The risk of malignancy in patients with secukinumab-treated psoriasis, psoriatic arthritis and ankylosing spondylitis: analysis of clinical trial and postmarketing surveillance data with up to five years of follow-up.

BACKGROUND: Data on the use of biologic therapy and malignancy risk are inconsistent due to limited long-term robust studies. OBJECTIVES: To assess the malignancy risk in patients with secukinumab-treated psoriasis, psoriatic arthritis (PsA) and ankylosing spondylitis (AS). METHODS: This integrated safety analysis from both the secukinumab clinical trial programme and postmarketing safety surveillance data included any patient receiving at least one approved dose of secukinumab with a maximum of 5 years of follow-up. Safety analyses evaluated the rate of malignancy using exposure-adjusted incidence rates [EAIR; incidence rates per 100 patient treatment-years (PTY)]. Standardized incidence ratios (SIRs) were reported using the Surveillance, Epidemiology, and End Results Program (SEER) database as a reference population. Crude incidence of malignancy was also reported using postmarketing surveillance data. RESULTS: Safety data from 49 clinical trials with secukinumab-treated patients were included: 10 685 patients with psoriasis, 2523 with PsA and 1311 with AS. Across indications over a 5-year period, the EAIR of malignancy was 0·85 per 100 PTY [95% confidence interval (CI) 0·74-0·98] in secukinumab-treated patients, corresponding to 204 patients per 23 908 PTY. Overall, the observed vs. expected number of malignancies from secukinumab clinical trial data were comparable, as indicated by an SIR of 0·99 (95% CI 0·82-1·19) across indications. The estimated crude cumulative incidence reporting rate per 100 PTY for malignancy was 0·27 in the postmarketing surveillance data across indications with a cumulative exposure of 285 811 PTY. CONCLUSIONS: In this large safety analysis, the risk of malignancy was low for up to 5 years of secukinumab treatment. These data support the long-term use of secukinumab in these indications.

Utilization of the validated Psoriasis Epidemiology Screening Tool to identify signs and symptoms of psoriatic arthritis among those with psoriasis: a cross-sectional analysis from the US-based Corrona Psoriasis Registry.

BACKGROUND: Despite increasing awareness of the disease, rates of undiagnosed psoriatic arthritis (PsA) are high in patients with psoriasis (PsO). The validated Psoriasis Epidemiology Screening Tool (PEST) is a five-item questionnaire developed to help identify PsA at an early stage. OBJECTIVES: To assess the risk of possible undiagnosed PsA among patients with PsO and characterize patients based on PEST scores. METHODS: This study included all patients enrolled in the Corrona PsO Registry with data on all five PEST questions. Demographics, clinical characteristics and patient-reported outcomes were compared in Corrona PsO Registry patients with PEST scores ≥3 and <3 using t-tests for continuous variables and chi-squared tests for categorical variables; scores ≥3 may indicate PsA. RESULTS: Of 1516 patients with PsO, 904 did not have dermatologist-reported PsA; 112 of these 904 patients (12.4%) scored ≥3 and were significantly older, female, less likely to be working, and had higher BMI than patients with scores <3. They also had significantly longer PsO duration, were more likely to have nail PsO and had worse health status, pain, fatigue, Dermatology Life Quality Index and activity impairment. CONCLUSIONS: Improved PsA screening is needed in patients with PsO because the validated PEST identified over one-tenth of registry patients who were not noted to have PsA as having scores ≥3, who could have had undiagnosed PsA. Appropriate, earlier care is important because these patients were more likely to have nail PsO, worse health-related quality of life and worse activity impairment.

Improvements in productivity at paid work and within the household, and increased participation in daily activities after 24†weeks of certolizumab pegol treatment of patients with psoriatic arthritis: results of a phase 3 double-blind randomised placebo-controlled study.

