Recombinant Human Tumor Necrosis Factor Receptor (Etanercept) for Treating Ankylosing Spondylitis

Transcription

1 ARTHRITIS & RHEUMATISM Vol. 48, No. 11, November 2003, pp DOI /art , American College of Rheumatology Recombinant Human Tumor Necrosis Factor Receptor (Etanercept) for Treating Ankylosing Spondylitis A Randomized, Controlled Trial John C. Davis, Jr., 1 Désirée van der Heijde, 2 Jurgen Braun, 3 Maxime Dougados, 4 John Cush, 5 Daniel O. Clegg, 6 Alan Kivitz, 7 Roy Fleischmann, 8 Robert Inman, 9 and Wayne Tsuji 10 for the Enbrel Ankylosing Spondylitis Study Group Supported by Immunex Corporation, Seattle, Washington, a wholly owned subsidiary of Amgen Inc., Thousand Oaks, California. 1 John C. Davis, Jr., MD, MPH: University of California, San Francisco; 2 Désirée van der Heijde, MD, PhD: University Hospital, Maastricht, The Netherlands; 3 Jurgen Braun, MD: Herne, Germany; 4 Maxime Dougados, MD: Hopital Cochin, Paris, France; 5 John Cush, MD: Presbyterian Hospital of Dallas, Dallas, Texas; 6 Daniel O. Clegg, MD: University of Utah Medical Center, Salt Lake City; 7 Alan Kivitz, MD: Altoona Center for Clinical Research, Duncansville, Pennsylvania; 8 Roy Fleischmann, MD: Radiant Research, Dallas, Texas; 9 Robert Inman, MD: Toronto Western Hospital, Toronto, Ontario, Canada; 10 Wayne Tsuji, MD: Amgen Inc., Thousand Oaks, California. Additional members of the Enbrel Ankylosing Spondylitis Study Group are as follows: Scott Baumgartner, MD: Physicians Clinic of Spokane, Spokane, Washington; Ken Bulpitt, MD: University of California Los Angeles Medical Center; Mark Genovese, MD: Stanford University Medical Center, Palo Alto, California; Christopher Jackson, MD: University of Utah Medical Center, Salt Lake City; Richard Jimenez, MD: Evergreen Clinical Research Associates, Edmonds, Washington; Arthur Kavanaugh, MD: University of California San Diego Medical Center, and Thornton Hospital, La Jolla, California; Edward Keystone, MD: Mt. Sinai Hospital, Toronto, Ontario, Canada; Joel Kremer, MD: The Center for Rheumatology, Albany, New York; James Louie, MD: Harbor University of California, Los Angeles Medical Center, Torrance; Maren Mahowald, MD: Veterans Affairs Medical Center, Minneapolis, Minnesota; Philip Mease, MD: Seattle Rheumatology Associates, Seattle, Washington; Jerry Molitor, MD, PhD: Benaroya Research Institute at Virginia Mason, Seattle, Washington; Larry Moreland, MD: University of Alabama at Birmingham; Eric Ruderman, MD: Northwestern University, Chicago, Illinois; Michael Schiff, MD: Denver Arthritis Clinic, Denver, Colorado; H. Ralph Schumacher, MD: University of Pennsylvania, and Veterans Affairs Medical Center, Philadelphia, Pennsylvania; Jon Stevenson, MD: Arthritis Northwest, Spokane, Washington; James Taborn, MD: Midwest Arthritis Center, Kalamazoo, Michigan; Robert Valente, MD: Arthritis Center of Nebraska, Lincoln; Daniel J. Wallace, MD: Cedars-Sinai Medical Center, Los Angeles, California; Michael H. Weisman, MD: Cedars-Sinai Medical Center, Los Angeles, California. Address correspondence and reprint requests to John C. Davis, Jr., MD, MPH, Division of Rheumatology, University of California San Francisco, 533 Parnassus Avenue, Room U383, Box 0633, San Francisco, CA jdavis@medicine.ucsf.edu. Objective. To determine the safety and efficacy of etanercept in a multicenter, randomized, placebocontrolled, double-blind trial of adults with moderate to severe active ankylosing spondylitis (AS). Methods. Patients (n 277) were treated with either etanercept 25 mg (n 138) or placebo (n 139) subcutaneously twice weekly for 24 weeks. The primary outcome measures were the percentages of patients achieving the Assessments in Ankylosing Spondylitis 20% response (ASAS20) at weeks 12 and 24. Other outcome measures included the percentage of patients achieving higher ASAS responses, and the safety of etanercept in patients with AS. All outcome measures were assessed at 2, 4, 8, 12, and 24 weeks. Results. Treatment with etanercept resulted in dramatic improvement. The ASAS20 was achieved by 59% of patients in the etanercept group and by 28% of patients in the placebo group (P < ) at week 12, and by 57% and 22% of patients, respectively, at week 24 (P < ). All individual ASAS components, acutephase reactant levels, and spinal mobility measures were also significantly improved. The safety profile of etanercept was similar to that reported in studies of patients with rheumatoid arthritis or psoriatic arthritis. The only adverse events that occurred significantly more often in the etanercept group were injection-site reactions, accidental injuries, and upper respiratory tract infections. Conclusion. Etanercept is a highly effective and well tolerated treatment in patients with active AS. Ankylosing spondylitis (AS) is an inflammatory arthritis and enthesitis involving the spine and peri- Submitted for publication March 26, 2003; accepted in revised form July 28,

