures of pain, physical measures, and patient and physician global assessments. HR-QOL is only one of seven items used to determine a response, and it is not a required one. Improvement in five out of seven items is required, and the only absolute item that must improve is joint count. While patients’ tender or swollen joint counts could improve on a particular treatment, if they feel unwell they will be reluctant to take it. Likewise, their joint counts may not improve, whereas their sense of general well-being might. Traditional measures would indicate the drug was ineffective although QOL measures would suggest efficacy. Combination therapy is becoming increasing more common in RA and adding a drug strictly for QOL reasons may be justifiable if its toxicity is low. Pharmacoeconomics 2003; 21 (13)

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Table I. Disease-specific instruments used to assess QOL in rheumatoid arthritis (RA) clinical trials Test

What it tests

Validated in RA

MCID

Pros/cons

PET (modified MACTAR)

Preference disability

Yes

0.5 units[5]

Patients volunteer problems so it often identifies items not on standard QOL tests

AIMS

Physical disability, psychological status, pain

Yes

Undefined

Fixed items

HAQ

Functional disability

Yes

0.19 units Fixed items (Redelmeier & Lorig[6] and Kosinski et al.[7]) HAQ scores vary with age, sex, disease duration, SES, genetic factors

RAQoL

Functional disability

Yes

Undefined

MACTAR

Preference disability

Yes

Undefined

Lee functional index Functional disability Yes Undefined AIMS = Arthritis Impact Measurement Scale; HAQ = Health Assessment Questionnaire; MACTAR = McMaster Toronto Arthritis Patient Preference Disability Questionnaire; MCID = minimal clinically important difference; PET = Problem Elicitation Technique; RAQoL = Rheumatoid Arthritis Quality of Life; SES = socioeconomic status.

QOL measures are also useful for outcomes research in RA therapy and could potentially help patients and physicians make treatment decisions. QOL information could also aid policy-making by showing the impact of a treatment being assessed for possible funding by insurance plans, etc. The aim of this paper was to review QOL issues in patients with RA, with special attention to refractory RA. Standard QOL measures used are discussed in terms of their strengths and weaknesses and evidence supporting their validity. The available evidence of the effect of individual DMARDs on QOL in patients with RA is discussed. Drugs other than DMARDs that affect QOL, such as epoetin-α (erythropoietin) and NSAIDs, are also discussed. When evidence is available, drugs affecting QOL in refractory RA are highlighted. 1. Literature Search The search strategy used is detailed in the Appendix. Essentially two separate literature searches were conducted, and the citations from each combined. The first was conducted to identify papers pertaining to specific DMARDs used in RA and the resultant effect on QOL. The second search was conducted to identify any paper discussing RAassociated QOL. The abstracts of all identified citations were reviewed. Any papers with experimental data as well as several comprehensive review arti© Adis Data Information BV 2003. All rights reserved.

cles were retrieved for further review. The bibliographies of all retrieved papers were reviewed to allow identification of other pertinent papers not identified by the initial literature search. 2. QOL Measures Many QOL measurement tools exist. For a tool to be a good measure of QOL it requires validation in populations with RA. Common QOL instruments are summarised in table I and table II. HR-QOL is either positively or negatively affected by individual rheumatoid arthritis treatments. Potential benefits include increased well-being, increased energy, and reduced pain, disability, early morning stiffness and fatigue. Potential negative outcomes include adverse drug events, end-organ damage, acceleration of other disease processes such as atherosclerosis or coronary artery disease and financial hardship secondary to drug costs. Overall life quality is a balance between the number and degree of positive and negative treatment effects. Using QOL instruments gives a measure of the patients’ QOL at that moment in their disease course. Administering these instruments at regular intervals gives a better estimate of cumulative health outcome. Since RA is a chronic disabling disease with cumulative disability, serial measurements are most logical as this shows the total effect of RA on Pharmacoeconomics 2003; 21 (13)

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Table II. Generic instruments to assess QOL in rheumatoid arthritis Test

What it tests

Validated

MCID

SF-36

PCS, MCS

Yes

Average change in PCS of 4.4 and MCS of 3.1 at 1 level of improvement[7]

Pros/cons

EuroQol

Mobility, self-care, usual activities, pain/discomfort, anxiety/depression

Variable

NHP

Physical mobility, pain, sleep, Yes May not detect long-term emotional reaction, social effects of treatment isolation, energy accurately EuroQol = EuroQOL instrument; MCID = minimal clinically important difference; MCS = mental component score; NHP = Nottingham Health Profile; PCS = physical component score; SF-36 = Medical Outcomes Study 36-item short form health survey.

QOL. Many methods exist to determine QOL numerically and in a reproducible fashion.[8] QOL instruments are either ‘disease specific’ such as the Arthritis Impact Measurement Scale (AIMS) or ‘generic’ (i.e. not disease specific) such as the Medical Outcomes Study 36-item short form health survey (SF-36). Disease-specific instruments can be used to compare outcomes of different treatment protocols among patients with the same medical condition such as RA, whereas generic instruments allow comparison of QOL among patients with different medical conditions.[5] It can be difficult to interpret what a given numerical change in a QOL instrument means clinically. This has lead to the concept of the minimal clinically important difference (MCID). The MCID is the minimal effect of a given treatment judged important (by the patient and/or the clinician), that a patient can perceive. The MCID is different for each QOL instrument and needs to be established experimentally in the patient population of interest. Once the MCID of an instrument is known, one can decide if the increase in QOL measured by that instrument in a clinical trial is clinically significant as well as statistically significant. The MCID can be established by several different approaches. Patients can be asked what the minimal important change would be or clinicians can rate scenarios of differing degrees of disease activity. The European League of Associations of Rheumatology (EULAR) group favour defining the minimal important change as the magnitude of © Adis Data Information BV 2003. All rights reserved.

