Adalimumab for Long-Term Treatment of Psoriatic Arthritis

Transcription

1 ARTHRITIS & RHEUMATISM Vol. 56, No. 2, February 2007, pp DOI /art , American College of Rheumatology Adalimumab for Long-Term Treatment of Psoriatic Arthritis Forty-Eight Week Data From the Adalimumab Effectiveness in Psoriatic Arthritis Trial Dafna D. Gladman, 1 Philip J. Mease, 2 Christopher T. Ritchlin, 3 Ernest H. S. Choy, 4 John T. Sharp, 5 Peter A. Ory, 6 Renee J. Perdok, 7 and Eric H. Sasso 7 Objective. To evaluate the efficacy and safety of treatment with adalimumab, a fully human anti tumor necrosis factor (anti-tnf) monoclonal antibody, over 48 weeks in patients with moderate to severe psoriatic arthritis (PsA). Methods. Patients who completed the Adalimumab Effectiveness in Psoriatic Arthritis Trial (ADEPT), a 24-week, double-blind study of adalimumab versus placebo in PsA, could elect to receive open-label adalimumab, 40 mg subcutaneously every other week after week 24. Radiographs were obtained at week 48 and were read with radiographs obtained previously. Clinical and radiographic efficacy data were analyzed Supported by Abbott Laboratories. 1 Dafna D. Gladman, MD, FRCPC: University of Toronto, and Toronto Western Hospital, Toronto, Ontario, Canada; 2 Philip J. Mease, MD: Seattle Rheumatology Associates, and University of Washington School of Medicine, Seattle, Washington; 3 Christopher T. Ritchlin, MD: University of Rochester School of Medicine and Dentistry, Rochester, New York; 4 Ernest H. S. Choy, MD, FRCP: King s College London, London, UK; 5 John T. Sharp, MD: University of Washington, Seattle; 6 Peter A. Ory, MD: Southwest Medical Imaging, Seattle, Washington; 7 Renee J. Perdok, MS, MBA, Eric H. Sasso, MD: Abbott Laboratories, Abbott Park, Illinois. Dr. Gladman has received consulting fees or honoraria (less than $10,000) from Abbott. Dr. Mease has received consulting fees, speaking fees, or honoraria (more than $10,000) from Abbott. Dr. Ritchlin has received consulting fees or honoraria (less than $10,000 each) from Abbott, Centocor, Wyeth, and Biogen. Dr. Choy has received consulting fees, speaking fees, or honoraria (less than $10,000) from Abbott. Dr. Sharp has received consulting fees or honoraria (more than $10,000 each) from Abbott and Amgen. Dr. Ory has received consulting fees or honoraria (more than $10,000) from Abbott. Ms Perdok and Dr. Sasso own stock in Abbott. Address correspondence and reprint requests to Dafna D. Gladman, MD, FRCPC, Toronto Western Hospital, Centre for Prognostic Studies in the Rheumatic Diseases, Edith Cavell Wing 5-034B, 399 Bathurst Street, Toronto, Ontario M5T 2S8, Canada. dafna.gladman@utoronto.ca. Submitted for publication June 15, 2006; accepted in revised form October 30, overall and in patient subsets. Safety data were collected over 48 weeks. Results. At week 48, patients from the adalimumab arm of ADEPT (n 151) had achieved American College of Rheumatology 20% improvement (ACR20), ACR50, and ACR70 response rates of 56%, 44%, and 30%, respectively. Among those evaluated with the Psoriasis Area and Severity Index (PASI) (n 69), PASI50, PASI75, PASI90, and PASI100 response rates (>50%, >75%, >90%, and 100% reduction in PASI scores, respectively) were 67%, 58%, 46%, and 33%, respectively (ACR and PASI response rates were analyzed using nonresponder imputation). Improvements in disability, as measured by the Disability Index of the Health Assessment Questionnaire (mean change in score 0.4) were sustained from week 24 to week 48. At week 24 and week 48, the mean changes from baseline in the modified total Sharp score were 0.1 and 0.1, respectively, for patients who received adalimumab for 48 weeks (n 133), and 0.9 and 1.0, respectively, for patients who received placebo for 24 weeks followed by adalimumab for 24 weeks (n 141). Adalimumab demonstrated clinical and radiographic efficacy regardless of whether patients were receiving methotrexate (MTX) at baseline. Adalimumab was generally safe and well tolerated through week 48. Conclusion. Adalimumab improved joint and skin manifestations, reduced disability, and inhibited radiographic progression over 48 weeks in patients with PsA who were participants in ADEPT. MTX use at baseline was not required for clinical or radiographic efficacy. Adalimumab had a good safety profile through week 48. Psoriatic arthritis (PsA) is an inflammatory arthritis that occurs in up to one-third of patients with 476

2 EFFECTIVENESS OF LONG-TERM ADALIMUMAB IN PsA 477 psoriasis and is usually diagnosed years after the appearance of psoriatic skin disease (1,2). More than half of patients with PsA exhibit progressive, erosive arthritis that often is associated with functional impairment (3 6). In a longitudinal study in which patients with PsA were observed for a mean of 7 years, the percentage of patients with at least 5 damaged joints increased from 19% to 41% despite treatments that included salicylates, indomethacin, disease-modifying antirheumatic drugs (DMARDs), or glucocorticoids (7). Other studies have confirmed that rapidly progressive joint damage occurs frequently among patients with PsA (6,8 10). Routine clinical assessments may often underestimate the amount of joint damage, both in patients with diagnosed PsA (11) and in patients who have psoriasis without apparent joint involvement (12). Patients with PsA have an increased risk of death (13), and the magnitude of this risk is greater if the erythrocyte sedimentation rate is elevated or if joint damage is evident on radiographs (14). These findings suggest that the control of inflammation and early prevention of structural damage may improve the long-term outcome in patients with PsA. Treatment of moderate to severe PsA has tended to include the same DMARDs used for rheumatoid arthritis (RA), e.g., methotrexate (MTX), azathioprine, leflunomide, gold, and sulfasalazine, even though there is much less evidence for the efficacy of DMARDs in PsA, and there is essentially no evidence that DMARDs slow radiographic joint destruction in PsA (15 20). In contrast, several clinical trials have demonstrated that tumor necrosis factor (TNF) antagonists are generally safe and efficacious for the treatment of PsA and can inhibit the associated progression of radiographic damage (21 28). The Adalimumab Effectiveness in Psoriatic Arthritis Trial (ADEPT) is a 24-week, randomized, doubleblind, placebo-controlled trial comparing the fully human anti-tnf monoclonal antibody adalimumab and placebo as therapy for moderate to severe PsA (26). With 313 patients, ADEPT is the largest double-blind, randomized, controlled trial to date of a TNF antagonist in PsA. Results of ADEPT demonstrated that therapy with the same dosage of subcutaneous adalimumab used in RA, 40 mg every other week, provided significant improvement in arthritis, skin disease, radiographic joint destruction, disability, and quality of life. Furthermore, adalimumab was generally safe and well tolerated (26). Patients who completed 24 weeks