2 ETANERCEPT IN ANKYLOSING SPONDYLITIS 3231 pheral joints. Approximately 350,000 people in the US have AS (1). Traditional therapies, including diseasemodifying antirheumatic drugs (DMARDs), nonsteroidal antiinflammatory drugs (NSAIDs), and corticosteroids, do not adequately control disease activity in most patients (2). The need for safe and effective therapy for patients with AS is substantial. Tumor necrosis factor (TNF) is important in the pathogenesis of AS. In patients with AS, TNF concentrations are elevated in the serum (3,4) and synovial tissue (5 7). Etanercept substantially reduces disease activity in patients with spondylarthropathies, as demonstrated in a study in psoriatic arthritis (8) and a pilot study in AS (9). These findings suggest that blockage of the proinflammatory effects of TNF may reduce the clinical signs and symptoms of AS and improve quality of life. We report the results of a 24-week, randomized, double-blind, controlled trial that compared etanercept with placebo in patients with AS. PATIENTS AND METHODS Patients. The study was conducted at 28 investigational sites in 5 countries (US, Canada, The Netherlands, Germany, and France) and was approved by the institutional review boards of all institutions. All patients signed an informed consent form before screening and enrollment. Men or women ages 18 to 70 years were eligible if they satisfied the modified New York criteria for AS (10). At the time of enrollment, patients had active AS, defined as 1) a score of 30 mm for morning stiffness (average of 2 scores on a 100-mm visual analog scale [VAS] analyzing duration or intensity of morning stiffness), and 2) scores of 30 mm for 2 of the following 3 parameters: patient s global assessment (on a 100-mm VAS) of disease activity, back pain (average of 2 VAS scores evaluating nocturnal back pain or total back pain), and the Bath Ankylosing Spondylitis Functional Index (BASFI) (11). Patients were excluded from the study if they had complete ankylosis (fusion) of the spine based on radiographic assessment, had previously received TNF inhibitor therapy, had a serious infection (associated with hospitalization or intravenous antibiotics) within 4 weeks before screening, or were pregnant. Patients were allowed to continue receiving hydroxychloroquine, sulfasalazine, or methotrexate at stable dosages during the study but were excluded if they had received any other DMARDs within 4 weeks of the baseline evaluation. Dosages of NSAIDs or prednisone (up to 10 mg/day or the equivalent) must have been stable for 2 weeks prior to the baseline evaluation, and were to continue to be stable during the study. Analgesics, including acetaminophen, codeine, hydrocodone, oxycodone, and tramadol, were permitted in standard dosages. All patients used a diary to record the date of each administration of the study medication, the presence of any adverse events, and the use of concomitant medications. Study staff reviewed the diary with the patient at each visit. Patient adherence to the protocol was monitored by a review of the patient diaries at the scheduled clinic visits. Study drug. Study drug was supplied to patients in prefilled syringes, each containing the contents of 1 reconstituted vial of etanercept (Enbrel; Immunex-Wyeth Research, Seattle, WA) or placebo, formulated without etanercept. Study drug was delivered by self-administered subcutaneous injection. Study design. The study was a double-blind, placebocontrolled 24-week trial in which patients received placebo or etanercept 25 mg subcutaneously twice weekly. Patients were stratified by concomitant use of DMARDs at the time of assignment to treatment. Patients were randomized in a 1:1 ratio to receive either etanercept or placebo, in blocks of 2 within each of the 2 strata. Patients, investigators, assessors, other study site personnel, and representatives of the sponsor were blinded to the randomization schedule and to treatment assignment until completion of the trial. In addition, to prevent influencing the assessments due to events such as injection-site reactions, assessors who were not otherwise involved