S100 proteins as potential predictive biomarkers of abatacept response in polyarticular juvenile idiopathic arthritis.

BACKGROUND: Juvenile idiopathic arthritis (JIA) comprises a heterogeneous group of conditions that can cause marked disability and diminished quality of life. Data on predictors of clinical response are insufficient to guide selection of the appropriate biologic agent for individual patients. This study aimed to investigate the propensity of S100A8/9 and S100A12 as predictive biomarkers of abatacept response in polyarticular-course juvenile idiopathic arthritis (pJIA). METHODS: Data from a phase 3 trial (NCT01844518) of subcutaneous abatacept in patients with active pJIA (n = 219) were used in this exploratory analysis. Association between biomarker levels at baseline and improvements in JIA-American College of Rheumatology (ACR) criteria responses or baseline disease activity (measured by Juvenile Arthritis Disease Activity Score in 27 joints using C-reactive protein [JADAS27-CRP]) were assessed. Biomarker level changes from baseline to month 4 were assessed for disease outcome prediction up to 21 months. RESULTS: At baseline, 158 patients had available biomarker samples. Lower baseline S100A8/9 levels (≤ 3295 ng/mL) were associated with greater odds of achieving JIA-ACR90 (odds ratio [OR]: 2.54 [95% confidence interval (CI): 1.25-5.18]), JIA-ACR100 (OR: 3.72 [95% CI: 1.48-9.37]), JIA-ACR inactive disease (ID; OR: 4.25 [95% CI: 2.03-8.92]), JADAS27-CRP ID (OR: 2.34 [95% CI: 1.02-5.39]) at month 4, and JIA-ACR ID (OR: 3.01 [95% CI: 1.57-5.78]) at month 16. Lower baseline S100A12 levels (≤ 176 ng/mL) were associated with greater odds of achieving JIA-ACR90 (OR: 2.52 [95% CI: 1.23-5.13]), JIA-ACR100 (OR: 3.68 [95% CI: 1.46-9.28]), JIA-ACR ID (OR: 3.66 [95% CI: 1.76-7.61]), JIA-ACR90 (OR: 2.03 [95% CI: 1.07-3.87]), JIA-ACR100 (OR: 2.14 [95% CI: 1.10-4.17]), and JIA-ACR ID (OR: 4.22 [95% CI: 2.15-8.29]) at month 16. From baseline to month 4, decreases in S100A8/9 and S100A12 generally exceeded 50% among JIA-ACR90/100/ID responders. CONCLUSION: Lower baseline levels of S100A8/9 and S100A12 proteins predicted better response to abatacept treatment than higher levels and may serve as early predictive biomarkers in pJIA. Decreases in these biomarker levels may also predict longer-term response to abatacept in pJIA.

Toward Accelerated Authorization and Access to New Medicines for Juvenile Idiopathic Arthritis.

A meeting was organized to bring together multiple stakeholders involved in the testing and authorization of new medications for juvenile idiopathic arthritis (JIA) to discuss current issues surrounding clinical trials and access to new medications for children and adolescents with JIA. The Childhood Arthritis and Rheumatology Research Alliance invited representatives of regulatory agencies (Food and Drug Administration and European Medicines Agency), and major pharmaceutical companies with JIA-approved products or products in development, patient and parent representatives, representatives of an advocacy organization (Arthritis Foundation), and pediatric rheumatology clinicians/investigators to a 1-day meeting in April 2018. The participants engaged in discussion regarding issues in clinical trials. As the pharmacologic options to treat inflammatory arthritis rapidly expand, registration trial designs to test medications in JIA patients must adapt. Many methodologies successfully used in the recent past are no longer feasible. The pool of patients meeting entry criteria who are willing to participate is shrinking while the number of medications to be tested is growing. Suggested solutions included proposing innovative clinical trial methods to regulatory agencies, as well as open discussions among stakeholders. Ensuring that new medications are authorized in a timely manner to meet the needs of JIA patients worldwide is critical. Approaches should include open dialog between regulatory agencies, pharmaceutical companies, and other stakeholders to develop and implement novel study designs, including patient and clinician perspectives to define meaningful trial outcomes, and changing existing study plans.

Psychometric characteristics of the short form 36 health survey and functional assessment of chronic illness Therapy-Fatigue subscale for patients with ankylosing spondylitis.

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.

Is the Health Utilities Index 3 valid for patients with ankylosing spondylitis?

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.

