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Objective.Beyond the exacerbation of pain in describing a flare in osteoarthritis (OA), patients and health professionals add other elements that deserve to be fully elucidated, such as effusion, swelling, and mobility limitation. To define and conceptualize the construct flare in OA, the objective was to identify the key variables, or symptoms, that worsen, and to clarify how these variables are described in the literature by patients and clinicians.Methods.A systematic review of the literature was conducted in Medline and PsychINFO. In brief, the search terms used were “osteoarthritis,” “knee,” “hip,” and “flare.” Specific characteristics of included studies were identified, including the type of study design, type of flare assessed, how the flare developed, and what definition of flare was used, including whether the definition was based on qualitative or quantitative analysis.Results.Pain was the major factor in the definition of flare within these studies. Four components of flare were identified: pain, other factors, composite criteria, and global assessment. While the majority of studies reported flare as an increase in pain using standardized outcome measures, only 1 study reported the antecedents and consequences of a pain flare using qualitative methods.Conclusion.The use of flare as an outcome or inclusion criterion in rheumatology trials is a common occurrence; however, this review highlights the wide variation in the definitions of OA flare currently in use and the emphasis on the measurement of pain. This variation in definition does not allow for direct comparison between trials and limits interpretation of evidence.

Summary:In this study, we report that self-perception of fracture risk captures some aspect of fracture risk not currently measured using conventional fracture prediction tools and is associated with improved medication uptake. It suggests that adequate appreciation of fracture risk may be beneficial and lead to greater healthcare engagement and treatment.Introduction:This study aimed to assess how well self-perception of fracture risk, and fracture risk as estimated by the fracture prediction tool FRAX, related to fracture incidence and uptake and persistence of anti-osteoporosis medication among women participating in the Global Longitudinal study of Osteoporosis in Women (GLOW).Methods:GLOW is an international cohort study involving 723 physician practices across 10 countries in Europe, North America and Australia. Aged ≥ 55 years, 60,393 women completed baseline questionnaires detailing medical history, including co-morbidities, fractures and self-perceived fracture risk (SPR). Annual follow-up included self-reported incident fractures and anti-osteoporosis medication (AOM) use. We calculated FRAX risk without bone mineral density measurement.Results:Of the 39,241 women with at least 1 year of follow-up data, 2132 (5.4%) sustained an incident major osteoporotic fracture over 5 years of follow-up. Within each SPR category, risk of fracture increased as the FRAX categorisation of risk increased. In GLOW, only 11% of women with a lower baseline SPR were taking AOM at baseline, compared with 46% of women with a higher SPR. AOM use tended to increase in the years after a reported fracture. However, women with a lower SPR who were fractured still reported lower AOM rates than women with or without a fracture but had a higher SPR.Conclusions:These results suggest that SPR captures some aspect of fracture risk not currently measured using conventional fracture prediction tools and is also associated with improved medication uptake.

Objective.The importance of contextual factors (CF) for appropriate patient-specific care is widely acknowledged. However, evidence in clinical trials on how CF influence outcomes remains sparse. The 2014 Outcome Measures in Rheumatology (OMERACT) Handbook introduced the role of CF in outcome assessment and defined them as “potential confounders and/or effect modifiers of outcomes in randomized controlled trials.” Subsequently, the CF Methods Group (CFMG) was formed to develop guidance on how to address CF in clinical trials.Methods.First, the CFMG conducted an e-mail survey of OMERACT working groups (WG) to analyze how they had addressed CF in outcome measurement so far. The results facilitated an informed discussion at the OMERACT 2016 CFMG Special Interest Group (SIG) session, with the aim of gaining preliminary consensus regarding an operational definition of CF and to make a first selection of potentially relevant CF.Results.The survey revealed that the WG had mostly used the OMERACT Handbook and/or the International Classification of Functioning, Disability and Health (ICF) definition. However, significant heterogeneity was found in the methods used to identify, refine, and categorize CF candidates. The SIG participants agreed on using the ICF as a framework along with the OMERACT Handbook definition. A list with 28 variables was collected including person-related factors and physical and social environments. Recommendations from the SIG guided the CFMG to formulate 3 preliminary projects on how to identify and analyze CF.Conclusion.New methods are urgently needed to assist researchers to identify and characterize CF that significantly influence the interpretation of results in clinical trials. The CFMG defined first steps to develop further guidance.

Objective.The aim of this Outcome Measures in Rheumatology (OMERACT) Working Group was to determine the core set of outcome domains and subdomains for measuring the effectiveness of shared decision-making (SDM) interventions in rheumatology clinical trials.Methods.Following the OMERACT Filter 2.0, and based on a previous literature review of SDM outcome domains and a nominal group process at OMERACT 2014, (1) an online Delphi survey was conducted to gather feedback on the draft core set and refine its domains and subdomains, and (2) a workshop was held at the OMERACT 2016 meeting to gain consensus on the draft core set.Results.A total of 170 participants completed Round 1 of the Delphi survey, and 116 completed Round 2. Respondents came from 29 countries, with 49% being patients/caregivers. Results showed that 14 out of the 17 subdomains within the 7 domains exceeded the 70% criterion (endorsement ranged from 83% to 100% of respondents). At OMERACT 2016, only 8% of the 96 attendees were patients/caregivers. Despite initial votes of support in breakout groups, there was insufficient comfort about the conceptualization of these 7 domains and 17 subdomains for these to be endorsed at OMERACT 2016 (endorsement ranged from 17% to 68% of participants).Conclusion.Differences between the Delphi survey and consensus meeting may be explained by the manner in which the outcomes were presented, variations in participant characteristics, and the context of voting. Further efforts are needed to address the limited understanding of SDM and its outcomes among OMERACT participants.

