Showing papers in "Annals of the Rheumatic Diseases in 2014"

EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2016 update

Abstract: In this article, the 2010 European League against Rheumatism (EULAR) recommendations for the management of rheumatoid arthritis (RA) with synthetic and biological disease-modifying antirheumatic drugs (sDMARDs and bDMARDs, respectively) have been updated. The 2013 update has been developed by an international task force, which based its decisions mostly on evidence from three systematic literature reviews (one each on sDMARDs, including glucocorticoids, bDMARDs and safety aspects of DMARD therapy); treatment strategies were also covered by the searches. The evidence presented was discussed and summarised by the experts in the course of a consensus finding and voting process. Levels of evidence and grades of recommendations were derived and levels of agreement (strengths of recommendations) were determined. Fourteen recommendations were developed (instead of 15 in 2010). Some of the 2010 recommendations were deleted, and others were amended or split. The recommendations cover general aspects, such as attainment of remission or low disease activity using a treat-to-target approach, and the need for shared decision-making between rheumatologists and patients. The more specific items relate to starting DMARD therapy using a conventional sDMARD (csDMARD) strategy in combination with glucocorticoids, followed by the addition of a bDMARD or another csDMARD strategy (after stratification by presence or absence of adverse risk factors) if the treatment target is not reached within 6 months (or improvement not seen at

The global burden of hip and knee osteoarthritis: estimates from the Global Burden of Disease 2010 study

Abstract: Objective To estimate the global burden of hip and knee osteoarthritis (OA) as part of the Global Burden of Disease 2010 study and to explore how the burden of hip and knee OA compares with other conditions. Methods Systematic reviews were conducted to source age-specific and sex-specific epidemiological data for hip and knee OA prevalence, incidence and mortality risk. The prevalence and incidence of symptomatic, radiographic and self-reported hip or knee OA were included. Three levels of severity were defined to derive disability weights (DWs) and severity distribution (proportion with mild, moderate and severe OA). The prevalence by country and region was multiplied by the severity distribution and the appropriate disability weight to calculate years of life lived with disability (YLDs). As there are no deaths directly attributed to OA, YLDs equate disability-adjusted life years (DALYs). Results Globally, of the 291 conditions, hip and knee OA was ranked as the 11th highest contributor to global disability and 38th highest in DALYs. The global age-standardised prevalence of knee OA was 3.8% (95% uncertainty interval (UI) 3.6% to 4.1%) and hip OA was 0.85% (95% UI 0.74% to 1.02%), with no discernible change from 1990 to 2010. Prevalence was higher in females than males. YLDs for hip and knee OA increased from 10.5 million in 1990 (0.42% of total DALYs) to 17.1 million in 2010 (0.69% of total DALYs). Conclusions Hip and knee OA is one of the leading causes of global disability. Methodological issues within this study make it highly likely that the real burden of OA has been underestimated. With the aging and increasing obesity of the world9s population, health professions need to prepare for a large increase in the demand for health services to treat hip and knee OA.

The global burden of low back pain: estimates from the Global Burden of Disease 2010 study

Abstract: Supported by the Bill and Melinda Gates Foundation (to Dr Hoy and Prof Vos), the Australian Commonwealth Department of Health and Ageing (to Dr Smith (University of Sydney, Institute of Bone and Joint Research) and Prof March), the Australian National Health and Medical Research Council (Postgraduate Scholarship 569772 to Dr Hoy and Practitioner Fellowships 334010 (2005–2009) and 606429 (2010–2014) to Prof Buchbinder, and the Ageing and Alzheimers Research Foundation (Asst Prof Blyth).

2016 updated EULAR evidence-based recommendations for the management of gout

Abstract: Background New drugs and new evidence concerning the use of established treatments have become available since the publication of the first European League Against Rheumatism (EULAR) recommendations for the management of gout, in 2006. This situation has prompted a systematic review and update of the 2006 recommendations. Methods The EULAR task force consisted of 15 rheumatologists, 1 radiologist, 2 general practitioners, 1 research fellow, 2 patients and 3 experts in epidemiology/methodology from 12 European countries. A systematic review of the literature concerning all aspects of gout treatments was performed. Subsequently, recommendations were formulated by use of a Delphi consensus approach. Results Three overarching principles and 11 key recommendations were generated. For the treatment of flare, colchicine, non-steroidal anti-inflammatory drugs (NSAIDs), oral or intra-articular steroids or a combination are recommended. In patients with frequent flare and contraindications to colchicine, NSAIDs and corticosteroids, an interleukin-1 blocker should be considered. In addition to education and a non-pharmacological management approach, urate-lowering therapy (ULT) should be considered from the first presentation of the disease, and serum uric acid (SUA) levels should be maintained at<6 mg/dL (360 µmol/L ) and <5 mg/dL (300 µmol/L ) in those with severe gout. Allopurinol is recommended as first-line ULT and its dosage should be adjusted according to renal function. If the SUA target cannot be achieved with allopurinol, then febuxostat, a uricosuric or combining a xanthine oxidase inhibitor with a uricosuric should be considered. For patients with refractory gout, pegloticase is recommended. Conclusions These recommendations aim to inform physicians and patients about the non-pharmacological and pharmacological treatments for gout and to provide the best strategies to achieve the predefined urate target to cure the disease.

