Patient-reported outcomes better discriminate active treatment from placebo in randomized controlled trials in rheumatoid arthritis

V. Strand, S. Cohen1, B. Crawford2, J. S. Smolen3 for the Leflunomide Investigators Groups and D. L. Scott4

Division of Immunology, Stanford University School of Medicine, Palo Alto, CA,1St Paul Medical Center, Dallas, TX, 2Mapi Values, Boston, MA, USA, 3Centre for Rheumatic Diseases at Lainz Hospital, Vienna, Austria and 4Guy’s, King’s and St Thomas’s School of Medicine, King’s College, London, UK.

Correspondence to: V. Strand, Division of Immunology, Stanford University School of Medicine, 306 Ramona Road, Portola Valley, CA 94028, USA. E-mail: Vstrand{at}aol.com


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion and conclusions
 References
 
Background. Recent randomized controlled trials (RCTs) in rheumatoid arthritis (RA) have used patient- and physician-reported outcomes, ESR and/or CRP as components of ACR response criteria to assess efficacy.

Objectives. Mean changes from baseline in patient- and physician-reported outcome measures, ESR and CRP were compared in two RCTs in patients with active RA. Comparisons between active and placebo treatment used mean percentage improvements and standard effect sizes (SESs).

Results. In both protocols, patient-reported assessments of disease activity, pain and physical function reflected little or no improvement with placebo, best discriminating between active and placebo therapy, as did ESR and CRP.

Conclusion. Improvements in signs and symptoms of active RA in placebo RCTs appear to be best reflected by patient-reported measures of physical function, as long as reported changes in global assessments of disease activity and/or pain reflect similar benefit. Patient-reported outcome measures should be considered objective; treatment-associated changes are congruent with measures of inflammation, and appear less susceptible to the placebo response.

KEY WORDS: Placebo effect, Rheumatoid arthritis, Patient-reported outcome measures, ACR response criteria.


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion and conclusions
 References
 
The American College of Rheumatology (ACR) response criteria in RA, which combine physician-reported and patient-reported measures, have been successfully used in randomized controlled trials (RCTs) to facilitate approval of five new disease-modifying anti-rheumatic drugs (DMARDs) [1]. These trials also underlined the importance of patient-reported measures of physical function and health-related quality of life [25]. Instruments such as the Health Assessment Questionnaire (HAQ), Problem Elicitation Technique (PET), and Medical Outcomes Study Short-Form-36 (SF-36) are sensitive to change and closely reflect patient-reported improvements in global disease activity and pain [3, 621]. These RCTs have all included placebo therapy. Despite the complex ethical issues surrounding placebo treatment in active RA, regulatory approval of new agents still depends upon comparison with placebo treatment [22]. However, the use of placebo therapy is likely to be restricted to short time periods or superimposed on failed background DMARD therapy.

Placebo treatment often shows benefit in RA [23, 24]. The Paulus criteria were initially developed to distinguish active from placebo treatment in Cooperative Systematic Studies of Rheumatic Diseases protocols and provided the basis for development of the ACR response criteria [25]. In recent RCTs of DMARDs in RA, 15–35% of patients receiving placebo are responders by ACR >=20% criteria; improvements are evident within 1–3 months, and may persist as long as 12 months [6, 10, 14, 2636].

However, interpreting placebo responses is complex. Experience using non-steroidal anti-inflammatory drugs (NSAIDs) shows that patients report less efficacy with active treatment in placebo-controlled than active-controlled RCTs [37]. There are difficulties differentiating perceived from true placebo effects [38]. Other factors obscuring placebo effects include the natural course of the disease, regression to the mean and the impact of comorbidities [39]. Variations in placebo responses cannot be attributed to selection bias, unblinding and other methodological shortcomings [4044]. Learning may have an impact, especially when patients participate in several RCTs [45].

Better understanding of the placebo response in RA will facilitate its judicious use in future RCTs. We therefore evaluated which outcome measures most contribute to placebo responses after 6 and 12 months of blinded treatment in two large RCTs of DMARDs. These may be among the last large RCTs employing 4–6 months of placebo treatment without background DMARDs or rescue therapy [6, 10], as RA patients receiving placebo for over 6 months may experience irreversible deterioration in physical function [44, 46, 47].