Background The RA-FQ is a new tool to measure RA flares. We have previously provided evidence of construct validity and reliability.1 Objectives We evaluated sensitivity to change of the RA-FQ in clinical trials and observational studies of RA patients with low disease activity. Methods RA patients in observational studies [CATCH-Canada (n=896) and STPR-France (n=138)], and an RCT (DRESS-Netherlands; n=178) completed 5 items asking whether they were in flare (yes/no), and if so, the severity and duration. We selected patients who said they were not in flare and had a DAS28 7 days [to increase this reflected increased inflammatory disease activity]; and c) DAS definition often used in studies (DAS28 Results The mean difference in RA-FQ scores at V2 ranged from 7.3 (95% CI 1.4, 13.2) in STPR (DAS def) to 19.6 (95% CI 16.7, 22.6) in CATCH (patient report-stringent). The standardized mean difference effect sizes (SMDES) ranged from 0.82–1.95, and were largest for patient report-stringent in 2 studies. SMDE were strong (range 0.84–2.42) for patient global, MD global, HAQ, DAS28, and other clinical indicators except ESR. The mean difference in RA-FQ scores at V2 ranged from 7.3 (95% CI 1.4, 13.2) in STPR (DAS def) to19.6 (95% CI 16.7, 22.6) in CATCH (patient report-stringent). The standardized mean difference effect sizes (SMDES) ranged from 0.82–1.95, and were largest for patient report-stringent in 2 studies. SMDE were strong (range 0.84–2.42) for patient global, MD global, HAQ, DAS28, and other clinical indicators except ESR. Conclusions Data from clinical and observational studies support the responsiveness of the RA-FQ in detecting change over time. The robust psychometric properties of the RA-FQ suggest it reliably detects clinically relevant worsening of RA symptoms consistent with increased disease activity and support its use in research and clinical care. References Bykerk V et al. RMD Open 2016;2(1):e000225. Disclosure of Interest None declared

Background Disease flares in RA are common. The RA Flare Questionnaire (RA-FQ) can be used to identify and quantify flares in rheumatoid arthritis (RA). Objectives To further explore the psychometric properties RA-FQ, we used Rasch analysis and reviewed results with RA patients research partners (PRPs) and clinicians to gain additional insight into the interpretability, meaningfulness, and utility of results. Methods People with RA in observational trials in Canada (CATCH; n=896) and France (STPR; n=138), and an RCT in the Netherlands (n=178) completed the RA-FQ. RUMM2030 was used to evaluate unidimensionality, targeting of items to people, reliability, response options, redundancy, local dependence, and response bias by sex, across age categories, and by country/language. ROC curves were used to identify sensitivity and specificity across potential threshold values to identify flares in different contexts of use. We reviewed results with RA patients research partners (PRPs) to gain additional insight into the interpretability, meaningfulness, and utility of results. Ten PRPs first completed the questionnaire then reviewed individual and group findings to provide feedback. RA clinicians provided feedback on utility and relevance of proposed cut points to identify flares. Results Rasch results supported the simple summation of items for a total score ranging from 0–50. Each item had ordered thresholds and acceptable fit. Reliability, was high (PSI =.91). Items and people covered a continuum ranging from -3.2 to +3.4 logits, and items were well-targeted to respondents. Overall model fit was excellent (χ2 =31.6, df=45; p=0.935). There was little evidence of differential item functioning by sex, age, or country/language. Items suggest flare symptoms and impacts increased together showing a consistent story of how individuals experience worsening RA disease activity. Among PRPs, scores ranged from 10 to 41. There was unanimous agreement from the patients that the story depicted and individual results obtained were easily understood, meaningful, and very reflective of their current state. Many patients noted that beyond clinical trials, the RA-FQ could also enhance communication between doctors and patients at routine visits. Several noted potential applicability in monitoring day-to-day status and with self management. Thresholds for clinically important worsening to identify flare varied by setting, patient population, and context of use. Conclusions Taken together, results from classical and Rasch analyses support for the robust psychometric properties of the RA-FQ. The 5-item measure is easy to complete and simple to score. Feedback from RA PRPs and clinicians increase confidence in the relevance, meaningfulness, and easy interpretation of RA-FQ results for clinicians, researchers, and patients. Disclosure of Interest None declared

Background Falls are the leading injury type in elderly populations and a major health burden and cause of death globally. Most of such burden is due to bone fractures. In the Global Burden of Diseases (GBD) Initiative, the attributable burden of falls due to low bone mineral density (BMD) was analysed through its relationship with fractures. Objectives To measure the percentage of disability-adjusted life years (DALYs), years lived with disability (YLDs) and deaths due to falls attributable to low BMD in European population for the year 2015. Methods The estimates followed the Counterfactual Risk Assessment Methodology used in the GBD study (1). Systematic review was performed seeking population-based studies with femoral neck (FNBMD) measured by Dual-X-Ray-Absorptiometry in people 50 years and over. Age- and sex- specific levels of mean +/-SD FNBMD (g/cm2) were extracted from eligible studies, and this was used as the exposure variable. The age and sex-specific 99th percentile from non-Hispanic whites in the National Health and Nutrition Examination Survey (NHANES) 2009–2010 was used as theoretical minimum risk factor exposure distribution, to estimate the potential impact fraction (PIF) of FNBMD for fractures. Relative risks of FNBMD for fractures were obtained from a previous meta-analysis (2). Coded hospital data was used to calculate the fraction of falls-related deaths due to fractures. Disability levels were established by applying disability weights to each type of fracture. Then, PIFs were applied to obtain attributable deaths and disability due to low BMD. Results The percentage of falls-related preventable deaths attributable to low BMD is around 9% in the 50–54 age group, increasing to 84% in those aged 80 years and over. Total health burden (DALYs) and disability attribution (YLDs) also increase with age, from 19% and 25% in 50–54 years old, respectively, to 61% and 44% and population aged 80 years and above, respectively. Low BMD constitutes the most important preventable risk factors for falls-related DALYs from 50 years and above, followed by alcohol, occupational risk and smoking. Conclusions Low BMD is a major preventable risk factor that explains a very remarkable proportion of falls health burden in Europe, in particular in those aged 70 years and above. This is a growing concern, given the population trajectories, and requires urgent attention. References Forouzanfar M et al, Lancet 2016. , Johnell O et al, JBMR 2015. Disclosure of Interest None declared