change that influences clinicians to continue patients on therapy rather than change to a new drug. 2.1 Disease-Specific QOL Scales

Disease-specific QOL scales are discussed first and are summarised in table I. The HAQ has been used as an estimate of HRQOL, although it is more a measure of function than of QOL since it has no items on emotional status. The HAQ is a self-administered questionnaire that asks two to three questions each about dressing and grooming, arising, feeding, walking, hygiene, reach, grip and activities. Each item is scored as 0 = no difficulty, 1 = some difficulty, 2 = much difficulty or requires assistance and 3 = unable to perform. Any item requiring help from another person or the use of an assistive device is scored 2. The highest score from each area is summed, giving a maximum score of 24. This score is then divided by eight to produce a disability index ranging from 0–3, with 3 being the worst possible score.[9] The HAQ also incorporates a 15cm horizontal visual analogue scale (VAS) for pain. This is a 15cm horizontal line upon which the patient places a mark representing their level of pain. Zero represents no pain and 15cm very severe pain. The distance from 0 to the mark is measured in cm and multiplied by 0.2 to derive a pain scale score ranging from 0–3, with 3 being the worst possible score. The HAQ has been modified (m-HAQ) to an eight-question instrument (that can be completed in approximately 5 minutes), which has also been validated for RA.[9] The MCID for the HAQ has been estimated at 0.19.[6,7] Pharmacoeconomics 2003; 21 (13)

QOL in Patients with Rheumatoid Arthritis

The Problem Elicitation Technique (PET) is a specific disability questionnaire that determines which arthritis-associated problems patients would most like improved by treatment. It is a revision of the McMaster Toronto Arthritis Patient Preference Disability Questionnaire (MACTAR) that was published in 1987.[5] Problems can be volunteered or elicited by open-ended questions inquiring about problems with self-care, mobility, role activities, leisure activities, social activities, emotion, communication, sleep and appearance. Standard questionnaires may lack questions that capture the most important disabilities and, furthermore, the weighting may not reflect the relative importance – the PET does this. Psychometrically this failure to assess and weight the relevant areas could reduce sensitivity to change and the ability to discriminate between individual patients.[9] Scoring methods for the PET vary but a recently suggested method is described below. Patients indicate the degree of difficulty associated with each problem using a 7-point scale, with 0 = no difficulty and 7 = unable to do. Each problem is then assigned a level of importance using a 7-point scale, with 0 = not at all important and 7 = most important. Patients then rank all of the elicited problems in order from most to least important. Each identified problem is scored by multiplying the magnitude of the problem by the importance of the problem. The scores for the top five problems are summed to produce the PET score. Overall global health is also assessed using a 10-point scale, with 1 = worst possible to 10 = perfect health. The response of problems most bothersome to the individual patient is followed longitudinally by comparing baseline with follow-up scores.[9] The MCID of the PET is 0.5 units if the 7-point scale scoring system is used.[5] It has been shown that for QOL questionnaires that use a 7-point scale, a change of 0.5 points corresponds to a global rating change of a little or somewhat better.[6] The AIMS is an arthritis-specific self-administered questionnaire composed of 69 fixed items assessing nine scales: mobility, physical activity, dexterity, household activities, activities of daily living, © Adis Data Information BV 2003. All rights reserved.

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social activity, anxiety, depression and pain. These nine scales are summarised into three components: physical disability, psychological status and pain. All scale and component scores are standardised on a 0–10 range with higher numbers equalling worse health status. The AIMS also has a standardised pain scale with scores ranging from 0–10, with higher scores representing higher levels of pain. The AIMS has been validated in RA clinical trials and changes in the AIMS score have been shown to parallel changes in traditional outcome measures.[9] 2.2 Generic QOL Scales

Several generic QOL scales exist and are summarised in table II. The SF-36 is a commonly used generic health measure that measures physical functioning, physical and emotional role functioning, social functioning, bodily pain, mental health, vitality and general health perceptions. These individual areas are then combined into a physical component score (PCS) and a mental component score (MCS). The MCID has been estimated as an average change in the PCS of 4.4 and MCS of 3.1 as these are the values associated with one level of functional improvement.[7] The SF-36 has been validated in many chronic diseases including RA. Other generic scales include the European Quality of life (EuroQoL) instrument and the Nottingham Health Profile (NHP).[10] 3. Disease-Modifying Antirheumatic Drugs (DMARDs): Effect on Health-Related QOL Numerous studies assessing QOL with individual DMARDs exist. DMARDs used to treat RA are discussed individually in sections 3.1–3.9 with respect to their effect on QOL; these data are summarised in table III. 3.1 Methotrexate

A secondary analysis using QOL measures of treatment with methotrexate, leflunomide or placebo from a 52-week, multicentre, double-blind conPharmacoeconomics 2003; 21 (13)

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Table III. The effect of disease-modifying antirheumatic drugs on rheumatoid arthritis QOL as measured by various QOL instrumentsa Drug

PET

HAQ

m-HAQ

SF-36 PCS

Mean Δ oral gold –0.31 ± 0.05 vs placebo –0.17 ± 0.04 (p = 0.01)[11]

