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Objective: The Psoriatic Arthritis Long-term Assessment of Clinical Efficacy (PALACE) clinical trial programme findings demonstrated that apremilast, an oral phosphodiesterase 4 inhibitor, is effective for treating psoriatic arthritis (PsA). Enthesitis and dactylitis are difficult-to-treat features of PsA leading to disability and affecting quality of life. PALACE 1, 2 and 3 data were pooled to assess the efficacy of apremilast on enthesitis and dactylitis outcomes in patients with these conditions at baseline., Methods: Patients with enthesitis (n=945) or dactylitis (n=633) at baseline were analysed after receiving double-blind treatment with placebo, apremilast 30 mg two times per day or apremilast 20 mg two times per day up to 52 weeks and continuing up to 5 years. Data were analysed through 156 weeks. Enthesitis was evaluated by Maastricht Ankylosing Spondylitis Enthesitis Score (MASES) and dactylitis via dactylitis count., Results: At week 24, patients receiving apremilast 30 mg two times per day demonstrated a significantly greater mean change in enthesitis (-1.3 vs -0.9; p<0.05) and dactylitis (-1.8 vs -1.3; p<0.01) vs placebo. Patients in the 30 mg dose group showed significantly greater mean (-23.6% vs -7.0%; p<0.05) and median (-50.0% vs -21.1%; p<0.05) per cent changes in MASES; mean and median per cent changes in dactylitis count were numerically, but not significantly, different for either apremilast dose in patients with dactylitis. In the patient population remaining on apremilast, observed mean and median improvements in both conditions were sustained through 156 weeks., Conclusion: Apremilast is effective for the treatment of active PsA, including improvements in enthesitis and dactylitis up to 3 years., Trial Registration Numbers: NCT01172938, NCT01212757 and NCT01212770., Competing Interests: Competing interests: DDG has received grant/research support and has served as a consultant to AbbVie, Amgen, Bristol-Myers Squibb, Celgene Corporation, Janssen, Novartis, Pfizer and UCB. AK has received grant/research support from Abbott, Amgen, AstraZeneca, BMS, Celgene Corporation, Centocor-Janssen, Pfizer, Roche and UCB. JJG-R has received grant/research support from Roche and Schering-Plough. JW has received research support from and served as a consultant for Abbott, Bristol-Myers Squibb, Merck Sharp & Dohme, Pfizer and UCB. MC has received research support from and served as a consultant for Actelion, Bristol-Myers Squibb and Sanofi-Aventis. GS has received research support from and served as a consultant for Abbott, Celgene Corporation, Roche and UCB. EL has received research support from and served on a speakers bureau for Amgen, Eli Lilly, Novartis and Servier. ND, BG and LT are employees of Celgene Corporation. CJE has received research support from Celgene Corporation, Pfizer, Roche and Samsung and has served on a speakers bureau for Abbott, GlaxoSmithKline, Pfizer and Roche. CAB has received research support from Amgen, Bristol-Myers Squibb, Incyte, Eli Lilly, Merck and Pfizer. PJM has received research support from and served as a consultant for Abbott, Amgen, Biogen Idec, Bristol-Myers Squibb, Celgene Corporation, Eli Lilly, Genentech, Janssen, Novartis, Pfizer, Roche and UCB and has served on a speakers bureau for Abbott, Amgen, Biogen Idec, Bristol-Myers Squibb, Eli Lilly, Genentech, Janssen, Pfizer and UCB.

Objective: To evaluate apremilast treatment in patients with active psoriatic arthritis, including current skin involvement, despite prior therapy with conventional disease-modifying antirheumatic drugs and/or biologic agents., Methods: Patients (N=505) were randomised (1:1:1) to placebo, apremilast 20 mg twice daily, or apremilast 30 mg twice daily. Rescue therapy with apremilast was designated at week 16 for placebo patients not achieving 20% improvement in swollen and tender joint counts. At week 24, the remaining placebo patients were then randomised to apremilast 20 mg twice daily or 30 mg twice daily. The efficacy and safety of apremilast were assessed over 52 weeks., Results: At week 16, significantly more patients receiving apremilast 20 mg twice daily (28%) and 30 mg twice daily (41%) achieved 20% improvement in American College of Rheumatology response criteria versus placebo (18%; p=0.0295 and p<0.0001, respectively), and mean decrease in the Health Assessment Questionnaire-Disability Index score was significantly greater with apremilast 30 mg twice daily (-0.20) versus placebo (-0.07; p=0.0073). In patients with baseline psoriasis body surface area involvement ≥3%, significantly more apremilast 30 mg twice daily patients achieved 50% reduction from baseline Psoriasis Area and Severity Index score (41%) versus placebo (24%; p=0.0098) at week 16. At week 52, observed improvements in these measures demonstrated sustained response with continued apremilast treatment. Most adverse events were mild to moderate in severity; the most common were diarrhoea, nausea, headache and upper respiratory tract infection., Conclusions: Apremilast demonstrated clinically meaningful improvements in psoriatic arthritis and psoriasis at week 16; sustained improvements were seen with continued treatment through 52 weeks. Apremilast was generally well tolerated and demonstrated an acceptable safety profile., Trial Registration Number: NCT01212770., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Objective: To evaluate the long-term effectiveness and safety of 10 years of adalimumab (ADA) treatment in DMARD-refractory RA patients and to analyse efficacy based on RF status and baseline disease duration., Methods: DE020 was a multicentre, phase 3, open-label continuation study. Adult RA patients who received s.c. ADA (40 mg every other week or monthly) in one of four early assessment studies could receive ADA for ≤10 years in DE020. Assessments included the 28-joint DAS with CRP (DAS28-CRP), Simplified Disease Activity Index (SDAI), HAQ Disability Index (HAQ-DI) and safety as events per 100 patient-years., Results: Of 846 enrolled patients, mean age at baseline was 55.6 years, 78.1% were women, mean disease duration was 11.7 years and 27.0% were RF(-). Among 286 (33.8%) patients who completed 10 years of ADA, 168/236 (71.2%) achieved DAS28-CRP ≤3.2, 101/238 (42.4%) achieved HAQ-DI <0.5 and 90/241 (37.3%) achieved DAS28-CRP ≤3.2 plus HAQ-DI <0.5. DAS28-CRP- or SDAI-based remission was observed in 135/236 (57.2%) and 70/236 (29.7%) patients, respectively. Effectiveness outcomes were similar regardless of RF status. Higher proportions of patients with shorter vs longer baseline disease duration (≤2 vs >2 years) achieved HAQ-DI <0.5 (60.6% vs 39.5%; P = 0.023) and DAS28-CRP ≤3.2 plus HAQ-DI <0.5 (58.1% vs 32.5%; P = 0.006). Adverse events (317.2 events per 100 patient-years) during ADA exposure were consistent with the expected safety profile for TNF inhibitors., Conclusion: ADA led to sustained clinical and functional responses in the 33.8% of treatment-refractory RA patients who completed 10 years of treatment. Patients with shorter disease duration achieved better outcomes, highlighting the need for early treatment. No unexpected safety findings were observed., Trial Registration: ClinicalTrials.gov, http://www.clinicaltrials.gov, NCT00195650., (© The Author 2015. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Objective: To evaluate the effects of the anti-TNF-α monoclonal antibody golimumab, administered by s.c. injection or i.v. infusion, on markers of inflammation in patients with RA., Methods: In this phase 1, open-label study, patients with active RA were randomized to receive s.c. golimumab 100 mg at baseline and every 4 weeks through week 20 (n = 33; group 1) or i.v. golimumab 2 mg/kg at baseline and week 12 (n = 16; group 2). Serum levels of CRP, IL-6, serum amyloid A (SAA), TNF receptor II (TNFRII), MMP-3, hyaluronic acid, haptoglobin, ferritin and haemoglobin and serum/urine hepcidin were measured at various time points. Associations between the biomarkers were assessed with Spearman's correlations., Results: In both groups 1 and 2, decreases in mean serum levels of CRP, IL-6, SAA, TNFRII, MMP-3, haptoglobin, ferritin and hepcidin, and mean urine levels of hepcidin occurred within 1 week and were sustained through week 8. Decreases in concentrations of serum CRP, IL-6, SAA, MMP-3, hepcidin, ferritin and haptoglobin and urine hepcidin were maintained through week 24 in group 1, but began to reverse after week 8 in group 2. Among all patients, decreases in serum hepcidin correlated significantly with decreases in serum CRP and ferritin., Conclusion: Decreases in serum and urine concentrations of markers of inflammation occurred as early as 24 h after treatment with golimumab, and most of these improvements were sustained through week 24 in group 1.

Background: Increased expression of nerve growth factor in injured or inflamed tissue is associated with increased pain. This proof-of-concept study was designed to investigate the safety and analgesic efficacy of tanezumab, a humanized monoclonal antibody that binds and inhibits nerve growth factor., Methods: We randomly assigned 450 patients with osteoarthritis of the knee to receive tanezumab (administered at a dose of 10, 25, 50, 100, or 200 μg per kilogram of body weight) or placebo on days 1 and 56. The primary efficacy measures were knee pain while walking and the patient's global assessment of response to therapy. We also assessed pain, stiffness, and physical function using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC); the rate of response using the criteria of the Outcome Measures for Rheumatology Committee and Osteoarthritis Research Society International Standing Committee for Clinical Trials Response Criteria Initiative (OMERACT-OARSI); and safety., Results: When averaged over weeks 1 through 16, the mean reductions from baseline in knee pain while walking ranged from 45 to 62% with various doses of tanezumab, as compared with 22% with placebo (P<0.001). Tanezumab, as compared with placebo, was also associated with significantly greater improvements in the response to therapy as assessed with the use of the patients' global assessment measure (mean increases in score of 29 to 47% with various doses of tanezumab, as compared with 19% with placebo; P≤0.001). The rate of response according to the OMERACT-OARSI criteria ranged from 74 to 93% with tanezumab treatment, as compared with 44% with placebo (P<0.001). The rates of adverse events were 68% and 55% in the tanezumab and placebo groups, respectively. The most common adverse events among tanezumab-treated patients were headache (9% of the patients), upper respiratory tract infection (7%), and paresthesia (7%)., Conclusions: In this proof-of-concept study, treatment with tanezumab was associated with a reduction in joint pain and improvement in function, with mild and moderate adverse events, among patients with moderate-to-severe osteoarthritis of the knee. (Funded by Rinat Neuroscience; ClinicalTrials.gov number, NCT00394563.).

Objective: This study, known as STAR (Safety Trial of Adalimumab in Rheumatoid Arthritis), evaluated the safety and efficacy of adalimumab (Humira), a fully human monoclonal tumor necrosis factor-alpha (TNF-a) antibody, when given with standard antirheumatic therapy in patients with active rheumatoid arthritis (RA) not adequately responding to such therapies. Standard antirheumatic therapy included traditional disease modifying antirheumatic drugs (DMARD), low dose corticosteroids, nonsteroidal antiinflammatory drugs (NSAID), and/or analgesics., Methods: In this 24-week, double-blind, placebo-controlled study, 636 patients with RA were randomly assigned to receive adalimumab 40 mg subcutaneously (sc) every other week (n = 318) or placebo (n = 318) while continuing standard antirheumatic therapy. The frequencies of adverse events, serious adverse events, severe or life-threatening adverse events, adverse events leading to withdrawal, infection, or serious infection were the primary endpoints. Secondary endpoints were determined by American College of Rheumatology (ACR) response criteria., Results: During the study, the majority of patients received concomitant traditional DMARD (83.5%) and/or corticosteroids, NSAID, and/or analgesics (97.3%). Overall, 56.0% of patients continued treatment with one, 23.6% with 2, and 3.9% with > or = 3 traditional DMARD. At 24 weeks, there were no statistically significant differences between the adalimumab and placebo groups in their respective rates of adverse events (86.5% vs 82.7%), serious adverse events (5.3% vs 6.9%), severe or life-threatening adverse events (11.9% vs 15.4%), or those leading to withdrawal (2.8% vs 2.2%). There were also no statistically significant differences in the rates of infections (52.2% vs 49.4%) or serious infections (1.3% vs 1.9%) between the groups. The incidence and types of adverse events did not vary between adalimumab- and placebo-treated patients by the number of concomitant traditional DMARD (0, 1, or 2). Adalimumab-treated patients compared with placebo-treated patients achieved statistically superior ACR20 (52.8% vs 34.9%), ACR50 (28.9% vs 11.3%), and ACR70 (14.8% vs 3.5%) response rates at Week 24 (p < or = 0.001)., Conclusion: This study demonstrated that addition of adalimumab 40 mg given sc every other week to concomitant standard antirheumatic therapy is well tolerated and provides significant improvements in signs and symptoms of RA. The data indicate that adalimumab is a safe and effective therapeutic option in patients with active RA who have an inadequate response to standard antirheumatic therapy, including one or more traditional DMARD, corticosteroids, NSAID, and analgesics.

We evaluated etoricoxib, a novel COX-2-specific inhibitor, in 319 patients with chronic low back pain (LBP) in this double-blind, placebo-controlled trial. Patients were randomized to a 60 mg dose (n = 103) or 90 mg dose (n = 107) of etoricoxib, or placebo (n = 109), daily for 12 weeks. The primary endpoint was low back pain intensity scale (Visual Analog Scale of 0- to 100-mm) time-weighted average change from baseline over 4 weeks. Other endpoints included evaluation over 3 months of low back pain intensity scale, Roland-Morris Disability Questionnaire (RMDQ), low back pain bothersomeness scale, patient- and investigator-global assessments, Patient Health Survey (MOS SF-12), rescue acetaminophen use, and discontinuation due to lack of efficacy. Etoricoxib provided significant improvement from baseline versus placebo in pain intensity (4 weeks: 12.9 mm and 10.3 mm for 60-mg and 90-mg doses, P <.001 for each; 12 weeks: 10.5 mm and 7.5 mm for 60-mg and 90-mg doses, P =.001 and.018, respectively). Etoricoxib at either dose led to significant improvement in other endpoints, including RMDQ scores, bothersomeness scores and global assessments. Etoricoxib given once daily provided significant relief of symptoms, and disability associated with chronic LBP that was observed 1 week after initiating therapy, was maximal at 4 weeks, and was maintained over 3 months.

Objective: To evaluate the efficacy and safety of adalimumab (D2E7), a fully human monoclonal tumor necrosis factor alpha antibody, in combination with methotrexate (MTX) in patients with active rheumatoid arthritis (RA) despite treatment with MTX., Methods: In a 24-week, randomized, double-blind, placebo-controlled study, 271 patients with active RA were randomly assigned to receive injections of adalimumab (20 mg, 40 mg, or 80 mg subcutaneously) or placebo every other week while continuing to take their long-term stable dosage of MTX. The primary efficacy end point was the American College of Rheumatology criteria for 20% improvement (ACR20) at 24 weeks., Results: An ACR20 response at week 24 was achieved by a significantly greater proportion of patients in the 20-mg, 40-mg, and 80-mg adalimumab plus MTX groups (47.8%, 67.2%, and 65.8%, respectively) than in the placebo plus MTX group (14.5%) (P < 0.001). ACR50 response rates with the 20-mg, 40-mg, and 80-mg adalimumab dosages (31.9%, 55.2%, and 42.5%, respectively) were significantly greater than that with placebo (8.1%) (P = 0.003, P < 0.001, and P < 0.001, respectively). The 40-mg and 80-mg doses of adalimumab were associated with an ACR70 response (26.9% and 19.2%, respectively) that was statistically significantly greater than that with placebo (4.8%) (P < 0.001 and P = 0.020). Responses were rapid, with the greatest proportion of adalimumab-treated patients achieving an ACR20 response at the first scheduled visit (week 1). Adalimumab was safe and well tolerated; comparable numbers of adalimumab-treated patients and placebo-treated patients reported adverse events., Conclusion: The addition of adalimumab at a dosage of 20 mg, 40 mg, or 80 mg administered subcutaneously every other week to long-term MTX therapy in patients with active RA provided significant, rapid, and sustained improvement in disease activity over 24 weeks compared with MTX plus placebo.

Objective: There are 2 classes of serum amyloid A (SAA) protein, acute phase (A-SAA) and constitutive (C-SAA). Hepatic synthesis of A-SAA is dramatically upregulated by inflammatory cytokines, while C-SAA is constitutively produced in the absence of inflammation. A-SAA has been shown to attract monocytes, neutrophils, and T lymphocytes, but the function of C-SAA remains to be determined. SAA proteins have been found in both serum and synovial fluid (SF) of patients with rheumatoid arthritis (RA), but have not been characterized with respect to isoform distribution. We determined the relative distribution of A-SAA and C-SAA in serum and SF of patients with RA and compared their abundance to the classic acute phase response protein, C-reactive protein (CRP)., Methods: A-SAA (isoforms SAA1, SAA2) and CRP were measured by commercially available ELISA kits. ELISA were developed for C-SAA (SAA4) and apolipoprotein AI (apo AI) in paired serum and SF from 56 patients with RA., Results: Concentrations (mean +/- SD) of A-SAA (SAA1,2) in serum and SF are 124 +/- 247, 20 +/- 32 micrograms/ml; CRP 75 +/- 70, 33 +/- 37 micrograms/ml; C-SAA (SAA4) 106 +/-49, 91 +/- 39 micrograms/ml; and apo AI 1.19 +/- 0.32, 0.37 +/- 0.12 mg/ml, respectively. CRP correlated positively with A-SAA in serum or SF and negatively with apo AI in serum. There was no correlation with apo AI in SF. In contrast, there was no correlation between C-SAA and CRP, A-SAA, or apo AI in serum or in SF. Median concentrations of A-SAA in serum and SF (44, 10 micrograms/ml) and CRP (46, 20 micrograms/ml), respectively, markedly differed from the mean values, whereas median concentrations of C-SAA (104, 85 micrograms/ml) and apo AI (1.17, 0.37 mg/ml), respectively, did not., Conclusion: C-SAA concentrations vary in serum and SF independently of A-SAA and CRP levels. The lower concentration of A-SAA relative to C-SAA and CRP in SF suggests that A-SAA could be selectively catabolized in SF or alternatively not well transported into the synovial space.