Combination of Infliximab and Methotrexate Therapy for Early Rheumatoid Arthritis

Transcription

1 ARTHRITIS & RHEUMATISM Vol. 50, No. 11, November 2004, pp DOI /art , American College of Rheumatology Combination of Infliximab and Methotrexate Therapy for Early Rheumatoid Arthritis A Randomized, Controlled Trial E. William St.Clair, 1 Désirée M. F. M. van der Heijde, 2 Josef S. Smolen, 3 Ravinder N. Maini, 4 Joan M. Bathon, 5 Paul Emery, 6 Edward Keystone, 7 Michael Schiff, 8 Joachim R. Kalden, 9 Ben Wang, 10 Kimberly DeWoody, 10 Roberta Weiss, 10 and Daniel Baker, 10 for the Active-Controlled Study of Patients Receiving Infliximab for the Treatment of Rheumatoid Arthritis of Early Onset Study Group Objective. To compare the benefits of initiating treatment with methotrexate (MTX) and infliximab (anti tumor necrosis factor [anti-tnf ] monoclonal antibody) with those of MTX treatment alone in patients with rheumatoid arthritis (RA) of <3 years duration. Supported by Centocor, Inc., a subsidiary of Johnson & Johnson. 1 E. William St.Clair, MD: Duke University Medical Center, Durham, North Carolina; 2 Désirée M. F. M. van der Heijde, MD: University Hospital Maastricht, Maastricht, The Netherlands; 3 Josef S. Smolen, MD: Medical University of Vienna, Vienna, Austria; 4 Ravinder N. Maini, MD: Kennedy Institute of Rheumatology, London, UK; 5 Joan M. Bathon, MD: Johns Hopkins University, Baltimore, Maryland; 6 Paul Emery, MD: University of Leeds, Leeds, UK; 7 Edward Keystone, MD: Center for Advanced Therapeutics, Mt. Sinai Hospital, Toronto, Ontario, Canada; 8 Michael Schiff, MD: Denver Arthritis Clinic, Denver, Colorado; 9 Joachim R. Kalden, MD: Institute for Clinical Immunology, Erlangen, Germany; 10 Ben Wang, PhD, Kimberly DeWoody, PhD, Roberta Weiss, MD, Daniel Baker, MD: Centocor, Inc., Malvern, Pennsylvania. Drs. St.Clair, van der Heijde, Smolen, Maini, Bathon, Emery, Keystone, and Kalden have received consultancies and/or honoraria from Centocor, Inc., totaling less than $10,000 per year. In 2002, Drs. van der Heijde and Maini gave expert testimony to the FDA hearing on inhibition of structural damage and received a fee. The Kennedy Institute of Rheumatology has a patent and a research and licensing agreement from Centocor, Inc., under which it has received royalties for the use of infliximab in rheumatoid arthritis. As a coinventor, Dr. Maini receives a percentage of these royalties under the Kennedy Institute s formula for the division of royalties. Drs. Maini, Wang, DeWoody, Weiss, and Baker own stock in Johnson & Johnson, of which Centocor, Inc., is a subsidiary. Address correspondence and reprint requests to Josef S. Smolen, MD, Division of Rheumatology, Department of Medicine III, Medical University Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria. josef.smolen@wienkav.at. Submitted for publication March 9, 2004; accepted in revised form June 30, Methods. RA patients were eligible if they had active disease and no prior treatment with MTX or a TNF inhibitor. One thousand forty-nine patients were randomly assigned in a 4:5:5 ratio to 3 treatment groups: MTX placebo, MTX 3 mg/kg infliximab, and MTX 6 mg/kg infliximab. MTX dosages were rapidly escalated to 20 mg/week, and infliximab or placebo infusions were given at weeks 0, 2, and 6, and every 8 weeks thereafter through week 46. Results. At week 54, the median percentage of American College of Rheumatology improvement (ACR-N) was higher for the MTX 3 mg/kg infliximab and MTX 6 mg/kg infliximab groups than for the MTX placebo group (38.9% and 46.7% versus 26.4%, respectively; P < for both comparisons). Patients in the MTX 3 mg/kg infliximab and MTX 6 mg/kg infliximab groups also showed less radiographic progression than those receiving MTX alone (mean SD changes in van der Heijde modification of the total Sharp score at week 54: and versus , respectively; P < for each comparison). In addition, physical function improved significantly more in the MTX 3 mg/kg infliximab and MTX 6 mg/kg infliximab groups than in the MTX placebo group. Infliximab therapy was associated with a significantly higher incidence of serious infections, especially pneumonia. Conclusion. For patients with active RA in its early stages, combination therapy with MTX and infliximab provides greater clinical, radiographic, and functional benefits than treatment with MTX alone. 3432

2 INFLIXIMAB THERAPY FOR RHEUMATOID ARTHRITIS 3433 Rheumatoid arthritis (RA) is a chronic, inflammatory polyarthritis with frequent progression to joint destruction and disability (1). Often, only a brief period of time elapses between the onset of joint inflammation and the development of bone erosions and cartilage injury (2 4). These pathologic events are at least in part dependent on increased expression of tumor necrosis factor (TNF ) (5). In support of this premise, clinical trials have shown that TNF blocking agents, such as etanercept, infliximab, and adalimumab, significantly reduce joint inflammation, slow radiographic progression of joint damage, and improve physical function in advanced RA (6 10). Early treatment with a TNF blocking agent may be an effective strategy for suppressing joint inflammation and preventing subsequent joint damage in RA. In a 1-year controlled trial, 25-mg twice weekly injections of etanercept, a soluble TNF receptor Fc fusion protein, more rapidly controlled the signs and symptoms in patients with RA of 3 years duration compared with methotrexate (MTX) therapy, but its use alone was no better than MTX for slowing radiographic progression of joint destruction, as determined by the primary radiographic end point (11). However, it was determined in a subanalysis that patients who received etanercept had lower erosion scores than those who received MTX (11). In the 2-year, open-label, completer-only followup study, the patients receiving etanercept had higher American College of Rheumatology (ACR) response rates and less radiographic progression of joint damage than those receiving MTX alone (12). Current evidence further indicates that aggressive disease-modifying antirheumatic drug (DMARD) therapy in early RA, particularly with 2- and 3-drug combinations of DMARDs, produces greater clinical, radiographic, and functional benefits than less intensive regimens (13 18). However, these studies have not evaluated, in comparison with MTX therapy, the relative efficacy of a combination strategy incorporating a potent anti-tnf drug. We therefore compared the treatment benefits of the combination of MTX and infliximab with those of MTX alone in patients with RA of 3 years duration. PATIENTS AND METHODS Patients. Patients eligible for this trial were at least 18 years old but no older than 75 years, met the 1987 revised criteria of the ACR (formerly, the American Rheumatism Association) for the classification of RA (19), and had persistent synovitis for 3 months and 3 years, 10 swollen joints, and 12 tender joints. In addition, eligible patients had one or more of the following: a positive test result for serum rheumatoid factor, radiographic erosions of the hands or feet, or a serum C-reactive protein (CRP) level 2.0 mg/dl. Patients were excluded if they had any prior treatment with MTX, had received other DMARDs within 4 weeks of entry (or leflunomide within the past 6 months), or had been treated with infliximab, etanercept, adalimumab, or other anti-tnf agent. Three or fewer prestudy doses of MTX were allowed to enhance enrollment of patients who might have been started on this medication recently by their physicians. Because MTX therapy generally requires a minimum of 6 8 weeks to achieve a clinical effect, we reasoned that 3 or fewer doses probably would not bias the selection of patients on the basis of a treatment response. Other exclusion criteria were infection