Improved Health-related Quality of Life With Effective Disease-modifying Antirheumatic Drugs: Evidence From Randomized Controlled Trials

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Supplements and Featured Publications, Health-related Quality of Life in Rheumatoid Arthritis, Volume 13, Issue 9 Suppl

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Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by inflammation of the articular synovium, resulting in bony erosions, deformity, and, ultimately, joint destruction. With associated comorbid conditions, especially cardiovascular, it can result in significant morbidity as well as early mortality. Patients with RA report impairments in health-related quality of life (HRQOL) in comparison with age- and sex-matched populations without arthritis. These decreases in HRQOL are attributed to the pain, impairment in physical function, and fatigue associated with this disease. The introduction of new disease-modifying antirheumatic drugs has revolutionized the treatment of RA, particularly the biologic agents: etanercept, infliximab, adalimumab, abatacept, and rituximab. Importantly, administration of these agents has resulted in statistically significant and clinically meaningful improvements in physical function and HRQOL. Many clinical studies confirm that with these therapies, RA patients report improvements in HRQOL, reflected by improved physical function, less fatigue, and better emotional and mental function. Maintenance of physical function is no longer the only treatment goal for RA but also to improve, restore, and preserve HRQOL. Results from pivotal clinical trials are analyzed in this article and the relevance of the data derived from the clinical studies to day-to-day clinical practice are also discussed.

(Am J Manag Care. 2007;13:S237-S251)

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by inflammation of the articular synovium, resulting in bony erosions, deformity, and ultimately joint destruction. With associated comorbid conditions, especially cardiovascular conditions, RA can result in significant morbidity as well as early mortality.1,2 Patients with RA report significant decrements in health-related quality of life (HRQOL) in comparison with age- and sex-matched populations without arthritis. These decreases in HRQOL are attributed to the pain, impairment in physical function, and fatigue associated with this disease.3

Since 1996, the American College of Rheumatology (ACR) criteria (ACR 20%/50%/70% responses) have been used to differentiate effective therapies from placebo in randomized controlled trials (RCTs).4 They are defined as ≥20%/50%/70% improvement in tender and swollen joint counts and 3 of the following 5 measures: physician global assessment, acute phase reactants (erythrocyte sedimentation rate or C-reactive protein), patient global assessment of disease activity, patient-reported pain, and patient-reported physical function by the Health Assessment Questionnaire (HAQ). ACR responses, in association with improvements in the Disease Activity Score (DAS), have been utilized to demonstrate the efficacy of 7 new disease-modifying antirheumatic drugs (DMARDs) approved since 1998. In addition, these trials have demonstrated “inhibition of radiographic disease progression” and, importantly, “improvement in physical function and HRQOL”—now established labeling claims. In part, data were collected in response to US Food and Drug Administration (FDA) requirements for “durability of response,” requesting evaluation of physical function and HRQOL during 24 months of treatment. The HAQ Disability Index (HAQ-DI) and its modifications— modified (MHAQ) and multidimensional (MDHAQ)—have become the primary measure of physical function in RA, accompanied by use of generic measures such as Medical Outcomes Study 36- Item Short Form (SF-36), Euro QOL (EQ-5D), and Health Utilities Index-3 to assess HRQOL in RA.5 Uhlig et al compared reported scores using HAQ-DI, MHAQ, SF-36, and the Arthritis Impact Measurement Scale (AIMS).6 As expected, HAQ-DI and MHAQ scores correlated well, but HAQ-DI discriminated more precisely in those patients with significant disability.6 Although both may be utilized in RCTs, standard effect sizes are larger, and the minimum clinically important difference (MCID) is lower with HAQ-DI (−0.22) than MHAQ (−0.25).7

Joint pain and range of motion influence performance of physical activities, including activities of daily living, discretionary activities such as shopping and sports, and participation in family and social events. A study investigated associations between HAQ-DI and clinical variables of disease in 304 patients with RA.8 Decreased range of motion and grip strength, higher swollen joint counts, and pain correlated with more impairments in physical function were assessed by HAQ-DI. In addition to physical function, age and socioeconomic factors such as education, employment status, race, living setting, and economic status affect patientreported HRQOL; those older, less educated, not employed, and/or less affluent reported significantly lower HRQOL.9,10

This article reviews patient-reported physical function and HRQOL from RCTs with traditional DMARDs methotrexate and leflunomide, as well as biologic agents, including etanercept, infliximab, adalimumab, abatacept, and rituximab. The relevance of HRQOL data derived from RCTs to day-to-day clinical practice will be discussed in this article.