Gold

Methotrexate

AIMS

(Top 5) mean Δ –3.41; mean Δ vs placebo 13%[13]b

Mean Δ –0.26; mean Δ vs placebo 22%[13]b

Other

MCS Improved psychological and pain health status with oral and parenteral gold; no Δ physical[12]

Mean Δ –0.15; mean Δ vs placebo 27%[13]b

Mean Δ 4.6; mean Mean Δ 0.9 (NS); Δ vs placebo mean Δ vs 12%[13]b placebo 0% (NS)[13]b

AIMS2 (french): SRM physical 0.61 (p = 0.0001); symptom 0.77 (p = 0.0001); affect 0.12 (p = 0.0001), role 0.32 (p = 0.02)[14]

MACTAR: 0.41± 0.22[15]

MHIQ (physical): 0.36 ± 0.27[15] Lee functional index: 0.57 ± 0.23[15] Disability mean Δ –0.41 vs –0.15 with placebo (p < 0.001)

Corticosteroids

Cyclosporin

–19.41 for cyclosporin vs placebo[16]

>–0.19 for cyclosporin vs placebo[17]

Minocycline

No difference between minocycline 200mg and placebo[18] Mean Δ –0.57 (etanercept 10mg) and –0.6 (etanercept 25mg)[19]

Etanercept

(Top 5) mean Δ –6.9; mean Δ vs placebo 29%[13]b

Mean Δ –0.45; mean Δ vs placebo 37%[13]b

Mean Δ –0.29; mean Δ vs placebo 45%[13]b

Mean Δ 7.6; mean Mean Δ 1.5 (NS); Δ vs placebo mean Δ vs 22%[13]b placebo 1% (NS)[13]b

Continued next page

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Pharmacoeconomics 2003; 21 (13)

Leflunomide

All p values < 0.05 unless otherwise indicated.

High (52%) withdrawal rate.

a

b

© Adis Data Information BV 2003. All rights reserved.

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AIMS = Arthritis Impact Measurement Scale; AIMS2 = Arthritis Impact Measurement Scale 2; HAQ = Health Assessment Questionnaire; MACTAR = McMaster Toronto Arthritis Patient Preference Disability Questionnaire; MCS = mental component score; m-HAQ = modified HAQ; MHIQ = McMaster Health Index Questionnaire; NS = not significant; PCS = physical component score; PET = Problem Elicitation Technique; SF-36 = Medical Outcomes Study 36-item short form health survey; SRM = standard response mean; SSZ = sulfasalazine; Δ indicates change.

Mean Δ 7.1–13.3 for infliximab vs 5.1 for placebo

PCS Mean Δ –0.50 vs –0.04 for placebo (p = 0.0001) and vs –0.29 for SSZ (p = 0.008)[20]

Mean Δ –0.30 to –0.52 for infliximab vs –0.18 for placebo Infliximab

Drug

Table III. Contd

PET

HAQ

m-HAQ

SF-36

MCS

AIMS

Other

QOL in Patients with Rheumatoid Arthritis

trolled trial was reported.[13] Outcome measures included tender joint count (TJC), swollen joint count (SJC), patient global assessment, physician global assessment, pain intensity, m-HAQ score, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), PET top 5, HAQ disability index, and SF-36 MCS, SF-36 PCS, SF-36 physical functioning and SF-36 bodily pain scores. The relative efficiency (RE; a measure of the relative discriminatory ability of the different endpoints) for each instrument was calculated in relation to the TJC. The TJC was 1 by definition and an RE >1 implies that the instrument is more efficient than the TJC in detecting a treatment effect. Sixty percent of the patients were taking methotrexate 15mg per week and 40% were taking 7.5mg per week. When comparing methotrexate with placebo, the patient and physician global health assessments were most responsive, with an RE of 1.55 and 1.44, respectively. The pain intensity scale and CRP, each with an RE of 1.19, were more responsive than the TJCs. The SF-36 MCS was least responsive, with an RE of 0. The m-HAQ and HAQ disability index each had an RE of 0.91, which approached the RE of the TJC. The RE for the PET top 5 was 0.42 and for the SF-36 was 0.80. Improvements in the PET, SF-36 PCS, bodily pain and physical functioning scales correlated with the ACR response rates. Table III shows the mean changes in these scales and the mean change as compared with placebo. This study showed that methotrexate was associated with a statistically significant improvement in QOL. The mean change in the HAQ score exceeded the MCID, indicating that the improvement was clinically significant as well. Unfortunately, this paper (and the others reviewed below) did not indicate what percentage of patients achieved an improvement beyond the respective cut-off for HAQ score. These patients were also not truly refractory to treatment, as the mean number of DMARDs failed averaged 0.9 ± 1 and up to 45% had never received DMARD treatment. However, the results are still interesting.[21] Another study[15] reported a consecutive subgroup analysis of patients in an 18-week doublePharmacoeconomics 2003; 21 (13)

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blind, multicentre, randomised trial comparing methotrexate with placebo. Patients had to have failed either parenteral gold or penicillamine and all had evidence of active disease. The MACTAR and Lee functional index percentage improvement for methotrexate compared with placebo was 29% and 11%, respectively. The RE for the MACTAR, Lee functional index, McMaster Health Index Questionnaire (MHIQ) physical, MHIQ social and MHIQ emotional was 4.1, 1.1, 1.0, 0.88 and 0.53, respectively. The RE for clinical examination measures varied from 0.03–4.3. A french version of the Arthritis Impact Measurement Scale 2 (AIMS2) was validated for patients taking methotrexate.[14] Patients had active disease and had received a mean of 2.3 DMARDs prior to study entry. Standardised response mean was used to determine responsiveness to treatment. This is the mean change in score divided by the standard deviation of the change in scores; a larger standard response mean indicates greater sensitivity to change. The french AIMS2 showed a statistically significant increase in QOL in patients receiving methotrexate versus placebo for the physical, symptom, affect and role components but not the social components. 3.2 Leflunomide