    Patients and methods
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion and conclusions
 References
 
Study design
In MN301, a 6-month multicentre RCT, 358 patients were randomized to leflunomide, placebo, or sulphasalazine in a 3:2:3 ratio; 92 patients received placebo [10]. US301, a 24-month multicenter RCT, enrolled 482 patients to receive leflunomide, placebo or methotrexate in a 3:2:3 ratio; 118 patients received placebo [6]. When MN301 was designed, it was considered unethical to allow patients with active RA to receive placebo for > 6 months; those completing 6 months’ protocol treatment were offered blinded continuation therapy with sulphasalazine in an extension trial, MN303. In US301, with documented lack of efficacy [failure to achieve ACR >=20% response criteria] on or after 4 months of protocol treatment, blinded alternate active therapy was offered to all patients, determined at initial randomization. Patients randomized to receive leflunomide were switched to methotrexate, and those initially receiving methotrexate or placebo to leflunomide treatment.

Patients
Patients >=18 yr old with RA by ACR criteria were enrolled in both RCTs with protocol-specified criteria for active disease [48]. Patients could not have received prior treatment with the active comparator (MN301: sulphasalazine; US301: methotrexate). Other DMARDs were to have been discontinued >=28 days prior to enrolment; concomitant prednisone (<=10 mg/d or equivalent) and NSAID doses were to remain stable >=28 days prior to enrolment and during protocol participation. The RCTs were conducted in accordance with ethical review boards, good clinical research practice and the Declaration of Helsinki [22].

Efficacy measures
Primary outcome measures in both trials were ACR20 responses at 6 (MN301) and 12 (US301) months. In MN301, mean HAQ scores were used and in US301 modified health assessment questionnaire (MHAQ) scores were used to calculate ACR responses. In both studies the HAQ Disability Index [HAQ DI] was assessed at baseline and 6-month intervals [6, 10]. In US301, PET and SF-36 were also included [7, 8]. Physician-reported measures included swollen joint count (SJC), tender joint count (TJC) and global assessment of disease activity. Both protocols used 28-joint counts; mean changes from baseline were assessed. Patient-reported outcomes included global assessments of disease activity, pain, mean HAQ and MHAQ as components of ACR response criteria and HAQ DI (as well as PET and SF-36 in US301). Changes in ESR and CRP were also compared.

Statistical analyses
Statistical analyses used the intent-to-treat (ITT) population, with last observation carried forward (LOCF) and analysis of covariance (ANCOVA) for continuous variables. Five-point Likert scores used in MN301 for patient and physician global assessments were converted to 1–100 visual analogue scale (VAS) scores. Observed treatment effects were calculated as percentage differences between mean changes in active and placebo treatment groups as follows: gross percentage change at endpoint = (mean change at endpoint/mean baseline) x 100 and individual percentage change at endpoint = sum (individual change at endpoint/individual baseline)/n x 100. (Percentage improvements are positive; deteriorations are negative.) To evaluate relative magnitudes of change, SESs were calculated for each ACR response component and for HAQ DI, PET and SF-36. To be consistent with the majority of response components, for which improvements are reported as decreased scores, SESs are presented with negative changes indicating improvement. Direct statistical comparisons between active and placebo treatments for each efficacy measure have been published; statistical comparisons of derived SES were not conducted.


    Results
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion and conclusions
 References
 
Demographic and baseline disease characteristics were comparable between treatment groups in both RCTs. Efficacy between active treatments were superior to placebo and did not differ statistically from each other, as published previously [6, 10].