Before the introduction of the new DMARDs, longitudinal series reported progressive deterioration in physical function or, at best, stabilization in RA with standard of care (including methotrexate). Summarizing data from 12 studies, Scott et al demonstrated average increases of 0.033 per year in HAQ-DI scores.11,12 A J-shaped curve plotting disability measured by HAQ-DI versus disease duration was observed, reflecting that patients with early disease reported more impairments in physical function, which were dramatically improved when treatment with the first DMARD was initiated.13 West et al compared SF-36 in RA patients at disease onset and after 2 years, with patients with long-term disease duration of 21 to 25 years.14 Two years after diagnosis, patients reported significant improvements in role physical and bodily pain domains of SF-36 compared with disease onset. As expected, impairments in physical function were fewer in patients with early versus longer-duration RA. As with physical function, HRQOL is negatively impacted in early RA. Therefore, comparisons of reported improvements in HAQ-DI and SF-36 scores across treatment groups must account for disease duration as well as baseline characteristics in protocol populations.

Differences in results with active therapy versus placebo are most pronounced in patient-reported outcomes of pain, physical function, and global disease activity and best differentiate active from placebo therapy.15,16 When comparing changes from baseline in HAQ-DI scores at 6 and 12 months in RCTs, mean improvements in patients who received active treatment ranged from −0.25 to −0.80, compared with patients receiving placebo, where mean change scores did not meet or exceed the MCID of −0.22.17 As noted earlier, it is difficult to compare changes across RCTs and treatments; the proportion of patients reporting improvements ≥MCID offers another way to interpret data from RCTs. Recent publications have reported proportion of patients with improvements in HAQ-DI scores ≥−0.25, ≥-0.50, or ≥-0.80 or attaining final scores of 0 to 0.5, representing non-RA population norms18 and considered to reflect clinically meaningful improvements.

Values for MCID in domain and SF-36 summary scores (physical component summary [PCS] and mental component summary [MCS]) have been derived in RA, osteoarthritis, psoriatic arthritis, ankylosing spondylitis, systemic lupus erythematosus, and fibromyalgia, based on correlations with patient-reported improvements in global disease activity, on an individual patient basis, as reviewed by Khanna and Tsevat in this supplement. Changes of 5 to 10 points in domain scores and 2.5 to 5.0 points in PCS and MCS are considered to represent MCID.7,19-29 Changes that meet or exceed 0.5 standard deviation (SD) of the mean can be considered to reflect “minimally important differences” (MIDs), statistical definitions not specifically anchored to patientreported outcomes.

Another interpretation of the “clinical meaningfulness” of changes in reported HRQOL is to compare baseline and end point domain and summary scores of SF-36 to age- and sex- matched norms in relevant cultural populations. Baseline scores reported by patients in RA RCTs reflect large decrements in physical function, role physical, pain, vitality, and general health perception domains, as well as PCS scores, often approaching 2 SDs below the expected norm of 50. Changes in SF-36 scores at end point can be evaluated by how closely they approach a “goal” of normative scores (Figure 1).

Reported changes in specific queries in SF-36 (eg, decreases in walking limitations; less time lost at work because of health reasons; less inability to work because of pain; less time felt tired or worn out; less interference of health in social activities; and fewer patients reporting feeling downhearted or blue most of the time) offer another method for interpreting clinically meaningful changes attributed to treatment. Answers to the “transition question” of SF-36 (ie, “compared with a year ago…”) also offer a way to interpret clinically meaningful treatment-associated changes. Importantly, changes from baseline in RCTs may exceed those reported in longitudinal studies, largely attributed to “expectation bias” on the part of patients (as well as treating physicians).