Tugwell et al. showed a statistically significant improvement in QOL with leflunomide (see section 3.1 for study details), as measured by the HAQ, mHAQ, PET top 5 and SF-36 PCS.[13] The mean change in the HAQ of –0.45 exceeds the MCID of –0.19, showing that the improved QOL was clinically significant as well. The RE of the HAQ disability index (1.84), SF-36 bodily pain scale (1.63), mHAQ (1.37), physician global assessment (1.33), PET top 5 (1.29), SF-36 PCS (1.29), pain intensity scale (1.21) and SF-36 physical functioning scale (1.10), were more sensitive to treatment than the TJC (1). The SJC, ESR, CRP and SF-36 MCS were less sensitive than the TJC in showing a treatment group difference. However, not all patients in this group were refractory to treatment, as the mean number of DMARDs failed was only 0.8 ± 1.0. © Adis Data Information BV 2003. All rights reserved.

In another study, leflunomide 20mg daily was compared with placebo or sulfasalazine titrated to 2.0g daily by week 4 in a 6-month multicentre, double-blind, randomised controlled European trial.[20] Between 40% and 53% of patients were DMARD naive, making this a non-refractory RA population. The reduction of HAQ scores for leflunomide versus placebo of –0.50 vs –0.04 was statistically significant (p = 0.0001) and exceeded the MCID of –0.19. The reduction of HAQ scores was significantly better with leflunomide than with sulfasalazine (–0.50 vs –0.29; p = 0.0086) and both exceeded the MCID for the HAQ. Therefore, both improved QOL although leflunomide was superior to sulfasalazine, and the improvement occurred more rapidly with leflunomide than with sulfasalazine or placebo.[22] 3.3 Cyclosporin

QOL data from a 6-month, double-blind, randomised trial comparing cyclosporin with placebo has been reported.[9,16] Patients had active disease and had failed gold salts, penicillamine or both. The PET was reported for all patients and the HAQ and AIMS for one-half of the patients. Statistically significant and clinically important improvements were found on all three scales. Outcome measures were compared by using a relative efficiency calculation to detect a treatment effect in comparison with TJC (RE for TJC = 1). The REs for tender joint score, physician-rated global efficacy, patient-related global efficacy and physician-related global disease activity were 1.1, 1.68, 1.17 and 1.32, respectively, although none of these were statistically different from the TJC RE. Other scales, including the pain 5 and 10cm VAS and PET, had an RE less than 1, although these were not statistically different from the RE of 1 for the TJC. This and other studies showed a statistically significant improvement in QOL scores with cyclosporin.[16,23] In a further randomised trial of cyclosporin in patients maintained on methotrexate, statistically significant benefits were shown in the HAQ.[17] When compared with the decrease with placebo, the HAQ decreased more than 0.19 (the MCID for the Pharmacoeconomics 2003; 21 (13)

QOL in Patients with Rheumatoid Arthritis

HAQ), making the changes clinically as well as statistically significant. 3.4 Gold

Gold can be taken orally (auranofin) or can be injected. Little information regarding QOL in patients with RA receiving gold treatment is available. This likely reflects the fact that gold is an older drug which was tested when QOL effects in RA were not routinely measured. A 6-month randomised, doubleblind trial compared auranofin 3mg orally twice daily with placebo.[11] Response was measured with several different outcome measures for each of four areas: clinical, functional, global and pain. Each individual measure was then combined into a composite score for each of the four areas. Auranofin was shown to be superior to placebo in the clinical, functional and global composite scores and tended towards significance with the pain composite score. Notably, the HAQ scores decreased –0.31 ± 0.05 for auranofin versus –0.17 ± 0.04 for placebo (p = 0.01). The Quality of Well-Being Questionnaire scores increased by 0.023 ± 0.007 for auranofin versus –0.001 ± 0.007 for placebo. Both of these show increased QOL with auranofin. Although these patients had unremitting disease, it is unclear if they had failed at least two DMARDs as patients had to only fail 3 months of rest, physical therapy and NSAIDs for study entry, which was standard care at the time the study was performed. Another double-blind, multicentre, parallel, 21-week trial compared placebo, and oral and injectable gold in 193 patients with active RA who had failed therapeutic doses of salicylates and at least one NSAID.[12] All patients took oral tablets (gold or placebo) and received weekly injections of either active drug or placebo depending upon their treatment assignment. Those patients taking oral gold received 3mg twice daily. Those patients receiving parenteral gold received 50mg once weekly (after receiving two test doses.) Patients were assessed with clinical efficacy outcome variables and the AIMS. Complete data were available for 161 patients, of whom 121 had completed the AIMS questionnaire at baseline and study end. © Adis Data Information BV 2003. All rights reserved.