in ADEPT were permitted to enroll in an open-label extension trial, during which they received adalimumab at a dosage of 40 mg every other week. Here, we describe the efficacy and safety of adalimumab in ADEPT patients during 24 weeks of blinded treatment plus 24 weeks of open-label treatment. Emphasis is placed on radiographic outcomes, which were determined using a modified version of the Sharp scoring system designed to measure PsArelated radiographic changes in addition to changes routinely assessed in RA. The results show that 48 weeks of adalimumab therapy inhibited radiographic progression, provided sustained improvement of arthritis, skin disease, and disability, and had an acceptable safety profile in patients with longstanding moderate to severe PsA. PATIENTS AND METHODS Patients and protocol of the open-label extension study. Patients who completed the 24-week blinded phase of ADEPT were eligible for treatment with subcutaneous adalimumab, 40 mg every other week, for up to 120 weeks or until adalimumab was commercially available in their respective countries. Nonsteroidal antiinflammatory drugs (NSAIDs), prednisone, and/or DMARDs could not be initiated during the open-label extension phase of the study but were continued in patients who were already receiving them at the time of entry into the open-label extension trial; tapering was allowed after 6 weeks of treatment. Patients who failed to demonstrate 20% improvement compared with baseline in the tender joint count (TJC) and the swollen joint count (SJC) after 12 weeks of treatment in the open-label extension phase (36 weeks in the study) were allowed to increase the adalimumab dosage to 40 mg weekly. Data from evaluations at weeks 26, 30, 36, 42, and 48 of the open-label extension phase are included in this report, as are data from weeks 0 24 of ADEPT. Clinical efficacy and safety assessments. The American College of Rheumatology (ACR) core set criteria and the ACR 20% improvement (ACR20), ACR50, and ACR70 response rates were calculated for the open-label extension phase using the same methodologies that were used for the blinded phase of ADEPT (26,29). The ACR responses were based on a 76- or 78-joint count of tender or swollen joints, respectively (reflecting inclusion of the first carpometacarpal joints and the distal interphalangeal joints of the feet) (26). In the open-label extension phase, skin disease responses were assessed only in patients who had psoriasis involving at least 3% of the body surface area (BSA) at baseline, as was done previously (26). The Psoriasis Area and Severity Index (PASI) (30) and the Disability Index (DI) of the Health Assessment Questionnaire (HAQ) were used according to the same methodologies that were used in the blinded phase of ADEPT, with the addition of a 100% reduction in the PASI score (PASI100) (26,31). Safety assessments were conducted throughout the open-label extension phase, as was done prior to week 24 (26). Statistical analysis of clinical efficacy data. For patients who initially were randomized to the adalimumab arm of ADEPT, all nonradiographic data from baseline to week 48 were analyzed for an intent-to-treat (ITT) cohort of 151 patients. For patients who initially were randomized to the

3 478 GLADMAN ET AL placebo arm of ADEPT, all nonradiographic data from baseline to week 24 were analyzed for an ITT cohort of 162 patients. All subsequent nonradiographic data until week 48 for patients in the placebo arm were analyzed for a cohort of patients who entered the open-label extension trial (n 147). For all patients, changes in nonradiographic measurements were calculated relative to measurements obtained at week 0 (baseline) of ADEPT. The analysis of ACR20, ACR50, ACR70, and PASI50, PASI75, PASI90, and PASI100 response rates used nonresponder imputation (NRI) for missing data. The analysis of all other nonradiographic measurements used the last observation carried forward (LOCF) method for missing data. Unless stated otherwise, nonradiographic data for patients who chose DMARD rescue therapy during weeks (4 patients assigned to adalimumab and 16 patients assigned to placebo) (26) or for patients who increased their adalimumab dosage to 40 mg weekly on or after week 36 were analyzed (until week 24 or week 48, respectively) as if these patients had withdrawn from the study upon changing treatment. To establish statistical significance, Fisher s exact test combining baseline strata was used for analysis of the ACR and PASI response rates. An analysis of covariance model including factors for treatment group and MTX treatment at baseline was used to determine the mean changes from baseline in PASI responses, and an analysis of variance (ANOVA) model including factors for treatment group and category of baseline MTX use/extent of psoriasis (yes/ 3% BSA; yes/ 3% BSA; no/ 3% BSA; or no/ 3% BSA) was used to analyze the mean changes from baseline in the HAQ DI. Radiographic efficacy assessments. Radiographs of the hands and feet were obtained at the ADEPT baseline visit and at weeks 24 and 48. Radiographs were collected and processed for evaluation at a core imaging laboratory (Bio- Imaging, Newtown, PA), which controlled protocol compliance, overall imaging quality, film digitizing, and masking of digital image files. Radiographs were read by 2 independent radiologists (PAO and JTS) who were blinded to radiograph chronology, type of therapy, and patient clinical status. Radiographs were read on 2 separate occasions: first, after completion of the blinded phase of ADEPT, called the week 24 radiographic reading (baseline and week 24 radiographs only), and second, after completion of the first 48 weeks of study, called the week 48 radiographic reading (baseline, week 24, and week 48 radiographs). Radiographs from the same patient were always read together. ADEPT used a modified version of the total Sharp score that is based on the Sharp scoring method for RA (32) and was developed for use in trials of biologic response modifiers in PsA (26). Joint erosion (JE) and joint space narrowing (JSN) were scored for the same articular sites as in RA (33), except as follows: inclusion of the 4 distal interphalangeal joints of each hand (JE and JSN), addition of the triquetrium/pisiform complex (JE only), exclusion of the hallux interphalangeal joint (JSN only), and addition of the scapholunate joint (JSN only). Thus, a total of 54 sites were evaluated for JE, and 48 sites were evaluated for JSN. Scoring scales were essentially the same as those used for RA, except that the JE scale was expanded from 0 5 to 0 7, with scores of 6 and 7 used to indicate the degree of osteolysis. The JSN scale remained 0 4. The maximum modified total Sharp score was 570 (378 Sharp units for joint erosions and 192 units for JSN). Radiographic features commonly observed in PsA (joint space widening, gross osteolysis, subluxation, pencil-in-cup, juxtaarticular periostitis, shaft periostitis, phalangeal tuft resorption) were scored