Background Context Vertebral compression fractures (VCFs) are the most common type of osteoporotic fracture comprising approximately 1.4 million cases worldwide. Clinical practice guidelines can be powerful tools for promoting evidence-based practice as they integrate research findings to support decision making. However, currently available clinical guidelines and recommendations, established by different medical societies, are sometimes contradictory. Purpose The aim of this study was to appraise the recommendations and the methodological quality of international clinical guidelines for the management of VCFs. Study Design This is a systematic review of clinical guidelines for the management of VCF. Methods Guidelines were selected by searching MEDLINE and PubMed, PEDro, CINAHL, and EMBASE electronic databases between 2010 and 2016. We also searched clinical practice guideline databases, including the National Guideline Clearinghouse and the Canadian Medical Association InfoBase. The methodological quality of the guidelines was assessed by two authors independently using the Appraisal of Guidelines, Research and Evaluation (AGREE) II Instrument. We also classified the strength of each recommendation as either strong (ie, based on high-quality studies with consistent findings for recommending for or against the intervention), weak (ie, based on a lack of compelling evidence resulting in uncertainty for benefit or potential harm), or expert consensus (ie, based on expert opinion of the working group rather than on scientific evidence). Guideline recommendations were grouped into diagnostic, conservative care, interventional care, and osteoporosis treatment and prevention of future fractures. Our study was prospectively registered on PROSPERO. Results Four guidelines from three countries, published in the period 2010–2013, were included. In general, the quality was not satisfactory (50% or less of the maximum possible score). The domains scoring 50% or less of the maximum possible score were rigor of development, clarity of presentation, and applicability. The use of plain radiography or dual-energy X-ray absorptiometry for diagnosis was recommended in two of the four guidelines. Vertebroplasty or kyphoplasty was recommended in three of the four guidelines. The recommendation for bed rest, trunk orthoses, electrical stimulation, and supervised or unsupervised exercise was inconsistent across the included guidelines. Conclusions The comparison of clinical guidelines for the management of VCF showed that diagnostic and therapeutic recommendations were generally inconsistent. The evidence available to guideline developers was limited in quantity and quality. Greater efforts are needed to improve the quality of the majority of guidelines.

OBJECTIVE Patients can potentially monitor disease activity of RA through self-assessed swollen joints (clinical synovitis), but reliability is poor. The objective is to evaluate the use of education by US feedback on the ability of patients to assess for clinical synovitis in RA. METHODS We performed a 6 month, single-centre, randomized controlled trial on patients with established RA to study the effect of education on self-assessment of joints that included initial brief patient training on tender (TJC) and swollen (SJC) joint counts followed by US feedback every 3 months vs standard care without education. Patient and physician independently performed 28-joint counts at each visit. Outcome variables included the percentage of patients with good agreement with physician-derived swollen joints [prevalence-adjusted bias-adjusted kappa (PABAK) >0.6] as well as agreement in the SJC (Bland and Altman 95% limits of agreement), feasibility/patient satisfaction survey and disease activity at 6 months. RESULTS Of the 101 randomized patients, 95 were included (51 in the education arm and 44 in the standard care arm). At 6 months there was a significant difference in the proportion of patients with swollen joint PABAK >0.6 in the education arm compared with standard care (98 vs 85%, P = 0.02). Limits of agreement for the SJC difference between physician and patients were reduced only in the education arm. The training method is considered feasible, with 94% of patients reporting it as useful. A trend of higher rates of disease remission (28-joint DAS

Introduction Many people at high risk of fractures are not following traditional guidelines and not being recommended for intervention. This study aimed to propose and evaluate a new set of intervention thresholds. Methods Participants were 213,375 men and women aged ≥ 50 years living in New South Wales, Australia. Fracture Risk Assessment Paper Charts (Australia) was used to estimate the 10-year fracture risk. The standardized rates (to Australia population distribution 2007) for intervention were calculated for different thresholds: our proposed new thresholds (i.e. 10-year probability of hip fracture: ≥ 3%, 5% or 7% for 50–69, 70–79 and ≥ 80 years respectively), thresholds by the National Osteoporosis Guideline Group (NOGG) approach, UK thresholds and US thresholds. Results The NOGG, UK and US thresholds did not work well in the Australian population. For example, the NOGG and UK thresholds respectively qualified only 1 in 12 (8.1%) and 1 in 9 (11.3%) Australian men aged ≥ 70 years and the US thresholds qualified about 9 in 10 (90.6%) Australian women aged ≥ 70 years. For men or women aged ≥ 70 years, our proposed new thresholds gave more realistic treatment rates of 21.6% for men and 70.5% for women. Compared to the current Australian guidelines (i.e. T-score ≤ − 2.5 and age ≥ 70 years or a fragility fracture), our thresholds identified an additional 4.9% of men and 18.2% of women aged ≥ 70 years for treatment. Conclusion The proposed new thresholds could identify currently under-recognised high-risk individuals for treatment. It should be considered as a recommendation for osteoporosis management in Australia.

Conclusion: As CAM use is a key component of the self-management strategies for a substantial proportionof Australians with OA, users need to be more fully informed about evidence of efficacy. Methods: A self-administered questionnaire was used to assess CAM use and its relationship with selfratedhealth status, patient knowledge of OA and attitudes towards OA management. Objectives: To investigate complementary and alternative medicine (CAM) use amongst a cohort ofosteoarthritis (OA) sufferers and to explore reasons for use. Results: Sixty-nine percent of respondents (95% CI, 64%e73%) reported that they had tried CAM, withlittle difference between age groups and genders. Patients who had a better knowledge of their conditionand excellent self-rated health were more likely to use CAM. An aversion to the side effects of conventionalmedicine, failure to engage in exercise, and a belief in the efficacy of CAM were the principalfactors underlying use. Refereed/Peer-reviewed

Summary Background Pyoderma gangrenosum (PG) is a systemic disease that presents with cutaneous necrotizing ulceration, producing deep necrotic ulcers, usually with a raised, undermined, violaceous border. Treatment typically involves high dose immunosuppressive drugs, but more recently anti-tumour necrosis factor and monoclonal antibodies have been used. Activated protein C (APC) stimulates wound healing in patients with treatment-refractory skin ulcers, possibly by stimulating angiogenesis and re-epithelialization, and preventing inflammation. Aim To investigate whether APC may be beneficial as a treatment for ulcers related to cutaneous PG. Methods Two patients were recruited with a clinical history and physical and histopathological evidence of acute PG. A total of 400 μg (1.0 mL) of APC was injected subcutaneously into the dermal edge of necrotic PG ulcers weekly for a total treatment period of 6 weeks. Photographs were taken, and clinical progress, ulcer size and pain score were monitored during this period and after the cessation of treatment, at weeks 8 and 12. Results Over the 12 weeks of the trial, APC led to a reduction in wound size from 3.8 cm2 to 0.8 cm2 in patient 1 (78.9% decrease) and from 41 cm2 to 16 cm2 in patient 2 (70.0% decrease, respectively), and a reduction in pain scores from 10 to 0 (100% decrease) in both patients. Conclusion Although this study has limited because of its small sample size and lack of a true placebo group, it does indicate that APC has potential as a therapeutic option for patients with chronic skin ulcers from PG.