with human immunodeficiency virus, hepatitis B virus, or hepatitis C virus as well as a history of active or past tuberculosis, congestive heart failure, or lymphoma or other malignancy within the past 5 years (excluding excised skin cancers). Study protocol. The protocol was approved by an institutional review board at each study center and was carried out in accordance with the Helsinki Declaration and all subsequent revisions. In addition to the authors of this article, the members of the Active-Controlled Study of Patients Receiving Infliximab for the Treatment of Rheumatoid Arthritis of Early Onset Study Group are listed in Appendix A. Patients were enrolled between July 21, 2000 and February 28, 2002 and randomly assigned to receive 1 of the following 3 treatments in a 4:5:5 ratio: MTX plus placebo, MTX plus 3 mg/kg infliximab, or MTX plus 6 mg/kg infliximab. Patient allocation to a treatment group was performed using a dynamic process in which patients were randomly assigned to 1 of the 3 treatment groups by the Interactive Voice Response System (IVRS). The IVRS assigned a treatment group to patients such that the numbers of patients in the 3 treatment groups were as balanced as possible within each investigational site, while maintaining 300 (placebo arm) or 375 (the 2 infliximab arms) patients per treatment group. Infliximab (Remicade; Centocor, Malvern, PA) was supplied in 20-ml vials containing 100 mg of the lyophilized concentrate; placebo was supplied in an identical manner except that it did not contain infliximab. Oral MTX was started at 7.5 mg/week and escalated in a graduated manner (2.5 mg/week every 1 2 weeks) to 15 mg/week by week 4 and 20 mg/week by week 8, with at least 5 mg/week of oral folic acid. The MTX dosage could be tapered only for toxicity. An algorithm was used to make dosage adjustments for mild, moderate, and severe suspected MTX-related toxicity. If toxicity did not improve after withholding MTX therapy for 4 weeks, then the MTX and study drug infusions were permanently discontinued. The study drugs were also stopped if the dosage of MTX dropped below 7.5 mg/week for 4 weeks. Infliximab or placebo infusions were given at weeks 0, 2, and 6, and every 8 weeks thereafter through week 46. Oral corticosteroids ( 10 mg/day prednisone or its equivalent) and nonsteroidal antiinflammatory drugs were maintained at baseline dosages. Other DMARDs were not permitted during the study. Joint examinations were performed by an independent assessor who had no knowledge of the patient s treatment assignment. Other assessments included the patient s selfevaluation of pain, patient s and evaluator s global disease assessment, patient s self-evaluation of fatigue, patient s selfevaluation of functional status using the Disability Index of the

3 3434 ST.CLAIR ET AL Health Assessment Questionnaire (HAQ) (20), and patient s self-evaluation of quality of life using the Medical Outcomes Study Short Form 36 (SF-36) (21). Blood samples were obtained for measuring the erythrocyte sedimentation rate and serum CRP levels, as well as for determining the presence of antinuclear antibodies (ANAs), anti double-stranded DNA (anti-dsdna) antibodies, and antibodies to infliximab (22). For antiinfliximab antibody assays, the results were considered to be inconclusive if the sample was negative but contained detectable concentrations of infliximab (the presence of infliximab in the serum is known to interfere with the interpretation of the assay for antibodies to infliximab). Radiographs of the hands and feet were obtained within 4 weeks of the first dose of study drug and at weeks 30 and 54, or upon premature withdrawal of the patient from the study. The protocol was amended on February 22, 2001 to include mandatory tuberculosis screening for study patients. All study patients in the US and Canada received a purified protein derivative (PPD) tuberculin skin test, and investigators followed the American Thoracic Society/Centers for Disease Control and Prevention guidelines for immunocompromised patients. Outside the US and Canada, local country guidelines were followed for screening, diagnosis, and treatment of latent tuberculosis. Study end points. Signs and symptoms. The primary end point for reduction of signs and symptoms was the percentage of ACR improvement (ACR-N) from baseline to week 54. The ACR-N is defined as the minimum of the following 3 items: the percentage change from baseline in the number of tender joints, the percentage change from baseline in the number of swollen joints, and the median of the percentage change from baseline for the patient s global assessment, physician s global assessment, pain, disability, and serum levels of CRP (11). A negative ACR-N indicates worsening of disease activity from baseline. The reduction in signs and symptoms was also evaluated using the ACR 20% criteria for clinical improvement (ACR20) (23). Improvement of 50% (ACR50), 70% (ACR70), and 90% (ACR90) was similarly defined using these criteria. A major clinical response was defined as an ACR70 response for 6 consecutive months. Clinical improvement was also assessed using the Disease Activity Score in 28 joints (DAS28), a validated composite index with measures of joint tenderness and swelling, global disease activity, and serum levels of acute-phase reactants (24 26). Radiographic changes. The primary end point for radiographic progression of joint damage was the change from baseline to week 54 in the van der Heijde modification of the total Sharp score (vdh-s) (27). Two readers scored the radiographs independently without knowledge of treatment assignment, clinical response, or the order of the radiographs. For each set of radiographs, the mean score of the 2 readers was used for the analyses. Radiographic progression of disease was defined as an increase from baseline in the vdh-s that was larger than the smallest detectable difference (SDD). The SDD was 9.03 for this trial and reflects that component of a measure that was statistically attributable to error from the measurement process (28,29). Physical function. The primary end point for improvement in physical function was the change from baseline in HAQ scores averaged over weeks 30 54; this time period was prespecified so that treatment comparisons were made during the time when MTX had reached peak efficacy. This effect was evaluated with changes in quality of life, as measured by the SF-36. Statistical analysis. The statistical analyses of the 3 co primary end points were performed hierarchically in a predefined order to control for Type I error. First, a 2-sided t-test on the van der Waerden normal score (30) was performed for the ACR-N. The test was positive if the global test showed statistical significance for the combined MTX infliximab groups compared with the MTX-alone group and at least one of the MTX infliximab groups showed statistically significant improvement over the MTX-alone group (both at the 0.05 level). Two-sided t-tests were then sequentially performed for the primary radiographic and functional end points. Nominal 2-sided P values were reported for secondary analyses. Patients were assigned an ACR-N value of 0 if they received prohibited medications, had 2 joint injections or surgeries, withdrew due to lack of efficacy, or withdrew before week 30 without followup measurements. The actual ACR-N value at week 54 was used for subjects who discontinued treatment because of study drug toxicity but continued to be followed up to determine drug efficacy. A last observation carried forward principle was used to handle missing data between weeks 30 and 54. Data obtained prior to week 30 were not carried over for the week 54 analysis. Patients with no data after week 30 had values set to 0. If a patient had evaluable radiographs either at