Thresholds of patient-reported outcomes that define the patient acceptable symptom state in ankylosing spondylitis vary over time and by treatment and patient characteristics.

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.

Clinical manifestations and responsiveness to adalimumab are similar in patients with ankylosing spondylitis with and without concomitant psoriasis.

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.

Validity, reliability and responsiveness of the Work Productivity and Activity Impairment Questionnaire in ankylosing spondylitis.

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.

Impact of age, sex, physical function, health-related quality of life, and treatment with adalimumab on work status and work productivity of patients with ankylosing spondylitis.

OBJECTIVE: To determine factors associated with work in patients with ankylosing spondylitis (AS). METHODS: Three hundred fifteen patients with AS were enrolled in a 24-week, randomized controlled study of adalimumab with a longterm, open-label, adalimumab extension phase. Patient-reported outcome (PRO) measures included the Medical Outcome Study Short Form 36 Health Survey (SF-36), AS Quality of Life Questionnaire (ASQOL), Health Utilities Index Mark 3 (HUI-3), and Work Productivity and Activity Impairment-Specific Health Problem Questionnaire (WPAI-SHP). Multivariate logistic regression was used to analyze differences between working and nonworking patients. The relationships between PRO and WPAI-SHP scores were assessed using Pearson correlation coefficients. Multivariate modeling was applied to determine factors associated with productivity while at work. WPAI-SHP was assessed through 3 years of adalimumab exposure. RESULTS: Younger age (p = 0.002) and male sex (p < 0.001) were significantly and independently associated with working patients with AS. The SF-36 Physical Component Summary score (p < 0.001), ASQOL score (p < 0.001), HUI-3 scores (p < 0.001), and both patient's global assessment of disease activity (p < 0.001) and nocturnal pain (p < 0.001) scores were independently associated with working status. Work absenteeism due to AS was weakly correlated with all PRO scores. WPAI-SHP components of work presenteeism (lack of productivity at work), activity impairment, and overall work productivity loss due to AS were moderately correlated with quality of life as measured by the ASQOL, the SF-36 Physical Component Summary score, and the SF-36 Bodily Pain domain. Linear multivariate analyses indicated that work presenteeism was significantly associated with pain, functioning, and disease activity. Longterm adalimumab treatment was associated with sustained improvements in WPAI-SHP scores. CONCLUSIONS: Quality of life and the physical consequences associated with AS have a direct relationship with a patient's ability to work. Adalimumab sustains improvements in work outcomes in patients with AS.

Physical function, disease activity, and health-related quality-of-life outcomes after 3 years of adalimumab treatment in patients with ankylosing spondylitis.

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.

Adalimumab is effective and well tolerated in treating patients with ankylosing spondylitis who have advanced spinal fusion.

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) > or =4] 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 <80% involvement in more than two spinal segments) and V (> or =80% spinal involvement, including bamboo spine) disease were considered as advanced AS. Effectiveness parameters included Assessment of SpondyloArthritis international Society (ASAS) criteria, BASDAI response and achievement of optimal sleep. Adverse events were reported throughout therapy and at a 70-day follow-up. RESULTS: The analysis population included 897 patients whose AS was not advanced (i.e. Stages I-III), 31 with Stage IV disease and 41 with Stage V disease. At Week 12, ASAS40/BASDAI 50 responses were achieved by 54%/57% of patients with AS Stages I-III, 48%/58% with AS Stage IV and 54%/66% with AS Stage V, respectively. ASAS partial remission rates were 30, 26 and 7% for patients with Stages I-III, IV and V disease, respectively. Serious infections occurred in three (<1%) patients with AS Stages I-III and in one (1%) patient with AS Stage V. CONCLUSIONS: After 12 weeks of adalimumab therapy, patients with advanced but active AS, including those with structural damage of > or =80% of the vertebrae, achieved improvements in signs and symptoms similar to those attained by patients whose AS was not advanced.

Beneficial effects of adalimumab on biomarkers reflecting structural damage in patients with ankylosing spondylitis.

OBJECTIVE: We analyzed the effects of adalimumab on biomarkers predictive of structural damage in inflammatory arthritis. METHODS: 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. RESULTS: 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 (p<0.001). Significant baseline correlations were noted between CRP and CTX-II (r=0.71), MMP-3 (r=0.45), and NTX (r=0.37) (p

Efficacy of adalimumab in the treatment of axial spondylarthritis without radiographically defined sacroiliitis: results of a twelve-week randomized, double-blind, placebo-controlled trial followed by an open-label extension up to week fifty-two.