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Treatment with injectable gold significantly improved the physical activity, anxiety, depression, pain and arthritis impact health status scales as did oral gold, except for the physical activity and depression scales. Both injectable and oral gold improved the psychological and pain health status component but not the physical component. The adjusted change score for the psychological health status component was 0.246, –0.579 and –0.781 for placebo, oral gold and gold injections, respectively (p = 0.025 for placebo vs oral, p = 0.004 for placebo vs parenteral; p = 0.331 for parenteral vs oral gold). The adjusted change scores in the pain health status component were –0.31, –1.54 and –2.72 for placebo, oral gold and parenteral gold, respectively (p = 0.002 for placebo vs oral, p = 0.0001 for placebo vs parenteral; p = 0.005 for parenteral vs oral gold). Both oral and injectable gold were shown to have superior efficacy when measuring clinical response variables, so gold improved both clinical status and QOL in these patients; however, these patients did not meet the definition of refractory RA. 3.5 Glucocorticoids

Glucocorticoids are often used for treating acute flares or for maintenance treatment in patients resistant to traditional DMARD therapy. Although, it is generally believed they give patients an improved sense of well-being although the extensive adverse effects of corticosteroids limit their use, little objective information on QOL in patients receiving corticosteroid therapy for RA exists. A randomised, double-blind trial compared oral prednisolone 7.5mg daily for 2 years with placebo in 128 adult patients with active RA of less than 2 years duration.[24] At entry, only 40% of patients had received any specific antirheumatic therapy so they did not fulfil a refractory disease category. However, they could receive any specific treatment during the trial (with the exception of additional corticosteroids); 8% of patients received intramuscular gold, 26% sulfasalazine, 30% penicillamine, 4% methotrexate and 3% other agents. A significantly reduced rate of radiographic progression was seen in the prednisolone compared Pharmacoeconomics 2003; 21 (13)

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with placebo recipients. Joint inflammation (measured by an articular index of tender and swollen peripheral joints, weighted for joint size) decreased by 41% less in the placebo group than in the treatment group. Range of motion pain scores were also reduced at 3 and 6 months and disability scores decreased at 3, 6, 12 and 15 months in prednisolone recipients compared with placebo recipients. The mean change in the disability index of the HAQ was –0.41 for prednisolone recipients versus –0.15 for the placebo group (p < 0.001), exceeding the MCID of –0.19, which indicates a clinically significant improvement in QOL. This study showed not only a disease-modifying effect, but also an improved QOL with corticosteroids. 3.6 Etanercept

Over the last several years interest in cytokines, especially tumour necrosis factor-α (TNFα), has increased. Cytokines are chemical mediators involved in cell to cell communication and modulation of inflammation, which makes them attractive targets for RA therapy. Etanercept, a recombinant TNF receptor immunoglobulin G1-Fc fusion protein has been approved for the treatment of refractory arthritis in both the US and Canada. Studies to date have shown good clinical response with etanercept. Etanercept is given twice weekly as a subcutaneous injection that patients can self-administer. QOL data from a 6-month, randomised, doubleblind, placebo-controlled trial with 234 patients compared subcutaneous etanercept 10 and 25mg twice weekly with placebo.[19] Patients had to have had an inadequate response to one to four DMARDs and have active disease for enrolment. QOL was assessed with the HAQ, the SF-36, 9 items from the Medical Outcome Scales (MOS) and a rating scale presented as a ‘feeling thermometer’ (patients rated their current health on a scale ranging from 0 [worst health imaginable] to 100 [best health imaginable]). A statistically significant improvement between the baseline and last score for both dosages of etanercept compared with placebo was found for the HAQ disability index and all of its domains except grip. These differences all exceeded the MCID of © Adis Data Information BV 2003. All rights reserved.

–0.19, making the results clinically significant as well as statistically significant. SF-36 scores are available for a subset of 48 patients only as it was included after the trial had started. For the SF-36 PCS, both etanercept 10mg and etanercept 25mg showed statistically significant improvement at 3 and 6 months versus placebo, while etanercept 25mg also showed significant improvement at 1 month (all p < 0.01). For the SF-36 MCS, etanercept 25mg showed statistically significantly improved at 3 and 6 months, and etanercept 10mg at 6 months (both p < 0.02). Unfortunately, the absolute changes were not included in this paper, so one cannot comment whether these changes were clinically significant. The MOS showed statistically significant improvement in energy with etanercept 10 and 25mg compared with placebo, with values of 17.38 ± 2.29, 16.35 ± 2.21 and 4.74 ± 2.20, respectively (p < 0.01). MOS mental health also improved significantly with etanercept 10 and 25mg compared with placebo, with values of 12.95 ± 1.95, 13.88 ± 1.87 and 4.41 ± 1.87, respectively (p < 0.01). MCID for these scales have not been determined so it is difficult to comment on the clinical importance of these changes. The feeling thermometer showed significant improvement at follow-up compared with baseline for etanercept 10mg (19.97 ± 3.27 vs 8.15 ± 3.17 for placebo; p = 0.019), although etanercept 25mg showed only borderline significant improvement (18.19 ± 3.23 vs 8.15 ± 3.17 for placebo; p = 0.054). 3.7 Infliximab

Infliximab is a chimeric (human/mouse) antiTNFα monoclonal antibody administered as an intravenous infusion. The Anti-Tumour Necrosis Factor Trial in Rheumatoid Arthritis With Concomitant Therapy Study Group (ATTRACT trial) randomised 428 patients with active RA, despite at least 12.5 mg/week of methotrexate treatment, to placebo or infliximab 3 or 10 mg/kg every 4 or 8 weeks. Response was measured by the ACR response criteria, the HAQ and SF-36. The 54-week results showed significant reduction in signs and symptoms of Pharmacoeconomics 2003; 21 (13)