in studyrelated patient care evaluated all non-patient reported efficacy measures in a blinded manner. Efficacy end points. The primary outcome of the study was a comparison between the placebo and etanercept groups of the proportion of patients achieving the Assessments in Ankylosing Spondylitis 20% response (ASAS20) (12) at 12 weeks. If a significant difference was observed between treatment groups at 12 weeks, the proportion of ASAS20 responders was compared at 24 weeks. The ASAS20 is a validated end point that requires an improvement of 20% and a positive change of at least 10 units on a 100-mm VAS in at least 3 of the 4 ASAS domains, as well as the absence of deterioration (defined as a worsening of at least 20% and a negative change of at least 10 units on a 100-mm scale) in the remaining domain. Anderson et al (12) define the 4 ASAS domains as: the patient s global assessment of disease activity, pain, physical function, and inflammation. In this study, patient s global assessment was measured on a 100-mm VAS with extremes labeled none and severe ; total back pain was assessed on a 100-mm VAS with extremes labeled no pain and most severe pain ; function, regarding the ability to perform specific tasks, was measured by the BASFI (11); and inflammation was measured as the average of the scores for the last 2 questions on the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) (13). Secondary outcome measures included achievement of the ASAS50 and ASAS70. In our study, these responses were computed in a manner similar to that used to compute the ASAS20 response, except that they required improvements of 50% and 70%, respectively, in at least 3 of the 4 ASAS domains, with a positive change of at least 10 units on a 100-mm VAS in each domain. Absence of deterioration in the remaining domain was required and was defined as for the ASAS20 response. An additional secondary outcome was the proportion of patients who experienced a significant decrease in disease activity and achievement of near remission of disease symptoms, or partial remission. Partial remission has been defined (12) as a value of less than 20 units (on a 100-mm scale) in each of the 4 ASAS domains (patient s global assessment, pain, BASFI, and inflammation).

3 3232 DAVIS ET AL Other outcome measures included the effect of etanercept on independent components of the ASAS response criteria, the BASDAI (13), spinal mobility (using the modified Schober test, chest expansion score, and occiput-to-wall measurements), peripheral joint counts (swollen, n 68; tender, n 70), acute-phase reactants (erythrocyte sedimentation rate and C-reactive protein level), and assessor s global assessments (measured on a 100-mm VAS) over time. Safety end points. All patients who were randomized and received at least 1 dose of study drug were evaluated for safety, including adverse events, infections, premature discontinuation from the study, and standard laboratory tests (including hematologic analysis, serum chemistry, and urinalysis profiles). Adverse events and abnormal laboratory values were graded on a scale derived from the National Cancer Institute Common Toxicity Criteria (online at Serum samples obtained at baseline and week 24 were tested for antibody to etanercept using an enzyme-linked immunosorbent assay (ELISA) (14). Samples that were positive by ELISA were tested in a binding assay for neutralizing antibodies. Statistical analysis. Sample size determinations were based on an earlier randomized, double-blind, placebocontrolled trial in patients with AS (9). Power calculations indicated that a sample size of 200 patients, with equal allocation to etanercept or placebo, provided 93% power to detect a difference in response rate, assuming a response rate of 40% in the placebo group and 65% in the etanercept group, using a 2-sided Fisher s exact test. All patients who received at least 1 dose of the study drug were included in intent-to-treat analyses of efficacy and safety. The percentage of patients in the etanercept and placebo groups who achieved the ASAS20 was compared at each time point using the Cochran-Mantel-Haenszel test, stratified by the presence or absence of concomitant DMARDs at baseline. The proportions of patients achieving the ASAS50, the ASAS70, and partial remission were analyzed in a manner similar to that used for the ASAS20. Patients were considered nonresponders for binary end points at all time points after study drug discontinuation. For continuous measures, such as the individual