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.

Adalimumab reduces pain, fatigue, and stiffness in patients with ankylosing spondylitis: results from the adalimumab trial evaluating long-term safety and efficacy for ankylosing spondylitis (ATLAS).

OBJECTIVE: To evaluate the effect of adalimumab on pain, fatigue, and stiffness in patients with active ankylosing spondylitis (AS). METHODS: The Adalimumab Trial Evaluating Long-Term Safety and Efficacy for Ankylosing Spondylitis (ATLAS) was an ongoing 5-year study that included an initial 24-week, randomized, placebo-controlled, double-blind period. Patients were randomized to adalimumab 40 mg or placebo by subcutaneous injection every other week. Pain was assessed by the bodily pain domain scores of the Medical Outcomes Study Short Form-36 Health Survey (SF-36) and also by total back pain and nocturnal pain using visual analog scales. Fatigue was measured by the SF-36 vitality domain and question 1 of the Bath AS Disease Activity Index (BASDAI). Morning stiffness was measured by the mean of BASDAI questions 5 and 6. RESULTS: Of 315 patients enrolled, 208 received adalimumab 40 mg and 107 received placebo. At Week 12, adalimumab-treated patients experienced significant improvement compared with placebo-treated patients in the SF-36 bodily pain score (p < 0.001), total back pain score (p < 0.001), nocturnal pain score (p < 0.001), fatigue (p < 0.01), and morning stiffness (p < 0.001). Pain, fatigue, and morning stiffness were significantly correlated (p < 0.001) with baseline values of patient-reported health-related quality of life (HRQOL), and physical function, and with improvements in these values at Week 12 by regression analysis. Treatment effects occurred rapidly (within 2 wks) and were maintained through 24 weeks of treatment. CONCLUSION: Adalimumab significantly improved symptoms of pain, fatigue, and stiffness in patients with AS. Improved symptoms were associated with improved physical function and HRQOL.

Evaluation of the patient acceptable symptom state as an outcome measure in patients with ankylosing spondylitis: data from a randomized controlled trial.

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 (kappa = 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 > or =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.

Adalimumab significantly reduces both spinal and sacroiliac joint inflammation in patients with ankylosing spondylitis: a multicenter, randomized, double-blind, placebo-controlled study.

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.

Health-related quality of life outcomes in patients with active ankylosing spondylitis treated with adalimumab: results from a randomized controlled study.

OBJECTIVE: To evaluate the impact of adalimumab on health-related quality of life (HRQOL) in patients with active ankylosing spondylitis (AS). METHODS: Patients >or=18 years enrolled in the Adalimumab Trial Evaluating Long-Term Efficacy and Safety in Ankylosing Spondylitis, a randomized controlled study, were randomly assigned to receive either adalimumab 40 mg subcutaneously or placebo every other week for 24 weeks. ASsessment of Ankylosing Spondylitis (ASAS) International Working Group criteria were used to evaluate clinical efficacy. HRQOL outcomes were assessed using the Short Form 36 (SF-36) Health Survey and Ankylosing Spondylitis Quality of Life (ASQoL) Questionnaire. RESULTS: A total of 315 patients enrolled (208 in the adalimumab group and 107 in the placebo group). Patients in the adalimumab group showed significant improvements in SF-36 Physical Component Summary (PCS) and ASQoL scores versus placebo at weeks 12 and 24 (P < 0.001). The observed differences between adalimumab and placebo patients exceeded the a priori minimum important difference (MID) at the group level, and significantly more adalimumab-treated patients achieved improvements greater than the MID on the patient level. These data suggest the HRQOL improvements were clinically meaningful. No differences were observed in SF-36 Mental Component Summary (MCS) scores. Significant differences favoring adalimumab were observed for SF-36 domains physical function, bodily pain, role-physical, general health, vitality, social function, and role-emotional. There was significant association between HRQOL improvements (measured by SF-36 PCS and MCS, and ASQoL scores) and ASAS clinical responses (P < 0.001). CONCLUSION: Adalimumab significantly improved physical health status and overall HRQOL through 24 weeks in patients with active AS.

Translation and validation of non-English versions of the Ankylosing Spondylitis Quality of Life (ASQOL) questionnaire.

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.

Efficacy and safety of adalimumab in patients with ankylosing spondylitis: results of a multicenter, randomized, double-blind, placebo-controlled trial.

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.

Headache Caused by Giant Cell Arteritis.

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.