QOL in Patients with Rheumatoid Arthritis

RA as well as radiographic joint damage in patients receiving infliximab and methotrexate compared with those receiving methotrexate alone.[25] Infliximab and methotrexate in combination produced a greater improvement in HAQ than did methotrexate with placebo for all infliximab-treated groups except the one receiving infliximab 3 mg/kg every 8 weeks. Using baseline mean HAQ scores given in the paper and extracting the mean improvement in HAQ score (%) from the graph in the paper, the mean decrease in HAQ score could be estimated for each group at 54 weeks. The obtained values were 0.18, 0.30, 0.47, 0.54 and 0.52 for the methotrexate/placebo group, infliximab 3 mg/kg every 8 weeks plus placebo, infliximab 3 mg/kg every 4 weeks plus placebo, infliximab 10 mg/kg every 8 weeks plus placebo and infliximab 10 mg/kg every 4 weeks plus placebo, respectively. When compared with the decrease produced by placebo, each dosage of infliximab produced a decrease of more than 0.19 (the MCID for the HAQ), making the changes clinically as well as statistically significant. The combination also significantly increased the SF-36 physical component scores at 54 weeks for each infliximab-treated group except infliximab 3 mg/kg every 8 weeks. Using baseline mean PCS scores and extracting the mean improvement in the MCS (%) at the end of the study from the graph in the paper, the mean increase in the SF-36 PCS could be estimated as 5.1, 7.1, 11.6, 13.3 and 10.5 for the groups treated with methotrexate/placebo, infliximab 3 mg/kg every 8 weeks, infliximab 3 mg/kg every 4 weeks, infliximab 10 mg/kg every 8 weeks and infliximab 10 mg/kg every 4 weeks, respectively. These values give change scores (compared with placebo) that would exceed 4.4 for the groups treated with infliximab 3 mg/kg every 4 weeks and infliximab 10 mg/kg every 4 and 8 weeks, suggesting the results are clinically as well as statistically significant. It is unclear how many DMARDs these patients had taken in terms of having truly refractory RA, but they were refractory to methotrexate 12.5 mg/week, suggesting infliximab can improve QOL in patients with potentially refractory RA. © Adis Data Information BV 2003. All rights reserved.

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3.8 Minocycline

In a double-blind, placebo-controlled trial with 219 patients, minocycline 200 mg/day was compared with placebo. Patients had mild to moderate active disease, were allowed stable doses of NSAIDs and corticosteroids but were not allowed other DMARDs for at least 4 weeks prior to study entry. Patients could have received a therapeutic trial with hydroxychloroquine and only one other DMARD (unless it had been discontinued for toxicity and not lack of efficacy), as the aim of the study was to recruit patients who were not refractory to treatment. Patients receiving minocycline had better improvement in joint swelling, joint tenderness, ESR, platelet counts and IgM rheumatoid factor levels than those receiving placebo. Although the mHAQ score decreased by 0.3 ± 0.5 at study end, this was not significantly different compared with placebo. Patient and physician global function was also not statistically significantly different between the minocycline and placebo groups.[18] 3.9 Other DMARDs

Other DMARDs, including hydroxychloroquine, mycophenolate mofetil and penicillamine, have been used in RA but QOL data have not been reported to our knowledge. 4. Non-DMARD Drugs: Effect on Health-Related QOL QOL data for epoetin-α and NSAIDs are discussed in sections 4.1 and 4.2, respectively. 4.1 Epoetin-α

Anaemia is a common complication of RA because of chronic inflammation interfering with iron utilisation. Anaemia can contribute to a patient’s fatigue and general sense of illness. Epoetin-α is a hormone produced by the kidney, which stimulates red blood cell production in the bone marrow. It has been extensively used for the treatment of anaemia associated with chronic renal disease. This led to studies to determine if the anaemia of chronic disease associated with RA was responsive to epoetinPharmacoeconomics 2003; 21 (13)

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α. Studies have shown that anaemia associated with RA is epoetin-α-responsive, and this led to formal studies to determine if epoetin-α improves patients’ HR-QOL. In a 52-week, double-blind, placebo-controlled trial in 70 patients with active RA, subcutaneous epoetin-α 240 U/kg 3 times weekly was compared with placebo.[26] Effect on QOL was determined using the Maastricht Utility Measurement Questionnaire (MUMQ), which is a Dutch translation and adapted version of the McMaster Utility Measurement Questionnaire. The MUMQ is a generic measure of the patients’ health over the preceding 2 weeks according to six criteria: physical state and mobility, self-care, emotions, leisure activities, pain and treatment adverse effects. A number between 0 (death) and 100 (perfect health) is derived. The median change from baseline in the rating scale utility was +14 and +15 for epoetin-α at week 24 and 52, respectively, and 0 for placebo at week 24 and 52. The p values for epoetin-α versus placebo were 0.03 and 0.002 for week 24 and 52, respectively. The median increase in haemoglobin level was 22 g/L in the epoetin-α group versus 2 g/L in the placebo group, and disease activity as measured by the Disease Activity Score also significantly improved with epoetin-α compared with placebo. Another double-blind, randomised, controlled trial compared epoetin-α with placebo in 20 patients with RA.[27] At 20 weeks, there was a significant improvement in the haemoglobin concentration and Nottingham Health Profile score for energy in the epoetin-α-treated patients compared with placebo recipients; no significant change was seen in the patients treated with placebo. The HAQ scores in the epoetin-α and placebo groups were not significantly different. The actual haemoglobin, Nottingham Health Profile score and HAQ score were not reported. A third study found no improvement in the HAQ, although the haemoglobin level did improve significantly in the group treated with epoetin-α.[28] Therefore, it is unclear if epoetin-α affects QOL using disease-specific measures, although improved QOL with generic measures has been shown. © Adis Data Information BV 2003. All rights reserved.