Mean percentage change (gross %) and individual percentage changes (individual %) from baseline in physician- and patient-reported and laboratory outcomes in active and placebo-treated groups in MN301 and US301 are presented in Table 1 and are similar to each other. In MN301, physician-based assessments at 6 months (TJC, SJC and physician global assessments) improved by 38–52% with leflunomide, 40–49% with sulphasalazine and 11–26% with placebo; at 12 months in US 301 they improved by an average of 41–53% with leflunomide, 39–43% with methotrexate and 15–20% with placebo. At 6 months in MN301, patient-reported outcomes (patient global assessment, pain, mean HAQ and HAQ DI) improved by 33–43% with leflunomide and 24–40% with sulphasalazine, and ranged from 20% worsening to 15% improvement with placebo treatment (Table 1, Fig. 1). In US301, patient-reported assessments at 12 months (patient global assessment, pain, MHAQ, HAQ DI, PET and SF-36 Physical Component Score) improved by 24–38% with leflunomide and 5–29% with methotrexate, and ranged from 16% worsening to 6% improvement with placebo (Table 1, Fig. 2). Laboratory-based assessments (ESR and CRP) improved with active treatment in both trials, with no change or worsening with placebo (Table 1, Figs 1 and 2). Consistently, mean gross and individual percentage changes in physician-reported measures at 6 and 12 months in both placebo treatment groups demonstrated more improvement than patient-reported measures (improvements are shown as positive; deteriorations as negative changes in Figs 1 and 2).


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TABLE 1. ACR responses, percentage changes from baseline in components of ACR response criteria and patient reported outcomes (MN301, 6 months; US301, 6 and 12 months)

 


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FIG. 1. Mean of the individual percentage changes from baseline in patient- and physician-reported measures for placebo patients at 6 months (MN301) The arrow to the left denotes improvement, indicating that deterioration in pain, physical function and laboratory assessments were reported with placebo treatment. CRP data exclude one outlier subject in the placebo group (percentage change more than 2 S.D. from the mean). Phys Global, physician global assessment of disease activity; Pt Global, patient global assessment of disease activity.

 


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FIG. 2. Mean of the individual percentage changes from baseline in patient- and physician-reported measures for placebo patients at 6 and 12 months (US301). The arrow at the left denotes improvement; indicating that deterioration in patient global assessment, physical function and laboratory assessments were reported with placebo treatment. Phys Global, physician global assessment of disease activity; Pt Global, patient global assessment of disease activity.

 
In US301, mean individual percentage changes in patient-reported pain and global assessment deteriorated with placebo treatment, whereas in MN301 patient global assessments improved (11.6%) and pain worsened (–20.4%). However, the magnitude of improvement in patient reported pain at 6 months (10.9%) was much less at 12 months (3.7%) in US301; global assessments deteriorated from 4.3% to 4.1%.

The percentage changes from baseline are reflected in the SESs shown in Figs 3 and 4. The pattern of change was similar in the two trials. Large SESs were evident by physician-assessed outcomes with active treatment: improvements ranged between 0.94 and 1.86. However, relatively large improvements with placebo therapy were also observed: SESs ranged from 0.47 to 0.68. Changes in SESs with active treatment were smaller by patient-assessed measures, ranging from 0.30 to 1.64. Following placebo administration, SESs ranged from smaller improvements of 0.56 to deteriorations of 0.13. Finally, laboratory assessments reflected improvements in SESs from 0.23 to 0.68 with active treatment compared with deteriorations of 0.09 to 0.17 with placebo.



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FIG. 3. Standard effect sizes at 6 months for physician-, patient- and laboratory-based measures in the MN301 trial. Phys Global, physician global assessment of disease activity; Pt Global, patient global assessment of disease activity.

 


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FIG. 4. Standard effect sizes at 6 months for physician-, patient- and laboratory-based measures in the US301 trial. Phys Global, physician global assessment of disease activity; Pt Global, patient global assessment of disease activity.

 
Improvements in outcomes reported by patients with placebo treatment were less than physician-assessed measures, and uniformly showed deterioration in individual percentage changes in physical function. The laboratory measures ESR and CRP reflected worsening following placebo administration, according to mean gross and individual percentage changes and SES. In the placebo treatment groups, physician-reported measures showed improvement by mean gross and individual percentage changes as well as SES. In MN301, at 6 months, small improvements indicated by mean gross percentage changes and SES in patient-reported pain, mean HAQ and HAQ DI were actually worsenings according to mean individual percentage changes (Fig. 1). At 12 months, despite small improvements in gross percentage changes in patient global assessment of disease activity, pain and PET, worsening was evident by mean individual percentage changes in patient global assessment, MHAQ, HAQ DI and PET, as well as SES in both global assessments and MHAQ.