Objective The aim of this study was to investigate the effect of endogenous matrix metalloproteinases 2 and 9 (MMP-2 and MMP-9) on the invasive characteristics of RA synovial fibroblasts. Methods Synovial fibroblasts isolated from patients with RA or OA were treated with MMP small interfering RNA (siRNA), inhibitors and recombinant proteins or TNF-α, with or without cartilage explants. Cell viability and proliferation were measured by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide and 5-bromo-2-deoxyuridine (BrdU) proliferation assays, respectively; apoptosis by an in situ cell death detection kit; migration and invasion by CytoSelect invasion assay, scratch migration and collagen gel assays; cartilage degradation by 1,9-dimethylmethylene blue assay; and inflammatory mediators and MMPs by ELISA, western blot and zymography. Results MMP-2 was expressed by both OA and RA synovial fibroblasts, whereas only RA synovial fibroblasts expressed MMP-9. Suppressing MMP-2 or MMP-9 reduced RA synovial fibroblast proliferation equally. However, MMP-9 siRNA had greater effects compared with MMP-2 siRNA on promoting apoptosis and suppressing RA synovial fibroblast viability, migration and invasion. Suppression/inhibition of MMP-9 also decreased the production of IL-1β, IL-6, IL-8 and TNF-α, inactivated nuclear factor κB (NF-κB), extracellular signal-regulated kinase (ERK) and c-Jun NH2-terminal kinase (JNK) and suppressed RA synovial fibroblast-mediated cartilage degradation. In contrast, suppression/inhibition of MMP-2 stimulated TNF-α and IL-17 secretion and activated NF-κB, while recombinant MMP-2 (rMMP-2) inactivated NF-κB and suppressed RA synovial fibroblast-mediated cartilage degradation. Results using specific inhibitors and rMMPs provided supportive evidence for the siRNA results. Conclusion Endogenous MMP-2 or MMP-9 contribute to RA synovial fibroblast survival, proliferation, migration and invasion, with MMP-9 having more potent effects. Additionally, MMP-9 stimulates RA synovial fibroblast-mediated inflammation and degradation of cartilage, whereas MMP-2 inhibits these parameters. Overall, our data indicate that MMP-9 derived from RA synovial fibroblasts may directly contribute to joint destruction in RA.

The objective of this paper is to provide an overview of the strengths, limitations and lessons learned from estimating the burden from musculoskeletal (MSK) conditions in the Global Burden of Disease 2010 Study (GBD 2010 Study). It should be read in conjunction with the other GBD 2010 Study papers published in this journal. The strengths of the GBD 2010 Study include: the involvement of a MSK expert group; development of new and more valid case definitions, functional health states, and disability weights to better reflect the MSK conditions; the extensive series of systematic reviews undertaken to obtain data to derive the burden estimates; and the use of a new, more advanced version of the disease-modelling software (DisMod-MR). Limitations include: many regions of the world did not have data; the extent of heterogeneity between included studies; and burden does not include broader aspects of life, such as participation and well-being. A number of lessons were learned. Ongoing involvement of experts is critical to ensure the success of future efforts to quantify and monitor this burden. A paradigm shift is urgently needed among global agencies in order to alleviate the rapidly increasing global burden from MSK conditions. Prevention and control of MSK disability are required, along with health system changes. Further research is needed to improve understanding of the predictors and clinical course across different settings, and the ways in which MSK conditions can be better managed and prevented.

Objective.The OMERACT Rheumatoid Arthritis (RA) Flare Group (FG) is developing a data-driven, patient-inclusive, consensus-based RA flare definition for use in clinical trials, longterm observational studies, and clinical practice. At OMERACT 11, we sought endorsement of a proposed core domain set to measure RA flare.Methods.Patient and healthcare professional (HCP) qualitative studies, focus groups, and literature review, followed by patient and HCP Delphi exercises including combined Delphi consensus at Outcome Measures in Rheumatology 10 (OMERACT 10), identified potential domains to measure flare. At OMERACT 11, breakout groups discussed key domains and instruments to measure them, and proposed a research agenda. Patients were active research partners in all focus groups and domain identification activities. Processes for domain selection and patient partner involvement were case studies for OMERACT Filter 2.0 methodology.Results.A pre-meeting combined Delphi exercise for defining flare identified 9 domains as important (> 70% consensus from patients or HCP). Four new patient-reported domains beyond those included in the RA disease activity core set were proposed for inclusion (fatigue, participation, stiffness, and self-management). The RA FG developed preliminary flare questions (PFQ) to measure domains. In combined plenary voting sessions, OMERACT 11 attendees endorsed the proposed RA core set to measure flare with ≥ 78% consensus and the addition of 3 additional domains to the research agenda for OMERACT 12.Conclusion.At OMERACT 11, a core domain set to measure RA flare was ratified and endorsed by attendees. Domain validation aligning with Filter 2.0 is ongoing in new randomized controlled clinical trials and longitudinal observational studies using existing and new instruments including a set of PFQ.

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).

Objective To estimate disability from the remainder of musculoskeletal (MSK) disorders (categorised as other MSK) not covered by the estimates made specifically for osteoarthritis (OA), rheumatoid arthritis (RA), gout, low back pain and neck pain, as part of the Global Burden of Disease (GBD) 2010 study. Methods Systematic reviews were conducted to gather the age-sex-specific epidemiological data for other MSK. The focus was on finding health surveys and published studies that measured the overall amount of MSK disorders and complaints, and classified the remainder of MSK disorders that was not RA, OA, gout, low back or neck pain. Six levels of severity were defined to derive disability weights (DWs) and severity distribution. The data, DWs and severity distribution were used to calculate years of life lived with disability (YLDs). Mortality was estimated for MSK-related deaths classified under other MSK. YLDs were added to years of life lost (YLLs) from the mortality estimates to derive overall burden in disability-adjusted life years (DALYs). Results Global prevalence of other MSK was 8.4% (95% uncertainty interval (UI) 8.1% to 8.6%). DALYs increased from 20.6 million (95% UI 17.0 to 23.3 million) in 1990 to 30.9 million (95% UI 25.8 to 34.6 million) in 2010. The burden of other MSK increased with age. Globally, other MSK disability burden (YLD) ranked sixth. Conclusions Ageing of the global population will further increase the burden of other MSK. Specific MSK conditions within this large category should be considered separately to enable more explicit estimates of their burden in future iterations of GBD.