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4.2 NSAIDs

NSAIDs are frequently used in RA and can provide symptomatic relief of pain and stiffness although they are not disease-modifying drugs. There are substantial risks associated with NSAIDs including oedema, hypertension, congestive heart failure, confusion in the elderly and gastrointestinal bleeding and perforation. One must therefore balance the potential benefit of NSAID treatment against the potential risk to the patient. Unfortunately, little data regarding QOL in NSAID users exists to help guide this decision. 5. Conclusions RA is a common, chronic, disabling condition that significantly affects a patient’s general wellbeing and QOL. While many DMARDs are available to control RA disease activity, patients are frequently refractory to treatment. Response to treatment includes not only improvement in clinical efficacy variables but often improved QOL as well, which is frequently the most important outcome to the patient. Many instruments are available to measure QOL and they can be generic or disease-specific. Refractory RA is poorly defined, but we have chosen the definition of failing at least two DMARDs, and preferably one being methotrexate. Using this definition, the medical literature was reviewed in an evidence-based manner to determine which drugs could impact on patients’ QOL when they have refractory RA. Unfortunately, most studies enrolled non-refractory patients or specific information was lacking to determine if the treatment population was refractory. Methotrexate, leflunomide, cyclosporin, glucocorticoids, etanercept and infliximab showed a statistically and clinically significant improvement in QOL in patients with RA. Gold and epoetin-α showed a statistically significant improvement in QOL, although the clinical significance of the change could not be determined from the studies. Minocycline did not affect QOL in patients with RA. The inclusion criteria of almost all of the studies reviewed allowed patients who had failed less than Pharmacoeconomics 2003; 21 (13)

QOL in Patients with Rheumatoid Arthritis

two drugs to be entered; many of the trials included some patients who had failed two or more DMARDs, but the classical ‘table I’ (i.e. baseline patient characteristics) usually only gives mean numbers of DMARDs taken, so exact proportions of refractory patients and how they fared are not reported. Therefore, although a number of trials contained at least some patients with refractory RA, no DMARD, to our knowledge, has been shown to significantly affect QOL in homogeneous samples of patients with refractory RA. It is encouraging that QOL does respond to treatment with DMARDs and that the QOL measures correlate with clinical efficacy outcomes. However, further work on QOL needs to done in a refractory population using instruments with a defined MCID so that the clinical, in addition to the statistical, significance of the results can be determined. Acknowledgements The authors would like to thank Jessie McGowan for her assistance with the literature search for this article. Dr Tugwell is a paid consultant for and has received grants from a variety of pharmaceutical companies. There was no specific funding for this study.

Appendices Search Strategy 1 1. (quality adj3 life).tw. 2. exp Quality of Life/ 3. health status indicators/ 4. or/1-3 5. clinical trial.pt. 6. randomized controlled trial.pt. 7. tu.fs. 8. dt.fs. 9. random$.tw. 10. (double adj blind$).tw. 11. placebo$.tw. 12. or/5-11 13. exp Methotrexate/tu [Therapeutic Use] 14. leflunomide.tw. 15. exp Auranofin/tu [Therapeutic Use] 16. exp Hydroxychloroquine/tu [Therapeutic Use] © Adis Data Information BV 2003. All rights reserved.

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17. exp Glucocorticoids/tu [Therapeutic Use] 18. exp Cyclosporine/tu [Therapeutic Use] 19. exp Azathioprine/tu [Therapeutic Use] 20. exp Sulfasalazine/tu [Therapeutic Use] 21. exp Cyclophosphamide/tu [Therapeutic Use] 22. exp Penicillamine/tu [Therapeutic Use] 23. exp Anti-Inflammatory Agents, Non-Steroidal/ tu [Therapeutic Use] 24. or/13-23 25. 4 and 12 and 13 Search Strategy 2 1. exp arthritis,rheumatoid/ 2. (rheumat$ adj2 arthritis).tw. 3. stills diseas$.tw. 4. caplans syndrome$.tw. 5. feltys syndrome$.tw. 6. rheumatoid nodule$.tw. 7. sjogrens syndrome$.tw. 8. ankylosing spondylitis.tw. 9. rheumat$.tw. 10. or/1-9 11. (quality adj3 life).tw. 12. exp Quality of Life/ 13. health status indicators/ 14. or/11-13 15. 10 and 14 16. clinical trial.pt. 17. randomized controlled trial.pt. 18. tu.fs. 19. dt.fs. 20. random$.tw. 21. (double adj blind$).tw. 22. placebo$.tw. 23. or/16-22 24. 15 and 23 25. 15 and 17 References 1. Krause D, Schleusser B, Herborn G, et al. Response to methotrexate treatment is associated with reduced mortality in patients with severe rheumatoid arthritis. Arthritis Rheum 2000; 43: 14-21 2. Van de Putte LBA, Kroot EJA, van Riel PLCM. Management of refractory rheumatoid arthritis. Rheumatology 1999; 38 Suppl. 2: 32-4