    Discussion and conclusions
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion and conclusions
 References
 
These results show that patient-reported outcome measures are less susceptible to placebo effects than physician-reported measures. Self-report questionnaires and acute-phase reactants (ESR and CRP) better differentiated between active and placebo treatment. Physician-reported measures showed substantial improvements in group means and individual percentage changes in patients receiving placebo, although absolute differences in SESs between active and placebo treatments are similar to those with patient reported outcomes.

An early large meta-analysis of 130 placebo RCTs with NSAIDs showed that patient global assessment was the most sensitive effect measure, followed by patient-reported pain [49]. This study suggested that there was little justification for the widespread use of the Ritchie index. A subsequent RCT examining withdrawal of DMARDs in RA showed no differences between observer evaluations of joint counts despite significant differences in patient perceptions of treatment effect [50]. A later meta-analysis of 114 RCTs showed that in 32 trials with binary outcome measures there was no evidence of a placebo effect [41]. However, it also showed that in 82 RCTs with continuous outcome measures placebo treatment only showed benefits when subjective, not objective, endpoints were assessed. Significant, but small, improvements in patient reported pain with placebo treatment decreased with increasing sample size.

Placebo responses in patient-reported outcomes may reflect non-specific effects in the patient–physician relationship, including attention, compassionate care, modulation of expectations, anxiety and self-awareness [51]. The two RCTs we have evaluated used a double-dummy treatment regimen in which all patients received three oral medications with control treatments identical to active therapies. The magnitude of placebo responses in both trials was similar to those reported in recent RCTs with biological DMARDs, where parenteral administration and separate observers were required for safety and efficacy, with potentially different expectation biases [52].

Reported improvements and deteriorations were analysed by mean gross and individual percentage changes and SES. As all but PET and SF-36 are components of the ACR >=20% response criteria, there is no gold standard that can be independently applied to the analyses. The Disease Activity Score (DAS28), which includes TJC, SJC, ESR and patient global assessment of disease activity, was retrospectively applied to both RCTs [53] Results indicated by DAS28 ‘good or moderate’ improvements with placebo treatment were very similar to ACR20 responses. In MN301 at 6 months, 37% of patients receiving placebo were responders according to DAS28 compared with 29% according to ACR20 criteria in US301 at 12 months: 30 vs 26% respectively were identified as responders, indicating reasonable concordance assessing the placebo response by the use of both criteria [54]. In US301, 17% patients receiving placebo were classified as responders by ACR >=20% criteria but not DAS28; 11% were classified as responders by DAS28 and not ACR criteria. [55] Less concordance identifying responders following active treatment was evident in US301: 0 and 7% by ACR but not DAS28 criteria with leflunomide and methotrexate respectively, and 28 and 33% by DAS28 but not ACR criteria.

The analyses, using prespecified outcome measures, depict differing views of the placebo response. Reported improvements with placebo administration are more prevalent with physician-reported measures. In both RCTs, differences in SES between active and placebo treatment were largest with patient-reported outcomes, particularly physical function. Whether assessed by HAQ DI, mean changes in HAQ or MHAQ scores, lack of improvement or deterioration was reported following placebo administration. The results indicate that patient-reported outcomes are objective, congruent with laboratory measures of inflammation, are less susceptible to the placebo response, and best discriminate active from placebo treatment. Results using these outcome measures should be emphasized in RCTs designed to measure clinical benefit in RA. Provided these observations can be replicated in analyses of other placebo RCTs in RA (with or without background therapy), the balance of evidence suggests that improvement in signs and symptoms of active disease is most accurately assessed using patient-reported physical function, provided similar changes are reported in global assessments of disease activity and pain, subsequently supported by improvements in other domains, including laboratory and imaging measures. Caution is needed when using the term ‘placebo response’, and the analysis of active and placebo treatment effects should separate patient-reported, physician-reported and laboratory measures.

The authors have declared no conflicts of interest.