separately, each according to a unique scale (26). Evaluable radiographs and use of imputation. Radiography outcomes were determined only for patients whose radiographs from baseline and week 24 were evaluable. A set of radiographs was considered evaluable if 50% of articular sites could be evaluated for JE and 50% of sites could be evaluated for JSN. When 50% but 100% of sites could be evaluated, the JE and/or JSN scores were normalized by multiplying the obtained score by 100 and dividing by the percentage of sites that could be evaluated. When baseline or week 24 radiographs were missing or could be evaluated for 50% of sites, the patient was excluded from radiographic analyses. The week 48 radiographic reading was restricted to patients who had received 1 dose of adalimumab in the open-label extension study and had evaluable radiographs at baseline and week 24, as defined above. When week 48 radiographs were absent or not evaluable, the radiographic change score from week 24 to week 48 was imputed. For those patients who were initially randomized to receive adalimumab, the radiographic change score was imputed to be equal to the normalized change in the modified total Sharp score from baseline to week 24 (from the week 48 radiographic reading). For those patients who were initially randomized to receive placebo, the radiographic change score was imputed to be zero. Subgroup analyses of radiographic data. Data from the week 24 radiographic reading were used to determine the mean change in the modified total Sharp score from baseline to week 24 for patients grouped post hoc according to baseline parameters of age ( 40 years, 40 years to 60 years, and 60 years), sex, race, weight ( 86 kg and 86 kg), C-reactive protein (CRP) concentration ( 2 mg/dl and 2 mg/dl), rheumatoid factor status (positive/negative), TJC ( 20 and 20), SJC ( 20 and 20), and HAQ DI score ( 1.5 and 1.5). Data from the week 24 and week 48 radiographic readings were used to determine the mean change in the modified total Sharp score from baseline to week 24 or week 48, respectively, for patients grouped according to documented treatment with MTX at baseline (yes/no). Statistical analysis of radiographic data. Continuous modified total Sharp score data were evaluated by ranked ANOVA, with treatment group and category of baseline MTX use/extent of psoriasis (yes/ 3% BSA; yes/ 3% BSA; no/ 3% BSA; no/ 3% BSA) as factors, and the ranked baseline modified total Sharp score as the covariate. All statistical tests were 2-sided, with an alpha level of The effect of interreader variance on the discriminatory power of the radiographic data was assessed by calculating the smallest detectable change (34). Categorical data (decrease, no change, or increase in the modified total Sharp score) were analyzed by the Cochran-Mantel-Haenszel mean score test, with baseline MTX use (yes/no) and extent of psoriasis ( 3% BSA and 3% BSA) as stratification factors. Statistical significance was not calculated for comparisons involving radiographic or

4 EFFECTIVENESS OF LONG-TERM ADALIMUMAB IN PsA 479 Table 1. Patient disposition during the double-blind and open-label extension phases of ADEPT* Double-blind (weeks 0 24) Open-label adalimumab, 40 mg every other week (weeks 24 48) Characteristic Placebo every other week (n 162) Adalimumab 40 mg every other week (n 151) Patients from placebo arm (n 147) Patients from adalimumab arm (n 138) Methotrexate use at baseline Completed study Evaluable radiographs at baseline and week Premature termination Primary reason for termination Adverse event Withdrew consent Abnormal laboratory value(s) Unsatisfactory therapeutic effect Other * Values are the number of patients. ADEPT Adalimumab Effectiveness in Psoriatic Arthritis Trial. Includes 4 placebo patients and 6 adalimumab patients who withdrew prior to week 24 and subsequently had radiographs obtained for week 24. nonradiographic data for patients from the placebo arm after week 24. RESULTS In the overall ADEPT population of 313 treated patients (151 patients in the adalimumab group and 162 patients in the placebo group), the mean SD baseline TJC was 25 18, SJC was 14 12, HAQ DI score was , and modified total Sharp score was , which is consistent with longstanding, moderate to severe PsA (26). The 24-week blinded period of ADEPT was completed by 289 patients, 285 of whom subsequently enrolled in the open-label extension trial (138 from the adalimumab arm, 147 from the placebo arm) (Table 1). Baseline characteristics of patients entering the open-label extension phase were similar to those of the 313 patients who enrolled in ADEPT. Twelve patients withdrew before week 48 (1 because of an adverse event and 3 because of an unsatisfactory therapeutic effect as the primary reason) (Table 1). Response of PsA to 48 weeks of treatment. The ACR responses that were established with adalimumab treatment in the double-blind phase of ADEPT were maintained in the open-label extension phase, with ACR20, ACR50, and ACR70 response rates of 56%, 44%, 30%, respectively, observed at week 48 (Figure 1A). Patients who received placebo in ADEPT had poor ACR responses at week 24 but had ACR20, ACR50, and ACR70 response rates of 48%, 34%, and 20%, respectively, at week 48, after 24 weeks of open-label treatment with adalimumab (Figure 1A). These week 48 results provide a conservative estimate of the efficacy of adalimumab, because they encompass all patients who were randomized to the adalimumab arm in ADEPT (intentto-treat) or who entered the open-label extension phase from the placebo arm, and they consider all patients in these cohorts who withdrew from the study to be nonresponders (NRI). In addition, patients who changed to weekly adalimumab on or after week 36 (15 in the adalimumab group and 23 in the placebo group) were thereafter classified as nonresponders. If the week 48 ACR20, ACR50, and ACR70 response rates were calculated using the measured responses of patients who received weekly doses of adalimumab instead of using NRI, they would be 60%, 46%, and 31%, respectively, for the 151 patients from the adalimumab arm and 54%, 37%, and 21%, respectively, for the 147 patients who entered the open-label extension phase from the placebo arm. Thus, 48 weeks of treatment with adalimumab at a dosage of 40 mg every other week provided sustained efficacy for the treatment of arthritis in patients with PsA. Response of psoriasis to 48 weeks of treatment. For patients with PASI evaluations who received adalimumab during the blinded phase of ADEPT (n 69; mean baseline PASI score 7.4) (26), the week 24 improvements were sustained through week 48, when the mean percentage change from baseline in the PASI score was 68% and the PASI50, PASI75, PASI90, and PASI100 response rates were 67%, 58%, 46%, and 33%, respectively (Figures 1B and C). For patients with PASI evaluations who received placebo during ADEPT (n 69; mean baseline PASI score 8.3) (26), there was virtually no improvement in skin disease at week 24.