Objective Gout is the most common cause of inflammatory arthritis in men, but has not previously been included in Global Burden of Disease (GBD) studies. As part of the GBD 2010 Study, the Musculoskeletal Disorders and Risk Factors Expert Group estimated the global burden of gout. Methods The American Rheumatism Association 1977 case definition of primary gout was used in the study. A series of systematic reviews were conducted to gather the age-specific and sex-specific epidemiological data for gout prevalence, incidence, mortality risk and duration. Two main disabling sequelae of gout were identified; acute episode gout and chronic polyarticular gout, and used in the surveys to collect data to derive disability weights. The epidemiological data together with disability weights were then used to calculate years of life lived with disability (YLDs) for gout, for 1990 and 2010. No evidence of cause-specific mortality associated with gout was found. Gout disability-adjusted life years (DALYs), therefore, have the same value as YLDs. Results Global prevalence of gout was 0.08% (95% uncertainty interval (UI) 0.07 to 0.08). DALYs increased from 76 000 (95% UI 48 to 112) in 1990 to 114 000 (95% UI 72 to 167) in 2010. Out of all 291 conditions studied in the GBD 2010 Study, gout ranked 138th in terms of disability as measured by YLDs, and 173rd in terms of overall burden (DALYs). Conclusions The burden of gout is rising. With increasing ageing populations globally, this evidence is a significant prompt to optimise treatment and management of gout at individual, community and national levels.

Objective To compare the relative effectiveness of anti–tumor necrosis factor (anti-TNF) therapies on health-related quality of life (HRQOL) by inflammatory arthritis types. Methods Patients with rheumatoid arthritis (RA), ankylosing spondylitis (AS), and psoriatic arthritis (PsA) who had anti-TNF therapy (etanercept, adalimumab, or infliximab) in the Australian Rheumatology Association Database during 2001–2011 were assessed using the Medical Outcomes Study Short Form 36 (SF-36), Assessment of Quality of Life (AQoL), and Health Assessment Questionnaire (HAQ) disability index (DI) on a biannual basis. Linear regression was used for the analysis; the lack of independence in outcomes for multiple assessments in the same patient was taken into account using generalized estimating equations. Results There were 18,119 assessments (first-time drug use n = 12,274, subsequent use n = 3,098, and no use n = 2,747) provided by 3,033 patients (2,240 RA, 507 AS, and 286 PsA patients) with the anti-TNF therapies. The effects of subsequent use versus first-time use were reduced on the SF-36 physical component summary, AQoL, and HAQ DI scores among RA patients. After adjusting for therapy order, calendar year, sex, age, smoking status, and various medication uses, the 3 anti-TNF preparations had similar effects on the HRQOL measures for patients with RA, AS, or PsA. However, differences between anti-TNF therapies were observed in the AQoL score among PsA patients (infliximab versus etanercept: −0.06 [95% confidence interval (95% CI) −0.12, −0.004]) and in the SF-36 mental component summary score among RA patients (adalimumab versus etanercept: −1.17 [95% CI −1.88, −0.46]). Conclusion This study revealed similar effectiveness of etanercept, adalimumab, and infliximab on the HRQOL measures among Australians with RA, AS, and PsA.

International audience; 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 world's population, health professions need to prepare for a large increase in the demand for health services to treat hip and knee OA.

The objective of this paper is to provide an overview of methods used for estimating the burden from musculoskeletal (MSK) conditions in the Global Burden of Diseases 2010 study. It should be read in conjunction with the disease-specific MSK papers published in Annals of Rheumatic Diseases. Burden estimates (disability-adjusted life years (DALYs)) were made for five specific MSK conditions: hip and/or knee osteoarthritis (OA), low back pain (LBP), rheumatoid arthritis (RA), gout and neck pain, and an 'other MSK conditions' category. For each condition, the main disabling sequelae were identified and disability weights (DW) were derived based on short lay descriptions. Mortality (years of life lost (YLLs)) was estimated for RA and the rest category of 'other MSK', which includes a wide range of conditions such as systemic lupus erythematosus, other autoimmune diseases and osteomyelitis. A series of systematic reviews were conducted to determine the prevalence, incidence, remission, duration and mortality risk of each condition. A Bayesian meta-regression method was used to pool available data and to predict prevalence values for regions with no or scarce data. The DWs were applied to prevalence values for 1990, 2005 and 2010 to derive years lived with disability. These were added to YLLs to quantify overall burden (DALYs) for each condition. To estimate the burden of MSK disease arising from risk factors, population attributable fractions were determined for bone mineral density as a risk factor for fractures, the occupational risk of LBP and elevated body mass index as a risk factor for LBP and OA. Burden of Disease studies provide pivotal guidance for governments when determining health priority areas and allocating resources. Rigorous methods were used to derive the increasing global burden of MSK conditions.

To estimate the global burden of neck pain.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.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.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.

Low body mass index (BMI) is a well-established risk factor for fracture in postmenopausal women. Height and obesity have also been associated with increased fracture risk at some sites. We investigated the relationships of weight, BMI, and height with incident clinical fracture in a practice-based cohort of postmenopausal women participating in the Global Longitudinal study of Osteoporosis in Women (GLOW). Data were collected at baseline and at 1, 2, and 3 years. For hip, spine, wrist, pelvis, rib, upper arm/shoulder, clavicle, ankle, lower leg, and upper leg fractures, we modeled the time to incident self-reported fracture over a 3-year period using the Cox proportional hazards model and fitted the best linear or nonlinear models containing height, weight, and BMI. Of 52,939 women, 3628 (6.9%) reported an incident clinical fracture during the 3-year follow-up period. Linear BMI showed a significant inverse association with hip, clinical spine, and wrist fractures: adjusted hazard ratios (HRs) (95% confidence intervals [CIs]) per increase of 5 kg/m(2) were 0.80 (0.71-0.90), 0.83 (0.76-0.92), and 0.88 (0.83-0.94), respectively (all p

This study aimed to determine the effect that level of concern for osteoporosis, as well as self-perceived risk of osteoporosis and fracture, has on supplementation use, seeking medical advice, bone mineral density (BMD) testing, and antiosteoporosis medication (AOM) use. Study subjects were 1,095 female Australian participants of the Global Longitudinal study of Osteoporosis in Women (GLOW) untreated for osteoporosis at baseline. Study outcomes from self-administered questionnaires included calcium and vitamin D supplementation, self-reported seeking of medical advice regarding osteoporosis, BMD testing, and AOM use in the last 12 months at the late assessment. Logistic regression was used in the analysis. Concern significantly increased the likelihood of seeking medical advice and, however, had no significant impact on screening or treatment. Heightened self-perceived risks of osteoporosis and fracture both significantly increased the likelihood of seeking medical advice and BMD testing while elevated self-perceived risk of fracture increased AOM use. Supplementation use was not significantly associated with concern levels and risk perception. Concern and risk perceptions to osteoporosis and fracture were significantly associated with certain bone-protective behaviours. However, the disconnect between perceived osteoporosis risk and AOM use illustrates the need to emphasize the connection between osteoporosis and fracture in future education programs.

Objective To describe the associations between overweight measures in childhood and knee pain, stiffness and dysfunction among adults 25 years later. Methods Subjects broadly representative of the Australian population (n=449, aged 31–41 years, female 48%) were selected from the Australian Schools Health and Fitness Survey of 1985. Height, weight and knee injury were recorded and knee pain was assessed using the Western Ontario and McMaster Universities osteoarthritis index (WOMAC). Childhood height, weight and knee injury had been measured according to standard protocols 25 years earlier and body mass index (BMI) and percentage overweight were calculated. Results The prevalence of knee pain was 34% and overweight in childhood and adulthood was 7% and 48%, respectively. Overall, there were no significant associations between childhood overweight measures and total WOMAC knee pain, stiffness and dysfunction scores in adulthood. However, in men, overweight in childhood was associated with adulthood WOMAC pain (relative risk (RR) 1.72, 95% CI 1.11 to 2.69) and childhood weight and BMI were associated with WOMAC stiffness and dysfunction. Childhood weight, BMI and overweight were all associated with the presence of adulthood walking knee pain in men and the whole sample. Most of these associations were independent of adult overweight measures. Subjects who were overweight in both childhood and adult life had a significant increase in the risk and prevalence of adulthood walking pain (RR=2.42, 95% CI 1.06 to 5.53). Conclusions Childhood overweight measures were significantly associated with adulthood knee mechanical joint pain, stiffness and dysfunction among men, independent of adult overweight, suggesting that childhood overweight may lead to later knee symptoms in men.

The latest Global Burden of Disease Study, published at the end of 2012, has highlighted the enormous global burden of low back pain. In contrast to the previous study, when it was ranked 105 out of 136 conditions, low back pain is now the leading cause of disability globally, ahead of 290 other conditions. It was estimated to be responsible for 58.2 million years lived with disability in 1990, increasing to 83 million in 2010. This chapter illustrates the ways that the Global Burden of Disease data can be displayed using the data visualisation tools specifically designed for this purpose. It also considers how best to increase the precision of future global burden of low back pain estimates by identifying limitations in the available data and priorities for further research. Finally, it discusses what should be done at a policy level to militate against the rising burden of this condition.

Lower leg ulcers are a serious and long-term complication in patients with diabetes and pose a major health concern because of the increasing number of patients diagnosed with diabetes each year. This study sought to evaluate the clinical benefit of topical activated protein C (APC) on chronic lower leg ulcers in patients with diabetes. Twelve patients were randomly assigned to receive either APC (N = 6) or physiological saline (placebo; N = 6) in a randomised, placebo-controlled, double-blind pilot clinical trial. Treatment was administered topically, twice weekly for 6 weeks with final follow-up at 20 weeks. Wound area was significantly reduced to 34·8 ± 16·4% of week 0 levels at 20 weeks in APC-treated wounds (p = 0·01). At 20 weeks, three APC-treated wounds had completely healed, compared to one saline-treated wound. Full-thickness wound edge skin biopsies showed reduced inflammatory cell infiltration and increased vascular proliferation following APC treatment. Patient stress scores were also significantly reduced following APC treatment (p < 0·05), demonstrating improved patient quality of life as assessed by the Cardiff Wound Impact Questionnaire. This pilot trial suggests that APC is a safe topical agent for healing chronic lower leg ulcers in patients with diabetes and provides supporting evidence for a larger clinical trial.

Objective.The Outcome Measures in Rheumatology (OMERACT) Rheumatoid Arthritis (RA) Flare Group was established to develop a reliable way to identify and measure RA flares in randomized controlled trials (RCT). Here, we summarized the development and field testing of the RA Flare Questionnaire (RA-FQ), and the voting results at OMERACT 2016.Methods.Classic and modern psychometric methods were used to assess reliability, validity, sensitivity, factor structure, scoring, and thresholds. Interviews with patients and clinicians also assessed content validity, utility, and meaningfulness of RA-FQ scores.Results.People with RA in observational trials in Canada (n = 896) and France (n = 138), and an RCT in the Netherlands (n = 178) completed 5 items (11-point numerical rating scale) representing RA Flare core domains. There was moderate to high evidence of reliability, content and construct validity, and responsiveness. Factor analysis supported unidimensionality. Rasch analysis showed acceptable fit to the Rasch model, with items and people covering a broad measurement continuum and evidence of appropriate targeting of items to people, ordered thresholds, minimal differential item functioning by language, sex, or age. A summative score across items is defensible, yielding an interval score (0–50) where higher scores reflect worsening flare. The RA-FQ received endorsement from 88% of attendees that it passed the OMERACT Filter 2.0 “Eyeball Test” for instrument selection.Conclusion.The RA-FQ has been developed to identify and measure RA flares. Its review through OMERACT Filter 2.0 shows evidence of reliability, content and construct validity, and responsiveness. These properties merit its further validation as an outcome for clinical trials.

Background and Objectives: The extent to which greater frailty among American compared with European women reflects individual-level characteristics has not been well studied. To test the hypothesis that cardiometabolic conditions and depression and anxiety confound the relationship between region and incident prefrailty and frailty in American compared with European women. Materials and Methods: The Global Longitudinal Study of Osteoporosis in Women (GLOW) is a 5-year observational cohort study of women aged ≥55 years. A total of 19,674 participants from the United States and Europe were nonfrail at baseline and provided information on characteristics, including body mass index, depression and anxiety, and cardiovascular disease. We used multivariable Cox proportional hazards models to examine the relationship between region and incident frailty and prefrailty. Results: Over 40% of respondents became prefrail or frail during follow-up. Adjusting for age, body mass index, depression and anxiety, cardiovascular disease, and other health-related characteristics, European respondents had a decreased risk of developing prefrailty (2-year hazard ratio [HR]: 0.78, 95% confidence interval [CI]: 0.73-0.84; 3-year HR: 0.74, 95% CI: 0.67-0.81) and frailty (2-year HR: 0.65, 95% CI: 0.56-0.76; 3-year HR: 0.82, 95% CI: 0.68-0.99) compared with American respondents. Risk of incident frailty and prefrailty did not vary by region at 5 years of follow-up. Conclusions: Cardiometabolic conditions and depression and anxiety did not account for increased frailty and prefrailty onset among American compared with European women. Differences in smaller regions and environmental characteristics may contribute to frailty and prefrailty.

The most significant impact of obesity on the musculoskeletal system is associated with osteoarthritis (OA), a disabling degenerative joint disorder characterized by pain, decreased mobility and negative impact on quality of life. OA pathogenesis relates to both excessive joint loading and altered biomechanical patterns together with hormonal and cytokine dysregulation. Obesity is associated with the incidence and progression of OA of both weight-bearing and non weight-bearing joints, to rate of joint replacements as well as operative complications. Weight loss in OA can impart clinically significant improvements in pain and delay progression of joint structural damage. Further work is required to determine the relative contributions of mechanical and metabolic factors in the pathogenesis of OA.

Objective.The objectives of the Outcome Measures in Rheumatology (OMERACT) Stiffness special interest group (SIG) are to characterize stiffness as an outcome in rheumatic disease and to identify and validate a stiffness patient-reported outcome (PRO) in rheumatology.Methods.At OMERACT 2016, international groups presented and discussed results of several concurrent research projects on stiffness: a literature review of rheumatoid arthritis (RA) stiffness PRO measures, a qualitative investigation into the RA and polymyalgia rheumatica patient perspective of stiffness, data-driven stiffness conceptual model development, development and testing of an RA stiffness PRO measure, and a quantitative work testing stiffness items in patients with RA and psoriatic arthritis.Results.The literature review identified 52 individual stiffness PRO measures assessing morning or early morning stiffness severity/intensity or duration. Items were heterogeneous, had little or inconsistent psychometric property evidence, and did not appear to have been developed according to the PRO development guidelines. A poor match between current stiffness PRO and the conceptual model identifying the RA patient experience of stiffness was identified, highlighting a major flaw in PRO selection according to the OMERACT filter 2.0.Conclusion.Discussions within the Stiffness SIG highlighted the importance of further research on stiffness and defined a research agenda.

There is increasing interest in making patient participation an integral component of medical research. However, practical guidance on optimizing this engagement in healthcare is scarce. Since 2002, patient involvement has been one of the key features of the Outcome Measures in Rheumatology (OMERACT) international consensus effort. Based on a review of cumulative data from qualitative studies and internal surveys among OMERACT participants, we explored the potential benefits and challenges of involving patient research partners in conferences and working group activities. We supplemented our review with personal experiences and reflections regarding patient participation in the OMERACT process. We found that between 2002 and 2016, 67 patients have attended OMERACT conferences, of whom 28 had sustained involvement; many other patients contributed to OMERACT working groups. Their participation provided face validity to the OMERACT process and expanded the research agenda. Essential facilitators have been the financial commitment to guarantee sustainable involvement of patients at these conferences, procedures for recruitment, selection and support, and dedicated time allocated in the program for patient issues. Current challenges include the representativeness of the patient panel, risk of pseudo-professionalization, and disparity in patients’ and researchers’ perception of involvement. In conclusion, OMERACT has embedded long-term patient involvement in the consensus-building process on the measurement of core health outcomes. This integrative process continues to evolve iteratively. We believe that the practical points raised here can improve participatory research implementation.

The overall aim of this study was to identify risk factors for knee osteoarthritis (OA) structural disease progression. More specifically, we aimed to identify what personal factors (age, sex, obesity, co-morbidity, Herberden’s nodes, history of injury, manual occupation and medication use), radiographic findings (Kellgren and Lawrence (K&L) grade, joint space width, alignment) and activity limitations (self-reported physical activity and physical function) independently predict medial knee joint space narrowing (JSN) over 2 years in people with painful medial knee OA.

Persistent pain, impaired mobility and function, and reduced quality of life and mental well-being are the most common experiences associated with musculoskeletal conditions, of which there are more than 150 types. The prevalence and impact of musculoskeletal conditions increase with aging. A profound burden of musculoskeletal disease exists in developed and developing nations. Notably, this burden far exceeds service capacity. Population growth, aging, and sedentary lifestyles, particularly in developing countries, will create a crisis for population health that requires a multisystem response with musculoskeletal health services as a critical component. Globally, there is an emphasis on maintaining an active lifestyle to reduce the impacts of obesity, cardiovascular conditions, cancer, osteoporosis, and diabetes in older people. Painful musculoskeletal conditions, however, profoundly limit the ability of people to make these lifestyle changes. A strong relationship exists between painful musculoskeletal conditions and a reduced capacity to engage in physical activity resulting in functional decline, frailty, reduced well-being, and loss of independence. Multilevel strategies and approaches to care that adopt a whole person approach are needed to address the impact of impaired musculoskeletal health and its sequelae. Effective strategies are available to address the impact of musculoskeletal conditions; some are of low cost (e.g., primary care-based interventions) but others are expensive and, as such, are usually only feasible for developed nations. In developing nations, it is crucial that any reform or development initiatives, including research, must adhere to the principles of development effectiveness to avoid doing harm to the health systems in these settings.