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion and conclusions
 References
 

  1. Felson DT, Anderson JJ, Boers M et al. The American College of Rheumatology preliminary core set of disease activity measures for rheumatoid arthritis clinical trials. The Committee on Outcome Measures in Rheumatoid Arthritis Clinical Trials. Arthritis Rheum 1993;36:729–40.[ISI][Medline]
  2. Bombardier C. The optimal use of cyclosporine A in rheumatoid arthritis: efficacy and outcome measures including quality of life. Br J Rheumatol 1993;32(Suppl. 1):47–50.[Medline]
  3. Bombardier C, Buchbinder R, Tugwell P. Efficacy of cyclosporine A in rheumatoid arthritis: long term followup data and the effect on quality of life. Scand J Rheumatol 1992;21:29–33.
  4. Buchbinder R, Bombardier C, Yeung M, Tugwell P. Which outcome measures should be used in rheumatoid arthritis clinical trials? Clinical and quality-of-life measures’ responsiveness to treatment in a randomized clinical trial. Arthritis Rheum 1995; 38:1568–80.[ISI][Medline]
  5. 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. Minocycline in Rheumatoid Arthritis Trial Group. J Rheumatol 1997;24:1910–5.[ISI][Medline]
  6. Strand V, Cohen S, Schiff M et al. Leflunomide Rheumatoid Arthritis Investigators Group. Treatment of active rheumatoid arthritis with leflunomide compared with placebo and methotrexate. Arch Intern Med 1999;159:254–50.
  7. Strand V, Tugwell P, Bombardier C et al. Leflunomide Rheumatoid Arthritis Investigators Group. Function and health-related quality of life: results from a randomized controlled trial of leflunomide versus methotrexate or placebo in patients with active rheumatoid arthritis. Arthritis Rheum 1999;42:187–8.[CrossRef][ISI][Medline]
  8. Tugwell P, Wells G, Strand V et al. Leflunomide Rheumatoid Arthritis Investigators Group. 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. Arthritis Rheum 2000;43:506–14.[CrossRef][ISI][Medline]
  9. Scott DL, Strand V. The effects of disease-modifying anti-rheumatic drugs on the Health Assessment Questionnaire score. Lessons from the leflunomide clinical trials database. Rheumatology 2002;41:899–909.[Abstract/Free Full Text]
  10. Smolen JS, Kalden JR, Scott DL et al. The European Leflunomide Study Group. Efficacy and safety of leflunomide compared with placebo and sulfasalazine in active rheumatoid arthritis: a double-blind, randomised, multicentre trial. Lancet 1999;353:259–66.[CrossRef][ISI][Medline]
  11. Kalden JR, Scott DL, Smolen JS et al. Improved functional ability in patients with rheumatoid arthritis—Longterm treatment with leflunomide versus sulfasalazine. J Rheumatol 2001;28:1983–91.[ISI][Medline]
  12. Kosinski M, Zhao SZ, Didhiya S, Osterhaus JT, Ware JE Jr. Determining minimally important changes in generic and disease-specific health-related quality of life questionnaires in clinical trials of rheumatoid arthritis. Arthritis Rheum 2000;43:147–87.
  13. Mathias SD, Colwell HH, Miller DP, Moreland LW, Buatti M, 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;22:128–39.[CrossRef][ISI][Medline]
  14. Lipsky PE, van der Heijde DM, St Clair EW et al. Infliximab and methotrexate in the treatment of rheumatoid arthritis. N Engl J Med 2000;343:1594–602.[Abstract/Free Full Text]
  15. Kavanaugh A, Lipsky P, Furst D et al. Infliximab improves long term quality of life and functional status in patients with rheumatoid arthritis. Arthritis Rheum 2000;43:S147.
  16. Bathon JM, Martin RW, Fleishmann RM et al. A comparison of etanercept and methotrexate in patients with early rheumatoid arthritis. N Engl J Med 2000;343:1586–93.[Abstract/Free Full Text]
  17. Genovese M, Bathon J, Martin R et al. Etanercept versus methotrexate in patients with early rheumatoid arthritis: Two-year radiographic and clinical outcomes. Arthritis Rheum 2002;46:1443–51.[CrossRef][ISI][Medline]
  18. Sigal LH. Outcomes in studies of rheumatoid arthritis: attention to quality of life issues, their determinants, and measurement. Dis Manage Clin Outcomes 2000;1:6–14.
  19. Bruce G, Fries J. The Health Assessment Questionnaire. A review of its history, issues, progress, and documentation. J Rheumatol 2003;30:167–78.[ISI][Medline]
  20. Pincus T, Summey JA, Soraci SA Jr, Wallston KA, Hummon NP. Assessment of patient satisfaction in activities of daily living using a modified Stanford Health Assessment Questionnaire. Arthritis Rheum 1983;26:1346–53.[ISI][Medline]
  21. Ware JE, Snow KK, Kosinski M, Gandek B. SF-36® Health Survey: Manual and Interpretation Guide. Lincoln, RI: QualityMetric Incorporated, 2000.
  22. World Medical Association Declaration of Helsinki. Ethical principles for medical research involving human subjects. Available at: http://www.wma.net//policy/17c.pdf. Accessed 27 September 2001.
  23. Temple R, Ellenberg SS. Placebo-controlled trials and active-control trials in the evaluation of treatments. Part 1: Ethical and scientific issues. Ann Intern Med 2000;133:455–63.[Abstract/Free Full Text]
  24. Ellenberg SS, Temple R. Placebo-controlled trials and active-control trials in the evaluation of treatments. Part 2: Practical issues and specific cases. Ann Intern Med 2000;133:464–70.[Abstract/Free Full Text]
  25. Paulus HE, Egger MJ, Ward JR, Williams HJ. Analysis of improvement in individual rheumatoid arthritis patients treated with disease-modifying antirheumatic drugs, based on the findings in patients treated with placebo. The Cooperative Systematic Studies of Rheumatic Diseases Group. Arthritis Rheum 1990;33:477–84.[ISI][Medline]
  26. Tugwell P, Pincus T, Yocum D et al. Combination therapy with cyclosporine and methotrexate in severe RA. New Engl J Med 1995;333:137–41.[Abstract/Free Full Text]
  27. Weinblatt ME, Kremer JM, Bankhurst AD et al. A trial of etanercept, a recombinant tumor necrosis factor receptor-Fc fusion protein, in patients with rheumatoid arthritis receiving methotrexate. New Engl J Med 1999;340:253–9.[Abstract/Free Full Text]
  28. Cohen SB, Hurd E, Cush J et al. Treatment of rheumatoid arthritis with anakinra, a recombinant human interleukin-1 receptor antagonist (IL-1ra), in combination with methotrexate. Arthritis Rheum 2002;46:614–24.[CrossRef][ISI][Medline]
  29. Kremer JM, Genovese MC, Cannon GW et al. Concomitant leflunomide therapy in patients with active rheumatoid arthritis despite stable doses of methotrexate: a randomized comparison of efficacy, safety, and tolerability compared to methotrexate alone. Ann Intern Med 2002;137:726–33.[Abstract/Free Full Text]
  30. den Broeder A, van de Putte LBA, Rau R et al. A single dose, placebo controlled study of the fully human anti TNFa antibody adalimumab in patients with rheumatoid arthritis. J Rheumatol 2002;29:2288–98.[ISI][Medline]
  31. Weinblatt ME, Keystone EC, Furst DE et al. Adalimumab, a fully human anti-tumor necrosis factor {alpha} monoclonal antibody, for the treatment of rheumatoid arthritis in patients taking concomitant methotrexate. Arthritis Rheum 2003;48:35–45.[CrossRef][ISI][Medline]
  32. Keystone E, Kavanaugh AF, Sharp J et al. Adalimumab (D2E7), a fully human anti-TNF-{alpha} monoclonal antibody, inhibits the progression of structural joint damage in patients with active RA despite concomitant methotrexate therapy. Arthritis Rheum 2002;46:S205.
  33. Furst DE, Schiff M, Fleischmann R et al. Adalimumab, a fully human anti–TNF-{alpha} monoclonal antibody, and concomitant standard antirheumatic therapy for the treatment of rheumatoid arthritis: results of STAR (Safety Trial of Adalimumab in Rheumatoid Arthritis). J Rheumatol 2003;30:2563–71.[ISI][Medline]
  34. Cohen SB, Moreland LW, Cush JJ et al. Anakinra: a large, placebo controlled efficacy trial of anakinra in patients with erosive rheumatoid arthritis disease. Arthritis Rheum 2001;44:SLB 1.
  35. Shergy WJ, Kaine JL, Hurd ER et al. Disease activity score in a large placebo controlled randomized study of rheumatoid arthritis patients treated with anakinra. Ann Rheum Dis 2003;62:S186.
  36. Fleischmann RM, Schechtman J, Bennett R et al. Anakinra, a recombinant human interleukin-1 receptor antagonist, in patients with RA. Arthritis Rheum 2003;48:927–34.[CrossRef][ISI][Medline]
  37. Rochon PA, Binns MA, Litner JA et al. Are randomized control trial outcomes influenced by the inclusion of a placebo group? A systematic review of nonsteroidal antiinflammatory drug trials for arthritis treatment. J Clin Epidemiol 1999;52:113–22.[CrossRef][ISI][Medline]
  38. Ernst E, Resch KL. Concept of true and perceived placebo effects. BMJ 1995;311:551–3.[Free Full Text]
  39. Bailar JC: The powerful placebo and the Wizard of Oz. N Engl J Med 2001;344:1630–2.[Free Full Text]
  40. Talbot M. The placebo prescription. NY Times Magazine, 9 January 2000:34–9.
  41. Hróbjartsson A, Gøtzsche PC. Is the placebo powerless? An analysis of clinical trials comparing placebo with no treatment. N Engl J Med 2001;344:1594–602.[Abstract/Free Full Text]
  42. Bailar JC. The powerful placebo and the Wizard of Oz. N Engl J Med 2001;344:1630–2.[Free Full Text]
  43. Vickers AJ, de Craen AJ. Why use placebos in clinical trials? A narrative review of the methodological literature. J Clin Epidemiol 2000;53:157–61.[CrossRef][ISI][Medline]
  44. Stein CM, Pincus T. Placebo-controlled studies in rheumatoid arthritis: ethical issues. Lancet 1999;353:400–3.[CrossRef][ISI][Medline]
  45. Turner JA, Deyo RA, Loeser JD, Von Korff M, Fordyce WE. The importance of placebo effects in pain treatment and research. JAMA 1994;271:1609–14.[Abstract]
  46. Olsen N, Schiff M, Strand V. Alternate therapy with leflunomide or methotrexate after switch from initial treatment in patients with active rheumatoid arthritis (RA). Arthritis Rheum 1999;42:S241.
  47. Kremer JM, Genovese MC, Cannon GW et al. Combination of leflunomide and methotrexate therapy for patients with active rheumatoid arthritis failing methotrexate monotherapy: an open-label extension of a randomized, double-blind, placebo-controlled trial. J Rheum, in press.
  48. Arnett FC, Edworthy SM, Bloch DA et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 1988;31:315–24.[ISI][Medline]
  49. Gotzsche PC. Sensitivity of effect of variables in rheumatoid arthritis: a meta-analysis of 130 placebo controlled NSAID trials. J Clin Epidemiol 1990;43:1313–8.[ISI][Medline]
  50. Gotzsche PC, Hansen M, Stoltenberg M et al. Randomized, placebo controlled trial of withdrawal of slow-acting antirheumatic drugs and of observer bias in rheumatoid arthritis. Scand J Rheumatol 1996;25:194–9.[ISI][Medline]
  51. Kaptchuck TJ. The placebo effect in alternative medicine: can the performance of a healing ritual have clinical significance? Ann Intern Med 2002;136:817–25.[Abstract/Free Full Text]
  52. Kaptchuk TJ, Goldman P, Stone DA, Stason WB. Do medical devices have enhanced placebo effects? J Clin Epidemiol 2000;53:786–92.[CrossRef][ISI][Medline]
  53. van Gestel AM, Haagsma CJ, van Riel PLCM. Validation of the rheumatoid arthritis improvement criteria that includes simplified joint counts. Arthritis Rheum 1998;41:1845–50.[CrossRef][ISI][Medline]
  54. Strand V, Emery P, Scott DL et al. Comparison of the EULAR Response Criteria [DAS28] and the ACR responder index in 3 trials of leflunomide. Ann Rheum Dis 1999; Abstract 401.
  55. Strand V, Hurley F, Cohen S and the Leflunomide US Investigators Group. Comparison of the ACR Responder Index to the Disease Activity Score [DAS28] in a randomized controlled trial of leflunomide vs placebo or methotrexate. Ann Rheum Dis 1999; Abstract 400.
Submitted 22 August 2003; revised version accepted 23 December 2003.



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