5 480 GLADMAN ET AL Figure 1. Clinical efficacy outcomes over 48 weeks in participants in the Adalimumab Effectiveness in Psoriatic Arthritis Trial (ADEPT). A, Percentage of patients from the adalimumab and placebo arms of ADEPT who met the American College of Rheumatology criteria for 20%, 50%, and 70% improvement (ACR20, ACR50, ACR70 responses) over 48 weeks (for the placebo arm, n 162 patients assessed from baseline to week 24, and n 147 patients assessed after week 24; for the adalimumab arm, n 151 patients). B, Mean percentage improvement in Psoriasis Area and Severity Index (PASI) scores over 48 weeks in patients with psoriasis involving at least 3% of body surface area (BSA) at baseline (for the placebo arm, n 69 patients assessed from baseline to week 24, and n 59 patients assessed after week 24; for the adalimumab arm, n 69 patients). C, Percentage of patients with psoriasis involving at least 3% of BSA at baseline who met the PASI criteria for 50%, 75%, 90%, and 100% improvement (PASI50, PASI75, PASI90, PASI100) at week 24 (69 patients receiving placebo and 69 patients receiving adalimumab) and week 48 (59 patients who received placebo during the double-blind phase and adalimumab during the open-label phase, and 69 patients who received adalimumab continuously). D, Percentage of patients from the adalimumab cohorts described in A and C who met the ACR20, ACR50, or ACR70 response criteria or the PASI50, PASI75, PASI90, or PASI100 response criteria at week 48, according to whether patients were receiving methotrexate (MTX) at baseline. Missing data for all patients and postescalation data for patients who began weekly adalimumab on or after week 36 were analyzed using nonresponder imputation for ACR and PASI response rates and last observation carried forward for PASI scores. Values above the bars in C and D are percentages. P 0.001; P 0.01 versus placebo, by Fisher s exact test combining baseline strata (A and C) and by an analysis of variance model including factors for treatment group and baseline MTX use (B); P 0.05 versus adalimumab without MTX, by Fisher s exact test. P values were not calculated for comparisons of clinical efficacy between treatment arms after week 24.

6 EFFECTIVENESS OF LONG-TERM ADALIMUMAB IN PsA 481 However, following 24 weeks of open-label adalimumab (n 59), the mean percentage change from baseline in the PASI score was 64% (Figure 1B), and the PASI50, PASI75, PASI90, and PASI100 response rates were 61%, 53%, 44%, and 31%, respectively (Figure 1C). If, for patients who began weekly dosing on or after week 36, the measured PASI data were used instead of LOCF or NRI (8 patients from the adalimumab arm and 12 from the placebo arm), the mean percentage improvement in the PASI score and the PASI50, PASI75, PASI90, and PASI100 response rates at week 48 would be 67%, 70%, 58%, 46%, and 33%, respectively, for the 69 patients from the adalimumab arm and 72%, 76%, 63%, 47%, and 34%, respectively, for the 59 patients from the placebo arm. Thus, 48 weeks of treatment with adalimumab at a dosage of 40 mg every other week provided sustained efficacy for the treatment of skin disease in patients with PsA. Effect of MTX use on ACR and PASI responses at week 48. To examine the relationship between baseline MTX use and longer-term efficacy of adalimumab, ACR and PASI response rates at week 48 were determined for patients from the adalimumab arm who were grouped post hoc according to MTX use (yes/no) at baseline. At week 48, the ACR and PASI response rates for the with-mtx and without-mtx subgroups of the adalimumab arm were high (Figure 1D) and were similar in magnitude to those for the total adalimumab group at week 48 (Figures 1A and C). Thus, adalimumab appeared to be efficacious through week 48 for the treatment of the arthritis and skin disease of PsA, whether or not patients were receiving MTX at baseline. For adalimumab-treated patients, ACR and PASI response rates at week 48 were numerically greater in the with-mtx subgroups, but a significant difference (P 0.05) between the with-mtx and without-mtx subgroups was observed only for the PASI50 results. Improvement in disability with 48 weeks of treatment. For patients treated with adalimumab, the mean change from baseline to week 24 in the HAQ DI score ( 0.4) (26) exceeded the minimum clinically important difference for PsA (0.3) (35) and RA (0.22) (36). At week 48, this mean improvement in the HAQ DI score was maintained in the 151 patients in the adalimumab arm ( 0.4) and was replicated in the 147 patients from the placebo arm ( 0.4). Radiographic data from 2 independent readings. The effect of adalimumab on structural damage in PsA was analyzed using data sets from 2 independent readings of radiographs. The first reading was of baseline and week 24 radiographs and provided data from 296 Table 2. Changes in the mtss from baseline to week 24 of ADEPT by treatment arm* Change in mtss Placebo (n 152) Adalimumab (n 144) According to Sharp units Increase ( 0.5) 44 (28.9) 13 (9.0) No change ( 0.5 to 0.5) 100 (65.8) 104 (72.2) Decrease ( 0.5) 8 (5.3) 27 (18.8) According to SDC Increase ( 1.88) 23 (15.1) 6 (4.2) No change ( 1.88 to 1.88) 126 (82.9) 129 (89.6) Decrease ( 1.88) 3 (2.0) 9 (6.2) * Values are the number (%) of patients. Week 0 (baseline) to week 24 comprised the blinded phase of the Adalimumab Effectiveness in Psoriatic Arthritis Trial (ADEPT). mtss modified total Sharp score; SDC smallest detectable change. P by Cochran-Mantel-Haenszel mean score test, with baseline methotrexate use (yes/no) and extent of psoriasis ( 3% body surface area, 3% body surface area) as stratification factors. ADEPT patients with evaluable radiographs at both time points (144 patients in the adalimumab group and 152 in the placebo group). Of these 296 patients, 286 had completed the randomized controlled trial, and 10 patients (6 adalimumab and 4 placebo) had withdrawn from ADEPT but had radiographs obtained subsequently (7 at week 24 [ 1 week], and 1 each at weeks 15, 29, and 35). The second reading was of baseline, week 24, and week 48 radiographs from the 274 ADEPT patients who received adalimumab in the open-label extension and had evaluable radiographs at baseline and week 24 (133 from the adalimumab arm and 141 from the placebo arm) (Table 1). Among patients with evaluable radiographs in the second reading, 99.3%, 99.1%, and 99.0% of articular sites could be evaluated for JE, and 98.2%, 98.0%, and 98.0% could be evaluated for JSN at baseline, week 24, and week 48, respectively. The week 48 radiographic scores were imputed for 12 patients (5 from the adalimumab arm and 7 from the placebo arm). All other scores are for actual radiographs. Frequency of radiographic progression at week 24. At week 24, the mean change from baseline in the modified total Sharp score was 0.2 for adalimumabtreated patients (n 144) versus 1.0 for placebo-treated patients (n 152) (P 0.001) (26). At week 24, 91.0% of adalimumab-treated patients had no radiographic progression (defined as a change in the modified total Sharp score of 0.5), compared with 71.1% of patients treated with placebo, and the modified total Sharp score was improved (change in modified total Sharp score of less than 0.5) in 18.8% of adalimumab-treated patients compared with 5.3% of placebo-treated patients (P

7 482 GLADMAN ET AL Figure 2. Cumulative probability plots of changes in the modified total Sharp score (mtss) from baseline to week 24 according to treatment with placebo (n 152) or adalimumab (n 144) (A) and according to whether these patients were or were not receiving MTX at ADEPT baseline (B). Data are from the week 24 radiographic evaluation. The upturning parts of the curves represent radiographic progression. See Figure 1 for other definitions ) (Table 2). For the week 24 reading, the smallest detectable change in the modified total Sharp score was The smallest detectable change is the smallest change in the modified total Sharp score needed to exceed the amount of change attributable to reader error. A change in the modified total Sharp score of 1.88 from baseline to week 24 occurred in 95.8% of adalimumab-treated patients and in 84.9% of placebotreated patients. A change in the modified total Sharp score of less than 1.88 from baseline to week 24 occurred in 6.2% of adalimumab-treated patients and 2.0% of placebo-treated patients (P 0.001) (Table 2). These differences in the frequency of radiographic progression are apparent in the cumulative probability plots shown in Figure 2A. Subgroup analyses of week 24 radiographic efficacy data. Post hoc analyses were performed to determine whether radiographic efficacy was observed in subgroups defined by baseline demographics or clinical data. Compared with placebo, adalimumab resulted in statistically significant inhibition of radiographic progression at week 24 in all subgroups that had adequate numbers of patients available for comparison (Table 3). Excluding the small subgroup of nonwhite patients, the subgroups with the greatest radiographic progression with placebo at week 24 were those with a baseline CRP concentration of 2.0 mg/dl, SJC of 20, or HAQ DI score of 1.5. For each of these subgroups, the mean change in the modified total Sharp score with adalimumab at week 24 was less than zero.