Methotrexate and LeflunomideMethotrexate is the most commonly prescribed DMARD in RA, with proven efficacy as monotherapy and in combination with other DMARDs, including biologic agents. Symptomatic benefit is typically maximal at 6 months.30 Leflunomide, a synthetic DMARD approved by the FDA in 1998 for treatment of active RA, has been shown in RCTs to be equivalent to methotrexate and offers an alternative for patients who have failed on or are intolerant to methotrexate.31

A 24-month, placebo-controlled RCT (US 301) was the first to show that SF-36 was a valid and sensitive instrument to measure HRQOL in patients with active RA.7,32,33 Subsequently, results from 3 phase 3 RCTs over 2 years of blinded treatment with leflunomide, methotrexate, or sulfasalazine demonstrated that improvements in physical function and HRQOL were sustained and clinically meaningful.34 In the 2 studies that compared methotrexate and leflunomide, US 301 and MN 302/4, patient-reported outcomes included HAQ-DI, MHAQ, and SF-36. After 12 and 24 months of treatment with leflunomide or methotrexate, 74% to 84% of leflunomide-treated and 69% to 78% of methotrexate- treated patients reported improvements in HAQ-DI ≥MCID in US 301 and MN 302/4. Mean disease duration was 6.7 years in US 301 and 3.2 years in MN 302/4, and baseline HAQ-DI scores were 1.2 and 1.5, respectively (Table 1).32-34 Despite these overall differences, 40% to 45% of patients in each study had disease duration of ≤2 years.34

In the year-2 cohorts from both trials,34 improvements from baseline in HAQ-DI that were evident at 6 months were sustained over 24 months of treatment and statistically significant (P = .005 at 24 months) (Table 1). These values were consistent with HAQ-DI values reported in the intent-to-treat population at 12 months. For SF-36 PCS, mean change scores reported by patients receiving leflunomide or methotrexate were not statistically different and met or exceeded MCID in 80% of leflunomide-treated and 77% of methotrexate-treated patients. Baseline SF-36 MCS scores approached US norms and did not demonstrate statistically or clinically meaningful improvements. Reported improvements in SF-36 domains were equivalent between leflunomide and methotrexate except in bodily pain, vitality, and role emotional; for these domains, patients treated with leflunomide demonstrated statistically significantly greater improvements (P <.05 vs methotrexate). With the exception of physical function, role physical, and bodily pain domain scores, reflecting largest decrements at baseline, final mean SF-36 scores approached age- and sex-matched US norms in 5 of 8 domains with leflunomide but none of 8 with methotrexate (Figure 1).

Based on improvements in HAQ-DI and SF-36, the number needed to treat (NNT) to achieve another patient reporting improvements in HAQ-DI &#8804;MCID and/or normative PCS levels were 3 to 5 for leflunomide versus 6 to 17 with methotrexate versus placebo.

Biologic Agents: TNF-alpha InhibitorsInhibition of the activity of tumor necrosis factor (TNF)-alpha, a pleiotropic proinflammatory cytokine pathogenic in RA, has revolutionized treatment of this disease.35 Phase 3 RCTs with infliximab, etanercept, and adalimumab have demonstrated a significant and clinically meaningful impact on physical function and HRQOL in patients with active RA, many of whom have failed methotrexate.27 HAQ-DI and SF- 36 were studied in the phase 3 RCT Anti-tumour Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy (ATTRACT),36 in the phase 4 Trial of Etanercept and Methotrexate with Radiographic Patient Outcomes (TEMPO),37 and in all phase 3 adalimumab38 RCTs.

Infliximab. In ATTRACT, 428 RA patients with mean disease duration of 9 to 12 years and failing methotrexate received infliximab or placebo in addition to methotrexate over 12 and 24 months of treatment.36 Baseline HAQ-DI scores and SF-36 PCS scores were more than 2 SDs below US norms, whereas MCS scores were within 1 SD.39 All activetreatment groups reported statistically significant and clinically meaningful improvements in physical function and HRQOL that were evident at 6 to 10 weeks, with the greatest changes in role physical and bodily pain domains.

Treatment with infliximab plus methotrexate over 24 months or placebo plus methotrexate in ATTRACT resulted in significant improvements in HAQ-DI (overall median improvement in infliximab groups of 0.4 vs 0.1 in the placebo group; P &#8804;.006) and SF-36 PCS scores (median changes of 2.8 with placebo vs 6.4 with infliximab; P &#8804;.011). Changes from baseline in HAQ-DI and SF-36 scores in ATTRACT are presented in Table 2.36,39-41 The impact of RA on MCS was not as marked at baseline, yet median changes in all active-treatment groups reflected statistically and clinically meaningful improvements over 2 years of treatment versus placebo. More active-treatment patients versus patients receiving placebo reported changes &#8805;MCID (defined as 10 points) from baseline to first assessment at week 6 or 10 in PCS scores (51% vs 32%) and MCS scores (40% vs 32%). Median changes from baseline in all active-treatment groups met or exceeded MCID in 5 of 8 domains compared with none receiving methotrexate plus placebo (Figure 2). Furthermore, 21% of patients with improvements in HAQ-DI exceeding MCID (&#8805;0.25) versus 3% with changes less than 0.25 gained employment during this trial.41