The global burden of rheumatoid arthritis: estimates from the Global Burden of Disease 2010 study

Abstract: Objectives To estimate the global burden of rheumatoid arthritis (RA), as part of the Global Burden of Disease 2010 study of 291 conditions and how the burden of RA compares with other conditions. Methods The optimum case definition of RA for the study was the American College of Rheumatology 1987 criteria. A series of systematic reviews were conducted to gather age-sex-specific epidemiological data for RA prevalence, incidence and mortality. Cause-specific mortality data were also included. Data were entered into DisMod-MR, a tool to pool available data, making use of study-level covariates to adjust for country, region and super-region random effects to estimate prevalence for every country and over time. The epidemiological data, in addition to disability weights, were used to calculate years of life lived with disability (YLDs). YLDs were added to the years of life lost due to premature mortality to estimate the overall burden (disability-adjusted life years (DALYs)) for RA for the years 1990, 2005 and 2010. Results The global prevalence of RA was 0.24% (95% CI 0.23% to 0.25%), with no discernible change from 1990 to 2010. DALYs increased from 3.3 million (M) (95% CI 2.6 M to 4.1 M) in 1990 to 4.8 M (95% CI 3.7 M to 6.1 M) in 2010. This increase was due to a growth in population and increase in aging. Globally, of the 291 conditions studied, RA was ranked as the 42nd highest contributor to global disability, just below malaria and just above iodine deficiency (measured in YLDs). Conclusions RA continues to cause modest global disability, with severe consequences in the individuals affected.

Safety of synthetic and biological DMARDs: a systematic literature review informing the 2013 update of the EULAR recommendations for management of rheumatoid arthritis

Abstract: Objectives To update the evidence for the safety of synthetic disease-modifying antirheumatic drugs (sDMARDs), glucocorticoids (GC) and biological DMARDs (bDMARDs) in patients with rheumatoid arthritis (RA) to inform the European League Against Rheumatism (EULAR) recommendations for the management of RA. Methods Systematic literature review (SLR) of observational studies (including registries). Interventions were any bDMARD (anakinra, infliximab, etanercept, adalimumab, rituximab, abatacept, tocilizumab, golimumab or certolizumab pegol) or sDMARD (methotrexate, leflunomide, hydroxychloroquine, sulfasalazine, gold/auranofin, azathioprine, chlorambucil, chloroquine, cyclosporin, cyclophosphamide, mycophenolate, minocycline, penicillamine, tacrolimus or tofacitinib) and a comparator was required. Information on GCs was collected from the included studies. All safety outcomes were included. Results Forty-nine observational studies addressing diverse safety outcomes of therapy with bDMARDs met eligibility criteria. Substantial heterogeneity precluded meta-analysis of any of the outcomes. Patients on tumour necrosis factor inhibitors (TNFi) compared to patients on conventional sDMARDs had a higher risk of serious infections (adjusted HR (aHR) 1.1–1.8), a higher risk of tuberculosis, and an increased risk of infection by herpes zoster cannot be excluded. Patients on TNFi did not have an increased risk for malignancies in general, lymphoma or non-melanoma skin cancer, but the risk of melanoma may be slightly increased (aHR 1.5). From the studies identified on conventional sDMARDs, no new safety signals were found. Conclusions The findings from this SLR confirm the known safety pattern of sDMARDs and bDMARDs for the treatment of RA.

FRI0298 The Impact of DMARD Co-Therapy on Abatacept Effectiveness in Rheumatoid Arthritis Patients. A Pan-European Analysis of RA Registries

Abstract: Background Biological disease-modifying anti-rheumatic drugs (bioDMARDs) are generally used in combination with conventional synthetic DMARDs (csDMARDs) in the treatment of rheumatoid arthritis (RA). Anti-TNF agents are more effective in combination with csDMARDs (COMBO) than as monotherapy (MONO), while this is debated with some of the newer bioDMARDs.(1) In particular, no difference was found in patients (pts) with insufficient response to TNF-inhibitors taking abatacept (ABA) in MONO vs. COMBO.(2) Objectives To compare the effectiveness of ABA started as MONO or in COMBO in RA pts treated in routine care. Methods This is a pooled observational database analysis of 9 prospective cohorts of RA pts (Czech Republic, Denmark, France, Italy, Norway, Portugal, Spain, Sweden, Switzerland). We included all RA pts treated with ABA with information on concomitant csDMARDs use at initiation of ABA treatment. Primary endpoint was drug retention of ABA, defined as the time between drug initiation and last administration plus one dispensation interval, and analyzed using a Cox proportional hazards model. A secondary endpoint was EULAR good or moderate response rate at one year, estimated by longitudinal interpolation and corrected for drug retention (Lundex (3)). All analyses were adjusted for potential confounders, e.g. calendar year, demographics, country and disease characteristics. Results We identified 3461 pts initiating ABA with 5475 pt-years of follow-up. Of these, 2314 pts (67%) received ABA in COMBO (53% - methotrexate, 8% - leflunomide, 6% - other csDMARDs) and 1147 pts (33%) in MONO. Pts on MONO were older (mean 59 vs. 57 years, p The median retention time of ABA in MONO was 2.02 years (IQR: 1.76 – 2.27) compared to 2.05 years (IQR: 1.90 – 2.22) in COMBO (p=0.76). No significant difference in ABA retention rates was found with or without sDMARD cotherapy (Hazard Ratio (HR) MONO vs COMBO: 1.02 (95%CI: 0.92 – 1.13)). Furthermore, ABA drug retention did not differ between the various sDMARDs cotherapy combinations. Results remained similar when examining only ABA treatment discontinuations for ineffectiveness (HR MONO vs COMBO: 0.97 (95%CI: 0.84 – 1.13)). Furthermore, both the EULAR response rates and the Lundex based on EULAR response rates at one year were similar with or without sDMARD cotherapy (81% EULAR good or moderate responses on ABA MONO vs. 80% on COMBO, p=0.55. Lundex responders 55% on ABA MONO vs. 55% on COMBO, p=0.91). We found no effect modification by country. Conclusions The results of this large pooled RA population of mostly inadequate responders to anti-TNFs, suggest that ABA retention and response to ABA treatment are not influenced by csDMARDs cotherapy. References Emery P. et al. Ann Rheum Dis. 2013 Dec;72(12):1897-904. Schiff M et al. Ann Rheum Dis 2009;68:1708–14. Kristensen LE. et al. Arthritis Rheum. 2006 Feb;54(2):600-6. Disclosure of Interest A. Finckh Grant/research support: Unrestricted Research grant from BMS, D. Neto Grant/research support: Unrestricted Research grant from BMS, J. Gomez-Reino: None declared, F. Iannone: None declared, E. Lie: None declared, H. Canhao: None declared, K. Pavelka: None declared, C. Turesson: None declared, X. Mariette: None declared, J.-E. Gottenberg: None declared, M. Hetland: None declared DOI 10.1136/annrheumdis-2014-eular.3004