8 EFFECTIVENESS OF LONG-TERM ADALIMUMAB IN PsA 483 Table 3. Modified total Sharp scores (mtss) at week 24 according to characteristics of patients at baseline* Placebo every other week (n 152) Adalimumab 40 mg every other week (n 144) Characteristic n Baseline mtss, mean Change from baseline in mtss, mean SD n Baseline mtss, mean Change from baseline in mtss, mean SD P Age 40 years years to 60 years years Sex Male Female Race White Nonwhite Weight 86 kg kg CRP concentration 2 mg/dl mg/dl Rheumatoid factor status Positive Negative Missing NA Tender joint count Swollen joint count HAQ DI score Methotrexate use Yes No * CRP C-reactive protein; NA not applicable (a statistical comparison was not performed because there were no patients in the adalimumab group); HAQ DI Disability Index of the Health Assessment Questionnaire. Differences between treatment groups from a ranked analysis of covariance, with treatment group, baseline methotrexate use (yes/no), and extent of psoriasis ( 3% or 3% body surface area) as factors and the ranked baseline modified total Sharp score as the covariate. The mean change in the modified total Sharp score from baseline to week 24 was significantly smaller with adalimumab than placebo, both for patients who were receiving MTX at baseline ( 0.2 versus 1.2; P 0.001) and for patients who were not receiving MTX at baseline ( 0.2 versus 0.9; P 0.001) (Table 3). Figure 2B shows cumulative probability plots displaying these MTX-related comparisons. Therefore, the overall ability of adalimumab to control radiographic progression to week 24 in ADEPT was not dependent on the use of MTX at baseline. Radiographic efficacy through week 48. For patients who received adalimumab in the blinded and open-label extension phases of ADEPT, the mean changes from baseline in the modified total Sharp score were 0.1 at week 24 and 0.1 at week 48 (n 133 patients), indicating sustained control of radiographic progression by adalimumab for 1 year (Figure 3). For patients who received placebo during the blinded phase of ADEPT and adalimumab during the open-label extension phase, the mean changes from baseline in the modified total Sharp score were 0.9 at week 24 and 1.0 at week 48 (n 141), indicating that the radiographic progression that occurred in patients receiving placebo from baseline to week 24 was essentially arrested by adalimumab during the open-label extension phase of the trial (Figure 3). From baseline to week 48, the mean changes in JE and JSN scores were 0.1 and 0.0, respectively, for patients in the adalimumab arm and 0.6 and 0.4, respectively, for patients in the placebo arm, suggesting that adalimumab controlled damage to bone and cartilage over 48 weeks.

9 484 GLADMAN ET AL Figure 3. Mean changes in the modified total Sharp score (mtss) from baseline to weeks 24 and 48. Patients received either adalimumab or placebo through week 24 (double-blind phase), and all patients received adalimumab thereafter (open-label phase). Data are from the week 48 radiographic evaluation. eow every other week. P 0.001, adalimumab at week 24 versus placebo at week 24, and adalimumab at week 48 versus placebo at week 24, by ranked analysis of covariance. If the week 48 radiographic analysis were limited to the 262 patients who had evaluable week 48 radiographs (i.e., excluding the 12 patients with imputed week 48 radiographic results), then the mean changes in the modified total Sharp score from baseline to week 48 would be 0.2 (adalimumab arm) and 1.1 (placebo arm). If the analysis were limited to patients who received adalimumab only at a dosage of 40 mg every other week (i.e., excluding patients who received weekly adalimumab), then the mean changes in the modified total Sharp score from baseline to week 48 would be 0.0 for patients from the adalimumab arm (n 117) and 1.0 for patients from the placebo arm (n 112). Thus, the ability of adalimumab to control radiographic progression through week 48 was independent of the analytic use of imputation and the clinical use of weekly adalimumab. Frequency of radiographic progression at week 48. For the week 48 radiographic reading, the smallest detectable change in the modified total Sharp score was The percentage of patients with no radiographic progression at week 48 was greater in the adalimumab arm compared with the placebo arm, regardless of whether radiographic progression was defined as a change in the modified total Sharp score from baseline of 0.5 (86.5% versus 74.5%) or 2.11 (93.2% versus 87.9%) (Table 4). Similarly, the percentage of patients with an improved modified total Sharp score at week 48 was also greater in the adalimumab arm (20.3% versus 9.9% had a change of less than 0.5, and 6.0% versus 1.4% had a change of less than 2.11). The use of imputation for 12 patients had essentially no effect on these results. Radiographic outcomes according to MTX use at week 48. Patients randomized to receive adalimumab in ADEPT had a smaller mean change in the modified total Sharp score from baseline to week 48 than did patients randomized to placebo, regardless of whether they received concomitant MTX at baseline (for adali- Table 4. Changes in the mtss from baseline to week 48 of ADEPT by treatment arm* Change in mtss Placebo/ adalimumab (n 141) Adalimumab (n 133) According to Sharp units Increase ( 0.5) 36 (25.5) 18 (13.5) No change ( 0.5 to 0.5) 91 (64.5) 88 (66.2) Decrease ( 0.5) 14 (9.9) 27 (20.3) According to SDC Increase ( 2.11) 17 (12.1) 9 (6.8) No change ( 2.11 to 2.11) 122 (86.5) 116 (87.2) Decrease ( 2.11) 2 (1.4) 8 (6.0) * Values are the number (%) of patients. Patients in the placebo/ adalimumab group received placebo from baseline to week 24 and adalimumab thereafter. Weeks comprised the open-label phase of ADEPT. See Table 2 for definitions.