OBJECTIVES: To evaluate the effect of certolizumab pegol (CZP) on productivity outside and within the home, and on participation in family, social and leisure activities in adult patients with psoriatic arthritis (PsA). METHODS: RAPID-PsA (NCT01087788) is a phase 3, double-blind, placebo-controlled trial. 409 patients with active PsA were randomised 1:1:1 to placebo, CZP 200 mg every 2 weeks (Q2W) or CZP 400 mg every 4 weeks (Q4W). The arthritis-specific Work Productivity Survey (WPS) assessed the impact of PsA on paid work and household productivity, and participation in social activities during the preceding month. WPS responses were compared between treatment arms using a non-parametric bootstrap-t method. RESULTS: At baseline, 56.6%, 60.1% and 61.5% of placebo, CZP 200 mg Q2W and CZP 400 mg Q4W patients were employed. By week 24, employed CZP patients reported an average of 1.0-1.8 and 3.0-3.9 fewer days of absenteeism and presenteeism, respectively, per month compared with 1.0 and 0.3 fewer days for placebo patients (p<0.05). Within the home, by week 24, CZP patients reported an average of 3.0-3.5 household work days gained per month versus 1.0 day for placebo (p<0.05). CZP patients also reported fewer days with reduced household productivity or days lost for participation in family, social and leisure activities. Improvements with CZP were seen as early as week 4 and continued to week 24. CONCLUSIONS: CZP treatment significantly improved productivity at paid work and within the home, and resulted in greater participation in social activities for PsA patients. TRIAL REGISTRATION NUMBER: NCT01087788.

The JAK inhibitor tofacitinib suppresses synovial JAK1-STAT signalling in rheumatoid arthritis.

OBJECTIVE: Tofacitinib is an oral Janus kinase (JAK) inhibitor for the treatment of rheumatoid arthritis (RA). The pathways affected by tofacitinib and the effects on gene expression in situ are unknown. Therefore, tofacitinib effects on synovial pathobiology were investigated. METHODS: A randomised, double-blind, phase II serial synovial biopsy study (A3921073; NCT00976599) in patients with RA with an inadequate methotrexate response. Patients on background methotrexate received tofacitinib 10 mg twice daily or placebo for 28 days. Synovial biopsies were performed on Days -7 and 28 and analysed by immunoassay or quantitative PCR. Clinical response was determined by disease activity score and European League Against Rheumatism (EULAR) response on Day 28 in A3921073, and at Month 3 in a long-term extension study (A3921024; NCT00413699). RESULTS: Tofacitinib exposure led to EULAR moderate to good responses (11/14 patients), while placebo was ineffective (1/14 patients) on Day 28. Tofacitinib treatment significantly reduced synovial mRNA expression of matrix metalloproteinase (MMP)-1 and MMP-3 (p<0.05) and chemokines CCL2, CXCL10 and CXCL13 (p<0.05). No overall changes were observed in synovial inflammation score or the presence of T cells, B cells or macrophages. Changes in synovial phosphorylation of signal transducer and activator of transcription 1 (STAT1) and STAT3 strongly correlated with 4-month clinical responses (p<0.002). Tofacitinib significantly decreased plasma CXCL10 (p<0.005) at Day 28 compared with placebo. CONCLUSIONS: Tofacitinib reduces metalloproteinase and interferon-regulated gene expression in rheumatoid synovium, and clinical improvement correlates with reductions in STAT1 and STAT3 phosphorylation. JAK1-mediated interferon and interleukin-6 signalling likely play a key role in the synovial response. TRIAL REGISTRATION NUMBER: NCT00976599.

Effect of different imputation approaches on the evaluation of radiographic progression in patients with psoriatic arthritis: results of the RAPID-PsA 24-week phase III double-blind randomised placebo-controlled study of certolizumab pegol.

OBJECTIVES: To report the effect of different imputation methodologies on the assessment of radiographic progression in clinical trials. METHODS: The 216-week RAPID-psoriatic arthritis (PsA) (NCT01087788) trial of certolizumab pegol (CZP) in patients with active PsA was double-blind and placebo-controlled until week 24. A primary end point was change from baseline in modified Total Sharp Score(s) (mTSS). Prespecified imputation methodology in patients with fewer than two analysable mTSS used minimum observed baseline score for missing baseline values and maximum observed week 24 score for missing week 24 values. Post hoc analyses used alternative methods of imputation in patients with fewer than two analysable mTSS. mTSS non-progressors were defined as patients with ≤0 (predefined) or ≤0.5 (post hoc) change in mTSS from baseline to week 24. Baseline mTSS and C-reactive protein levels as predictors of radiographic progression were investigated. RESULTS: 409 patients were randomised. Baseline demographics were similar between groups. Prespecified imputation analysis inappropriately overestimated radiographic progression (least squares mean placebo, 28.9; CZP, 18.3; p≥0.05). Multiple post hoc analyses demonstrated that CZP inhibited radiographic progression compared with placebo, particularly in patients with high baseline mTSS and C-reactive protein levels. mTSS non-progression rate was higher in CZP than placebo groups in all analyses. CONCLUSIONS: Inappropriate prespecified imputation methodology resulted in an unrealistic assessment of progression in all arms. Methodologies for imputing missing radiographic data can greatly affect assessment and reporting of mTSS progression.