Evidence-based detection of pulmonary arterial hypertension in systemic sclerosis: the DETECT study

Abstract: Objective Earlier detection of pulmonary arterial hypertension (PAH), a leading cause of death in systemic sclerosis (SSc), facilitates earlier treatment. The objective of this study was to develop the first evidence-based detection algorithm for PAH in SSc. Methods In this cross-sectional, international study conducted in 62 experienced centres from North America, Europe and Asia, adults with SSc at increased risk of PAH (SSc for >3 years and predicted pulmonary diffusing capacity for carbon monoxide <60%) underwent a broad panel of non-invasive assessments followed by diagnostic right heart catheterisation (RHC). Univariable and multivariable analyses selected the best discriminatory variables for identifying PAH. After assessment for clinical plausibility and feasibility, these were incorporated into a two-step, internally validated detection algorithm. Nomograms for clinical practice use were developed. Results Of 466 SSc patients at increased risk of PAH, 87 (19%) had RHC-confirmed PAH. PAH was mild (64% in WHO functional class I/II). Six simple assessments in Step 1 of the algorithm determined referral to echocardiography. In Step 2, the Step 1 prediction score and two echocardiographic variables determined referral to RHC. The DETECT algorithm recommended RHC in 62% of patients (referral rate) and missed 4% of PAH patients (false negatives). By comparison, applying European Society of Cardiology/European Respiratory Society guidelines to these patients, 29% of diagnoses were missed while requiring an RHC referral rate of 40%. Conclusions The novel, evidence-based DETECT algorithm for PAH detection in SSc is a sensitive, noninvasive tool which minimises missed diagnoses, identifies milder disease and addresses resource usage.

The global burden of neck pain

Abstract: Objective To estimate the global burden of neck pain. Methods Neck pain was defined as pain in the neck with or without pain referred into one or both upper limbs that lasts for at least 1 day. Systematic reviews were performed of the prevalence, incidence, remission, duration and mortality risk of neck pain. Four levels of severity were identified for neck pain with and without arm pain, each with their own disability weights. A Bayesian meta-regression method was used to pool prevalence and derive missing age/sex/region/year values. The disability weights were applied to prevalence values to derive the overall disability of neck pain expressed as years lived with disability (YLDs). YLDs have the same value as disability-adjusted life years as there is no evidence of mortality associated with neck pain. Results The global point prevalence of neck pain was 4.9% (95% CI 4.6 to 5.3). Disability-adjusted life years increased from 23.9 million (95% CI 16.5 to 33.1) in 1990 to 33.6 million (95% CI 23.5 to 46.5) in 2010. Out of all 291 conditions studied in the Global Burden of Disease 2010 Study, neck pain ranked 4th highest in terms of disability as measured by YLDs, and 21st in terms of overall burden. Conclusions Neck pain is a common condition that causes substantial disability. With aging global populations, further research is urgently needed to better understand the predictors and clinical course of neck pain, as well as the ways in which neck pain can be prevented and better managed.

Efficacy and safety of the anti-IL-12/23 p40 monoclonal antibody, ustekinumab, in patients with active psoriatic arthritis despite conventional non-biological and biological anti-tumour necrosis factor therapy: 6-month and 1-year results of the phase 3, multicentre, double-blind, placebo-controlled, randomised PSUMMIT 2 trial

Abstract: Objective Assess ustekinumab efficacy (week 24/week 52) and safety (week 16/week 24/week 60) in patients with active psoriatic arthritis (PsA) despite treatment with conventional and/or biological anti-tumour necrosis factor (TNF) agents. Methods In this phase 3, multicentre, placebo-controlled trial, 312 adults with active PsA were randomised (stratified by site, weight (≤100 kg/>100 kg), methotrexate use) to ustekinumab 45 mg or 90 mg at week 0, week 4, q12 weeks or placebo at week 0, week 4, week 16 and crossover to ustekinumab 45 mg at week 24, week 28 and week 40. At week 16, patients with Results More ustekinumab-treated (43.8% combined) than placebo-treated (20.2%) patients achieved ACR20 at week 24 (p Conclusions The interleukin-12/23 inhibitor ustekinumab (45/90 mg q12 weeks) yielded significant and sustained improvements in PsA signs/symptoms in a diverse population of patients with active PsA, including anti-TNF-experienced PsA patients.

Treat-to-target in systemic lupus erythematosus: recommendations from an international task force

Abstract: The principle of treating-to-target has been successfully applied to many diseases outside rheumatology and more recently to rheumatoid arthritis. Identifying appropriate therapeutic targets and pursuing these systematically has led to improved care for patients with these diseases and useful guidance for healthcare providers and administrators. Thus, an initiative to evaluate possible therapeutic targets and develop treat-to-target guidance was believed to be highly appropriate in the management of systemic lupus erythematosus (SLE) patients as well. Specialists in rheumatology, nephrology, dermatology, internal medicine and clinical immunology, and a patient representative, contributed to this initiative. The majority convened on three occasions in 2012-2013. Twelve topics of critical importance were identified and a systematic literature review was performed. The results were condensed and reformulated as recommendations, discussed, modified and voted upon. The finalised bullet points were analysed for degree of agreement among the task force. The Oxford Centre level of evidence (LoE, corresponding to the research questions) and grade of recommendation (GoR) were determined for each recommendation. The 12 systematic literature searches and their summaries led to 11 recommendations. Prominent features of these recommendations are targeting remission, preventing damage and improving quality of life. LoE and GoR of the recommendations were variable but agreement was >0.9 in each case. An extensive research agenda was identified, and four overarching principles were also agreed upon. Treat-to-target-in-SLE (T2T/SLE) recommendations were developed by a large task force of multispecialty experts and a patient representative. It is anticipated that 'treating-to-target' can and will be applicable to the care of patients with SLE.

Incidence and risk factors for clinically diagnosed knee, hip and hand osteoarthritis: influences of age, gender and osteoarthritis affecting other joints

Abstract: Objectives Data on the incidence of symptomatic osteoarthritis (OA) are scarce. We estimated incidence of clinical hip, knee and hand OA, and studied the effect of prevalent OA on joint-specific incident OA. Methods SIDIAP contains primary care records for>5 million people from Catalonia (Spain). Participants aged ≥40 years with an incident diagnosis of knee, hip or hand OA between 2006 and 2010 were identified using International Classification of Diseases (ICD)-10 codes. Incidence rates and female-to-male rate ratios (RRs) for each joint site were calculated. Age, gender and body mass index-adjusted HR for future joint-specific OA according to prevalent OA at other sites were estimated using Cox regression. Results 3 266 826 participants were studied for a median of 4.45 years. Knee and hip OA rates increased continuously with age, and female-to-male RRs were highest at age 70–75 years. In contrast, female hand OA risk peaked at age 60–64 years, and corresponding female-to-male RR was highest at age 50–55 years. Adjusted HR for prevalent knee OA on risk of hip OA was 1.35 (99% CI 1.28 to 1.43); prevalent hip OA on incident knee OA: HR 1.15 (1.08 to 1.23). Prevalent hand OA predicted incident knee and hip OA: HR 1.20 (1.14 to 1.26) and 1.23 (1.13 to 1.34), respectively. Conclusions The effect of age is greatest in the elderly for knee and hip OA, but around the menopause for hand OA. OA clusters within individuals, with higher risk of incident knee and hip disease from prevalent lower limb and hand OA.

International recommendations for the assessment of autoantibodies to cellular antigens referred to as anti-nuclear antibodies

Abstract: Anti-nuclear antibodies (ANA) are fundamental for the diagnosis of autoimmune diseases, and have been determined by indirect immunofluorescence assay (IIFA) for decades. As the demand for ANA testing increased, alternative techniques were developed challenging the classic IIFA. These alternative platforms differ in their antigen profiles, sensitivity and specificity, raising uncertainties regarding standardisation and interpretation of incongruent results. Therefore, an international group of experts has created recommendations for ANA testing by different methods. Two groups of experts participated in this initiative. The European autoimmunity standardization initiative representing 15 European countries and the International Union of Immunologic Societies/World Health Organization/Arthritis Foundation/Centers for Disease Control and Prevention autoantibody standardising committee. A three-step process followed by a Delphi exercise with closed voting was applied. Twenty-five recommendations for determining ANA (1-13), anti-double stranded DNA antibodies (14-18), specific antibodies (19-23) and validation of methods (24-25) were created. Significant differences between experts were observed regarding recommendations 24-25 (p<0.03). Here, we formulated recommendations for the assessment and interpretation of ANA and associated antibodies. Notably, the roles of IIFA as a reference method, and the importance of defining nuclear and cytoplasmic staining, were emphasised, while the need to incorporate alternative automated methods was acknowledged. Various approaches to overcome discrepancies between methods were suggested of which an improved bench-to-bedside communication is of the utmost importance. These recommendations are based on current knowledge and can enable harmonisation of local algorithms for testing and evaluation of ANA and related autoantibodies. Last but not least, new more appropriate terminologies have been suggested.

Treating spondyloarthritis, including ankylosing spondylitis and psoriatic arthritis, to target: recommendations of an international task force

Abstract: Background Therapeutic targets have been defined for diseases like diabetes, hypertension or rheumatoid arthritis and adhering to them has improved outcomes. Such targets are just emerging for spondyloarthritis (SpA). Objective To define the treatment target for SpA including ankylosing spondylitis and psoriatic arthritis (PsA) and develop recommendations for achieving the target, including a treat-to-target management strategy. Methods Based on results of a systematic literature review and expert opinion, a task force of expert physicians and patients developed recommendations which were broadly discussed and voted upon in a Delphi-like process. Level of evidence, grade and strength of the recommendations were derived by respective means. The commonalities between axial SpA, peripheral SpA and PsA were discussed in detail. Results Although the literature review did not reveal trials comparing a treat-to-target approach with another or no strategy, it provided indirect evidence regarding an optimised approach to therapy that facilitated the development of recommendations. The group agreed on 5 overarching principles and 11 recommendations; 9 of these recommendations related commonly to the whole spectrum of SpA and PsA, and only 2 were designed separately for axial SpA, peripheral SpA and PsA. The main treatment target, which should be based on a shared decision with the patient, was defined as remission, with the alternative target of low disease activity. Follow-up examinations at regular intervals that depend on the patient9s status should safeguard the evolution of disease activity towards the targeted goal. Additional recommendations relate to extra-articular and extramusculoskeletal aspects and other important factors, such as comorbidity. While the level of evidence was generally quite low, the mean strength of recommendation was 9–10 (10: maximum agreement) for all recommendations. A research agenda was formulated. Conclusions The task force defined the treatment target as remission or, alternatively, low disease activity, being aware that the evidence base is not strong and needs to be expanded by future research. These recommendations can inform the various stakeholders about expert opinion that aims for reaching optimal outcomes of SpA.

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

Abstract: Objectives To evaluate the efficacy and safety of certolizumab pegol (CZP) after 24 weeks in RAPIDaxSpA (NCT01087762), an ongoing Phase 3 trial in patients with axial spondyloarthritis (axSpA), including patients with ankylosing spondylitis (AS) and nonradiographic 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.

Treatment of psoriatic arthritis in a phase 3 randomised, placebo-controlled trial with apremilast, an oral phosphodiesterase 4 inhibitor

Abstract: Objectives Apremilast, an oral phosphodiesterase 4 inhibitor, regulates inflammatory mediators. Psoriatic Arthritis Long-term Assessment of Clinical Efficacy 1 (PALACE 1) compared apremilast with placebo in patients with active psoriatic arthritis despite prior traditional disease-modifying antirheumatic drug (DMARD) and/or biologic therapy. Methods In the 24-week, placebo-controlled phase of PALACE 1, patients (N=504) were randomised (1:1:1) to placebo, apremilast 20 mg twice a day (BID) or apremilast 30 mg BID. At week 16, patients without ≥20% reduction in swollen and tender joint counts were required to be re-randomised equally to either apremilast dose if initially randomised to placebo or remained on their initial apremilast dose. Patients on background concurrent DMARDs continued stable doses (methotrexate, leflunomide and/or sulfasalazine). Primary outcome was the proportion of patients achieving 20% improvement in modified American College of Rheumatology response criteria (ACR20) at week 16. Results At week 16, significantly more apremilast 20 mg BID (31%) and 30 mg BID (40%) patients achieved ACR20 versus placebo (19%) (p Conclusions Apremilast was effective in the treatment of psoriatic arthritis, improving signs and symptoms and physical function. Apremilast demonstrated an acceptable safety profile and was generally well tolerated. Clinical trial registration number NCT01172938.

Efficacy and safety of secukinumab, a fully human anti-interleukin-17A monoclonal antibody, in patients with moderate-to-severe psoriatic arthritis: a 24-week, randomised, double-blind, placebo-controlled, phase II proof-of-concept trial

Abstract: Objective To evaluate the efficacy and safety of secukinumab, a fully human, anti-interleukin (IL)-17A monoclonal antibody, in patients with psoriatic arthritis (PsA). Methods 42 patients with active PsA fulfilling ClASsification for Psoriatic ARthritis (CASPAR) criteria were randomly assigned (2:1) to receive two intravenous secukinumab doses (10 mg/kg; n=28) or placebo (n=14) 3 weeks apart. The primary endpoint was the proportion of American College of Rheumatology (ACR) 20 responses at week 6 for secukinumab versus placebo (one-sided p Results Primary endpoint: ACR20 responses at week 6 were 39% (9/23) for secukinumab versus 23% (3/13) for placebo (p=0.27). ACR20 responses were greater with secukinumab versus placebo at week 12 (39% (9/23) vs 15% (2/13), p=0.13) and week 24 (43% (10/23) vs 18% (2/11), p= 0.14). At week 6, ‘good’ European League Against Rheumatism response was seen in 21.7% (5/23) secukinumab versus 9.1% (1/11) placebo patients. Compared with placebo at week 6, significant reductions were observed among secukinumab recipients for C reactive protein (p=0.039), erythrocyte sedimentation rate (p=0.038), Health Assessment Questionnaire Disability Index (p=0.002) and Short Form Health Survey (SF-36; p=0.030) scores. The overall adverse event (AE) frequency was comparable between secukinumab (26 (93%)) and placebo (11 (79%)) recipients. Six serious AEs (SAEs) were reported in four secukinumab patients and one SAE in one placebo patient. Conclusions Although the primary endpoint was not met, clinical responses, acute-phase reactant and quality of life improvements were greater with secukinumab versus placebo, suggesting some clinical benefit. Secukinumab exhibited satisfactory safety. Larger clinical trials of secukinumab in PsA are warranted.

Proof of concept: enthesitis and new bone formation in spondyloarthritis are driven by mechanical strain and stromal cells

Abstract: Objectives Spondyloarthritides (SpA) are characterised by both peripheral and axial arthritis. The hallmarks of peripheral SpA are the development of enthesitis, most typically of the Achilles tendon and plantar fascia, and new bone formation. This study was undertaken to unravel the mechanisms leading towards enthesitis and new bone formation in preclinical models of SpA. Results First, we demonstrated that TNF ΔARE mice show typical inflammatory features highly reminiscent of SpA. The first signs of inflammation were found at the entheses. Importantly, enthesitis occurred equally in the presence or absence of mature T and B cells, underscoring the importance of stromal cells. Hind limb unloading in TNF ΔARE mice significantly suppressed inflammation of the Achilles tendon compared with weight bearing controls. Erk1/2 signalling plays a crucial role in mechanotransduction-associated inflammation. Furthermore, new bone formation is strongly promoted at entheseal sites by biomechanical stress and correlates with the degree of inflammation. Conclusions These findings provide a formal proof of the concept that mechanical strain drives both entheseal inflammation and new bone formation in SpA.

Efficacy and safety of epratuzumab in patients with moderate/severe active systemic lupus erythematosus: results from EMBLEM, a phase IIb, randomised, double-blind, placebo-controlled, multicentre study.

Abstract: Objective To identify a suitable dosing regimen of the CD22-targeted monoclonal antibody epratuzumab in adults with moderately to severely active systemic lupus erythematosus (SLE). Methods A phase IIb, multicentre, randomised controlled study (NCT00624351) was conducted with

Efficacy of biological disease-modifying antirheumatic drugs: a systematic literature review informing the 2013 update of the EULAR recommendations for the management of rheumatoid arthritis

Abstract: Objectives To update the evidence for the efficacy of biological disease-modifying antirheumatic drugs (bDMARD) in patients with rheumatoid arthritis (RA) to inform the European League Against Rheumatism(EULAR) Task Force treatment recommendations. Methods Medline, Embase and Cochrane databases were searched for articles published between January 2009 and February 2013 on infliximab, etanercept, adalimumab, certolizumab-pegol, golimumab, anakinra, abatacept, rituximab, tocilizumab and biosimilar DMARDs (bsDMARDs) in phase 3 development. Abstracts from 2011 to 2012 American College of Rheumatology (ACR) and 2011–2013 EULAR conferences were obtained. Results Fifty-one full papers, and 57 abstracts were identified. The randomised controlled trials (RCT) confirmed the efficacy of bDMARD+conventional synthetic DMARDs (csDMARDs) versus csDMARDs alone (level 1B evidence). There was some additional evidence for the use of bDMARD monotherapy, however bDMARD and MTX combination therapy for all bDMARD classes was more efficacious (1B). Clinical and radiographic responses were high with treat-to-target strategies. Earlier improvement in signs and symptoms were seen with more intensive initial treatment strategies, but outcomes were similar upon addition of bDMARDs in patients with insufficient response to MTX. In general, radiographic progression was lower with bDMARD use, mainly due to initial treatment effects. Although patients may achieve bDMARD- and drug-free remission, maintenance of clinical responses was higher with bDMARD continuation (1B), but bDMARD dose reduction could be applied (1B). There was still no RCT data for bDMARD switching. Conclusions The systematic literature review confirms efficacy of biological DMARDs in RA. It addresses different treatment strategies with the potential for reduction in therapy, particularly with early disease control, and highlights emerging therapies.

A patient-derived and patient-reported outcome measure for assessing psoriatic arthritis: elaboration and preliminary validation of the Psoriatic Arthritis Impact of Disease (PsAID) questionnaire, a 13-country EULAR initiative

Abstract: Introduction The objective was to develop a questionnaire that can be used to calculate a score reflecting the impact of psoriatic arthritis (PsA) from the patients’ perspective: the PsA Impact of Disease (PsAID) questionnaire. Methods Twelve patient research partners identified important domains (areas of health); 139 patients prioritised them according to importance. Numeric rating scale (NRS) questions were developed, one for each domain. To combine the domains into a single score, relative weights were determined based on the relative importance given by 474 patients with PsA. An international cross-sectional and longitudinal validation study was performed in 13 countries to examine correlations of the PsAID score with other PsA or generic disease measures. Test–retest reliability and responsiveness (3 months after a treatment change) were examined in two subsets of patients. Results Two PsAID questionnaires were developed with both physical and psychological domains: one for clinical practice (12 domains of health) and one for clinical trials (nine domains). Pain, fatigue and skin problems had the highest relative importance. The PsAID scores correlated well with patient global assessment (N=474, Spearman r=0.82–0.84), reliability was high in stable patients (N=88, intraclass correlation coefficient=0.94–0.95), and sensitivity to change was also acceptable (N=71, standardised response mean=0.90–0.91). Conclusions A questionnaire to assess the impact of PsA on patients’ lives has been developed and validated. Two versions of the questionnaire are available, one for clinical practice (PsAID-12) and one for clinical trials (PsAID-9). The PsAID questionnaires should allow better assessment of the patient9s perspective in PsA. Further validation is needed.

Bone loss before the clinical onset of rheumatoid arthritis in subjects with anticitrullinated protein antibodies

Abstract: Objective Anticitrullinated protein antibodies (ACPA) are a major risk factor for bone loss in rheumatoid arthritis (RA). We have recently shown that ACPA directly induce bone loss by stimulating osteoclast differentiation. As ACPA precede the clinical onset of RA by years, we hypothesised that ACPA positive healthy individuals may already show skeletal changes. Methods We performed a comparative micro-CT analysis of the bone microstructure in the metacarpophalangeal joints of ACPA positive and ACPA negative healthy individuals without clinical signs of arthritis. Results ACPA positive (n=15) and negative (n=15) healthy individuals were not different in age (48.2±4.1 vs 51.4±3.8 years, p=0.57) or gender (eight women and two men in both groups). Bone mineral density was significantly reduced in ACPA positive individuals (mean±SEM 280±11 mg/cm 3 ) compared with controls (327±6). Bone loss was based on cortical bone changes, with significant (p=0.044) reduction in cortical thickness in the ACPA positive group (mean±SEM 0.22±0.03 mm) compared with controls (0.32±0.03 mm). Areas of cortical porosity were significantly (p=0.0005) more widespread in ACPA positive (mean±SEM 7.4±1.4%) than in ACPA negative individuals (1.0±0.3%). Discussion Structural bone damage starts before the clinical onset of arthritis in subjects with ACPA. These findings revise the concept that bone damage is an exclusive consequence of synovitis in patients with RA.

Inequities in access to biologic and synthetic DMARDs across 46 European countries

Abstract: OBJECTIVES: We investigated access to biologic and synthetic disease modifying drugs (bDMARDs and sDMARDs) in patients with rheumatoid arthritis (RA) across Europe. METHODS: A cross-sectional study at national level was performed in 49 European countries. A questionnaire was sent to one expert, addressing the number of approved and reimbursed bDMARDs and sDMARDs, prices and co-payments, as well as acceptability of bDMARDs (barriers). Data on socio-economic welfare (gross domestic product per capita (GDP), health expenditure, income) were retrieved from web-based sources. Data on health status of RA patients were retrieved from an observational study. Dimensions of access (availability, affordability and acceptability) were correlated with the country's welfare and RA health status. RESULTS: In total, 46 countries (94%) participated. Six countries did not reimburse any of the five sDMARDs surveyed, and in ten countries no bDMARDs were reimbursed. While the price of annual treatment with an average sDMARD was never higher than GPD, the price of one year treatment with a bDMARD exceeded GPD in 26 countries. Perceived barriers for access to bDMARDs were mainly found among financial and administrative restrictions. All dimensions of access were positively correlated with the country's economic welfare (coefficients 0.69 to 0.86 for overall access scores). CONCLUSIONS: Patients with RA in lower income European countries have less access to bDMARDs and sDMARDs, with particularly striking unaffordability of bDMARDs in some of these countries. When accepting that sDMARDs and bDMARDs are equally needed across countries to treat RA, our data point to inequities in access to pharmacological treatment for RA in Europe.

FRI0296 Is There A Difference in the Effectiveness in the Treatment of Rheumatoid Arthritis with Rituximab in Patients with Rheumatoid Factor Positive and Negative? A Systematic Review

Abstract: Background Since the description of the efficacy of rituximab (RTX) in treating patients with rheumatoid arthritis (RA), the use of this drug has been extended. However it is not clearly established the patient profile in which the administration of RTX may show greater benefit. Objectives To systematically review the published evidence to date regarding on the difference in efficacy in the treatment of RA with RTX in patients with rheumatoid factor (RF) positive and negative. Methods A sensitive search of all published studies on the difference in the efficacy of RTX in RA patients with RF positive and negative was performed in Medline, Embase and Cochrane Central databases since its inception until July 2013. We selected all studies involving adult patients with RA seropositive for RF in which intervention was described as treatment with RTX and comparator as the administration of RTX to adult patients with RA seronegative for RF. Any standardized measure of efficacy in RA was considered as outcome measure. Although meta analysis, systematic reviews, clinical trials and cohorts well designed were preferably selected, finally we also included open studies and all studies that showed a methodologically correct subanalysis related to the question even if it had not been his main objective. After removing duplicates, an initial selection by reading titles, a second selection after reading abstracts and, finally, full reading of selected studies, assessing the methodological quality by levels of the Oxford Centre for Evidence Based Medicine Evidence (2001 update) where applicable, was carried out. A manual search of the references of included studies was also performed. Results A total of 362 citations about the treatment with RTX of RA patients seropositive and seronegative for RF were identified, which were reduced to 54 after removing duplicates and selection by reading titles and abstracts. Of the 54 selected articles, finally 36 were included in the review, one of which is a meta analysis that includes four of the clinical trials included in that review and their conclusions define de result of the same given the highest quality from the methodological point of view. The rest are 5 clinical trials, 7 prospective studies, 7 retrospective and 16 communications to Congresses or sub-analysis of previous studies. Conclusions RTX shows greater efficacy in the treatment of RA patients seropositive respect to seronegative, both in intensity and response rate (level of evidence 1a, grade of recommendation A). However, despite the level of evidence, due to the modest difference in efficacy between seropositive and seronegative patients and the results obtained after treatment with RTX in seronegative ones, it would be necessary the implementation of studies in this subgroup of patients to define the role of RTX in the treatment thereof. Acknowledgements This work has been funded by the Spanish Society of Rheumatology. Disclosure of Interest A. M. Ortiz Grant/research support: Spanish Society of Rheumatology, M. Rosario Lozano: None declared, C. Martinez Fernandez: None declared, I. Gonzalez-Άlvaro Grant/research support: Spanish Society of Rheumatology DOI 10.1136/annrheumdis-2014-eular.4000

Racial disparities in knee and hip total joint arthroplasty: an 18-year analysis of national medicare data

Abstract: Objective To examine whether racial disparities in usage and outcomes of total knee and total hip arthroplasty (TKA and THA) have declined over time. Methods We used data from the US Medicare Program (MedPAR data) for years 1991–2008 to identify four separate cohorts of patients (primary TKA, revision TKA, primary THA, revision THA). For each cohort, we calculated standardised arthroplasty usage rates for Caucasian and African–American Medicare beneficiaries for each calendar year, and examined changes in disparities over time. We examined unadjusted and adjusted outcomes (30-day readmission rate, discharge disposition etc.) for Caucasians and African–Americans, and whether disparities decreased over time. Results In 1991, the use of primary TKA was 36% lower for African–Americans compared with Caucasians (20.6 per 10 000 for African–Americans; 32.1 per 10 000 for Caucasians; p Conclusions In an 18-year analysis of US Medicare data, we found little evidence of declines in racial disparities for joint arthroplasty usage or outcomes.

Efficacy and safety of strontium ranelate in the treatment of knee osteoarthritis: results of a double-blind, randomised placebo-controlled trial

Abstract: Background Strontium ranelate is currently used for osteoporosis. The international, double-blind, randomised, placebo-controlled Strontium ranelate Efficacy in Knee OsteoarthrItis triAl evaluated its effect on radiological progression of knee osteoarthritis. Methods Patients with knee osteoarthritis (Kellgren and Lawrence grade 2 or 3, and joint space width (JSW) 2.5–5 mm) were randomly allocated to strontium ranelate 1 g/day (n=558), 2 g/day (n=566) or placebo (n=559). The primary endpoint was radiographical change in JSW (medial tibiofemoral compartment) over 3 years versus placebo. Secondary endpoints included radiological progression, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score, and knee pain. The trial is registered (ISRCTN41323372). Results The intention-to-treat population included 1371 patients. Treatment with strontium ranelate was associated with smaller degradations in JSW than placebo (1 g/day: −0.23 (SD 0.56) mm; 2 g/day: −0.27 (SD 0.63) mm; placebo: −0.37 (SD 0.59) mm); treatment-placebo differences were 0.14 (SE 0.04), 95% CI 0.05 to 0.23, p Conclusions Treatment with strontium ranelate 1 and 2 g/day is associated with a significant effect on structure in patients with knee osteoarthritis, and a beneficial effect on symptoms for strontium ranelate 2 g/day.

Ustekinumab, an anti-IL-12/23 p40 monoclonal antibody, inhibits radiographic progression in patients with active psoriatic arthritis: results of an integrated analysis of radiographic data from the phase 3, multicentre, randomised, double-blind, placebo-controlled PSUMMIT-1 and PSUMMIT-2 trials

Abstract: Objective Evaluate ustekinumab, an anti-interleukin (IL)-12 and IL-23 antibody, effects on radiographic progression in psoriatic arthritis (PsA). Methods We conducted preplanned integrated analyses of combined radiographic data from PSUMMIT-1 and PSUMMIT-2 phase 3, randomised, controlled trials. Patients had active PsA despite prior conventional and/or biologic disease-modifying antirheumatic drugs (≥5/66 swollen, ≥5/68 tender joints, C-reactive protein ≥3.0 mg/L, documented plaque psoriasis). Patients (PSUMMIT-1, n=615; PSUMMIT-2, n=312) were randomised to ustekinumab 45 mg, 90 mg, or placebo, at weeks (wk) 0, 4 and every (q) 12 wks. At wk 16, patients with Results Integrated data analysis results indicated that ustekinumab-treated patients (regardless of dose) demonstrated significantly less radiographic progression at wk 24 than did placebo recipients (wk 0–24 total vdH-S score mean changes: 0.4-combined/individual ustekinumab dose groups, 1.0-placebo; all p Conclusions Ustekinumab 45 and 90 mg treatments significantly inhibited radiographic progression of joint damage in patients with active PsA.

Continuous long-term anti-TNF therapy does not lead to an increase in the rate of new bone formation over 8 years in patients with ankylosing spondylitis

Abstract: Objective Compare the radiographic progression of ankylosing spondylitis (AS) patients treated with infliximab (INF) versus historical controls (Herne cohort, HC) never treated with tumour necrosis factor (TNF)-blockers over 8 years. Methods Patients were selected based on the availability of lateral cervical and lumbar radiographs at baseline (BL) and after 8 years. Radiographs were scored by two blinded readers using modified Stokes AS spinal score (mSASSS). Mixed linear models were applied to compare radiographic progression between cohorts after adjustment for baseline status. Results Patients in INF (n=22) and HC (n=34) did not differ in the mSASSS status: 13.2±17.6 in INF versus 14.2±13.8 in HC (p=0.254). Both showed progression at 8 years: mean mSASSS 20.2±21.4 in INF and 25.9±17.8 in HC. After adjustment for baseline damage the mean mSASSS (SEM) at 8 years was 21.0 (1.4) in INF and 25.5 (1.1) HC (p=0.047). The mean mSASSS difference was similar in the groups between baseline and 4 years but was more pronounced in HC between 4 and 8 years (p=0.03 between groups). The mean number of syndesmophytes, although similar at baseline, differed significantly at 8 years: 1.0±0.6 new syndesmophytes/patient in INF versus 2.7±0.8 in HC (p=0.007). Adjustment for age, symptom duration, HLA-B27, Bath AS disease activity index and Bath AS function index at baseline had no influence. Conclusions Despite limitations of patient numbers and retrospective study design, these data show increase in new bone formation in both patients treated with anti-TNF and those who did not. However, since there was even less bone formation in the INF treated group after 8 years, these data argue against a major role for the TNF-brake hypothesis.

Head-to-head comparison of subcutaneous abatacept versus adalimumab for rheumatoid arthritis: two-year efficacy and safety findings from AMPLE trial

Abstract: Objectives To compare over 2 years the safety, efficacy and radiographic outcomes of subcutaneous abatacept versus adalimumab, in combination with methotrexate (MTX), in patients with rheumatoid arthritis (RA). Methods AMPLE is a phase IIIb, 2-year, randomised, investigator-blinded study with a 1-year primary endpoint. Biologic-naive patients with active RA and an inadequate response to MTX were randomised to 125 mg abatacept weekly or 40 mg adalimumab bi-weekly, both with a stable dose of MTX. Results Of 646 patients randomised, 79.2% abatacept and 74.7% adalimumab patients completed year 2. At year 2, efficacy outcomes, including radiographic, remained comparable between groups and with year 1 results. The American College Rheumatology 20, 50 and 70 responses at year 2 were 59.7%, 44.7% and 31.1% for abatacept and 60.1%, 46.6% and 29.3% for adalimumab. There were similar rates of adverse events (AEs) and serious adverse events (SAEs). More serious infections occurred with adalimumab (3.8% vs 5.8%) including two cases of tuberculosis with adalimumab. There were fewer discontinuations due to AEs (3.8% vs 9.5%), SAEs (1.6% vs 4.9%) and serious infections (0/12 vs 9/19 patients) in the abatacept group. Injection site reactions (ISRs) occurred less frequently with abatacept (4.1% vs 10.4%). Conclusions Through 2 years of blinded treatment in this first head-to-head study between biologic disease-modifying antirheumatic drugs in RA patients with an inadequate response to MTX, subcutaneous abatacept and adalimumab were similarly efficacious based on clinical, functional and radiographic outcomes. Overall, AE frequency was similar in both groups but there were less discontinuations due to AEs, SAEs, serious infections and fewer local ISRs with abatacept. ClinicalTrials.gov Identifier NCT00929864.