10 EFFECTIVENESS OF LONG-TERM ADALIMUMAB IN PsA 485 mumab, 0.1 [n 72]; for placebo, 1.4 [n 73]) or did not receive concomitant MTX at baseline (for adalimumab, 0.4 [n 61]; for placebo, 0.6 [n 68]). These week 48 mean changes in the modified total Sharp score for the adalimumab subgroups are significantly smaller than the week 24 changes in the corresponding placebo subgroups ( 0.1 versus 1.0 with MTX [P 0.001]; 0.4 versus 0.8 without MTX [P 0.046]). The data thus show that MTX use at baseline was not required for radiographic efficacy of adalimumab through week 48, although the data suggest that a difference between the MTX subgroups might exist. Radiographic findings characteristic of PsA. Based on data from the week 48 radiographic reading, juxtaarticular periostitis scores increased in 3.7% of patients from the placebo arm (5 of 135) and 2.3% of patients from the adalimumab arm (3 of 130) from week 24 to week 48. Scores for each of the other 6 findings characteristic of PsA increased in 1% of patients from each arm, from week 24 to week 48. Safety. Compared with the 24-week safety data in ADEPT (26), there were no clinically meaningful changes in the occurrence of adverse events following adalimumab treatment in the open-label extension period. During weeks (weeks 1 24 of the open-label extension period), the 3 most frequently reported adverse events in 285 patients were upper respiratory tract infection not otherwise specified (13.7% of patients), nasopharyngitis (10.9% of patients), and injection-site reactions (8.4% of patients). During weeks 24 48, there was 1 serious infection (gastroenteritis not otherwise specified) and 10 other serious adverse events (nasal septum disorder not otherwise specified, pulmonary embolism, toe arthrodesis, convulsions not otherwise specified, Meckel s diverticulitis, cholelithiasis, abdominal pain not otherwise specified, myocardial infarction, calculus renal not otherwise specified, and amyloidosis not otherwise specified), none of which led to permanent discontinuation of adalimumab. During weeks 24 48, 9 of 285 patients had a serum transaminase value (alanine aminotransferase and/or aspartate aminotransferase) that was 3 times the upper limit of normal. Five of these patients were receiving concomitant MTX, and 2 others had concomitant rhabdomyolysis and a history of ethanol use, respectively. In 2 patients (1 of whom was receiving placebo), transient transaminase elevations 3 times the upper limit of normal had also occurred during the blinded phase of ADEPT. The transaminase elevations resolved in all 9 of these patients, without discontinuation of adalimumab in 8 patients. During the first 48 weeks of ADEPT, there were no deaths and no reports of tuberculosis or granulomatous infections, demyelination, lymphoma or carcinoma, new antinuclear antibody formation, drug-induced lupus, or congestive heart failure. DISCUSSION ADEPT is the largest randomized controlled study to date of a TNF antagonist in PsA. Results of the 24-week blinded phase of ADEPT established that adalimumab was more efficacious than placebo for treating arthritis and skin disease and inhibiting radiographic progression in PsA, and that treatment with adalimumab led to significant improvement in physical function and quality of life (26). Nearly all patients who completed 24 weeks in ADEPT entered the open-label extension trial, during which they received adalimumab at a dosage of 40 mg every other week. The present analysis of 48-week outcomes combined data from the blinded and openlabel extension phases of ADEPT, thereby providing both a reassessment of the de novo efficacy of adalimumab in patients who initially received placebo, and a longer-term assessment of adalimumab efficacy in patients who initially received adalimumab. The results confirmed the clinical and radiographic efficacy of adalimumab in PsA and established that these benefits were maintained over 48 weeks. In both the blinded and the open-label extension phases of ADEPT, the radiographic efficacy of adalimumab was shown to involve 3 effects: 1) a reduction in the percentage of patients with radiographic progression, 2) a reduction in the amount of radiographic progression sustained by these patients, and 3) a small increase in the percentage of patients with an improved modified total Sharp score. By week 24, radiographic progression occurred 3-fold as frequently among patients receiving placebo as among those receiving adalimumab, regardless of whether progression was defined as a change in the modified total Sharp score of 0.5 or a change in the modified total Sharp score exceeding the smallest detectable change (1.88). Larger increases in the modified total Sharp score (e.g., 4 Sharp units) were relatively frequent with placebo but were almost entirely prevented by adalimumab (Figure 2A). Therefore, the difference between the mean change in the modified total Sharp score from baseline to week 24 in adalimumab-treated and placebo-treated patients (1.2 Sharp units) was not only statistically significant (P 0.001) but probably underestimated the amount of radiographic benefit that adalimumab provided to the

11 486 GLADMAN ET AL patients who were at greatest risk of severe joint destruction. Previous reports have noted that peripheral joint involvement in PsA increased most rapidly in patients with a disease duration of 12 months (8), and that baseline radiographic damage in PsA was associated with increased mortality (14). The data presented here and elsewhere (22,26,27) suggest that anti-tnf therapy may offer the greatest benefit to the largest number of PsA patients if it is initiated when structural damage is minimal or absent. Post hoc subanalyses were performed to elucidate the relationship between adalimumab efficacy and selected baseline parameters in ADEPT. In all subgroups with adequate numbers of patients, adalimumab treatment conferred significant efficacy in terms of radiographic progression compared with placebo. The greatest difference between the week 24 mean change in the modified total Sharp score for adalimumab versus placebo (3.1) was observed in patients with a baseline CRP concentration of 2.0 mg/dl. This difference reflected a large mean increase in the modified total Sharp score with placebo ( 2.6) and a mean reduction in the modified total Sharp score with adalimumab ( 0.5). This result suggests that an elevated CRP concentration may be a risk factor for radiographic progression in PsA, as has been reported in RA, and that aggressive joint damage