Effect of certolizumab pegol on signs and symptoms in patients with psoriatic arthritis: 24-week results of a Phase 3 double-blind randomised placebo-controlled study (RAPID-PsA).

OBJECTIVES: To evaluate the efficacy and safety of certolizumab pegol (CZP) after 24 weeks in RAPID-PsA (NCT01087788), an ongoing Phase 3 trial in patients with psoriatic arthritis (PsA). METHODS: Patients were randomised 1:1:1 to placebo, 200 mg CZP every 2 weeks (Q2W) or 400 mg CZP every 4 weeks (Q4W). Patients could have had exposure to one previous tumour necrosis factor (TNF) inhibitor therapy. Primary endpoints were American College of Rheumatology 20% (ACR20) response at week 12 and modified Total Sharp Score change from baseline at week 24. Secondary endpoints included; Psoriatic Arthritis Response Criteria (PsARC) score, Health Assessment Questionnaire Disability Index (HAQ-DI), Psoriasis Area and Severity Index, Leeds Enthesitis Index, Leeds Dactylitis Index, and Modified Nail Psoriasis Severity Index. RESULTS: Of 409 patients randomised, 368 completed 24 weeks of treatment. ACR20 response was significantly greater in CZP 200 mg Q2W and 400 mg Q4W-treated patients than placebo (58.0% and 51.9% vs 24.3% (p<0.001)) at week 12, with improvements observed by week 1. There was a statistically significant improvement in physical function from baseline, measured by HAQ-DI in CZP patients compared with placebo (-0.50 vs -0.19, p<0.001) and more patients treated with CZP 200 mg Q2W and CZP 400 mg achieved an improvement in PsARC at week 24 than placebo (78.3% and 77.0% vs 33.1% (p<0.001)). Sustained improvements were observed in psoriatic skin involvement, enthesitis, dactylitis and nail disease. Higher ACR20 response with CZP was independent of prior TNF inhibitor exposure. No new safety signals were observed. CONCLUSIONS: Rapid improvements in the signs and symptoms of PsA, including joints, skin, enthesitis, dactylitis and nail disease were observed across both CZP dosing regimens.

Efficacy of certolizumab pegol on signs and symptoms of axial spondyloarthritis including ankylosing spondylitis: 24-week results of a double-blind randomised placebo-controlled Phase 3 study.

OBJECTIVES: To evaluate the efficacy and safety of certolizumab pegol (CZP) after 24 weeks in RAPID-axSpA (NCT01087762), an ongoing Phase 3 trial in patients with axial spondyloarthritis (axSpA), including patients with ankylosing spondylitis (AS) and non-radiographic axSpA (nr-axSpA). METHODS: Patients with active axSpA were randomised 1:1:1 to placebo, CZP 200 mg every 2 weeks (Q2W) or CZP 400 mg every 4 weeks (Q4W). In total 325 patients were randomised. Primary endpoint was ASAS20 (Assessment of SpondyloArthritis international Society 20) response at week 12. Secondary outcomes included change from baseline in Bath Ankylosing Spondylitis Functional Index (BASFI), Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), and Bath Ankylosing Spondylitis Metrology Index (BASMI) linear. RESULTS: Baseline disease activity was similar between AS and nr-axSpA. At week 12, ASAS20 response rates were significantly higher in CZP 200 mg Q2W and CZP 400 mg Q4W arms versus placebo (57.7 and 63.6 vs 38.3, p≤0.004). At week 24, combined CZP arms showed significant (p<0.001) differences in change from baseline versus placebo in BASFI (-2.28 vs -0.40), BASDAI (-3.05 vs -1.05), and BASMI (-0.52 vs -0.07). Improvements were observed as early as week 1. Similar improvements were reported with CZP versus placebo in both AS and nr-axSpA subpopulations. Adverse events were reported in 70.4% vs 62.6%, and serious adverse events in 4.7% vs 4.7% of All CZP versus placebo groups. No deaths or malignancies were reported. CONCLUSIONS: CZP rapidly reduced the signs and symptoms of axSpA, with no new safety signals observed compared to the safety profile of CZP in RA. Similar improvements were observed across CZP dosing regimens, and in AS and nr-axSpA patients.