components of the ASAS and the acute-phase reactant and spinal mobility parameters, the percent improvement from baseline was calculated, and the van Elteren stratified rank test was used to compare the percent improvement between the 2 treatment groups. A last observation carried forward approach was used to handle missing data. For the safety analyses, the types and intensities of adverse events and infections reported during the study were recorded. Treatment groups were compared with respect to the proportions of patients with adverse events and infections, using Fisher s exact test. All statistical tests were 2-sided, with set at RESULTS Data for the study were collected between December 2001 and October After screening, 277 patients received at least 1 dose of study drug and were evaluated for safety and efficacy (Figure 1). The groups Figure 1. Patient disposition in a randomized, controlled trial comparing etanercept with placebo in patients with ankylosing spondylitis. were well matched in most characteristics of demographics (Table 1) and disease history (Table 2). Ninety-six percent of patients in each group (132 of the 138 patients in the etanercept group and 134 of Table 1. Baseline demographics of patients with ankylosing spondylitis treated with etanercept or placebo* Characteristic Placebo (n 139) Etanercept (n 138) Age, mean (range) years 41.9 (18 65) 42.1 (24 70) Male sex 105 (76) 105 (76) Race White 127 (91) 130 (94) Hispanic 6 (4) 3 (2) Asian 3 (2) 3 (2) American Indian 3 (2) 0 African American 0 1 (1) Middle Eastern 0 1 (1) Concomitant therapy at baseline Any disease-modifying 43 (31) 44 (32) antirheumatic drug Sulfasalazine 30 (22) 29 (21) Methotrexate 17 (12) 15 (11) Hydroxychloroquine 1 (1) 3 (2) Nonsteroidal antiinflammatory 128 (92) 126 (91) drug Corticosteroids 20 (14) 18 (13) * Except where indicated otherwise, values are the number (%) of patients. Some patients were receiving 1 disease-modifying antirheumatic drug. Received within 6 months of the screening evaluation.

4 ETANERCEPT IN ANKYLOSING SPONDYLITIS 3233 Table 2. Baseline disease characteristics of patients with AS* Characteristic Placebo (n 139) Etanercept (n 138) Duration of AS, mean (range) years 10.5 (0 35.3) 10.1 (0 30.7) Extraspinal disease manifestation, no. (%) History of Crohn s disease or 6 (4) 7 (5) ulcerative colitis History of uveitis or iritis 43 (31) 39 (28) History of psoriasis 15 (11) 11 (8) HLA-B27 positive, no. (%) 109 (84) 108 (84) ASAS component, mean (range) score Patient s global assessment (100-mm VAS) 62.9 (9 100) 62.9 (16 100) Total back pain (100-mm VAS) 63.5 (0 99) 61.1 (7 100) BASFI 56.3 ( ) 51.7 ( ) Inflammation (0 100 scale) 64.3 (7 100) 61.4 (17 100) Spinal mobility measure, mean SEM Modified Schober test, cm Chest expansion, cm Occiput-to-wall, cm BASDAI score, mean SEM Acute-phase reactants, mean SEM CRP level, mg/dl (normal mg/dl) Erythrocyte sedimentation rate, mm/hour placebo group (P ). At 24 weeks, the ASAS20 was achieved by 78 patients in the etanercept group (57%) and by 31 patients in the placebo group (22%) (P ). The difference between groups was significant as early as week 2 and was maintained over the 24 weeks of the study (Figure 2). Similarly, the ASAS50 and ASAS70 responses in the etanercept and placebo groups were significantly different at week 2 of the study and thereafter. Partial remission of AS was achieved by a significantly higher proportion of patients in the etanercept group at all time points (17% of patients in the etanercept group compared with 4% in the placebo group at 24 weeks) (data not shown). In subgroup analyses, etanercept was effective despite previous treat- * HLA-B27 information was not available for all subjects. AS ankylosing spondylitis; ASAS Assessments in Ankylosing Spondylitis; VAS visual analog scale; BASFI Bath Ankylosing Spondylitis Functional Index; CRP C-reactive protein. Average of scores for 10 questions (possible range 0 100). Average of scores for the last 2 questions (regarding morning stiffness) on the 6-question Bath Ankylosing Spondylitis Disease Activity Index (BASDAI; possible range 0 100). Average of scores for 6 questions related to disease activity, measured on a 100-mm VAS. Normal 1 17 mm/hour for men, 1 25 mm/hour for women. the 139 patients in the placebo group) completed the first 12 weeks of the study, and 126 patients in the etanercept group (91%) and 120 patients in the placebo group (86%) completed the full 24-week study. In the etanercept group, 7 patients discontinued the