Adalimumab. The Anti-TNF Research Study Program of the Monoclonal Antibody Adalimumab (ARMADA or DE009) RCT was a 6-month comparison of adalimumab 20 or 40 mg biweekly versus placebo in 271 patients failing methotrexate.49 Baseline HAQ-DI scores reflected significant impairment of physical function.38,50 Mean improvements at weeks 1 and months 3 and 6 exceeded MCID in all activetreatment groups compared with placebo plus methotrexate and were statistically significant (P <.05). At 6 months, significant improvements in SF-36 PCS scores (Table 4)38,49-51 were observed, as well as improvements in 7 of 8 and 8 of 8 domains of SF-36 by patients receiving 20 and 40 mg of adalimumab plus methotrexate, respectively, versus only 4 of 8 domains with placebo plus methotrexate (P <.05). Mean increases in all domain scores exceeded MCID (>10 points) in all active-treatment groups compared with 2 of 8 domains with placebo plus methotrexate. At 6 months, mean improvement in scores on the fatigue scale of the Functional Assessment of Chronic Illness Therapy (FACIT) in the 40-mg active-treatment group (8.5) was statistically significant versus placebo plus methotrexate (3.0).49

Among those completing ARMADA or DE019, 505 RA patients received long-term adalimumab treatment over a mean of 19.2 months. Mean disease duration in this population was 12.4 years, patients having failed approximately 3 prior DMARDs. Baseline SF-36 scores in those enrolled in ARMADA overall were >10 points lower than in DE019; nonetheless, treatment-associated improvements in SF-36 scores confirmed rapid and sustained improvements in HRQOL over 6.5 months, from 25.4 to 34.4 and 43.7 to 50.0 in PCS and MCS scores, respectively.52 Mean baseline PCS scores in the entire population were similar to MCS, indicating patients with longer disease duration report more decrements in physical functioning, role physical, bodily pain, general health, and vitality. After long-term treatment, mean area under the curve of SF-36 scores demonstrated sustained and clinically meaningful improvements in HRQOL.

B- and T-cell Costimulation Modulator Abatacept, a B- and T-cell costimulation modulator, has been demonstrated to improve signs and symptoms of RA, to inhibit progression of structural damage, and to improve physical function and HRQOL over 24 months of treatment in adult patients with active RA with inadequate responses to methotrexate or TNF-alpha antagonists.53,54

In the Abatacept in Inadequate Responders to Methotrexate (AIM) trial, HAQ-DI and SF-36 scores were compared in 652 patients with inadequate responses to methotrexate, randomized 2:1 to receive abatacept plus methotrexate or placebo plus methotrexate over 12 months.55 Mean baseline HAQ-DI scores were 1.7, and SF-36 domain scores were >1 SD below US norms (Table 5).55-57 Mean PCS and MCS scores approximated 2 and 1 SD, respectively, below US norms of 50.56 A responder analysis determined the percentage of patients from each treatment group who reported improvements >0.5 SD at 12 months, representing MID.

In the Abatacept Trial in Treatment of Anti-TNF Inadequate Responders (ATTAIN), an RCT, 391 patients with an average of 11.4 to 12.2 years of disease duration, having failed etanercept and/or infliximab because of inadequate responses or adverse effects, were randomized to receive abatacept (n = 258) or placebo (n = 133) plus DMARDs over 6 months.57 Significantly more abatacept-treated versus patients receiving placebo reported improvements from baseline > 0.30 in HAQ, and clinically meaningful difference (defined as > 3 points) in PCS and MCS scores (P <.01) (Table 5). HAQ-DI and 7 of 8 SF-36 domains (all but role emotional) were significantly improved with abatacept treatment in those with lower 28 joint-count DAS scores at baseline. The percentage of patients reporting improvements > MID at 6 months was significantly higher with abatacept treatment (P <.0001).

