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.

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.

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.

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.