baseline or at week 54 and at one other time point, the value was estimated using linear extrapolation. Two sensitivity analyses were performed to assess the robustness of the ACR-N end point. The first analyzed ACR-N at week 54, with ACR-N set to 0 for subjects who discontinued the study medication because of an adverse event. The second sensitivity analysis analyzed ACR-N at week 54 using the actual ACR-N regardless of the use of study-prohibited medications, surgical procedures, or treatment discontinuations. If a patient s radiographs were missing at baseline and week 54, the change from baseline was estimated using the percentile of the entire patient population. Missing values were not imputed for the erosion and joint space narrowing scores when analyzed separately. If the baseline HAQ score was missing or no HAQ scores were obtained at and after week 30, the area under the curve of the HAQ change from baseline and from week 30 to week 54 was estimated using the percentile of the entire patient population. A sample size of 1,050 patients provided 90% power (under 0.05 each) to detect a significant difference between treatment groups in signs and symptoms, assuming a mean of 50% improvement in the ACR-N for the MTX placebo group and a mean of 60% improvement in the ACR-N for either MTX infliximab treatment group. This study also provided 90% power for detecting a difference in the changes of the vdh-s between the MTX infliximab groups and the MTX placebo group, assuming a progression of 2.0 vdh-s units for the MTX placebo group and a 65% reduction in damage for the groups receiving MTX and infliximab. Role of the funding source. Representatives of the sponsor assisted in the statistical design and data analysis of this trial. Otherwise, the study sponsor had no role in the data

4 INFLIXIMAB THERAPY FOR RHEUMATOID ARTHRITIS 3435 Figure 1. Flow of participation in the present study. All patients received concomitant methotrexate. The randomized study population consisted of 1,049 patients from 122 sites in North America and Europe. Prior to unblinding, 45 patients were excluded from the efficacy analysis because the data on case report forms at 2 sites could not be verified by source documents. Note that patients who discontinued study treatment could have completed their participation in the study through the last followup visit and could have been evaluated for study drug safety and efficacy at week 54. interpretation, the content of this article, or the decision to submit the manuscript for publication. RESULTS One thousand forty-nine patients were randomized to receive study medication as depicted in Figure 1. Prior to unblinding, 45 patients at 2 sites were excluded from the efficacy analysis (16 in the MTX placebo group, 14 in the MTX 3 mg/kg infliximab group, and 15 in the MTX 6 mg/kg infliximab group) because their study data could not be verified with source documents. Patients who discontinued study treatment might have completed study participation through the last followup visit, and therefore data for these patients were evaluated for safety and efficacy at week 54. Characteristics of the patients. The analyses were based on evaluable data for 1,004 patients. The characteristics of the 1,004 study patients with RA were similar among the 3 treatment groups, with a mean disease duration of 0.8 years for the MTX 3 mg/kg infliximab group and 0.9 years for each of the other 2 groups (Table 1). The magnitudes of the joint counts, pain ratings, global assessments, and HAQ scores indicated that the study patients had a moderate level of disease activity. Only 7 (2.5%), 5 (1.4%), and 7 (1.9%) patients in the MTX placebo, MTX 3 mg/kg infliximab, and MTX 6 mg/kg infliximab groups, respectively, had received 1 3 doses of MTX prior to baseline, as permitted in the protocol design. Maintenance of MTX therapy and withdrawals. Most patients among the 3 treatment groups were able to have their MTX dosages escalated to 20 mg/week and to have this dosage maintained through their last evaluation (217 [72.8%] in the MTX placebo group, 260 [69.7%] in the MTX 3 mg/kg infliximab group, and 254 [67.2%] in the MTX 6 mg/kg infliximab group). The remaining patients either did not reach 20 mg/week or could not maintain the target dosage of 20 mg/week through week 54. MTX toxicity was the primary reason for failure to reach or maintain 20 mg/week of MTX in

5 3436 ST.CLAIR ET AL Table 1. Baseline patient characteristics* MTX placebo (n 282) MTX 3 mg/kg infliximab (n 359) MTX 6 mg/kg infliximab (n 363) Age, mean SD years Women, % Glucocorticoid therapy, % NSAID therapy, % DMARD naive, % Duration of disease, mean SD years Positive test for serum rheumatoid factor, % Erosion score 0, % Tender joint count, mean SD Swollen joint count, mean SD HAQ score, mean SD SF-36 score, mean SD# Physical component Mental component ESR, mean SD mm/hour CRP level, mean SD mg/dl Total radiographic score** Mean SD Median (IQR) 5.1 (1.4, 14.6) 5.2 (1.8, 15.1) 5.3 (1.7, 14.6) Range Erosion score Mean SD Median (IQR) 3.0 (0.5, 10.5) 3.8 (1.0, 11.0) 3.8 (1.0, 10.8) Range JSN score Mean SD Median (IQR) 1.0 (0.0, 3.9) 1.0 (0.0, 3.8) 1.0 (0.0, 3.6) Range * MTX methotrexate; NSAID nonsteroidal antiinflaminatory drug; DMARD disease-modifying antirheumatic drug; HAQ Health Assessment Questionnaire; SF-36 Short-Form 36 health survey; ESR erythrocyte sedimentation rate; CRP C-reactive protein; IQR interquartile range; JSN joint space narrowing. Scores can range from 0 to 280. Sixty-six joints were assessed. Sixty-eight joints were assessed. Scores range from 0 (no difficulty) to 3 (unable to perform this activity). # Scores were grouped into physical and mental summary components and compared with normalized scores for the general US population, for which the mean SD is Higher scores indicate a better quality of life. ** Scores can range from 0 to 448, with higher scores indicating more joint damage. There were 279 patients in the MTX placebo group, 355 in the MTX 3 mg/kg infliximab group, and 360 in the MTX 6 mg/kg infliximab group. Scores can range from 0 to (39%), 45 (40%), and 41 (33%) patients in the MTX placebo, MTX 3 mg/kg infliximab, and MTX 6 mg/kg infliximab groups, respectively. Including all randomized patients, the mean SD dosages of MTX at week 54 were mg/week, mg/week, and mg/week for the MTX placebo, MTX 3 mg/kg infliximab, and MTX 6 mg/kg infliximab groups, respectively, indicating similar MTX dosing among the treatment groups. For this calculation, the MTX dose was set at 0 for withdrawals before week 54. Premature discontinuation by patients occurred in similar proportions among the 3 treatment groups (Figure 1). However, more patients from the MTX placebo group than from the MTX 3 mg/kg infliximab and MTX 6 mg/kg infliximab groups withdrew due to lack of efficacy (9.6% versus 1.9% and 3.3%, respectively). In contrast, withdrawals because of adverse events were more frequent in the MTX 3 mg/kg infliximab and MTX 6 mg/kg infliximab groups than in the MTX placebo group (9.5% and 9.6% versus 3.2%, respectively). Clinical efficacy. The patients receiving MTX 3 mg/kg infliximab and MTX 6 mg/kg infliximab achieved a significantly higher median (interquartile range [IQR]) ACR-N (38.9% [0.0, 77.3] and 46.7% [0.0, 82.1], respectively) than those in the MTX placebo group (26.4% [0.0, 64.3]) (P for both comparisons). Two sensitivity analyses (see Patients and Methods) showed statistically significant differences favoring the infliximab treatment groups, attesting to the robustness of