study due to adverse events, 3 withdrew due to lack of efficacy, and 2 were lost to followup. In the placebo group, 1 patient discontinued due to an adverse event, 13 withdrew due to lack of efficacy, 1 was lost to followup, 2 patients voluntarily withdrew, and 2 others were discontinued because of lack of adherence to the protocol. Efficacy results. At 12 weeks, the ASAS20 was achieved by 82 (59%) of the 138 patients in the etanercept group and by 39 (28%) of the 139 patients in the Figure 2. Achievement of the Assessments in Ankylosing Spondylitis 20% response (ASAS20), the ASAS50, and the ASAS70 in patients with ankylosing spondylitis treated with etanercept or placebo, by length of treatment. P 0.01 at all time points for all analyses.

5 3234 DAVIS ET AL Table 3. Outcomes among patients with AS treated with etanercept or placebo for 24 weeks* Placebo (n 139) Etanercept (n 138) Outcome measure Baseline 24 weeks Baseline 24 weeks P ASAS component Patient s global assessment (100-mm VAS) Back pain (100-mm VAS) BASFI Inflammation Acute-phase reactant CRP level, mg/dl (normal mg/dl) ESR, mm/hour Spinal mobility measure Modified Schober test, cm Chest expansion, cm Occiput-to-wall, cm BASDAI# * Values are the mean SEM. P values for continuous end points were based on percent change from baseline. ESR erythrocyte sedimentation rate (see Table 2 for other definitions). Average of scores for 10 questions (possible range 0 100). Average of the scores for the last 2 questions on the 6-question BASDAI. Normal 1 17 mm/hour for men, 1 25 mm/hour for women. Improvements in spinal mobility are represented by increases in the modified Schober test and chest expansion measurements and by a decrease in the occiput-to-wall measurement. # Average of scores for 6 questions related to disease activity, measured on a 100-mm VAS. ment with NSAIDs or corticosteroids and regardless of concomitant DMARD therapy. At weeks 12 and 24, the etanercept group had significantly greater improvements in all individual components of the ASAS response criteria, acute-phase reactants, and the BASDAI, compared with the placebo group (Table 3). Spinal mobility measures were also statistically significantly improved in the etanercept group at weeks 12 and 24, compared with the placebo group (Table 3 and Figure 3). Safety results. Adverse events occurred in similar proportions of patients in each treatment group during the study, and most were of mild or moderate intensity. The only adverse events that occurred more often (P 0.05) in the etanercept group were injection-site reaction, upper respiratory tract infection, and accidental injury (Table 4). One life-threatening event occurred (a suicide attempt in the placebo group). In the etanercept group, 4 patients with serious adverse events completed the study despite these events (lymphadenopathy, staphylococcal cellulitis after a spider bite, wound infection after a cat bite, and a bone fracture after a fall). Five patients in the etanercept group discontinued the study because of serious adverse events, including fever associated with injection-site reactions, a flare of ulcerative colitis, intestinal obstruction due to adhesions, and 2 bone fractures after trauma (1 fall, 1 motor vehicle accident). Two other patients in the etanercept group discontinued the study due to adverse events, including a patient with a gastrointestinal hemorrhage secondary to hemorrhoids, and a patient with ileitis secondary to Crohn s disease. In the placebo group, serious adverse events included chest pain, viral infection, 2 accidental injuries (1 motor vehicle, 1 industrial), and the previously cited suicide attempt, after which the patient withdrew from the study. No tuberculosis or opportunistic infections were observed during the study. Most laboratory abnormalities were of mild or moderate intensity, and no patient discontinued the study due to an abnormal laboratory result. Among the patients who had paired baseline and week-24 serum samples available for analysis, 3 patients in the etanercept group had samples that tested positive for nonneutralizing anti-etanercept antibodies as determined by ELISA and etanercept functional assay. Flares of extraarticular disease activity occurred in both treatment groups. Flares of inflammatory bowel disease occurred in 3 patients in the etanercept group and in 2 patients in the placebo group. Flares of inflammatory eye disease (uveitis or iritis) occurred in 3 patients in the etanercept group and in 8 patients in the placebo group.

6 ETANERCEPT IN ANKYLOSING SPONDYLITIS 3235 Figure 3. Median percent improvement from baseline over time in measures of spinal mobility. By week 12, the etanercept group had statistically significant improvements (P 0.04) for all measures. At week 24, P 0.01 for all measures. DISCUSSION Ankylosing spondylitis has been a challenging disorder with few therapeutic options. In previous studies, patients receiving traditional therapies such as NSAIDs and DMARDs have received only mild to moderate benefit. Importantly, no intervention has been shown to alter progressive loss of spinal mobility. The need for new alternatives for treating these patients is substantial. Etanercept is an approved and well-documented therapy for patients with other inflammatory disorders, including rheumatoid arthritis (RA) (15 17), juvenile RA (18), and psoriatic arthritis (8), and has shown efficacy in early studies in patients with psoriasis (19). The long-term safety of etanercept in patients with RA and juvenile RA has also been well established (18,20). Our study was the first large, multicenter trial to demonstrate the efficacy and tolerability of etanercept in patients with AS. In this 24-week study, etanercept demonstrated rapid and significant improvement in the validated composite measure, the ASAS20, and in all individual parameters of the ASAS20 as early as 2 weeks after initiation of therapy. Improvements in these response criteria and higher levels of the ASAS response (ASAS50 and ASAS70) continued throughout the study. Etanercept was effective in patients with persistent disease, despite previous treatment with NSAIDs or corticosteroids and regardless of concomitant DMARD therapy. In a previous study, Marzo-Ortega et al (21) reported resolution of entheseal abnormalities in the spine, as determined by magnetic resonance imaging, after treatment with etanercept. In the current study, etanercept improved measures of spinal mobility, suggesting that etanercept may modify the disease as well as control the symptoms of AS. Although these improvements may reflect the decrease in inflammation that occurs with etanercept therapy, they may also imply less progression of bony proliferation, which could decrease or even prevent long-term disability in these patients. Etanercept was well tolerated in this study in patients with AS. The safety profile of etanercept was comparable with that observed in patients with RA (15,16) and psoriatic arthritis (8), and no unexpected adverse events or infections were observed. Further research is needed to assess the longer-term effects of etanercept in patients with AS. Spinal imaging studies Table 4. Adverse events and infections of any intensity occurring in 5% of patients* Event Placebo (n 139) Etanercept (n 138) Injection-site reaction 13 (9) 41 (30) Injection-site bruising 23 (17) 29 (21) Upper respiratory tract infection 16 (12) 28 (20) Headache 16 (12) 19 (14) Accidental injury 6 (4) 17 (12) Diarrhea 13 (9) 11 (8) Rash 9 (6) 11 (8) Rhinitis 9 (6) 8 (6) Abdominal pain 7 (5) 8 (6) Dizziness 3 (2) 8 (6) Flu syndrome 10 (7) 5 (4) * Values are the number (%) of patients. All patients had received at least 1 dose of etanercept. P 0.05, by Fisher s exact test.

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