associated with an elevated CRP concentration in PsA can be blocked by anti-tnf therapy (37). Here, it was observed that regardless of whether MTX was used at baseline by patients in the adalimumab arm, the ACR and PASI response rates at week 48 were similar to those observed for the total adalimumab group at weeks 24 and 48, and the mean changes in the modified total Sharp scores at weeks 24 and 48 were smaller than that observed at week 24 for patients randomized to placebo. These results are consistent with a previous subanalysis of ACR response rates in ADEPT (26). The data thus demonstrate that the efficacy observed in the treatment of arthritis, skin disease, and joint damage after 24 weeks of blinded adalimumab treatment in ADEPT was maintained through week 48, both with adalimumab monotherapy and with adalimumab in combination with MTX. In MTX-naive patients with early RA (38) and in patients in whom RA was more established (39), direct randomized comparisons of a TNF antagonist given alone or in combination with MTX demonstrated that combination therapy had superior efficacy for treating arthritis and inhibiting radiographic progression. To date, no such randomized controlled trial has been conducted with a TNF antagonist in PsA. Results of the post hoc analyses presented here cannot establish whether MTX affects the efficacy of adalimumab in PsA, because the MTX subgroups in ADEPT were created by stratification at study entry and not by randomization (26). Furthermore, ADEPT patients who were receiving MTX at baseline were not MTX-naive but were partial responders or nonresponders to MTX. Therefore, numeric differences in the ACR or PASI responses of the subgroup of patients who received MTX versus the subgroup of patients who did not receive MTX (Figure 1D) must be interpreted with caution. Adalimumab was generally safe and well tolerated through 48 weeks of treatment in patients with PsA, with no meaningful differences in adverse events observed between the first and second 24 weeks of study. The safety profile of adalimumab in PsA has been consistent with that established with 10,000 patients in RA clinical trials (40 43). In clinical trials of patients with RA, the types and frequency of adverse events observed during treatment with adalimumab did not change from the blinded to open-label extension phases of clinical studies, and they are consistent with those in the adalimumab postmarketing safety database (43). Overall, adalimumab exhibits a favorable risk benefit profile in patients with PsA and those with RA. In conclusion, treatment with adalimumab for 48 weeks was shown to have a favorable safety profile and to be efficacious for improving arthritis and skin disease, reducing disability, and inhibiting radiographic progression in patients with PsA from ADEPT. Post hoc analyses showed that MTX did not appear to be necessary for the 48-week efficacy of adalimumab in terms of arthritis, skin disease, or radiographic progression, and that the efficacy in inhibiting radiographic progression was not restricted to any particular patient subgroup in ADEPT. These findings indicate that adalimumab has the potential to improve long-term outcomes in patients with PsA by improving signs and symptoms of disease and by inhibiting progressive joint destruction. AUTHOR CONTRIBUTIONS Dr. Gladman had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study design. Drs. Gladman, Mease, Ritchlin, Choy, Sharp, and Sasso, and Dr. Mark A. Weinberg (nonauthor; Abbott). Acquisition of data. Drs. Gladman, Mease, Ritchlin, Choy, and Sharp. Analysis and interpretation of data. Drs. Gladman, Mease, Ritchlin, Choy, and Sharp, Ms Perdok, and Dr. Sasso. Manuscript preparation. Drs. Gladman, Mease, Ritchlin, Choy, and Sharp, Ms Perdok, and Dr. Sasso, and Michelle L. Metelo (nonauthor;

12 EFFECTIVENESS OF LONG-TERM ADALIMUMAB IN PsA 487 Abbott [via JK Associates]) and Michael A. Nissen (nonauthor; Abbott). Statistical analysis. Ms Perdok and Dr. Sasso, and Dr. Mark A. Weinberg (nonauthor; Abbott). Blinded reading of radiographs. Drs. Sharp and Ory. ROLE OF THE STUDY SPONSOR Abbott Laboratories sponsored the study, and its biostatisticians generated the data and assisted with analysis of the data. The analysis and interpretation of the data, and the writing of the manuscript were led jointly by Drs. Dafna D. Gladman and Eric H. Sasso. As first author, Dr. Gladman had authority over the entire manuscript and had the final right of approval. All authors contributed to the analysis and interpretation of the data, reviewed the manuscript critically for content, and approved the final version. REFERENCES 1. Zachariae H, Zachariae R, Blomqvist K, Davidsson S, Molin L, Mork C, et al. Quality of life and prevalence of arthritis reported by 5,795 members of the Nordic Psoriasis Associations: data from the Nordic Quality of Life Study. Acta Derm Venereol 2002;82: Gladman DD, Antoni C, Mease P, Clegg DO, Nash P. Psoriatic arthritis: epidemiology, clinical features, course, and outcome. Ann Rheum Dis 2005;64 Suppl 2:ii Gladman DD, Shuckett R, Russell ML, Thorne JC, Schachter RK. Psoriatic arthritis (PsA): an analysis of 220 patients. Q J Med 1987;62: Gladman DD, Brockbank J. Psoriatic arthritis. Expert Opin Invest Drugs 2000;9: Torre Alonso JC, Rodriguez PA, Arribas Castrillo JM, Ballino Garcia J, Riestra Noriega JL, Lopez Larrea C. Psoriatic arthritis (PA): a clinical, immunological and radiological study of 180 patients. Br J Rheumatol 1991;30: Kane D, Stafford L, Bresnihan B, FitzGerald O. A prospective, clinical and radiological study of early psoriatic arthritis: an early synovitis clinic experience. Rheumatology (Oxford) 2003;42: Gladman DD, Stafford-Brady F, Chang CH, Lewandowski K, Russell ML. Longitudinal study of clinical and radiological progression in psoriatic arthritis. J Rheumatol 1990;17: McHugh NJ, Balachrishnan C, Jones SM. Progression of peripheral joint disease in psoriatic arthritis: a 5-year prospective study. Rheumatology (Oxford) 2003;42: Queiro-Silva R, Torre-Alonso JC, Tinture-Eguren T, Lopez- Lagunas I. A polyarticular onset predicts erosive and deforming disease in psoriatic arthritis. Ann Rheum Dis 2003;62: Gladman DD, Farewell VT, Nadeau C. Clinical indicators of progression in psoriatic arthritis: multivariate relative risk model. J Rheumatol 1995;22: Siannis F, Farewell VT, Cook RJ, Schentag CT, Gladman DD. Clinical and radiological damage in psoriatic arthritis. Ann Rheum Dis 2006;65: Offidani A, Cellini A, Valeri G, Giovagnoni A. Subclinical