In the Abatacept Study of Safety in Use with Other RA Therapies (ASSURE), 1441 patients received placebo or treatment with abatacept, added to background DMARD therapy; 1231 completed 12 months of protocol treatment.58 Baseline HAQ-DI scores ranged from 1.5 to 1.6; improvements of 30% and 22% were observed in those receiving abatacept plus background DMARDs, compared with 9% and 15% with placebo plus background DMARDs, respectively. Overall, mean improvements of &#8722;0.46 in HAQ-DI were reported with abatacept plus background DMARDs versus &#8722;0.25 with placebo plus DMARDs. In an RCT of 121 patients receiving etanercept randomized to receive abatacept or placebo in addition for 12 months, those receiving combination therapy reported clinically meaningful changes of > 3 points in PCS and MCS scores compared with baseline. Statistically significant improvements versus placebo were evident in PCS and 5 of 8 SF-36 domains.59

Selective Depletion of B CellsRituximab, a monoclonal antibody directed against the CD20 antigen on the surface of circulating B lymphocytes, is indicated in combination with methotrexate for treatment of patients with active RA who have had inadequate responses to > 1 TNF inhibitor. In an initial phase 2 RCT, 161 patients with active RA failing methotrexate were randomized to receive 1 of 4 treatments for 6 months: rituximab alone, rituximab plus methotrexate, rituximab plus cyclophosphamide, or methotrexate plus placebo.60 Patients remained in follow-up until re-treatment was required. A higher proportion of patients in active-treatment arms had continuing ACR responses and did not require re-treatment at 6, 12, and 18 months. Proportions of patients with clinically meaningful improvements in HAQ-DI (MCID > 0.25 reduction) are shown in Table 6.61,62 Differences favoring rituximab plus methotrexate persisted up to 24 months, with high dropout rates in the other treatment groups.

In the Dose-ranging Assessment: International Clinical Evaluation of Rituximab in Rheumatoid Arthritis (DANCER) trial, 465 patients received 1 of 3 treatments&#8212;2 infusions of rituximab 500 mg, 2 infusions of rituximab 1000 mg (days 1 and 15), or placebo&#8212;plus methotrexate, with intravenous (IV) glucocorticoids, both oral and IV glucocorticoids, or none at all.62 Baseline HAQ-DI score and proportions of patients with changes > MCID (defined as 0.22 reduction in score) are shown in Table 6. Similar improvements were seen in fatigue measured by FACIT, with mean changes > MCID in rituximab-treated patients.

In the Randomized Evaluation of Long-term Efficacy of Rituximab in RA trial (REFLEX), 520 patients with active RA on methotrexate following inadequate responses to TNF inhibitors received rituximab or placebo for 6 months. Baseline HAQ-DI scores were 1.9, with changes of &#8722;0.4 with rituximab versus &#8722;0.1 with placebo; 18% versus 0.5% (1 patient) achieved HAQ-DI scores of 0 at 6 months despite long disease duration of 11.7 to 12.1 years. Improvements in SF-36 PCS and MCS scores of 4.7 and 5.8, respectively, were reported with rituximab versus 1.3 and 0.9, respectively, with placebo; between-group differences were statistically significant and clinically meaningful, as they differed by >3 points.63 Changes from baseline in SF-36 scores at week 24 in the REFLEX trial are represented in Figure 5.64

Duration of RA Influences OutcomesIn patients with established disease, baseline PCS scores were low across trials: 30.2 to 30.9 in US 301; 23.9 to 25.8 in ATTRACT; 27.9 to 29.0 in ARMADA; 28.5 to 29.1 in protocol DE019; 30.6 to 30.7 in AIM; and 27.6 to 27.7 in ATTAIN. (Baseline PCS scores were not reported in etanercept or rituximab RCTs.) Mean and median improvements with active treatment over 12 and 24 months resulted in meaningful increases in PCS scores: Baseline scores were >2 SDs below normative values of 50, while results reached within 1 SD of the norm, and changes well exceeded MCID (2.5-5.0 points) in all trials. These improvements were reflected by reductions in the percentage of patients reporting limitations in performance of common activities. Changes in PCS scores alone do not reflect the full range of improvement in HRQOL, which occurs when treatments positively impact physical function in patients with active RA. All studies have demonstrated that treatment-related changes in HAQ-DI scores are closely reflected not only in improvements in physical domains of SF-36 but also social functioning, role emotional, and general health profile. As with HAQ, reported improvements are maximal within 6 months and sustained over 12 to 24 months of continuing therapy.

It is important to understand that a measure of physical function in RA such as HAQ-DI is an assessment of &#8220;state&#8221; as well as &#8220;change.&#8221; Development of joint damage, manifested by bony erosions and joint space narrowing, leads to irreversible structural changes that impact physical functioning and lead to irreversible impairments and ultimately inability to work or engage in desired activities, and thus disability. Baseline levels of physical functioning reported in RCTs are clearly influenced by disease activity, severity, and duration. To better understand the impact of disease duration on physical function, Aletaha and Ward conducted a combined analysis based on reports from 36 RCTs including 64 active-treatment arms and 7628 patients.65 In these trials, disease duration ranged from 2.5 months to 12.2 years and, as expected, less improvement in HAQ-DI was reported by patients with long-standing RA compared with early RA.65 In subsequent analyses, Aletaha et al demonstrated that HAQ-DI has both reversible and irreversible components.66 Scores were less likely to improve with longer disease duration, indicating irreversible impairments in physical function secondary to joint damage and deformities.66 After adjusting for pain scores and tender joint counts in separate regression analyses, baseline HAQ-DI scores were significantly associated with RA disease duration. Effect sizes for HAQ-DI decreased by 0.02 and 0.03, and there was an absolute increase in HAQ-DI scores of 0.01 and 0.02 for each additional year of RA disease duration, in 3- and 6- month assessments, respectively.

Subsequently, data from all RCTs published between 1980 and 2005 that reported changes from baseline in HAQ-DI at 6 and/or 12 months were analyzed.67 Treatments were grouped as &#8220;biologic&#8221; or &#8220;traditional&#8221; DMARDs compared with placebo, and patients were stratified by disease duration at baseline. A weighted generalized linear model estimated effect sizes of HAQ-DI in treatment groups and marginal means of this effect across different disease durations. Both analyses indicated that discrimination of improvement in physical function between biologic or traditional DMARDs and placebo is reduced in patients with a longer duration of RA. The effects of treatment on improvement in HAQ-DI scores were striking in early RA, but decreased significantly with increasing duration of RA.

In the Early Rheumatoid Arthritis (ERA) trial, 632 patients with mean disease duration of 11 months, 50% to 60% of whom were DMARD-naive, were randomized to receive etanercept 10 and 25 mg or methotrexate.68,69 Reported improvements in SF-36 scores in all 8 domains and summary scores were significant in all treatment groups but remained below US population norms. Both etanercept treatment groups reported earlier and greater improvements in HAQ-DI and physical domain scores of SF-36 than the methotrexate group. Over 24 months of treatment in ERA, 55% of patients receiving etanercept 25 mg reported improvements in HAQ-DI >0.5 versus 37% with methotrexate (P <.001).70 Despite low PCS scores at baseline (28.0 to 29.2), improvements at 12 and

The Active Controlled Study of Patients Receiving Inflixi

Address correspondence to: Vibeke Strand, MD, FACP, Division of Immunology/ Rheumatology, Stanford University School of Medicine, 306 Ramona Rd, Portola Valley, CA 94028. E-mail: vstrand@aol.com.1. Sacks JJ, Helmick CG, Langmaid G. Deaths from arthritis and other rheumatic conditions, United States, 1979-1998. J Rheumatol. 2004;31:1823-1828.2. Lee DM, Weinblatt ME. Rheumatoid arthritis. Lancet. 2001;358: 903-911.

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47. Breedveld FC,Weisman MH, Kavanaugh AF, et al. The PREMIER study: a multicenter, randomized, double-blind clinical trial of combination therapy with adalimumab plus methotrexate versus methotrexate alone or adalimumab alone in patients with early, aggressive rheumatoid arthritis who had not had previous methotrexate treatment. Arthritis Rheum. 2006;54:26-37.

49. 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: the ARMADA trial. Arthritis Rheum. 2003;48: 35-45.

51. Keystone EC, Kavanaugh AF, Sharp JT, et al. Radiographic, clinical, and functional outcomes of treatment with adalimumab (a human anti-tumor necrosis factor monoclonal antibody) in patients with active rheumatoid arthritis receiving concomitant methotrexate therapy: a randomized, placebo-controlled, 52-week trial. Arthritis Rheum. 2004;50:1400-1411.

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