Treating axial and peripheral spondyloarthritis, including psoriatic arthritis, to target: results of a systematic literature search to support an international treat-to-target recommendation in spondyloarthritis.

BACKGROUND: Current recommendations for the management of axial spondyloarthritis (SpA) and psoriatic arthritis are to monitor disease activity and adjust therapy accordingly. However, treatment targets and timeframes of change have not been defined. An international expert panel has been convened to develop 'treat-to-target' recommendations, based on published evidence and expert opinion. OBJECTIVE: To review evidence on targeted treatment for axial and peripheral SpA, as well as for psoriatic skin disease. METHODS: We performed a systematic literature search covering Medline, Embase and Cochrane, conference abstracts and studies in http://www.clinicaltrials.gov. RESULTS: Randomised comparisons of targeted versus routine treatment are lacking. Some studies implemented treatment targets before escalating therapy: in ankylosing spondylitis, most trials used a decrease in Bath Ankylosing Spondylitis Disease Activity Index; in psoriatic arthritis, protocols primarily considered a reduction in swollen and tender joints; in psoriasis, the Modified Psoriasis Severity Score and the Psoriasis Area and Severity Index were used. Complementary evidence correlating these factors with function and radiographic damage at follow-up is sparse and equivocal. CONCLUSIONS: There is a need for randomised trials that investigate the value of treat-to-target recommendations in SpA and psoriasis. Several trials have used thresholds of disease activity measures to guide treatment decisions. However, evidence on the effect of these data on long-term outcome is scarce. The search data informed the expert committee regarding the formulation of recommendations and a research agenda.

Hypertension and diabetes significantly enhance the risk of cardiovascular disease in patients with psoriatic arthritis.

OBJECTIVES: New evidence has lightened the linkage between psoriatic arthritis (PsA) and the development of atherosclerosis and cardiovascular disease (CVD). We aimed to describe the prevalence of cardiovascular events and associated risk factors among patients with PsA. METHODS: Retrospective evaluation of medical records from consecutive PsA patients who fulfilled the CASPAR criteria for PsA attending a specialised spondyloarthritis clinic at a single referral centre. CVD was defined based on the occurrence of coronary artery disease (CAD) or cerebrovascular ischaemic disease events. RESULTS: We evaluated 158 PsA patients, 48.7% females and 51.3% males, aged 53.7±13.9 yrs. Mean PsA duration was 13.7±8.9 yrs and polyarticular subtype affected 66 (42%) patients. According to drug therapy, 85 (54%) were using NSAIDs and 21 (13%) low-dose prednisone; 32 (20%) were on anti-TNF agents, 94 (60%) metothrexate, 18 (11%) leflunomide, 13 (8%) sulfasalazine, 5 (3%) other immunossupressors and 4 (2.5%) were on chloroquine. Over half patients (87, 55%) had arterial hypertension (AH); 51 (32%) had dyslipidaemia (DLP), 38 (29%) hypertriglyceridemia and 36 (23%) diabetes mellitus (DM). Lipid profile was similar for both genders with mean total cholesterol= 186.5±38.6mg/dl, LDL=112.3±30.6 mg/dl, HDL= 47.89±14.6 and triglycerides= 127.4± 65.6 mg/dl. Of note, 14% PsA patients have had CVD, namely cerebrovascular or coronary heart disease. Sex, age, disease duration, joint involvement subtype, disease activity, CRP and lipid levels were similar among patients with and without CVD. The prevalence of AH (95% vs. 45%, p<0.001), DLP (75% vs. 27.7%, p<0.001) and DM (60% vs. 19%, p<0.001) were significantly greater in PsA patients who have had CVD compared to those without CVD, conferring an odds ratio of 21.0 for AH and of 5.4 for DM. CONCLUSIONS: The high prevalence of CVD in PsA patients is influenced by increased AH and DM. Hence early recognition and specific treatment is mandatory in order to reduce the risk for CVD, avoiding early morbidity and mortality.

Safety and efficacy of ocrelizumab in patients with rheumatoid arthritis and an inadequate response to at least one tumor necrosis factor inhibitor: results of a forty-eight­week randomized, double-blind, placebo-controlled, parallel-group phase III trial.

OBJECTIVE: To evaluate the safety and efficacy of ocrelizumab plus methotrexate (MTX) or leflunomide (LEF) in patients with active rheumatoid arthritis (RA) and an inadequate response to tumor necrosis factor α inhibitors. METHODS: This was a multicenter randomized, double-blind, placebo-controlled, parallel-group study that continued over 48 weeks. Patients receiving stable doses of MTX or LEF were randomized to receive 2 infusions of placebo (n = 277), ocrelizumab 200 mg (n = 278), or ocrelizumab 500 mg (n = 285) on days 1 and 15 as well as at weeks 24 and 26. Coprimary end points were the proportion of patients with response according to the American College of Rheumatology 20% improvement criteria (ACR20) at weeks 24 and 48. Secondary end points included the change from baseline in the modified Sharp/van der Heijde score (SHS) and the ACR50/70 responses. RESULTS: ACR20 responses were 22.0% in the placebo group, 42.2% in the ocrelizumab 200 mg group, and 47.9% in the ocrelizumab 500 mg group at 24 weeks and 19.5%, 48.7%, and 50.7%, respectively, at 48 weeks (P < 0.0001 versus placebo for each comparison at each time point). At 48 weeks, patients receiving both doses of ocrelizumab showed significantly improved ACR50 and ACR70 responses of ~3-fold versus placebo. Only those in the ocrelizumab 500 mg group showed statistically significant (P = 0.0017) inhibition of joint damage progression (mean change in the SHS) relative to placebo (61% inhibition) at 48 weeks. Overall adverse events and infections during the 48 weeks of study were comparable in all treatment groups. Serious infections were observed more frequently in patients taking ocrelizumab (5.1% and 4.3%) than in those taking placebo (2.5%). CONCLUSION: Patients in both of the ocrelizumab groups met the clinical primary efficacy end points. Inhibition of change in the SHS was statistically significant at 48 weeks for those in the ocrelizumab 500 mg group. The rate of serious infections in this trial was higher for both ocrelizumab doses as compared with placebo.

A phase II, double-blind, randomised, placebo-controlled study of BMS945429 (ALD518) in patients with rheumatoid arthritis with an inadequate response to methotrexate.

BACKGROUND: Interleukin 6 (IL-6) plays a key role in the inflammatory cascade in rheumatoid arthritis. BMS945429 is a humanised, monoclonal antibody that potently binds IL-6. OBJECTIVE: To conduct aphase II study to determine the efficacy and safety of BMS945429 in patients with active rheumatoid arthritis and an inadequate response to methotrexate. METHODS: Patients were randomised 1:1:1:1 to BMS945429 (80, 160 or 320 mg; administered intravenously) or placebo plus methotrexate during this 16-week, double-blind trial. The primary efficacy end point was the proportion of patients with a 20% improvement in American College of Rheumatology responses (ACR20) at week 12. Additional end points included ACR50 and ACR70 responses and 28-joint Disease Activity Scores (DAS28). RESULTS: Of 127 randomised and treated patients, 116 completed the trial. ACR20 responders at week 12 were 81% (80 mg; p<0.0001 vs placebo), 71% (160 mg; p=0.0005 vs placebo), 82% (320 mg; p<0.0001 vs placebo) and 27% (placebo), respectively. By week 16, 14% (80 mg), 28% (160 mg) and 44% (320 mg) of BMS945429 patients were in DAS28 remission (DAS28 score <2.6). Statistically significant and clinically meaningful improvements in health-related quality of life (HRQoL) were reported in all active treatment groups. Administration of BMS945429 was associated with increases in liver enzymes and in serum cholesterol. There were no serious infections, infusion reactions or apparent immunogenicity. CONCLUSIONS: In this phase II study, BMS945429 was associated with rapid and significant improvements in disease activity and HRQoL in patients with active rheumatoid arthritis and an inadequate response to methotrexate.

Successful treatment of moderate to severe plaque psoriasis with the PEGylated Fab' certolizumab pegol: results of a phase II randomized, placebo-controlled trial with a re-treatment extension.

BACKGROUND: Certolizumab pegol (CZP) is a PEGylated antitumour necrosis factor agent. OBJECTIVES: To evaluate the efficacy and safety of CZP in patients with plaque psoriasis. METHODS: In a randomized, placebo-controlled, double-blind study, 176 patients with moderate to severe psoriasis received placebo or CZP 400 mg at week 0 followed by placebo or CZP (200 or 400 mg) every other week until week 10. Co-primary endpoints were ≥ 75% improvement from baseline in Psoriasis Area and Severity Index (PASI 75) and a Physician's Global Assessment (PGA) of clear-almost clear at week 12. A re-treatment extension study was conducted in 71 CZP PASI 75 responders who relapsed during a 12- to 24-week observation period without treatment. RESULTS: PASI 75 was achieved by 44/59 (75%), 48/58 (83%) and 4/59 (7%) patients in the CZP 200 mg, CZP 400 mg and placebo groups, respectively (P < 0·001 for both treatment arms vs. placebo). A PGA score of clear-almost clear was achieved by 53%, 72% and 2%, respectively (P < 0·001 for both treatment arms vs. placebo). In the re-treatment study median PASI scores were similar at week 12 in the first treatment and re-treatment periods for both CZP groups. Serious adverse events occurred in 3%, 5% and 2% of CZP 200 mg, CZP 400 mg and placebo patients, respectively. CONCLUSIONS: Treatment with CZP significantly improved psoriasis at week 12. Similar efficacy was observed at week 12 in patients receiving re-treatment for loss of response after drug withdrawal.

The potential roles for novel biomarkers in rheumatoid arthritis assessment.

Comprehensive management of rheumatoid arthritis (RA) requires regular monitoring of disease activity, functional status, and structural damage to facilitate optimal patient outcomes. Tight control strategies have been successfully used in other diseases including diabetes and hypertension. Tight control requires frequent disease activity measurements in order to tailor treatment for individual patients, resulting in improved patient outcomes. Current monitoring measures used in clinical practice are largely driven by subjective evaluation of signs and symptoms, which are critical but limited by assessor variability and may not reflect true biological change in a timely manner. Research suggests that novel biomarkers may provide quantitative, objective assessments of disease activity and structural damage risk in RA, which are not captured by current measures. The simultaneous use of multiple biomarkers in a single test algorithm may provide a more comprehensive quantitative representation of the overall complex heterogeneous biology of RA. This article reviews the current management strategies for monitoring RA and the potential impact that multi-biomarker assays may have on RA assessment, which may further improve clinical outcomes.

The ASAS-OMERACT core domain set for axial spondyloarthritis.

BACKGROUND: The current core outcome set for ankylosing spondylitis (AS) has had only minor adaptations since its development 20 years ago. Considering the significant advances in this field during the preceding decades, an update of this core set is necessary. OBJECTIVE: To update the ASAS-OMERACT core outcome set for AS into the ASAS-OMERACT core outcome set for axial spondyloarthritis (axSpA). METHODS: Following OMERACT and COMET guidelines, an international working group representing key stakeholders (patients, rheumatologists, health professionals, pharmaceutical industry and drug regulatory agency representatives) defined the core domain set for axSpA. The development process consisted of: i) Identifying candidate domains using a systematic literature review and qualitative studies; ii) Selection of the most relevant domains for different stakeholders through a 3-round Delphi survey involving axSpA patients and axSpA experts; iii) Consensus and voting by ASAS; iv) Endorsement by OMERACT. Two scenarios are considered based on the type of therapy investigated in the trial: symptom modifying therapies and disease modifying therapies. RESULTS: The updated core outcome set for axSpA includes 7 mandatory domains for all trials (disease activity, pain, morning stiffness, fatigue, physical function, overall functioning and health, and adverse events including death). There are 3 additional domains (extra-musculoskeletal manifestations, peripheral manifestations and structural damage) that are mandatory for disease modifying therapies and important but optional for symptom modifying therapies. Finally, 3 other domains (spinal mobility, sleep, and work and employment) are defined as important but optional domains for all trials. CONCLUSION: The ASAS-OMERACT core domain set for AS has been updated into the ASAS-OMERACT core domain set for axSpA. The next step is the selection of instruments for each domain.

Adalimumab safety and mortality rates from global clinical trials of six immune-mediated inflammatory diseases.

OBJECTIVES: Clinical trials of tumour necrosis factor antagonists have raised questions about the potential risk of certain serious adverse events (SAE). To assess the safety of adalimumab in rheumatoid arthritis (RA) over time and across five other immune-mediated inflammatory diseases and to compare adalimumab malignancy and mortality rates with data on the general population. METHODS: This analysis included 19,041 patients exposed to adalimumab in 36 global clinical trials in RA, psoriatic arthritis (PsA), ankylosing spondylitis (AS), Crohn's disease (CD), psoriasis and juvenile idiopathic arthritis (JIA) to 15 April 2007. Events per 100 patient-years were calculated using SAE reported after the first dose to 70 days after the last dose. Standardised incidence rates were calculated for malignancies using national and state-specific databases. Standardised mortality rates (SMR) were calculated for each disease using data from the World Health Organization. RESULTS: Cumulative rates of SAE of interest in RA have remained stable over time. Rates of SAE of interest for PsA, AS, CD, psoriasis and JIA were similar to or lower than rates for RA. Overall malignancy rates for adalimumab-treated patients were as expected for the general population. SMR across all six diseases indicated that no more deaths occurred with adalimumab than expected in the general population. CONCLUSIONS: Based on 10 years of clinical trial experience across six diseases, this safety report and the established efficacy of adalimumab in these diseases provide the foundation for a better understanding of its benefit-risk profile.

Local delivery of a recombinant adenoassociated vector containing a tumour necrosis factor alpha antagonist gene in inflammatory arthritis: a phase 1 dose-escalation safety and tolerability study.

OBJECTIVE: To examine the safety and tolerability of a single intra-articular injection of rAAV2-TNFR:Fc, an adenoassociated virus serotype 2 vector containing the cDNA for the human tumour necrosis factor-immunoglobulin Fc fusion gene (tgAAC94), in subjects with inflammatory arthritis. METHODS: In a double-blind, placebo-controlled, phase 1, dose-escalation study, 15 subjects with inflammatory arthritis (14 with rheumatoid arthritis and 1 with ankylosing spondylitis) not receiving tumour necrosis factor alpha (TNFalpha) inhibitors with persistent moderate (grade 2) or severe (grade 3) swelling in a target joint due to inflammatory arthritis received a single intra-articular injection of rAAV2-TNFR:Fc at 1 x 10(10) (n = 5) or 1 x 10(11) (n = 6) DNase resistant particles per ml joint volume or placebo (n = 4) into a knee (n = 14) or ankle (n = 1). Safety was assessed through adverse event monitoring. As a secondary objective, changes in injected joint tenderness and swelling scores, each measured on a four-point scale, were evaluated. RESULTS: Intra-articular injections of rAAV2-TNFR:Fc were well tolerated with no major safety issues. One event, mild knee pruritus, was considered probably related. Synovial fluid TNFR:Fc protein was not detected (nor expected) at the doses used. At 12 weeks after injection, a two-point decrease in swelling was noted in 2/11 and 2/4 subjects injected with rAAV2-TNFR:Fc and placebo, respectively. CONCLUSION: A single dose of intra-articular rAAV2-TNFR:Fc appears to be safe and well tolerated in subjects without concurrent systemic TNFalpha antagonist use. It is thus feasible to proceed with larger trials to further test the safety and efficacy of local TNFR:Fc gene transfer as a therapeutic modality for patients with inflammatory arthritis.

Adalimumab effectiveness for the treatment of ankylosing spondylitis is maintained for up to 2 years: long-term results from the ATLAS trial.

OBJECTIVE: To determine the long-term effect of adalimumab on patients with ankylosing spondylitis (AS) who participated in the Adalimumab Trial Evaluating Long-Term Efficacy and Safety in AS (ATLAS), a randomised, double-blind, placebo controlled, 24-week trial. METHODS: Patients received adalimumab 40 mg every other week (eow) or placebo for 24 weeks in ATLAS. At week 24, patients were switched to open-label adalimumab 40 mg eow. Efficacy measures included 20% improvement in the Assessment in SpondyloArthritis International Society (ASAS) criteria (ASAS20), ASAS40 and ASAS partial remission responses and changes in individual components of the ASAS20 response evaluations, for example, Bath AS Functional Index (BASFI) and Bath AS Disease Activity Index (BASDAI). Two-year interim data were analysed based on the total duration of adalimumab exposure, irrespective of the treatment randomisation group. RESULTS: At 2 years, 255 (82.0%) of the original 311 ATLAS patients continued receiving adalimumab treatment. Improvements in ASAS responses observed in ATLAS were sustained during long-term treatment; 64.5% (200/310) were ASAS20 responders, 50.6% (157/310) were ASAS40 responders and 33.5% (104/310) had maintained ASAS-defined partial remission. Changes in individual ASAS response components were sustained or improved during long-term adalimumab treatment. From ATLAS baseline to 2 years of adalimumab exposure, respectively, BASDAI improved from 6.3 (SD 1.7) to 2.4 (SD 2.3) and BASFI improved from 5.2 (SD 2.4) to 2.9 (SD 2.5). Adalimumab was well tolerated. No cases of tuberculosis, congestive heart failure, lupus-like symptoms, or demyelinating disease were reported. CONCLUSIONS: Adalimumab reduced the signs and symptoms of AS and induced partial remission for up to 2 years. The long-term safety profile was similar to the short-term safety profile. Trial registration information: NCT00085644.

Efficacy and safety of certolizumab pegol plus methotrexate in active rheumatoid arthritis: the RAPID 2 study. A randomised controlled trial.

BACKGROUND: Certolizumab pegol is a PEGylated tumour necrosis factor inhibitor. OBJECTIVE: To evaluate the efficacy and safety of certolizumab pegol versus placebo, plus methotrexate (MTX), in patients with active rheumatoid arthritis (RA). METHODS: An international, multicentre, phase 3, randomised, double-blind, placebo-controlled study in active adult-onset RA. Patients (n = 619) were randomised 2:2:1 to subcutaneous certolizumab pegol (liquid formulation) 400 mg at weeks 0, 2 and 4 followed by 200 mg or 400 mg plus MTX, or placebo plus MTX, every 2 weeks for 24 weeks. The primary end point was ACR20 response at week 24. Secondary end points included ACR50 and ACR70 responses, change from baseline in modified Total Sharp Score, ACR core set variables and physical function. RESULTS: Significantly more patients in the certolizumab pegol 200 mg and 400 mg groups achieved an ACR20 response versus placebo (p< or =0.001); rates were 57.3%, 57.6% and 8.7%, respectively. Certolizumab pegol 200 and 400 mg also significantly inhibited radiographic progression; mean changes from baseline in mTSS at week 24 were 0.2 and -0.4, respectively, versus 1.2 for placebo (rank analysis p< or =0.01). Certolizumab pegol-treated patients reported rapid and significant improvements in physical function versus placebo; mean changes from baseline in HAQ-DI at week 24 were -0.50 and -0.50, respectively, versus -0.14 for placebo (p< or =0.001). Most adverse events were mild or moderate, with low incidence of withdrawals due to adverse events. Five patients developed tuberculosis. CONCLUSION: Certolizumab pegol plus MTX was more efficacious than placebo plus MTX, rapidly and significantly improving signs and symptoms of RA and physical function and inhibiting radiographic progression. TRIAL REGISTRATION NUMBER: NCT00175877.

Treatment recommendations for psoriatic arthritis.

OBJECTIVE: To develop comprehensive recommendations for the treatment of the various clinical manifestations of psoriatic arthritis (PsA) based on evidence obtained from a systematic review of the literature and from consensus opinion. METHODS: Formal literature reviews of treatment for the most significant discrete clinical manifestations of PsA (skin and nails, peripheral arthritis, axial disease, dactylitis and enthesitis) were performed and published by members of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA). Treatment recommendations were drafted for each of the clinical manifestations by rheumatologists, dermatologists and PsA patients based on the literature reviews and consensus opinion. The level of agreement for the individual treatment recommendations among GRAPPA members was assessed with an online questionnaire. RESULTS: Treatment recommendations were developed for peripheral arthritis, axial disease, psoriasis, nail disease, dactylitis and enthesitis in the setting of PsA. In rotal, 19 recommendations were drafted, and over 80% agreement was obtained on 16 of them. In addition, a grid that factors disease severity into each of the different disease manifestations was developed to help the clinician with treatment decisions for the individual patient from an evidenced-based perspective. CONCLUSIONS: Treatment recommendations for the cardinal physical manifestations of PsA were developed based on a literature review and consensus between rheumatologists and dermatologists. In addition, a grid was established to assist in therapeutic reasoning and decision making for individual patients. It is anticipated that periodic updates will take place using this framework as new data become available.

Adalimumab for long-term treatment of psoriatic arthritis: 2-year data from the Adalimumab Effectiveness in Psoriatic Arthritis Trial (ADEPT).

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; p<0.001), and outcomes for all individual ACR component variables were significantly improved in adalimumab compared with placebo-treated patients. Compared with 24-week responses, inhibition of radiographic progression and improvements in joint disease were maintained in most patients during long-term, open-label adalimumab treatment. Also, improvements in skin disease were maintained, with >20% 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.