joint involvement in psoriasis: magnetic resonance imaging and X-ray findings. Acta Derm Venereol 1998;78: Wong K, Gladman DD, Husted J, Long JA, Farewell VT. Mortality studies in psoriatic arthritis: results from a single outpatient clinic. I. Causes and risk of death. Arthritis Rheum 1997;40: Gladman DD, Farewell VT, Wong K, Husted J. Mortality studies in psoriatic arthritis: results from a single outpatient center. II. Prognostic indicators for death. Arthritis Rheum 1998;41: Willkens RF, Williams HJ, Ward JR, Egger MJ, Reading JC, Clements PJ, et al. Randomized, double-blind, placebo controlled trial of low-dose pulse methotrexate in psoriatic arthritis. Arthritis Rheum 1984;27: Abu-Shakra M, Gladman DD, Thorne JC, Long J, Gough J, Farewell VT. Long-term methotrexate therapy in psoriatic arthritis: clinical and radiological outcome. J Rheumatol 1995;2: Lee JC, Gladman DD, Schentag CT, Cook RJ. The long-term use of azathioprine in patients with psoriatic arthritis. J Clin Rheumatol 2001;7: Kaltwasser JP, Nash P, Gladman D, Rosen CF, Behrens F, Jones P, et al. Efficacy and safety of leflunomide in the treatment of psoriatic arthritis and psoriasis: a multinational, double-blind, randomized, placebo-controlled clinical trial. Arthritis Rheum 2004;50: Mader R, Gladman DD, Long J, Gough J, Farewell VT. Does injectable gold retard radiologic evidence of joint damage in psoriatic arthritis? Clin Invest Med 1995;18: Rahman P, Gladman DD, Cook RJ, Zhou Y, Young G. The use of sulfasalazine in psoriatic arthritis: a clinical experience. J Rheumatol 1998;25: Mease PJ, Goffe BS, Metz J, VanderStoep A, Finck B, Burge DJ. Etanercept in the treatment of psoriatic arthritis and psoriasis: a randomised trial. Lancet 2000;356: Mease PJ, Kivitz AJ, Burch FX, Siegel EL, Cohen SB, Ory P, et al. Etanercept treatment of psoriatic arthritis: safety, efficacy, and effect on disease progression. Arthritis Rheum 2004;50: Antoni CE, Kavanaugh A, Kirkham B, Tutuncu Z, Burmester GR, Schneider U, et al. Sustained benefits of infliximab therapy for dermatologic and articular manifestations of psoriatic arthritis: results from the Infliximab Multinational Psoriatic Arthritis Controlled Trial (IMPACT). Arthritis Rheum 2005;52: Antoni C, Krueger GG, de Vlam K, Birbara C, Bentler A, Guzzo C, et al. Infliximab improves signs and symptoms of psoriatic arthritis: results of the IMPACT 2 trial. Ann Rheum Dis 2005;64: Van der Heijde D, Kavanaugh A, Beutler A, Guzzo C, Zhou B, Dooley L, et al. Infliximab inhibits progression of radiographic damage in patients with active psoriatic arthritis: results for IMPACT 2 trial [abstract]. Ann Rheum Dis 2005;64: Mease PJ, Gladman DD, Ritchlin CT, Ruderman EM, Steinfeld SD, Choy EH, et al. Adalimumab for the treatment of patients with moderately to severely active psoriatic arthritis: results of a double-blind, randomized, placebo-controlled trial. Arthritis Rheum 2005;52: Kavanaugh A, Antoni CE, Gladman D, Wassenberg S, Zhou B, Beutler A, et al. The Infliximab Multinational Psoriatic Arthritis Controlled Trial (IMPACT): results of radiographic analyses after 1 year. Ann Rheum Dis 2006;65: Mease PJ, Kivitz AJ, Burch FX, Siegel EL, Cohen SB, Ory P, et al. Inhibition of radiographic progression in patients with psoriatic arthritis following 2 years of treatment with etanercept. J Rheumatol 2006;33: Felson DT, Anderson JJ, Boers M, Bombardier C, Furst D, Goldsmith C, et al. American College of Rheumatology preliminary definition of improvement in rheumatoid arthritis. Arthritis Rheum 1995;38: Fredriksson T, Pettersson U. Severe psoriasis oral therapy with a new retinoid. Dermatologica 1978;157: Fries JF, Spitz PW, Young DY. The dimensions of health outcomes: the Health Assessment Questionnaire, disability and pain scales. J Rheumatol 1982;9: Sharp JT, Bluhm GB, Brook A, Brower AC, Corbett M, Decker JL, et al. Reproducibility of multiple-observer scoring of radiologic abnormalities in the hands and wrists of patients with rheumatoid arthritis. Arthritis Rheum 1985;28:6 24.

13 488 GLADMAN ET AL 33. Van der Heijde D, Sharp J, Wassenberg S, Gladman DD. Psoriatic arthritis imaging: a review of scoring methods. Ann Rheum Dis 2005;64 Suppl 2:ii Bruynesteyn K, Boers M, Kostense P, van der Linden S, van der Heijde D. Deciding on progression of joint damage in paired films of individual patients: smallest detectable difference or change? Ann Rheum Dis 2004;64: Mease PJ, Ganguly R, Wanke L, Yu E, Singh A. How much improvement in functional status is considered important by patients with active psoriatic arthritis: applying the outcome measures in rheumatoid arthritis clinical trials (OMERACT) group guidelines. Ann Rheum Dis 2004;63 Suppl 1: Goldsmith CH, Boers M, Bombardier C, Tugwell PJ. Criteria for clinically important changes in outcomes: development, scoring and evaluation of rheumatoid arthritis patient and trial profiles. Rheumatology (Oxford) 1993;20: Smolen JS, van der Heijde DM, St.Clair EW, Emery P, Bathon JM, Keystone E. Predictors of joint damage in patients with early rheumatoid arthritis treated with high-dose methotrexate with or without concomitant infliximab: results from the ASPIRE trial. Arthritis Rheum 2006;54: Breedveld FC, Weisman MH, Kavanaugh AF, Cohen SB, Pavelka K, van Vollenhoven R, 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: Klareskog L, van der Heijde D, de Jager JP, Gough A, Kalden J, Malaise M, et al. Therapeutic effect of the combination of etanercept and methotrexate compared with each treatment alone in patients with rheumatoid arthritis: double-blind randomized controlled trial. Lancet 2004;363: Keystone ED, Kavanaugh AF, Sharp JT, Tannenbaum H, Hua Y, Teoh LS, 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. Arthritis Rheum 2004;50: Van de Putte LB, Atkins C, Malaise M, Sany J, Russell AS, van Riel PL, et al. Efficacy and safety of adalimumab as monotherapy in patients with rheumatoid arthritis for whom previous disease modifying antirheumatic drug treatment has failed. Ann Rheum Dis 2004;63: Weinblatt ME, Keystone EC, Furst DE, Moreland LW, Weisman MH, Birbara CA, et al. Adalimumab, a fully human anti tumor necrosis factor monoclonal antibody for the treatment of rheumatoid arthritis in patients taking concomitant methotrexate: the ARMADA trial. Arthritis Rheum 2003;48: Schiff MH, Burmester GR, Kent JD, Pangan AL, Kupper H, Fitzpatrick SB, et al. Safety analyses of adalimumab (Humira) in global clinical trials and US postmarketing surveillance of patients with rheumatoid arthritis. Ann Rheum Dis 2006;65: