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Objective.Fatigue and sleep problems are significant in patients with ankylosing spondylitis (AS). This subanalysis of the RHAPSODY study (Review of Safety and Effectiveness with Adalimumab in Patients with Active Ankylosing Spondylitis) was conducted to evaluate the effect of adalimumab on sleep in patients with active AS.Methods.All patients (n = 1250) had active AS and received adalimumab 40 mg every other week during the 12-week open-label treatment period. Sleep was assessed by the Medical Outcomes Study Sleep Scale (MOS-SS) at screening and Weeks 6, 12, and 20 (optional continuation period). Effect sizes were calculated to determine clinical significance. Paired Student t tests compared the change in the MOS-SS domains from Week 12 to baseline. Correlation coefficients were calculated to determine the relationship between change in sleep domains and other Week 12 clinical and patient-reported outcomes (Bath AS Disease Activity Index, C-reactive protein, nocturnal pain, total back pain, Bath AS Functional Index, patient’s global assessment of disease activity, morning stiffness, Short Form-36 Health Survey, and Work Productivity and Activity Impairment questionnaire components).Results.At Week 12, adalimumab significantly improved sleep in each of the MOS-SS domains (p < 0.001). Effect sizes for 3 of the 6 domains (disturbance, −0.69; adequacy, 0.55; somnolence, −0.52) and both sleep problems indices (Index I, −0.68; Index II, −0.77) were moderate, suggesting clinical significance. Change in the MOS-SS Sleep Problem Index II was moderately correlated with change in most clinical and patient-reported outcomes. Sleep improvements were similar in patients with and without radiographically advanced AS.Conclusion.Adalimumab improves overall sleep and sleep quality in patients with active AS.

OBJECTIVES To compare the clinical manifestations of spinal disease, peripheral arthritis and enthesitis, and to evaluate the effectiveness of adalimumab in a large cohort of patients with AS in relation to the presence or absence of psoriasis. METHODS Patients aged > or = 18 years with active AS were enrolled in an open-label study of adalimumab 40 mg every other week. Clinical symptoms were measured at baseline and Week 12 using standard assessment criteria. Differences between patients with and those without psoriasis were assessed. The relationship between changes in skin and AS symptoms was also analysed. RESULTS Of 1250 patients with AS who were enrolled in the study, 148 (11.8%) had a history of psoriasis, including 108 patients with current (active) psoriasis at entry. Baseline disease characteristics, including spinal structural damage, peripheral arthritis (> or = 1 swollen joints) and enthesitis (> or = 1 inflamed entheses), were similar in both groups. At Week 12, Assessment of SpondyloArthritis international Society 40% response was achieved by 46.7 and 54.7% and Bath AS Disease Activity Index 50% response by 58.6 and 57.0% of patients with and without psoriasis, respectively. Median changes in swollen joint scores and Maastricht AS Enthesitis Scores were similar in both groups. Skin changes during adalimumab treatment in AS patients with a history of psoriasis did not correlate with changes in AS symptoms. CONCLUSIONS The presence of psoriasis had no influence on the other clinical manifestations of patients with AS. Treatment with adalimumab markedly improved axial disease, peripheral arthritis and enthesitis, regardless of history of psoriasis.

Background:Bone marrow oedema (BMO), synovitis, effusion and joint erosion on magnetic resonance imaging (MRI) may be used as outcome measures in psoriatic arthritis (PsA).Objective:To assess the impact of adalimumab on BMO, synovitis, effusion and erosions in PsA, as measured by MRI.Methods:Fifteen patients with active PsA (⩾3 tender and ⩾3 swollen joints) were enrolled in an open-label pilot study. Each received adalimumab subcutaneously every other week for 24 weeks. MRI was obtained at baseline and 24 weeks.Results:MRI was available for 11 patients, pre and post-therapy. BMO and effusion scores improved markedly after 24 weeks of adalimumab, while no significant change was noted in erosion score. An unanticipated finding, however, was the lack of improvement in the MRI synovitis score.Conclusions:Improvement in BMO and unchanged erosion scores may explain the “anti-erosive” effects of adalimumab in PsA. Persistence of BMO and synovitis on MRI suggests ongoing disease activity and supports the continuation of long-term anti-TNF therapy.

Objective To compare the efficacy of adalimumab versus placebo in reducing spinal and sacroiliac (SI) joint inflammation, by magnetic resonance imaging (MRI) in patients with active ankylosing spondylitis (AS). Methods This was a randomized, multicenter, double-blind, placebo-controlled study. Patients (n = 82) received 40 mg adalimumab or placebo every other week during an initial 24-week double-blind period. MRIs of both the spine and SI joints were obtained at baseline, week 12, and week 52. Spinal and SI joint inflammation were measured using the Spondyloarthritis Research Consortium of Canada (SPARCC) MRI index. Results The spine SPARCC score in placebo-treated patients increased by a mean of 9.4% from baseline, compared with a mean decrease of 53.6% in adalimumab-treated patients (P < 0.001); the SI joint SPARCC score decreased by a mean of 12.7% from baseline in placebo-treated patients and by 52.9% in adalimumab-treated patients (P = 0.017). The response in adalimumab-treated patients was maintained at week 52. Placebo-treated patients were switched to open-label adalimumab treatment at week 24 and experienced similar reductions in spinal and SI joint inflammation by week 52. Similar large reductions in the spine and SI joint SPARCC scores were noted, even in patients who failed to meet the ASsessment in Ankylosing Spondylitis (International Working Group) criteria (nonresponders) at 12 weeks. In adalimumab-treated patients, a reduced C-reactive protein concentration at week 12 was significantly associated with improvement in the spine SPARCC score (P = 0.018). Conclusion Adalimumab significantly reduced both spinal and SI joint inflammation in patients with active AS after 12 weeks of treatment, and these improvements were maintained for up to 52 weeks.

Objective: To evaluate the long-term safety and efficacy of adalimumab in patients with ankylosing spondylitis (AS) and total spinal ankylosis (TSA). Design: Patients (n = 315) with active AS were randomised in a 2:1 ratio to receive adalimumab 40 mg every other week or placebo for 24 weeks followed by open-label adalimumab for up to 5 years. Two-year efficacy and safety data for 11 patients with investigator-defined TSA were evaluated. The primary end point was the ASsessment in AS International Working Group criteria for 20% improvement (ASAS20) at Week 12. On or after Week 12, ASAS20 non-responders could switch to open-label adalimumab. Other efficacy measurements included ASAS40, ASAS 5/6, ASAS partial remission, and 50% improvement in the Bath AS Disease Activity Index (BASDAI 50). Results: 6 of 11 TSA patients were randomised to adalimumab and 5 to placebo. At Week 12, 50% of the adalimumab-treated patients achieved an ASAS20 response and 33% achieved an ASAS40, ASAS 5/6 and BASDAI 50. No placebo-treated patients achieved any response criteria at Week 12. 4 placebo- and 2 adalimumab-treated patients switched to open-label adalimumab before Week 24. After 1 year of adalimumab treatment, 8 of 11 patients achieved an ASAS20 response. After 2 years, 6 of the remaining 8 patients with TSA reported an ASAS20 response. There were no serious adverse events or adverse event-related study discontinuations. Conclusion: In patients with TSA, adalimumab treatment resulted in rapid and clinically significant improvement in the signs and symptoms of active disease. Adalimumab effectiveness and safety were sustained for at least 2 years. Trial registration number: NCT00085644.

Objective To evaluate the safety and efficacy of adalimumab, a fully human recombinant IgG1 monoclonal antibody that specifically targets human tumor necrosis factor, in patients with active ankylosing spondylitis (AS). Methods This was a multicenter, randomized (2:1 ratio), double-blind, placebo-controlled study to evaluate a subcutaneous injection of adalimumab, 40 mg every other week, compared with placebo for 24 weeks. The primary efficacy end point was the percentage of patients with a 20% response according to the ASsessment in Ankylosing Spondylitis International Working Group criteria for improvement (ASAS20) at week 12. Secondary outcome measures included the ASAS20 at week 24 and multiple measures of disease activity, spinal mobility, and function, as well as ASAS partial remission. Results At week 12, 58.2% of adalimumab-treated patients (121 of 208) achieved an ASAS20 response, compared with 20.6% of placebo-treated patients (22 of 107) (P < 0.001). More patients in the adalimumab group (45.2% [94 of 208]) than in the placebo group (15.9% [17 of 107]) had at least a 50% improvement in the Bath Ankylosing Spondylitis Disease Activity Index at week 12 (P < 0.001). Significant improvements in the ASAS40 response and the response according to the ASAS5/6 criteria at weeks 12 and 24 were also demonstrated (P < 0.001). Partial remission was achieved by more adalimumab-treated patients than placebo-treated patients (22.1% versus 5.6%; P < 0.001). Adalimumab-treated patients reported more adverse events (75.0% versus 59.8% of placebo-treated patients; P < 0.05), but there was no statistically significant difference in the incidence of infections. Most adverse events were mild or moderate in severity. Conclusion Adalimumab was well-tolerated during the 24-week study period and was associated with a significant and sustained reduction in the signs and symptoms of active AS.

It has become common to collect blood samples from patients for phase II/III clinical trials to investigate pharmacokinetic/pharmacodynamic relationships. However, the frequency of blood samples drawn from patients is limited due to clinical or pharmacoeconomic reasons. We discuss some sampling schemes for an immunosuppressive drug in phase III studies. Selection criteria and statistical approaches are discussed to select blood-sampling time points in four scenarios from a single study and from combined multiple studies: (1) Area under the curve (AUC) only without constraint, (2) AUC and Cmax simultaneously without constraint, (3) AUC only with constraint(s), and (4) AUC and Cmax simultaneously with constraint(s).

According to the current bioavailability/bioequivalence regulations by the Food and Drug Administration (FDA), comparison of mean bioequivalence values between two formulations of the same drug in pharmacokinetic studies is sufficient for approval of the new formulation in a new drug application. Intrasubject variability of pharmacokinetic parameters may still statistically differ between two bioequivalent formulations which cannot be proven based on the typical 2×2 crossover design if no repeated measures for the same formulation can be evaluated. When repeated meaures are required in a study protocol, a parallel group study design may be preferred over a crossover study design due to a pharmacological and/or clinical reason. This paper evaluates two issues regarding intrasubject variability based on a parallel group design with repeated measures by two different approaches: 1. Conventional analysis of variance and 2. Individual subjects with respect to: an estimation procedure for variance and coefficient of variation (CV) with an emphasis on the different estimates for the CV, and different methods (parametric or nonparametric) for the comparison of variability with regard to variance and CV.

Objective To assess the convergent and discriminative validity of the Health Utilities Index Mark 3 (HUI-3) for patients with ankylosing spondylitis (AS). Methods Data were derived from the Adalimumab Trial evaluating Long-term efficacy and safety for Ankylosing Spondylitis (ATLAS). The study team specified 90 a priori hypotheses regarding the direction and magnitude of the expected associations between the overall and single-attribute scores of the HUI-3 and other health status and quality-of-life measures: Short Form 36 Health Survey (SF-36), Ankylosing Spondylitis Quality-of-Life Questionnaire, Bath Ankylosing Spondylitis Functional Index, Bath Ankylosing Spondylitis Disease Activity Index, Bath Ankylosing Spondylitis Metrology Index, and Patient's and Physician's Global Assessments of Disease Activity. With baseline data, correlation coefficients were calculated and interpreted according to the guidelines suggested by Guyatt for negligible (0–0.19), weak (0.20–0.34), moderate (0.35–0.50), and strong (>0.5) associations. The a priori hypotheses were tested using Pearson's correlation coefficients. Results A total of 315 patients with active AS were randomized and enrolled in ATLAS. The correlation coefficients between the HUI-3 scores and other health-related quality-of-life instruments confirmed 61.1% of the a priori hypotheses, with an additional 35.5% being under- or overestimated by one correlation category. Conclusion These results provide evidence of the cross-sectional, convergent, and discriminative validity of the HUI-3 for deriving utility scores in patients with AS.

Objective The patient acceptable symptom state (PASS) is a single-question outcome tool to assess the level of symptoms at which patients with rheumatic diseases consider themselves well. We evaluated whether ankylosing spondylitis (AS) patient characteristics were associated with attaining the PASS and whether these characteristics influenced PASS thresholds for patient-reported outcome (PRO) tools. Methods The Adalimumab Trial Evaluating Long-term Efficacy and Safety for Ankylosing Spondylitis was a randomized, placebo-controlled study that evaluated the efficacy and safety of adalimumab in treating AS. The PASS and PROs were assessed over 24 weeks. PASS thresholds for PROs were set as either the 25th or 75th percentiles of the PRO response score. Logistic regression analyses were conducted to determine the associations of particular patient characteristics with the PASS and other response outcomes at 12 weeks (ASessment in Ankylosing Spondylitis International Working Group criteria for 20% improvement [ASAS20], ASAS40, ASAS5/6, ASAS partial remission, and Bath Ankylosing Spondylitis Disease Activity Index 50% improvement). Results Age >40 years, disease duration >10 years, female sex, placebo treatment, and English-speaking site were consistently associated with greater PASS thresholds for PROs. Age, male sex, disease duration, and treatment were each independently associated with attainment of the PASS at 12 weeks. Only age and treatment were independently associated with other response outcomes. PASS thresholds also decreased over 24 weeks. Conclusion PASS thresholds for PROs changed over time. These thresholds, as well as the attainment of the PASS, were affected by covariates unrelated to treatment. If confirmed in other studies, these results cast doubt on using the PASS to assess absolute health status in clinical research.

Objective. To determine the validity, reliability and responsiveness of the Work Productivity and Activity Impairment questionnaire in AS (WPAI:SpA). Methods. Baseline and Week-24 data from a randomized, double-blind study of adalimumab in patients with AS were used. Discriminative validity of WPAI:SpA absenteeism, presenteeism, overall work productivity loss and activity impairment scores was assessed relative to patient-reported outcomes: Bath AS Disease Activity Index (BASDAI), AS Quality of Life Questionnaire (ASQOL), Short-Form 36 Health Survey (SF-36), Physical and Mental Component Summaries (PCS and MCS, respectively) and Health Utilities Index Mark 3 (HUI-3). Responsiveness of the WPAI:SpA instrument was assessed for patients meeting the minimum clinically important differences (MCIDs) for ASQOL and BASDAI (i.e. quality of life and clinical responders, respectively) and quantified with standardized response mean (SRM) calculations. Results. Of 315 patients, 205 were employed at baseline. Patients with more severe AS (BASDAI > median) showed significantly greater impairment in work and daily activities than patients with lesser disease severity (P < 0.001). This trend was consistent for ASQOL, SF-36 PCS, SF-36 MCS and HUI-3. There were significant differences in WPAI:SpA scores for patients achieving BASDAI clinical response and ASQOL quality of life response vs non-responders. For responders, SRMs were large for work presenteeism, overall work impairment and activity impairment (0.86 to 1.29 for BASDAI; 0.89 to 1.18 for ASQOL) and small for absenteeism (0.25 for BASDAI; 0.31 for ASQOL). Conclusions. The WPAI:SpA is a valid, reliable and responsive tool for assessing work productivity for patients with AS. Trial registration: ClinicalTrials.gov, http://clinicaltrials.gov/ct2/home, NCT00085644.

Retraction of Revicki DA, Rentz AM, Luo MP, Wong RL, Doward LC, McKenna SP: Psychometric characteristics of the ankylosing spondylitis quality of life questionnaire, short form 36 health survey, and functional assessment of chronic illness therapy-fatigue subscale. Health and Quality of Life Outcomes 2009, 7: 6.

Objectives. To evaluate the effectiveness and safety of adalimumab in treating patients with AS and advanced structural damage. Methods. Patients with active AS [Bath AS Disease Activity Index (BASDAI) 54] received 40 mg of adalimumab every other week plus their standard anti-rheumatic therapies in this 12-week, open-label study. Investigators documented the presence or absence of advanced ankylosis based on previous radiographs. Stages IV (from 50 to

Objective:To evaluate the long-term effectiveness and tolerability of adalimumab in the treatment of psoriatic arthritis (PsA).Methods:Patients with PsA who completed a 24-week, double-blind study of adalimumab versus placebo were eligible to enroll in an open-label extension study and receive adalimumab 40 mg subcutaneously every other week for up to an additional 120 weeks. At the time of this analysis, available efficacy evaluations throughout 2 years of treatment (n = 245) included American College of Rheumatology (ACR) 20%, 50% and 70% improvement scores, measures of joint disease and skin disease, disability and quality of life; modified total Sharp scores (mTSS) were available for 2.75 years of treatment for patients who received adalimumab in the 24-week study.Results:After 24 weeks of double-blind treatment, the mean change in mTSS was −0.2 for the adalimumab group (N = 144) and 1.0 for the placebo group (N = 152; p20% of patients achieving the strict criterion of psoriasis area and severity index 100. The nature and frequency of adverse events during long-term adalimumab treatment were consistent with the safety profile during short-term treatment.Conclusions:The clinical and radiographic efficacy of adalimumab demonstrated during short-term treatment was sustained during long-term treatment. Adalimumab has a favourable risk–benefit profile in patients with PsA.Trial registration number:NCT00195689.

Retraction of Revicki DA, Rentz AM, Luo MP, Wong RL, Doward LC, McKenna SP: Psychometric characteristics of the ankylosing spondylitis quality of life questionnaire, short form 36 health survey, and functional assessment of chronic illness therapy-fatigue subscale. Health and Quality of Life Outcomes 2009, 7: 6.

Introduction Ankylosing spondylitis (AS) is a chronic rheumatic disease associated with spinal inflammation that subsequently leads to progression of structural damage and loss of function. The fully human anti-tumor necrosis factor (anti-TNF) antibody adalimumab reduces the signs and symptoms and improves overall quality of life in patients with active AS; these benefits have been maintained through 2 years of treatment. Our objective was to compare the progression of structural damage in the spine in patients with AS treated with adalimumab for up to 2 years versus patients who had not received TNF antagonist therapy. Methods Radiographs from patients with AS who received adalimumab 40 mg every other week subcutaneously were pooled from the Adalimumab Trial Evaluating Long-Term Efficacy and Safety for Ankylosing Spondylitis (ATLAS) study and a Canadian AS study (M03-606). Radiographic progression from baseline to 2 years in the spine of adalimumab-treated patients from these two studies (adalimumab cohort, n = 307) was compared with an historic anti-TNF-naïve cohort (Outcome in AS International Study [OASIS], n = 169) using the modified Stoke AS Spine Score (mSASSS) method. Results mSASSS results were not significantly different between the adalimumab cohort and the OASIS cohort, based on baseline and 2-year radiographs. Mean changes in mSASSS from baseline to 2 years were 0.9 for the OASIS cohort and 0.8 for the adalimumab cohort (P = 0.771), indicating similar radiographic progression in both groups. When results for patients in the OASIS cohort who met the baseline disease activity criteria for the ATLAS and Canadian studies (OASIS-Eligible cohort) were analyzed, there was no significant difference in mean change in mSASSS from baseline to 2 years between OASIS-Eligible patients and adalimumab-treated patients; the mean changes in mSASSS were 0.9 for the OASIS-Eligible cohort and 0.8 for the adalimumab cohort (P = 0.744). Conclusions Two years of treatment with adalimumab did not slow radiographic progression in patients with AS, as assessed by the mSASSS scoring system, when compared with radiographic data from patients naïve to TNF antagonist therapy. Trial registration Canadian study (M03-606) ClinicalTrials.gov identifier: NCT00195819; ATLAS study (M03-607) ClinicalTrials.gov identifier: NCT00085644.

We analyzed the effects of adalimumab on biomarkers predictive of structural damage in inflammatory arthritis.In a 24-week randomized controlled trial, patients with active ankylosing spondylitis (AS) received adalimumab 40 mg or placebo every other week. Efficacy measures included ASsessment in Ankylosing Spondylitis International Working Group response, Bath AS Disease Activity Index (BASDAI), Total Back Pain, Bath AS Functional Index, C-reactive protein (CRP), and patient's global assessment of disease activity. Urinary type II collagen C-telopeptides (CTX-II), serum type I collagen N-telopeptides (NTX), and serum metalloproteinase-3 (MMP-3) were assessed using ELISA for treatment-group differences at baseline, 12, and 24 weeks. We determined correlations between changes in biomarkers and AS efficacy outcomes.A total of 82 patients (38 adalimumab, 44 placebo) enrolled. At 12 and 24 weeks, significant reductions in urinary CTX-II and MMP-3, but not NTX concentrations, were observed for adalimumab versus placebo (p0.001). Significant baseline correlations were noted between CRP and CTX-II (r=0.71), MMP-3 (r=0.45), and NTX (r=0.37) (por=0.001), as well as between CTX-II and NTX (r=0.49; p0.0001). Changes in CTX-II and MMP-3 at 12 weeks correlated significantly with changes in BASDAI (r=0.31 and 0.33), and CRP (r=0.40 and 0.43) (por=0.005). Change in CTX-II at 12 weeks also correlated significantly with change in MMP-3 (r=0.41; p0.0001).Adalimumab suppresses biomarkers that reflect matrix turnover in patients with AS.

Objective To evaluate the efficacy and safety of the tumor necrosis factor (TNF) antagonist adalimumab in patients with axial spondylarthritis (SpA) without radiographically defined sacroiliitis refractory to conventional treatment. Methods Patients with active axial SpA (n = 46) were randomized to receive placebo or adalimumab at a dosage of 40 mg subcutaneously every other week for 12 weeks, followed by an open-label extension that continued up to week 52. The diagnosis of axial SpA required the presence of 3 of 6 diagnostic criteria, including 2 of the following 3 criteria: inflammatory back pain, HLA–B27 positivity, or acute inflammation of the spine or sacroiliac joints on magnetic resonance imaging, in the absence of radiographic evidence of sacroiliitis. The primary end point was a 40% response according to the improvement criteria of the Assessment of SpondyloArthritis international Society (ASAS40). Results All 46 patients (22 receiving adalimumab and 24 receiving placebo) completed the 12-week trial; 38 patients completed the extension period to week 52. At week 12, an ASAS40 response was achieved by 54.5% of the adalimumab-treated patients, as compared with 12.5% of the placebo-treated patients (P = 0.004). After switching to adalimumab, a similar degree of efficacy was also achieved by the patients who were initially treated with placebo. Efficacy was maintained in all patients until week 52. Young age at study entry and an elevated C-reactive protein concentration were the best predictors of achieving an ASAS40 response. Serious adverse events occurred in 5 patients, none of which was related to the study drug. Conclusion Adalimumab is the first TNF antagonist to demonstrate good clinical efficacy and safety in patients with axial SpA without radiographically defined sacroiliitis.

Enthesitis is a recommended core domain for assessment of ankylosing spondylitis (AS), but no measurement has yet been validated according to Outcome Measures in Rheumatoid Arthritis Clinical Trials (OMERACT) criteria.The purpose of this study was to seek to validate an enthesitis index for patients with AS according to OMERACT criteria.An enthesitis index was validated in two AS patient cohorts: (1) a longitudinal cohort (n = 223) and (2) 22 patients from three Canadian sites participating in a 24-week randomised placebo-controlled trial of adalimumab in AS. Construct validity was evaluated by correlation analysis with the Bath AS Disease Activity Index (BASDAI), the Bath AS Functional Index (BASFI) and quality of life instruments. Reproducibility was assessed by intraclass correlation coefficient (ICC), and responsiveness was assessed by Guyatt's effect size and standardised response mean.The most frequently affected sites were the greater trochanter and supraspinatus insertion ( approximately 20%). Patients with enthesitis had significantly greater scores for the BASDAI, BASFI, patient global, AS-specific quality of life index (ASQOL) and the Short Form 36 (SF-36) General Health Survey (p0.001). The enthesitis score contributed significantly to variance in the BASDAI and BASFI. Interobserver ICCs were 0.96 in the longitudinal cohort and 0.89 and 0.77 in the adalimumab clinical trial cohort (for status and change score, respectively). Significant differences in change scores were evident for all patients after 24 weeks of adalimumab treatment, (p = 0.04), this being more significant when a subset of the most commonly affected entheses were analysed (p = 0.01).AS patients with enthesitis constitute a more severe subset of disease, and the Spondyloarthritis Research Consortium of Canada (SPARCC) Enthesitis Index is feasible and reliable for measurement of this condition. Discrimination requires further study in larger trials.

Objective To evaluate the feasibility/acceptability, reliability, external validity, and discriminant capacity of the Patient Acceptable Symptom State (PASS) concept in patients with active ankylosing spondylitis (AS). Methods PASS was assessed by asking patients to respond yes or no to a single question: “Considering all the different ways your disease is affecting you, if you would stay in this state for the next months, do you consider that your current state is satisfactory?” during the 24-week, randomized (2:1 ratio), double-blind, placebo-controlled portion of an adalimumab study of 315 patients. Results PASS reliability was high (κ = 0.86) in patients with stable disease. Significantly more patients who answered yes to PASS than patients who answered no to PASS were responders based on the ASsessment in Ankylosing Spondylitis (ASAS) International Working Group criteria for 20% improvement (75% who answered yes versus 29% who answered no), the ASAS criteria for 40% improvement (61% versus 16%), the ASAS partial remission criteria (37% versus 3%), and ≥50% improvement on the Bath Ankylosing Spondylitis Disease Activity Index (65% versus 19%; P < 0.001 for all comparisons), demonstrating external validity of the PASS concept. More adalimumab-treated than placebo-treated patients achieved PASS at week 12 (42.3% versus 22.4%; P < 0.001), and more adalimumab-treated than placebo-treated patients achieved sustained PASS through week 20 (34.6% versus 12.3%; P < 0.001), indicating excellent discriminant capacity. Conclusion PASS is a feasible, acceptable, reliable, and valid assessment of satisfactory health state in patients with AS.

Cytoplasmic extracts prepared from T cell lines undergoing antigen-specific, interleukin-2 (IL-2)-dependent proliferation were tested for their ability to induce DNA synthesis in isolated, quiescent nuclei. A tetanus toxoid (TET)-specific T cell line, established from peripheral blood of a normal human volunteer, was stimulated in the presence of relevant antigen and 1 unit/ml IL-2. Cytoplasmic extracts prepared from these cells were capable of inducing DNA synthesis in isolated, quiescent nuclei. The ability of cytoplasmic extracts to induce DNA synthesis in isolated, quiescent nuclei. The ability of cytoplasmic extracts to induce DNA synthesis in isolated nuclei correlated positively with the degree of proliferation induced in these cells. In contrast, incubation of this T cell line in the absence of antigen failed to induce proliferation and cytoplasmic extracts prepared from these cells induced little to no DNA synthesis in isolated, quiescent nuclei. The factor present in the cytoplasm of T cells stimulated with relevant antigen in the presence of IL-2 is similar, if not identical, to a factor which we have previously demonstrated in cytoplasmic extracts prepared from transformed lymphoblastoid cell lines and from mitogenically stimulated normal human peripheral blood mononuclear cells. This factor, which we have called activator of DNA replication (ADR) is a heat-labile protein, and is inactivated by treatment with protease inhibitors, including aprotinin. The ability of cytoplasmic extracts from T cells undergoing antigen-specific, IL-2-dependent proliferation to induce DNA synthesis in isolated, quiescent nuclei was markedly inhibited in the presence of aprotinin, providing strong evidence that a cytoplasmic activator of DNA replication, ADR, is involved in the signal transduction process for antigen-specific, IL-2-dependent T cell proliferation. ADR may represent a common intracellular mediator of DNA synthesis in activated and transformed lymphocytes.