6 INFLIXIMAB THERAPY FOR RHEUMATOID ARTHRITIS 3437 Figure 2. Comparison of American College of Rheumatology 20% criteria for clinical improvement (ACR20), ACR50, ACR70, and ACR90 responses. Shown are the percentages of patients with ACR responses at week 54. In these secondary analyses, there were 274 patients in the methotrexate (MTX) placebo group, 351 in the MTX 3 mg/kg infliximab group, and 355 in the MTX 6 mg/kg infliximab group. Patients were excluded from these analyses if they had no baseline observations. Patients were considered to be ACR20 nonresponders if they received prohibited medications, had 2 joint injections or surgeries, or withdrew due to lack of efficacy. Missing values between weeks 30 and 54 were replaced with the last observation carried forward. If such a value was not available, then that component of the ACR response criteria was assigned a value of 0% improvement. P 0.028; P 0.001; P 0.001; and P versus MTX placebo group. over those receiving MTX alone (Table 2). The proportions of patients with radiographic progression exceeding the SDD (increase in vdh-s 9.03) were lower in the MTX 3 mg/kg infliximab and MTX 6 mg/kg infliximab groups (14/359 [3.9%] and 7/363 [1.9%], respectively) than in the MTX placebo group (31/282 [11.0%]) (P for both comparisons). Improvement in physical function. HAQ scores improved more in the MTX 3 mg/kg infliximab and MTX 6 mg/kg infliximab groups than in the group receiving MTX alone. The mean SD and median (IQR) decreases from baseline in HAQ scores from weeks averaged over time were and 0.78 (0.38, 1.18) for the MTX 3 mg/kg infliximab group and and 0.79 (0.48, 1.34) for the MTX 6 mg/kg this result. There were no significant differences in clinical efficacy between the 3 mg/kg and 6 mg/kg infliximab dosage groups. ACR20, ACR50, and ACR70 response rates were significantly higher in the MTX 3 mg/kg infliximab and MTX 6 mg/kg infliximab groups than in patients receiving MTX alone, while the ACR90 response rate was significantly higher in the MTX 6 mg/kg infliximab group than in the MTX placebo group (Figure 2). The proportions of patients achieving a sustained ACR70 response for at least 6 months were also greater in the MTX 3 mg/kg infliximab and MTX 6 mg/kg infliximab groups (12.4% and 17.3%, respectively) than in the MTX placebo group (7.7%) (P 0.06 and P 0.001, respectively). In addition, greater reductions in DAS28 scores and higher remission rates were observed in the groups receiving the MTX infliximab combinations (Figures 3 and 4). Radiographic evaluation of joint damage. From baseline to week 54, the mean SD change in the vdh-s was significantly less for the patients receiving MTX 3 mg/kg infliximab and MTX 6 mg/kg infliximab ( and , respectively) than it was for those receiving MTX alone ( ) (P for each comparison) (Table 2). Radiographic progression of joint damage was not significantly different between the 2 infliximab dosage groups. The separate analysis of the erosion and joint space narrowing scores also favored those receiving the MTX infliximab combinations Figure 3. Analysis of Disease Activity Score in 28 joints (DAS28) values. The DAS28 values at baseline and week 54 are shown for the 3 treatment groups. In this secondary analysis, there were 235 patients in the methotrexate (MTX) placebo group, 294 in the MTX 3 mg/kg infliximab group, and 289 in the MTX 6 mg/kg infliximab group. Patients with missing DAS28 values at baseline or week 54 were excluded from this analysis. The DAS28 value was calculated as follows: 0.56 the square root of the tender joint count 0.28 the square root of the swollen joint count 0.7 ln erythrocyte sedimentation rate patient s global assessment of disease activity. The DAS28 value was set to baseline whenever a prohibited medication was taken or surgery occurred, or if the patient withdrew from the study due to lack of efficacy. The mean SD (solid horizontal lines and bars) and median (interquartile range [IQR]) (dashed horizontal lines and boxed areas) DAS28 values at baseline were and 6.8 (6.1, 7.4) for the MTX placebo group, and 6.8 (5.9, 7.4) for the MTX 3 mg/kg infliximab group, and and 6.8 (6.1, 7.4) for the MTX 6 mg/kg infliximab group. The mean SD and median (IQR) DAS28 values at week 54 were and 4.7 (3.1, 5.9) for the MTX placebo group, and 3.7 (2.8, 5.2) for the MTX 3 mg/kg infliximab group, and and 3.5 (2.3, 4.9) for the MTX 6 mg/kg infliximab group. For comparisons of the change between baseline and week 54: P for MTX 3 mg/kg infliximab versus MTX placebo; P for MTX 6 mg/kg infliximab versus MTX placebo.

7 3438 ST.CLAIR ET AL Figure 4. DAS28 remission rates. The percentages of patients achieving remission of their disease according to the DAS28 at week 54 are shown for the 3 treatment groups. In this secondary analysis, there were 240 patients in the MTX placebo group, 302 in the MTX 3 mg/kg infliximab group, and 300 in the MTX 6 mg/kg infliximab group. Patients were excluded from this analysis if they had missing values at week 54. A DAS28 value 2.6 was considered to indicate remission of disease (23). For comparisons of rates of remission: P for MTX 3 mg/kg infliximab versus MTX placebo; P for MTX 6 mg/kg infliximab versus MTX placebo. See Figure 3 for definitions. infliximab group compared with and 0.75 (0.22, 1.04) for the MTX placebo group (median decreases of 0.78 versus 0.75 and 0.79 versus 0.75; P 0.03 and P 0.001, respectively). From baseline to week 54, more patients in the MTX 3 mg/kg infliximab and MTX 6 mg/kg infliximab groups improved their HAQ scores by at least 0.22 units (273/359 [76.0%] and 274/363 [75.5%], respectively) than those in the MTX placebo group (184/282 [65.2%]) (P and P 0.004, respectively). Of note, 0.22 is the minimum level of improvement considered to be clinically significant (31). Improvement in the SF-36 physical component summary score also favored the combination of MTX infliximab over MTX therapy alone. From baseline to week 54, the mean SD and median (IQR) increases in the physical component summary score of the SF-36 were and 10.9 (2.6, 19.8) for the MTX 3 mg/kg infliximab group and and 11.8 (4.4, 21.2) for the MTX 6 mg/kg infliximab group, but only and 8.9 (1.4, 18.9) for the MTX placebo group (median increases of 10.9 versus 8.9 and 11.8 versus 8.9; P 0.10 and P 0.003, respectively). Adverse events. Table 3 shows the frequencies of adverse events during this study. One or more infusion reactions occurred in 79 patients (21%) from the MTX 3 mg/kg infliximab group and in 56 patients (15%) from the MTX 6 mg/kg infliximab group compared with only 20 patients (7%) receiving MTX alone. Two patients (0.5%) in each of the MTX infliximab groups had infusion reactions classified as serious by the investigators according to the regulatory definition. Anaphylactic reactions were predefined in the protocol as the occurrence of urticaria and bronchospasm, dyspnea, or hypotension. Three patients from the MTX 6 mg/kg infliximab group had reactions meeting the definition of anaphylactoid; they were not among those classified as experiencing serious infusion reactions. The proportion of patients with 1 serious adverse events was higher in the MTX infliximab groups Table 2. Change in radiographic scores* MTX placebo (n 282) MTX 3 mg/kg infliximab (n 359) MTX 6 mg/kg infliximab (n 363) Change in van der Heijde modification of the total Sharp score from baseline to week 54 Mean SD Median (IQR) 0.43 (0.0, 4.5) 0.0 ( 0.8, 1.3) 0.0 ( 1.0, 1.3) P Change in erosion score from baseline to week 54 Mean SD Median (IQR) 0.3 (0.0, 3.8) 0.0 ( 0.8, 1.3) 0.0 ( 1.0, 1.0) P Change in JSN score from baseline to week 54 Mean SD Median (IQR) 0.0 (0.0, 0.4) 0.0 (0.0, 0.0) 0.0 (0.0, 0.20) P * See Table 1 for definitions. Values were imputed by linear extrapolation. Versus MTX placebo. Scores were analyzed separately without imputation rules, decreasing the numbers of patients available for these subanalyses (see Patients and Methods). There were 226 patients analyzed in the MTX placebo group and 306 analyzed in each of the MTX infliximab groups.

8 INFLIXIMAB THERAPY FOR RHEUMATOID ARTHRITIS 3439 Table 3. Adverse events in patients receiving at least 1 dose of study drug* MTX placebo (n 291) MTX 3 mg/kg infliximab (n 372) MTX 6 mg/kg infliximab (n 377) Adverse events occurring at a rate of 10% URI 60 (21) 94 (25) 106 (28) Nausea 53 (18) 73 (20) 65 (17) Headache 31 (11) 43 (12) 42 (11) Sinusitis 24 (8) 46 (12) 38 (10) Pharyngitis 17 (6) 33 (9) 40 (11) Patients with 1 serious adverse 32 (11) 52 (14) 51 (14) event Pneumonia 0 (0) 8 (2) 11 (3) Fever 0 (0) 0 (0) 5 (1.3) Myocardial infarction 2 (0.7) 1 (0.3) 4 (1.1) Asthma 0 (0) 2 (0.5) 2 (0.5) Tuberculosis 0 (0) 3 (0.8) 1 (0.3) Infusion reaction 0 (0) 2 (0.5) 2 (0.5) * Values are the number (%) of treated patients. MTX methotrexate; URI upper respiratory tract infection. Includes 2 patients with cardiac failure in the MTX 3 mg/kg infliximab and MTX 6 mg/kg infliximab groups. These events were not judged to be serious by the investigator. Four patients in the MTX 6 mg/kg infliximab group were diagnosed as having malignancies. These malignancies included endometrial cancer at week 3, pancreatic cancer with metastasis at week 18, adenocarcinoma of the colon at week 52, and acute myeloid leukemia at week 52. Four patients died, including 1 from respiratory failure attributed to MTX-related lung toxicity (in the MTX placebo group), 1 from an upper gastrointestinal bleed (in the MTX placebo group), 1 from cardiac arrest (in the MTX 3 mg/kg infliximab group), and 1 from metastatic pancreatic cancer (in the MTX 6 mg/kg infliximab group). (14%) than in the MTX placebo group (11%) (Table 3). Serious infections occurred more commonly in patients receiving MTX 3 mg/kg infliximab (21 patients [5.6%]) or MTX 6 mg/kg infliximab (19 patients [5.0%]) than in those receiving MTX alone (6 patients [2.1%]) (P 0.02 and P 0.04, respectively) (Table 4). Among the serious infections, pneumonia occurred more frequently in the infliximab-treated patients than in those treated with MTX alone (15/749 [2.0%] versus 0/291 [0.0%]). Most of these cases were community-acquired pneumonias that responded appropriately to antibiotic therapy. Among the cases of pneumonia, active tuberculosis was diagnosed in 4 patients from the infliximab treatment groups (1 in the US and 3 in Europe; 2 cases occurred after the third infusion, 1 after the fourth infusion, and 1 after the eighth infusion). Two of these patients had had a negative PPD skin test result at the screening visit. The other 2 patients had not received the PPD skin test at study entry because they had enrolled before the implementation of the protocol amendment that required PPD skin testing. Three of the patients were diagnosed as having pulmonary tuberculosis based on a positive sputum culture. The other patient was suspected of having tuberculosis because of a history of fever and weight loss and recent conversion of a PPD skin test result from negative to positive. None of these Table 4. Serious infections observed in 0.5% of patients who received at least 1 dose of study drug* MTX placebo (n 291) MTX 3 mg/kg infliximab (n 372) MTX 6 mg/kg infliximab (n 377) Patients with 1 serious infection 6 (2.1) 21 (5.6) 19 (5.0) Pneumonia 0 (0.0) 6 (1.6) 9 (2.4) Tuberculosis 0 (0.0) 3 (0.8) 1 (0.3) Sepsis 0 (0.0) 2 (0.5) 1 (0.3) Bronchitis 0 (0.0) 2 (0.5) 0 (0.0) Septic bursitis 0 (0.0) 0 (0.0) 2 (0.5) * Values are the number (%) of treated patients. MTX methotrexate. P 0.02 versus MTX placebo. P 0.04 versus MTX placebo.

9 3440 ST.CLAIR ET AL patients were considered by the investigator to have extrapulmonary tuberculosis. All of these patients were withdrawn from the study, discontinued their infliximab infusions, and were successfully treated with appropriate antituberculosis medications. Malignancy was diagnosed in 4 patients during the trial, all of whom were in the MTX 6 mg/kg infliximab group (see footnote in Table 3). Four patients died during the study: 2 were in the MTX placebo group, and 1 was in each of the MTX infliximab dose groups. One of the patients in the MTX placebo group died of respiratory failure attributed to MTX-related lung toxicity (see footnote in Table 3). Autoimmunity. Similar to findings in previous studies, infliximab therapy was associated with the development of ANAs. Overall, 118 of 298 patients (39.6%) in the MTX 3 mg/kg infliximab group, 106 of 309 patients (34.3%) in the MTX 6 mg/kg infliximab group, and 29 of 256 patients (11.3%) in the MTX placebo group became newly positive for ANAs during the study (P for both comparisons with the MTX placebo group). This analysis was restricted to those subjects with blood samples available at each time point. Serum anti-dsdna antibodies appeared in 71 of 298 patients (23.8%) and 64 of 309 patients (20.7%) in the MTX 3 mg/kg infliximab and MTX 6 mg/kg infliximab groups, respectively, while only 1 of 256 patients (0.4%) receiving MTX alone developed anti-dsdna antibodies (P for both comparisons with the MTX placebo group). One patient in the MTX 6 mg/kg infliximab group developed a skin rash and ANA positivity, but tested negative for serum anti-dsdna antibodies; this event was classified by the investigator as drug-induced lupus. Immunogenicity. Serum antibodies to infliximab were detected at some time in 46 of 317 patients (14.5%) and 21 of 312 patients (6.7%) in the MTX 3 mg/kg infliximab and MTX 6 mg/kg infliximab groups, respectively. Negative test results were obtained after the last infusion in 142 of 317 patients (44.8%) and 110 of 312 patients (35.3%) in the MTX 3 mg/kg infliximab and MTX 6 mg/kg infliximab groups, respectively. The results were inconclusive for the remaining samples. DISCUSSION This study demonstrates that treatment of early RA with the combination of MTX and infliximab improves the signs and symptoms of disease activity, inhibits the radiographic progression of joint damage, and improves physical function better than MTX therapy alone over 1 year. The primary and major secondary efficacy analyses were consistent in showing the superiority of the combination of MTX and infliximab over MTX alone. In a previous study, infliximab at 3 mg/kg and 10 mg/kg given every 4 8 weeks for up to 2 years produced significant clinical, radiographic, and functional benefits in RA when added to background MTX therapy (8,9,32). Since that study population consisted of partial responders to MTX therapy, the analysis could only show the incremental benefits of infliximab over placebo. In contrast, the parallel design of the present study allows for the benefits of the MTX infliximab combination to be distinguished from those of MTX alone, which is a widely accepted standard of care for the initial treatment of moderate-to-severe RA. An unbiased comparison of efficacy between these treatment groups requires that patients not have been previously exposed to these medications. Our design allowed up to 3 doses of MTX prior to randomization, which might have biased the results. However, only % of the study population had received any previous doses of MTX. Thus, our results reflect the superiority of the combination of infliximab and MTX therapy over MTX alone in a treatment-naive population. In patients with more advanced RA, results from a recent trial show the advantages of the combination of etanercept and MTX over either drug alone in terms of reducing disease activity, slowing radiographic progression of joint damage, and improving physical function (33). The safety profile of the MTX infliximab combination was similar to that observed in previous infliximab trials (8,9,22,32) except for an increased risk of serious infections in the MTX infliximab groups compared with MTX therapy alone. In particular, we found a higher incidence of pneumonia in patients receiving the MTX infliximab combinations than in those receiving MTX monotherapy. The 2.0% incidence of pneumonia in the MTX 3 mg/kg infliximab group in the present study is similar to the 1.9% incidence of pneumonia in the MTX infliximab groups (3 mg/kg or 10 mg/kg infliximab dosages) in the largest study previously conducted (32). However, caution must be used in comparing the rates of adverse events between these 2 studies due to differences in the patient populations. The 4 cases of tuberculosis in the infliximab treatment groups are consistent with previous reports indicating an increased risk for reactivation of latent tuberculosis with anti-tnf therapy (34). Two of the patients in the trial developed tuberculosis despite a negative PPD skin test result at screening. In RA,

10 INFLIXIMAB THERAPY FOR RHEUMATOID ARTHRITIS 3441 false-negative PPD skin test results may arise from impaired delayed-type hypersensitivity (35,36). The 4 cases of noncutaneous malignancy observed in the present study all occurred in the 6 mg/kg infliximab treatment group. In a recent summary, the incidences of nonlymphomatous malignancies, excluding nonmelanoma skin cancers, were not significantly different in infliximab-treated patients from clinical studies compared with the general population (37). None of the patients in the present study was diagnosed as having lymphoma. The optimal approach for treating RA in its early stages is not known with certainty. MTX is often used as the initial DMARD for patients with moderate-tosevere disease activity, and our results underscore the clinical efficacy of this approach. In a previous study, etanercept therapy was associated with significantly less radiographic progression over 2 years than MTX alone (12). Therefore, for some patients, early treatment with a TNF antagonist may afford superior protection against the development of radiographic damage compared with the use of MTX as a single DMARD. In the present trial, 1 of 3 patients in the MTX infliximab groups achieved an ACR70 response compared with 1 of 5 patients in the MTX-alone group. Similarly, 1 of 9 patients in the MTX-alone group had significant radiographic progression over 1 year (an increase from baseline in the vdh-s larger than the SDD of 9.03) compared with 1 of 30 patients in the MTX infliximab groups. Further studies are needed to determine which subsets of patients with early RA may benefit most from the combination regimen. Our study may have limitations. The ACR-N was chosen as a primary outcome for the present study. It is a continuous variable and allows for the use of a smaller sample size than a design employing the dichotomous ACR20 responder index. The ACR20 is a validated end point for evaluating the clinical effects of DMARD therapy for RA. The ACR-N utilizes the same disease measures for evaluating signs and symptoms as the ACR20 responder index, and it may therefore be expected to have similar validity as a treatment end point. Furthermore, the ACR-N was analyzed conservatively in our study, using a negative change score for worsening of signs and symptoms. This methodologic approach may partly explain the relatively low ACR-N values (compared with the ACR20 responses) across the treatment groups. Regardless, the co primary analysis using ACR-N as an end point was entirely consistent with the 2 sensitivity analyses and the secondary analyses of ACR20, ACR50, and ACR70 responses as well as DAS28 responses. The possibility that our results may not generalize to the population of RA patients as a whole is another consideration. Our study population had moderate-to-severe disease activity, with one or more factors indicating a poor prognosis: serum rheumatoid factor positivity, erosive disease, or elevated serum CRP level (38 40). Sokka and Pincus have reported that only 31% of patients from a private rheumatology practice would have been eligible for the early RA trial of etanercept versus MTX (41), which has inclusion criteria similar to those of the present study. Thus, the results from these 2 trials may not generalize to patients with less severe RA. Also, patients who were excluded from this trial (as they would have been from most other trials) because of older age or serious comorbid illnesses might have had more treatment-related complications than were observed in this study. This study has shown that patients with active RA in its early stages can benefit from aggressive therapy using a TNF inhibitor based combination regimen. However, these results also show that a significant proportion of patients with early RA can achieve disease control for 1 year by taking MTX alone. Thus, for the individual patient, the potential incremental benefits of the combination approach must be carefully weighed against the possibility of greater toxicity. These results nevertheless show that the combination of MTX and infliximab produces clinical, radiographic, and functional benefits exceeding those of MTX alone and may ultimately prove to be a highly effective strategy for preventing joint damage and functional disability in patients at high risk for disease progression. REFERENCES 1. Wolfe FE, Hawley DJ. The long-term outcome of rheumatoid arthritis. Work disability: a prospective 18 year study of 816 patients. J Rheumatol 1998;25: Fex E, Jonsson K, Johnson U, Eberhardt K. Development of radiographic damage during the first 5-6 yr of rheumatoid arthritis: a prospective follow-up study of a Swedish cohort. Br J Rheumatol 1996;35: Fuchs HA, Kaye JJ, Callahan LF, Nance EP, Pincus T. Evidence of significant radiographic damage in rheumatoid arthritis within the first 2 years of disease. J Rheumatol 1989;15: Mottonen TT. Prediction of erosiveness and rate of development of new erosions in early rheumatoid arthritis. Ann Rheum Dis 1988;47: Feldmann M, Maini RN. Anti-TNF therapy of rheumatoid arthritis: what have we learned? Annu Rev Immunol 2001;19: Moreland LW, Schiff MH, Baumgartner SW, Tindall EA, Fleischmann RM, Bulpitt KJ, et al. Etanercept therapy in rheumatoid

11 3442 ST.CLAIR ET AL arthritis: a randomized, controlled trial. Ann Intern Med 1999;130: Weinblatt ME, Kremer JM, Bankhurst AD, Bulpitt KJ, Fleischmann RM, Fox RI, et al. A trial of etanercept, a recombinant tumor necrosis factor receptor:fc fusion protein, in patients with rheumatoid arthritis receiving methotrexate. N Engl J Med 1999; 340: Maini R, St.Clair EW, Breedveld F, Furst D, Kalden J, Weisman M, et al. Randomised phase III trial of infliximab combined with ongoing methotrexate in the treatment of rheumatoid arthritis with persistent disease activity. Lancet 1999;354: Lipsky PE, van der Heijde DM, St.Clair EW, Furst DE, Breedveld FC, Kalden JR, et al. Infliximab and methotrexate in the treatment of rheumatoid arthritis. N Engl J Med 2000;343: 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: Bathon JM, Martin RW, Fleischmann RM, Tesser JR, Schiff MH, Keystone EC, et al. A comparison of etanercept and methotrexate in patients with early rheumatoid arthritis. N Engl J Med 2000; 343: Genovese MC, Bathon JM, Martin RW, Fleischmann RM, Tesser JR, Schiff MH, et al. Etanercept versus methotrexate in patients with early rheumatoid arthritis: two-year radiographic and clinical outcomes. Arthritis Rheum 2002;46: Van der Heijde A, Jacobs JW, Bijlsma JW, Heurkens AH, van Booma-Frankfort C, van der Veen MJ, et al. The effectiveness of early treatment with second-line antirheumatic drugs: a randomized, controlled trial. Ann Intern Med 1996;124: Bukhari MA, Wiles NJ, Lunt M, Harrison BJ, Scott DG, Symmons DP, et al. Influence of disease-modifying therapy on radiographic outcome in inflammatory polyarthritis at five years: results from a large observational inception study. Arthritis Rheum 2003;48: Mottonen T, Hannonen P, Leirisalo-Repo M, Nissila M, Kautiainen H, Korpela M, et al, the FIN-RACo trial group. Comparison of combination therapy with single-drug therapy in early rheumatoid arthritis: a randomised trial. Lancet 1999;353: Boers M, Verhoeven AC, Markusse HM, van de Laar MA, Westhovens R, van Denderen, et al. Randomised comparison of combined step-down prednisolone, methotrexate and sulphasalazine with sulphasalazine alone in early rheumatoid arthritis. Lancet 1997;350: Landewe RB, Boers M, Verhoeven AC, Westhovens R, van de Laar MA, Markusse HM, et al. COBRA combination therapy in patients with early rheumatoid arthritis: long-term structural benefits of a brief intervention. Arthritis Rheum 2002;46: Calguneri M, Pay S, Caliskaner Z, Apras S, Kiraz S, Ertenli I, et al. Combination therapy versus monotherapy for the treatment of patients with rheumatoid arthritis. Clin Exp Rheumatol 1999;17: Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 1988;31: Fries JF, Spitz PW, Kraines RG, Holman HR. Measurement of patient outcome in arthritis. Arthritis Rheum 1980;23: Ware JE Jr, Sherbourne CD. The MOS 36-item short-form health survey (SF-36). I. Conceptual framework and item selection. Med Care 1992;30: Maini RN, Breedveld FC, Kalden JR, Smolen JS, Davis D, Macfarlane JD, et al. Therapeutic efficacy of multiple intravenous infusions of anti tumor necrosis factor monoclonal antibody combined with low-dose weekly methotrexate in rheumatoid arthritis. Arthritis Rheum 1998;41: 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: Prevoo ML, van t Hof MA, Kuper HH, van Leeuwen MA, van de Putte LB, van Riel PL. Modified disease activity scores that include twenty-eight joint counts: development and validation in a prospective longitudinal study of patients with rheumatoid arthritis. Arthritis Rheum 1995;38: Van Gestel AM, Haagsma CJ, van Riel PL. Validation of rheumatoid arthritis improvement criteria that include simplified joint counts. Arthritis Rheum 1998;41: Prevoo ML, van Gestel AM, van t Hof MA, van Rijswijk MH, van de Putte LB, van Riel PL. Remission in a prospective study of patients with rheumatoid arthritis: American Rheumatism Association preliminary remission criteria in relation to the disease activity score. Br J Rheumatol 1996;35: Van der Heijde DM. Plain x-rays in rheumatoid arthritis: overview of scoring methods, their reliability and applicability. Baillieres Clin Rheumatol 1996;10: Van der Heijde D, Lassere M, Edmonds J, Kirwan J, Strand V, Boers M, the OMERACT Imaging Task Force. Minimal clinical important difference in plain films in RA: group discussions, conclusions, and recommendations. J Rheumatol 2001;28: Lassere MN, van der Heijde D, Johnson KR, Boers M, Edmonds J. Reliability of measures of disease activity and disease damage in rheumatoid arthritis: implications for smallest detectable difference, minimal clinically important difference, and analysis of treatment effects in randomized controlled trials. J Rheumatol 2001;28: Snedecor GW. Statistical methods. 7th ed. Ames (IA): Iowa State University Press; Wells GA, Tugwell P, Kraag GR, Baker PR, Groh J, Redelmeier DA. Minimum important difference between patients with rheumatoid arthritis: the patient s perspective. J Rheumatol 1993;20: Maini RN, Breedveld FC, Kalden JR, Smolen JS, Furst D, Weisman MH, et al. Sustained improvement over two years in physical function, structural damage, and signs and symptoms among patients with rheumatoid arthritis treated with infliximab and methotrexate. Arthritis Rheum 2004;50: 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 randomised trial. Lancet 2004;363: Keane J, Gershon S, Wise RP, Mirabile-Levens E, Kasznica J, Schwieterman WD, et al. Tuberculosis associated with infliximab, a tumor necrosis factor ( )-neutralizing agent. N Engl J Med 2001;345: Pope RM, Kniker WT, Talal N, Dauphinee M. Delayed type hypersensitivity in patients with rheumatoid arthritis. J Rheumatol 1993;20: Paimela L, Johansson-Stephansson EA, Koskimies S, Leirisalo- Repo M. Depressed cutaneous cell-mediated immunity in early rheumatoid arthritis. Clin Exp Rheumatol 1990;8: Information for the Arthritis Advisory Committee. Remicade (infliximab). Efficacy and safety review. Centocor. March 4, URL: A-Centocor-Remicade%20.pdf. 38. Scott DL. The diagnosis and prognosis of early arthritis: rationale for new prognostic criteria. Arthritis Rheum 2002;46: Dawes PT, Fowler PD, Clarke S, Fisher J, Lawton A, Shadforth MF. Rheumatoid arthritis: treatment which controls the C-reactive protein and erythrocyte sedimentation rate reduces radiological progression. Br J Rheumatol 1986;25: Van Leeuwen MA, van Rijswijk MH, Sluiter WJ, van Riel PL, Kuper IH, van de Putte LB, et al. Individual relationship between

12 INFLIXIMAB THERAPY FOR RHEUMATOID ARTHRITIS 3443 progression of radiological damage and the acute phase response in early rheumatoid arthritis: towards development of a decision support system. J Rheumatol 1997;24: Sokka T, Pincus T. Eligibility of patients in routine care for major clinical trials of anti tumor necrosis factor agents in rheumatoid arthritis. Arthritis Rheum 2003;48: APPENDIX A: THE ACTIVE-CONTROLLED STUDY OF PATIENTS RECEIVING INFLIXIMAB FOR THE TREATMENT OF RHEUMATOID ARTHRITIS OF EARLY ONSET STUDY GROUP Members of the Active-Controlled Study of Patients Receiving Infliximab for the Treatment of Rheumatoid Arthritis of Early Onset Study Group, in addition to the authors of this article, are as follows: Austria: Dr. Gabriele Eberl, MD, Krankenhaus Lainz (Vienna); Dr. Klaus Machold, Allgemeines Krankenhaus Wien (Vienna). Belgium: Professor Jean-Pierre Devogelaer, Clinique Universitaire St. Luc (Brussels); Dr. Piet Geusens, Biomedisch Onderzoek Centrum (Diepenbeek); Dr. R. Westhovens, Universitair Ziekenhuis Gasthuisberg (Leuven). Canada: Wiliam Martin, MD, University of Calgary (Calgary, Alberta); Boulos Haraoui, MD, Institut de Rhumatologie de Montreal (Montreal, Quebec); Carter Thorne, MD, The Arthritis Program Research Group (Newmarket, Ontario); Robert McKendry, MD, Ottawa Hospital (Ottawa, Ontario); Andre-Damien Beaulieu, MD, Laval University Hospital (Sainte Foy, Quebec); Majed Khraishi, MD, St. Clare s Mercy Hospital (St. John s, Newfoundland); Mary Bell, MD, Sunnybrook and Women s College Health Sciences Centre (Toronto, Ontario); Janice Canvin, MD, Hani El-Gabalawy, MD, University of Manitoba Arthritis Centre (Winnipeg, Manitoba). France: Professor Bernard G. Combe, Hopital Lapeyronie (Montpellier); Dr. Yves Maugars, CHU Hotel Dieu (Nantes); Professor Liana Euller-Ziegler, Hospital de L Archet (Nice); Professor Maxime Dougados, Professor Andre Kahan, Groupe Hospitalier Cochin (Paris). Germany: Dr. Andrea Rubbert, Universitätsklinikum Köln (Cologne); Dr. Hubert Nü lein, PhD, Städtisches Klinikum (Dresden); Dr. Maria Stoyanova-Scholz, Klinikum Duisburg (Duisburg); Dr. Gernot Key er, Martin-Luther-Universität (Halle); Professor Holm Häntzschel, Universitätsklinik Leipzig (Leipzig); Dr. Michael Schwarz-Eywill, des Evangelischen Krankenhauses (Oldenburg); Dr. Constanze Richter (Stuttgart); Dr. Tony Hans-Peter, Universität Würzburg (Wurzburg). Ireland: Dr. Oliver Fitzgerald, St. Vincent University Hospital (Dublin). Israel: Professor Abraham Menahim Nahir, Rambam Medical Center (Haifa); Professor Michael Yaron, Ichilov Hospital (Tel Aviv). Italy: Professor Francesco Trotta, Ospedale Sant Anna (Ferrara); Professor Marco Matucci Cerinic, Universita di Firenze (Florence); Professor Flavio Fantini, Istituto Ortopedico Gaetano Pini (Milan); Professor Silvano Todesco, Policlinico Universitario (Padua); Professor Stefano Bombardieri, Ospedale Santa Chiara (Pisa). The Netherlands: Dr. Robert Landewe, Atrium Medisch Centrum (Heerlen); Piet van Riel, MD, PhD, Academisch Ziekenhuis Nijmegen (Nijmegen). Norway: Dr. Anne Glennås, Diakonhjemmets Sykehus (Oslo). Spain: Dr. Raimon Sala San-Marti, Hospital Clinic of Barcelona (Barcelona); Dr. Jose M. Alvaro-Gracia, Hospital de la Princesa (Madrid); Dr. Emilio Martin Mola, Hospital Universitario La Paz (Madrid); Dr. Vicente Rodriguez Valverde, Hospital Universitario Marques de Valdecilla (Santander); Dr. Juan J. Gomez-Reino, Hospital Clinico Universitario (Santiago). Sweden: Professor Lars Klareskog, Professor Ronald van Vollenhoven, Karolinska Sjukhuset (Stockholm). United Kingdom: Dr. Andrei Calin, Royal National Hospital for Rheumatology Diseases (Bath); Dr. Simon Bowman, Birmingham Heartlands Hospital (Birmingham); Dr. John Kirwan, University of Bristol (Bristol); Professor Brian Hazleman, Addenbrookes Hospital (Cambridge); Dr. Rob Moots, University Hospital Aintree (Liverpool); Dr. David Doyle, Whipps Cross Hospital (London); Dr. Karl Gaffney, Norfolk and Norwich University Hospital (Norwich); Professor Paul Wordsworth, Nuffield Orthopaedic Centre (Oxford). United States: David McLain, MD, Alabama Research Center (Birmingham, AL); William Shergy, MD, Rheumatology Associates of North Alabama (Huntsville, AL); Christopher Adams, MD, Little Rock Diagnostic Clinic (Little Rock, AR); Paul Caldron, DO, Arizona Arthritis Research (Paradise Valley, AZ); Benjamin Harris, MD (Phoenix, AZ); Sanford Roth, MD (Phoenix, AZ); John Tesser, MD, Phoenix Center for Clinical Research (Phoenix, AZ); David Yocum, MD, University of Arizona Health Science Center (Tucson, AZ); Arthur Kavanaugh, MD, University of California San Diego Division of Rheumatology (La Jolla, CA); Daniel Wallace, MD (Los Angeles, CA); Irene Tong, MD (Pasadena, CA); Kathryn Hobbs, MD, Christopher Striebich, MD, University of Colorado Hospital (Aurora, CO); Deborah Desir, MD, Arthritis and Osteoporosis Center (Hamden, CT); Brian Peck, MD (Waterbury, CT); Howard Offenberg, MD, Radiant Research (Daytona Beach, FL); Mitchell Lowenstein, MD (Palm Harbor, FL); Jeffrey Kaine, MD, Sarasota Arthritis Research Center (Sarasota, FL); Michael Burnette, MD, Tampa Medical Group (Tampa, FL); Jeffrey Miller, MD (Tampa, FL); Craig Wiesenhutter, MD, Coeur D Alene Arthritis Clinic (Coeur D Alene, ID); Margaret Michalska, MD, Rush Presbyterian St. Luke s Medical Center (Chicago, IL); Michael Stack, MD, Indiana Internal Medicine Associates (Indianapolis, IN); James Anderson, MD, Heartland Research Associates (Wichita, KS); Richard Lies, MD, Wichita Clinic (Wichita, KS); Michael H. Edwards, MD, University Medical Associates (Louisville, KY); Seth Lourie, MD (Greenbelt, MD); Herbert Baraf, MD, Center for Rheumatology and Bone Research (Wheaton, MD); Larry Anderson, MD, Charles Radis, DO, Rheumatology Associates (Portland, ME); Richard Martin, MD, Arthritis Education and Treatment Center (Grand Rapids, MI); Justus Fiechtner, MD, MPH (Lansing, MI); David Zoschke, MD, Arthritis and Rheumatology Consultants (Edina, MN); John Ervin, MD, The Center for Pharmaceutical Research (Kansas City, MO); Suthin Songcharoen, MD (Jackson, MS); Elliot Kopp, MD, C.A.R.E. Center (Raleigh, NC); Melvin Churchill, MD, Arthur Weaver, MD, Arthritis Center of Nebraska (Lincoln, NE); Marc Goldberg, MD, New Jersey Physicians (Passaic, NJ); Joel Kremer, MD, Center for Rheumatology (Albany, NY); Michael Luggen, MD, Deaconess Arthritis Center (Cincinnati, OH); Alan Safdi, MD, Consultants for Clinical Research (Cincinnati, OH); Christine Codding, MD, ntouch Research (Oklahoma City, OK); Gary Sultany, MD (Portland, OR); Alan Kivitz, MD (Duncansville, PA); Marlin Wenger, MD, Lancaster Rheumatology Research (Lancaster, PA); John Abruzzo, MD, Thomas Jefferson University Hospital (Philadelphia, PA); Robert Griffin, Jr., DO (West Reading, PA); Charles Pritchard, MD, Rheumatic Disease Associates, Ltd. (Willow Grove, PA); Paul Wheeler, MD (Nashville, TN); Andrew Chubick, MD (Dallas, TX); Stanley Cohen, MD, Radiant Research (Dallas, TX); John Cush, MD, Presbyterian Hospital Dallas (Dallas, TX); David Karp, MD, The University of Texas Southwestern Medical Center at Dallas (Dallas, TX); Francis Burch, MD, San Antonio Center for Clinical Research (San Antonio, TX); Joel Rutstein, MD, Arthritis Diagnostic and Treatment Center (San Antonio, TX); Christopher Wise, MD, Virginia Commonwealth University (Richmond, VA); Garry Bayliss, MD (Salem, VA); Scott Baumgartner, MD, Physician s Clinic of Spokane (Spokane, WA); Robert Ettlinger, MD (Tacoma, WA); John Fahey, MD (Milwaukee, WI); Allan Goldman, MD, The Rheumatic Disease Center (Milwaukee, WI).