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3. Felson DT, Anderson JJ, Boers M, et al. American College of Rheumatology preliminary definition of improvement in rheumatoid arthritis. Arthritis Rheum 1995; 38: 727-35 4. Tuttleman M, Pillemer SR, Tilley BC, et al. A cross sectional assessment of health status instruments in patients with rheumatoid arthritis participating in a clinical trial. J Rheumatol 1997; 24: 1910-5 5. Clinch J, Tugwell P, Wells G, et al. Individualized functional priority approach to the assessment of health related quality of life in rheumatology. J Rheumatol 2001; 28: 445-51 6. Redelmeier DA, Lorig K. Assessing the clinical importance of symptomatic improvements. An illustration in rheumatology. Arch Intern Med 1993; 153: 1337-42 7. Kosinski M, Zhao SZ, Dedhiya S, et al. Determining minimally important changes in generic and disease-specific health-related quality of life questionnaires in clinical trials of rheumatoid arthritis. Arthritis Rheum 2000; 43 (7): 1478-87 8. Fries JF. How may quality of life for rheumatoid arthritis patients be enhanced by current and future treatments? Rheumatology 1999; 38 Suppl. 2: 35-40 9. Buchbinder R, Bombardier C, Yeung M, et al. Which outcome measures should be used in rheumatoid arthritis clinical trials? Arthritis Rheum 1995; 38 (11): 1568-80 10. Scott DL, Garrood T. Quality of life measures use and abuse. Baillieres Best Pract Res Clin Rheumatol 2000; 14 (4): 663-87 11. Bombardier C, Ware J, Russell IJ, et al. Auranofin therapy and quality of lie in patients with rheumatoid arthritis: results of a multicenter trial. Am J Med 1986; 81 (4): 565-78 12. Meenan RF, Anderson JJ, Kazis LE, et al. Outcome assessment in clinical trials: evidence for the sensitivity of a health status measure. Arthritis Rheum 1984; 27 (12): 1344-52 13. Tugwell P, Wells G, Strand V, et al. Clinical improvement as reflected in measures of function and health-related quality of life following treatment with leflunomide compared with methotrexate in patients with rheumatoid arthritis: sensitivity and relative efficiency to detect a treatment effect in a twelvemonth, placebo-controlled trial. Arthritis Rheum 2000; 43 (3): 506-14 14. Pouchot J, Guillemin F, Coste J, and the French Quality of Life Rheumatology Group, et al. Validity, reliability and sensitivity to change of a French version of the arthritis impact measurement scales2 (AIMS2) in patients with rheumatoid arthritis treated with methotrexate. J Rheumatol 1996; 23: 52-60 15. Tugwell P, Bombardier C, Buchanan WW. Methotrexate in rheumatoid arthritis: impact on quality of life assessed by traditional standard-item and individualized patient preference health status questionnaires. Arch Intern Med 1990; 150: 59-62 16. Tugwell P, Bombardier C, Gent M, et al. Low-dose cyclosporin versus placebo in patients with rheumatoid arthritis. Lancet 1990; 335: 1051-5 17. Tugwell P, Pincus T, Yocum D, et al. Combination therapy with cyclosporine and methotrexate in severe rheumatoid arthritis. N Engl J Med 1995; 333: 137-41

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18. Tilley BC, Alarcon GS, Heyse SP, for the MIRA Trial Group, et al. Minocycline in rheumatoid arthritis. A 48-week, double blind, placebo-controlled trial. Ann Intern Med 1995; 122: 81-9 19. Mathias SD, Colwell HH, Miller DP, et al. Health-related quality of life and functional status of patients with rheumatoid arthritis randomly assigned to receive etanercept or placebo. Clin Ther 2000; 22: 128-39 20. Smolen JS, Kalden JR, Scott DL, et al. Efficacy and safety of leflunomide compared to placebo and sulphasalazine in active rheumatoid arthritis: a double-blind, randomised, multicentre trial. European Leflunomide Study Group. Lancet 1999; 353 (9149): 259-66 21. Strand V, Tugwell P, Bombardier C, et al. Function and healthrelated quality of life: results from a randomized controlled trial of leflunomide versus methotrexate or placebo in patients with active rheumatoid arthritis. Arthritis Rheum 1999; 42 (9): 1870-8 22. Scott DL. Leflunomide improves quality of life in rheumatoid arthritis. Scand J Rheumatol 1999; 28 Suppl. 112: 23-9 23. Bombardier C, Buchbinder R, Tugwell P. Efficacy of cyclosporin A in rheumatoid arthritis: long-term follow-up data and the effect on quality of life. Scand J Rheumatol 1992; 21 Suppl. 95: 29-33 24. Kirwan JR, The Arthritis and Rheumatism Council Low-Dose Glucocorticoid Study Group. The effect of glucocorticoids on joint destruction in rheumatoid arthritis. N Engl J Med 1995; 333: 142-6 25. Lipsky PE, Van Der Heijde DMFM, St Clair EW, for the AntiTumour Necrosis Factor Trial In Rheumatoid Arthritis With Concomitant Therapy Study Group, et al. Infliximab and methotrexate in the treatment of rheumatoid arthritis. N Engl J Med 2000; 343: 1594-602 26. Peeters HRM, Jongen-Lavrencic M, Bakker CH, et al. Recombinant human erythropoietin improves health-related quality of life in patients with rheumatoid arthritis and anaemia of chronic disease; utility measures correlate strongly with disease activity measures. Rheumatol Int 1999; 18: 201-6 27. Murphy EA, Bell AL, Wojtulewski J, et al. Study of erythropoietin in treatment of anemia in patients with rheumatoid arthritis. BMJ 1994; 309: 1337-8 28. Pincus T, Olsen NJ, Russell IJ, et al. Multicenter study of recombinant human erythropoietin in correction of anemia in rheumatoid arthritis. Am J Med 1990; 89 (2): 161-8

Correspondence and offprints: Dr Peter Tugwell, The Ottawa Hospital, General Campus, 501 Smyth Road, Ottawa, Ontario, Canada K1H 8L6. E-mail: [email protected]

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