Background The Ankylosing Spondylitis Quality of Life (ASQOL) questionnaire is a unidimensional, disease-specific measure developed in the UK and the Netherlands. This study describes its adaptation into other languages. Methods The UK English ASQOL was translated into US English; Canadian French and English; French; German; Italian; Spanish; and Swedish (dual-panel methods). Cognitive debriefing interviews were conducted with AS patients. Psychometric/scaling properties were assessed using data from two Phase III studies of adalimumab. Baseline and Week-2 data were used to assess test-retest reliability. Validity was determined by correlation of ASQOL with SF-36 and BASFI and by discriminative ability of ASQOL based on disease severity. Item response theory (Rasch model) was used to test ASQOL's scaling properties. Results Cognitive debriefing showed the new ASQOL versions to be clear, relevant and comprehensive. Sample sizes varied, but were sufficient for: psychometric/scaling assessment for US English and Canadian English; psychometric but not scaling analyses for German; and preliminary evidence of these properties for the remaining languages. Test-retest reliability and Cronbach's alpha coefficients were high: US English (0.85, 0.85), Canadian English (0.87, 0.86), and German (0.77, 0.79). Correlations of ASQOL with SF-36 and BASFI for US English, Canadian English, and German measures were moderate, but ASQOL discriminated between patients based on perceived disease severities (p < 0.01). Results were comparable for the other languages. US English and Canadian English exhibited fit to the Rasch model (non-significant p-values: 0.54, 0.68), confirming unidimensionality. Conclusion The ASQOL was successfully translated into all eight languages. Psychometric properties were excellent for US English, Canadian English, and German, and extremely promising for the other languages.

Giant cell arteritis (GCA) is the most common primary systemic vasculitis in older adults. Patients usually are older than 50 years and have an erythrocyte sedimentation rate (Westergren) greater than 50 mm/h. Headache is a common symptom, occurring in approximately 90% of patients. However, the most serious complications of GCA, blindness and stroke, may occur in the absence of headache. Nonspecific constitutional symptoms such as weight loss, fever, and malaise may dominate the clinical presentation. Currently, corticosteroids are the mainstay of therapy for GCA. Treatment is initiated at 0.7 to 1 mg/kg mg of prednisone (or equivalent) per day as soon as the diagnosis is suspected. The medication is tapered based on laboratory parameters and symptoms. Relapse is common, especially during the first year of therapy. Side effects from steroids in the elderly are common and often serious. Steroid resistance (manifesting as continued high dose requirements after 3 to 6 months) may complicate therapy and place patients at increased risk of side effects. Methotrexate and azathioprine have been used as steroid-sparing agents based on anecdotal evidence. More recently, evidence is emerging that antitumor necrosis factor-alpha agents may be efficacious and act as steroid-sparing agents. New-onset headache or worsening headache in a patient older than 50 years should raise the possibility of GCA and appropriate therapeutic and diagnostic measures should be begun promptly.

The superconducting magnets in Fusion Reactors are subjected to pulsed, nuclear, and resistive heating. The thermo-hydraulic response of the helium forced-flow cooled conductors to the various heat sources is critical to magnet design and performance. Recently developed computer codes allow accurate modeling of conductor response and have been used as an aid to design of the toroidal field (TF) magnets for the Tokamak Physics eXperiment (TPX). We present results of design studies that determine the trade-off between double-and single-pancake helium flow configurations, the minimum-temperature margin, and the stability against rapid heat input. The results guide the choice and design of the liquid helium refrigerator.

Background We evaluated the psychometric characteristics of the Short Form 36 (SF-36) Health Survey and the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue subscale in patients with ankylosing spondylitis (AS). Methods We analyzed clinical and patient-reported outcome (PRO) data collected during 12-week, double-blind, placebo-controlled periods of two randomized controlled trials comparing adalimumab and placebo for the treatment of active AS. The Bath Ankylosing Spondylitis Disease Activity Index, Bath Ankylosing Spondylitis Functional Index, and other clinical measures were collected during the clinical trial. We evaluated internal consistency/reliability, construct validity, and responsiveness to change for the SF-36 and FACIT-Fatigue. Results The SF-36 (Cronbach alpha, 0.74-0.92) and FACIT-Fatigue (Cronbach alpha, 0.82-0.86) both had good internal consistency/reliability. At baseline, SF-36 and FACIT-Fatigue scores correlated significantly with Ankylosing Spondylitis Quality of Life scores (r = -0.36 to -0.66 and r = -0.70, respectively; all p < 0.0001). SF-36 scores varied by indicators of clinical severity, with greater impairment observed for more severe degrees of clinical activity (all p < 0.0001). FACIT-Fatigue scores correlated significantly with SF-36 scores (r = 0.42 to 0.74; all p < 0.0001) and varied by clinical severity (p < 0.05 to p < 0.0001). Conclusions The SF-36 is a reliable, valid, and responsive measure of health-related quality of life and the FACIT-Fatigue is a brief and psychometrically sound measure of the effects of fatigue on patients with AS. These PROs may be useful in evaluating effectiveness of new treatments for AS. Trial Registration ClinicalTrials.gov: NCT00085644 and NCT00195819

This article describes the effects of cyclosporin A (CsA) on the immunopathological mechanisms operative in psoriasis, a human skin disease. The main focus is the effect of CsA on keratinocytes, T cells and antigen-presenting cells, the key players in lesional psoriatic skin. The effect of CsA on other cells, such as neutrophils and endothelial cells, which are important in the maintenance of psoriasis, are also discussed.

Introduction The purpose of this study was to investigate the effectiveness of adalimumab in enthesitis and peripheral arthritis in patients with ankylosing spondylitis (AS). Methods Adults with active AS (Bath ankylosing spondylitis disease activity index [BASDAI] ≥ 4) received adalimumab 40 mg every other week with standard antirheumatic therapies in a 12-week, open-label study. Effectiveness in enthesitis was assessed using the Maastricht ankylosing spondylitis enthesitis score (MASES, 0-13) and by examining the plantar fascia in patients with enthesitis (≥ 1 inflamed enthesis) at baseline; effectiveness in peripheral arthritis was evaluated using tender and swollen joint counts (TJC, 0-46; SJC, 0-44) in patients with peripheral arthritis (≥ 1 swollen joint) at baseline. Overall effectiveness measures included Assessment of SpondyloArthritis International Society 20% response (ASAS20). Results Of 1,250 patients enrolled, 686 had enthesitis and 281 had peripheral arthritis. In 667 patients with MASES ≥ 1 at baseline, the median MASES was reduced from 5 at baseline to 1 at week 12. At week 12, inflammation of the plantar fascia ceased in 122 of 173 patients with inflammation at baseline. The median TJC in 281 patients with SJC ≥ 1 at baseline was reduced from 5 at baseline to 1 at week 12; the median SJC improved from 2 to 0. ASAS20 responses were achieved by 70.5% of 457 patients with no enthesitis and no arthritis; 71.0% of 512 patients with only enthesitis; 68.0% of 107 patients with only arthritis; and 66.7% of 174 patients with both. Conclusions Treatment with adalimumab improved enthesitis and peripheral arthritis in patients with active AS. Trial registration ClinicalTrials.gov NCT00478660.

Some T cells produce membrane-associated or soluble molecules which bind nominal antigen specifically (TABM) and effect immunoregulation or events similar to cell-mediated hypersensitivity. We have used polyclonal antisera raised against an azobenzene arsonate (ABA)-specific TABM secreted by an ABA-specific T cell hybrid or against TNP-specific polypeptides produced by immunoregulatory T cells to identify the expression of soluble (secreted) or membrane-associated TABM. Ascites fluid or culture medium containing a T cell hybrid or T cell lines, respectively, contain TABM recognized only by an antiserum specific for the secreted T cell hybrid (ABA-specific) derived TABM. Conversely, an antiserum that recognized the TNP-specific polypeptides detected cell-membrane associated TABM but did not bind TABM secreted by the T cell hybrid or cell lines.

Unidirectional diffusion and flow of O 2 COCO 2 gas mixtures undergoing heterogeneous chemical reaction within a porous CuO-on-alumina plug flow reactor are investigated. Experimental data for spatial distributions of pressure, temperature and composition and for feed-end species fluxes exhibit reasonable agreement with theoretical results drawn from appropriate extensions of the dusty gas model. Calculations for the individual contributions of bulk, Knudsen and thermal diffusion and thermal transpiration to the total species fluxes indicate that bulk diffusion is the major component under purely diffusive conditions; however, Knudsen diffusion assumes greater significance when forced flow is introduced. The theory indicates that the contributions of thermal diffusion and thermal transpiration to the total species fluxes become more significant as the species molecular weights become more disparate. The effects are demonstrated by means of companion calculations for the O 2 H 2 H 2 O system.

Cytoplasmic extracts from spontaneously proliferating and mitogen-activated lymphoid cells contain a protein factor called ADR (activator of DNA replication) that induces DNA synthesis in isolated quiescent nuclei. ADR-containing preparations have proteolytic activity, as indicated by their ability to degrade fibrin in a plasminogen-independent and plasminogen-dependent manner. In addition, aprotinin, a nonspecific protease inhibitor, abrogates ADR-induced DNA synthesis in a dose-dependent fashion. Preincubation studies demonstrated that the effect of aprotinin is not due to its suppressive effects on the nuclei themselves. Other protease inhibitors such as leupeptin, p-aminobenzamidine, and N-alpha-tosyllysine chloromethyl ketone are also inhibitory, but soybean trypsin inhibitor is without effect. ADR activity can be removed from active extracts by adsorption with aprotinin-conjugated agarose beads and can be recovered by elution with an acetate buffer (pH 5). These findings are consistent with the interpretation that the initiation of DNA synthesis in resting nuclei may be protease dependent and, further, that the cytoplasmic stimulatory factor we have called ADR may be a protease itself.

An elevated erythrocyte sedimentation rate is regarded as a hallmark of temporal arteritis. Thirty-five cases of biopsy-proved temporal arteritis without an elevated erythrocyte sedimentation rate are identified, and a 36th case is described. All patients had age-adjusted normal Westergren sedimentation rates, 16 with sedimentation rates of 20 mm per hour or less and 20 with sedimentation rates of 21 to 40 mm per hour. Twenty-two patients had sufficient clinical information for analysis and comparison with reported series of patients with biopsy-proved temporal arteritis with an elevated Westergren sedimentation rate. Headache (41 percent), temporal artery abnormalities (41 percent), and visual symptoms (36 percent) were the most common manifestations in patients without an elevated sedimentation rate. Headache (41 percent versus 75 percent, p less than 0.05) and jaw claudication (9 percent versus 43 percent, p less than 0.025) were found less often in the patients without an elevated sedimentation rate. History and physical examination are essential in the diagnosis of temporal arteritis with a normal Westergren sedimentation rate.

The association between dermatomyositis and Hodgkin's disease has been infrequently reported. A patient with advanced Hodgkin's disease and dermatomyositis is presented and an additional 11 cases obtained from the world literature are reviewed. The clinical features, response to treatment, and outcome of these diseases are discussed.

The dusty gas model is used to establish the effects of temperature and pressure gradients on catalyst pellet effectiveness factors for reaction systems in which species molecular weights and transport coefficients are indistinguishable and Σνi = 0. For this class of reactions, the total molar flux of species i is shown to be expressible simply as Ni = −cD ∇ϰi in terms of the molar concentration, the Bosanguet diffusivity, and the mole fraction gradient. The effects of temperature and pressure gradients are reflected only in variations in molar concentration and diffusivity. Furthermore, the temperature-pressure relationship is shown to be given by the thermal transpiration equation for a pure gas. Typical numerical results are reported for first order reactions in spherical pellets under diffusive conditions ranging from the Knudsen through the bulk diffusion regimes. The variation in diffusion regime is shown to be controlled by an additional parameter α, the Knudsen to bulk diffusion ratio. Comparisons are made with the classical Weisz-Hicks nonisothermal pellet solutions based on Ni = −Deff∇ci. For highly exothermic reactions, effectiveness factors are 18% lower in the Knudsen regime and 30% higher in the bulk diffusion regime than are the Weisz—Hicks values. For highly endothermic reactions with a significant diffusion limitation, the effectiveness factors are 30% lower than the Weisz—Hicks values. The classical Damkoehler relationship for pellet temperature rise is shown to apply in the Knudsen regime, with the maximum dimensionless center temperature given by (1 + β), where β is the heat of reaction parameter. This temperature is accompanied by a maximum dimensionless center pressure of (1 + β)12. In the bulk diffusion regime, the maximum center temperature is shown to be increased by the additional term β2/4. This additional temperature rise accounts for the 42% increased bulk diffusion effectiveness for highly exothermic reactions.

Proliferating cell nuclear antigen (PCNA) is expressed in the nuclei of proliferating cells, but is not detected in resting cells. The kinetics of PCNA expression suggest that it is associated with a phase preceding active DNA synthesis. DNA synthesis is under cytoplasmic control, and there is a cytoplasmic protein, ADR (activator of DNA replication), that induces DNA synthesis in isolated quiescent nuclei. We now report that a human antibody preparation monospecific for PCNA, but not two monoclonal antibodies directed against different epitopes on PCNA, can inhibit the ability of ADR to induce DNA synthesis in isolated quiescent nuclei. This effect is not due to inhibition of DNA polymerase alpha activity. Thus, the anti-PCNA antibody exerts its effect either by directly influencing the initial interaction of ADR with the nucleus, or by inhibiting subsequent synthetic events.

Granulocyte-macrophage colony-stimulating factor (GmCSF) is a lymphokine secreted by class II major histocompatibility complex (MHC)-restricted T cells after lectin or antigen stimulation. To investigate the relationship between interleukin-2 (IL-2) and GmCSF production, we utilized long-term cultures of porcine myelin basic protein (PMBP)-specific T helper cell clones that were maintained with IL-2 in the absence of antigen or irradiated antigen-presenting cells (APC). We have found that supernatants of these T cell clones contained GmCSF activity after IL-2 stimulation. Inhibition of cell proliferation by irradiation failed to stop GmCSF production. When these clones were stimulated with PMBP and irradiated APC in the presence of anti-IL-2 receptor antibody, the T cell supernatants still contained GmCSF activity. These results indicate that (1) GmCSF production by T helper clones after IL-2 stimulation is independent of cell proliferation and (2) antigen/MHC-stimulated GmCSF production by T cell clones can occur by an IL-2-independent pathway.

The specificity of the preliminary and the revised American Rheumatism Association criteria for the classification of systemic lupus erythematosus (SLE) was tested in 207 of our patients with other rheumatic diseases which were considered to be important in the differential diagnosis of SLE. Using the preliminary criteria, the data revealed that 5 patients were falsely classified as having SLE (2 with scleroderma, 2 with Raynaud's disease, and 1 with systemic necrotizing vasculitis), whereas using the revised criteria, only 2 patients (1 with scleroderma and 1 with systemic necrotizing vasculitis) were falsely classified. The calculated specificity was 99% for the revised criteria and 98% for the preliminary criteria. Thus, the data revealed that the specificity of the revised criteria is high and comparable with that of the preliminary criteria when applied to a group of patients with related rheumatic diseases.

Introduction We evaluated the three-year impact of adalimumab on patient-reported physical function and health-related quality-of-life (HRQOL) outcomes in patients with active ankylosing spondylitis (AS). Methods The Adalimumab Trial Evaluating Long-Term Efficacy and Safety in AS (ATLAS) is an ongoing five-year study that included an initial 24-week, randomized, placebo-controlled, double-blind period, followed by open-label extension treatment with adalimumab. Clinical and HRQOL data collected for up to three years from ATLAS were used for these analyses. Patients were randomized to receive adalimumab 40 mg or placebo by subcutaneous injection every other week. Physical function was assessed by the Bath AS Functional Index (BASFI), as well as by the Short Form 36 (SF-36) Health Survey Physical Component Summary (PCS) and Physical Function subscale scores. HRQOL was assessed using the AS Quality of Life (ASQOL) questionnaire. Disease activity was assessed by the Bath AS Disease Activity Index (BASDAI). Results Of 315 patients enrolled in ATLAS, 288 (91%) participated in an open-label adalimumab treatment extension and 82% provided three-year outcome data. During the 24-week double-blind phase, adalimumab-treated patients experienced significant improvement compared with placebo-treated patients in the BASDAI (P < 0.001), BASFI (P < 0.001), ASQOL (P < 0.001), and both the SF-36 PCS (P < 0.001) and Physical Function subscale (P < 0.001) scores, but not the SF-36 Mental Component Summary score (P = 0.181) and Mental Health subscale scores (P = 0.551). Mean changes from baseline through three years of adalimumab treatment were statistically significant for the BASDAI (change score: -3.9, P < 0.001), BASFI (change score: -29.6, P < 0.001), SF-36 PCS (change score: 11.6, P < 0.001), and Physical Function (change score: 23.3, P < 0.001). Comparable results were observed for the other SF-36 scores and for the ASQOL (all P < 0.001). Conclusions Adalimumab significantly improved disease activity, patient-reported physical function, and HRQOL. These benefits were maintained over three years of treatment in patients with AS. Trial registration ClinicalTrials.gov NCT00085644.