To evaluate the long-term benefit of providing a post-acute, outpatient group exercise program for patients following primary total knee replacement (TKR) surgery for osteoarthritis.A multicenter randomized clinical trial was conducted in 12 Australian public and private hospital centers. A total of 422 participants, ages 45-75 years, were randomly allocated prior to hospital discharge to the post-acute group exercise program or to usual care and were assessed at 6 weeks, 6 months, and 12 months after surgery. The main outcomes were operated knee pain and activity limitations at 12 months using the Western Ontario and McMaster Universities Osteoarthritis Index questionnaire. Secondary outcomes included health-related quality of life (Short Form 12 health survey), knee extension and flexion strength, stair-climb power, 50-foot walk speed, and active knee range of motion.While both allocation groups achieved significant improvements in knee pain and activity limitations over the 12-month followup period, there were no significant differences in these main outcomes, or in the secondary physical performance measures, between the 2 treatment allocations. Twelve months after TKR, 69% and 72% of participants allocated to post-acute exercise and usual acute care, respectively, were considered to be treatment-responders. While population normative values for self-report measures of pain, activity limitation, and health-related quality of life were attained 12 months after TKR, marked deficits in physical performance measures remained.Providing access to a post-acute group exercise program did not result in greater reductions in long-term knee pain or activity limitations than usual care. Patients undergoing primary TKR retain marked physical performance deficits 12 months after surgery.

International audience; BACKGROUND: Reliable and timely information on the leading causes of death in populations, and how these are changing, is a crucial input into health policy debates. In the Global Burden of Diseases, Injuries, and Risk Factors Study 2010 (GBD 2010), we aimed to estimate annual deaths for the world and 21 regions between 1980 and 2010 for 235 causes, with uncertainty intervals (UIs), separately by age and sex. METHODS: We attempted to identify all available data on causes of death for 187 countries from 1980 to 2010 from vital registration, verbal autopsy, mortality surveillance, censuses, surveys, hospitals, police records, and mortuaries. We assessed data quality for completeness, diagnostic accuracy, missing data, stochastic variations, and probable causes of death. We applied six different modelling strategies to estimate cause-specific mortality trends depending on the strength of the data. For 133 causes and three special aggregates we used the Cause of Death Ensemble model (CODEm) approach, which uses four families of statistical models testing a large set of different models using different permutations of covariates. Model ensembles were developed from these component models. We assessed model performance with rigorous out-of-sample testing of prediction error and the validity of 95% UIs. For 13 causes with low observed numbers of deaths, we developed negative binomial models with plausible covariates. For 27 causes for which death is rare, we modelled the higher level cause in the cause hierarchy of the GBD 2010 and then allocated deaths across component causes proportionately, estimated from all available data in the database. For selected causes (African trypanosomiasis, congenital syphilis, whooping cough, measles, typhoid and parathyroid, leishmaniasis, acute hepatitis E, and HIV/AIDS), we used natural history models based on information on incidence, prevalence, and case-fatality. We separately estimated cause fractions by aetiology for diarrhoea, lower respiratory infections, and meningitis, as well as disaggregations by subcause for chronic kidney disease, maternal disorders, cirrhosis, and liver cancer. For deaths due to collective violence and natural disasters, we used mortality shock regressions. For every cause, we estimated 95% UIs that captured both parameter estimation uncertainty and uncertainty due to model specification where CODEm was used. We constrained cause-specific fractions within every age-sex group to sum to total mortality based on draws from the uncertainty distributions. FINDINGS: In 2010, there were 52*8 million deaths globally. At the most aggregate level, communicable, maternal, neonatal, and nutritional causes were 24*9% of deaths worldwide in 2010, down from 15*9 million (34*1%) of 46*5 million in 1990. This decrease was largely due to decreases in mortality from diarrhoeal disease (from 2*5 to 1*4 million), lower respiratory infections (from 3*4 to 2*8 million), neonatal disorders (from 3*1 to 2*2 million), measles (from 0*63 to 0*13 million), and tetanus (from 0*27 to 0*06 million). Deaths from HIV/AIDS increased from 0*30 million in 1990 to 1*5 million in 2010, reaching a peak of 1*7 million in 2006. Malaria mortality also rose by an estimated 19*9% since 1990 to 1*17 million deaths in 2010. Tuberculosis killed 1*2 million people in 2010. Deaths from non-communicable diseases rose by just under 8 million between 1990 and 2010, accounting for two of every three deaths (34*5 million) worldwide by 2010. 8 million people died from cancer in 2010, 38% more than two decades ago; of these, 1*5 million (19%) were from trachea, bronchus, and lung cancer. Ischaemic heart disease and stroke collectively killed 12*9 million people in 2010, or one in four deaths worldwide, compared with one in five in 1990; 1*3 million deaths were due to diabetes, twice as many as in 1990. The fraction of global deaths due to injuries (5*1 million deaths) was marginally higher in 2010 (9*6%) compared with two decades earlier (8*8%). This was driven by a 46% rise in deaths worldwide due to road traffic accidents (1*3 million in 2010) and a rise in deaths from falls. Ischaemic heart disease, stroke, chronic obstructive pulmonary disease (COPD), lower respiratory infections, lung cancer, and HIV/AIDS were the leading causes of death in 2010. Ischaemic heart disease, lower respiratory infections, stroke, diarrhoeal disease, malaria, and HIV/AIDS were the leading causes of years of life lost due to premature mortality (YLLs) in 2010, similar to what was estimated for 1990, except for HIV/AIDS and preterm birth complications. YLLs from lower respiratory infections and diarrhoea decreased by 45-54% since 1990; ischaemic heart disease and stroke YLLs increased by 17-28%. Regional variations in leading causes of death were substantial. Communicable, maternal, neonatal, and nutritional causes still accounted for 76% of premature mortality in sub-Saharan Africa in 2010. Age standardised death rates from some key disorders rose (HIV/AIDS, Alzheimer's disease, diabetes mellitus, and chronic kidney disease in particular), but for most diseases, death rates fell in the past two decades; including major vascular diseases, COPD, most forms of cancer, liver cirrhosis, and maternal disorders. For other conditions, notably malaria, prostate cancer, and injuries, little change was noted. INTERPRETATION: Population growth, increased average age of the world's population, and largely decreasing age-specific, sex-specific, and cause-specific death rates combine to drive a broad shift from communicable, maternal, neonatal, and nutritional causes towards non-communicable diseases. Nevertheless, communicable, maternal, neonatal, and nutritional causes remain the dominant causes of YLLs in sub-Saharan Africa. Overlaid on this general pattern of the epidemiological transition, marked regional variation exists in many causes, such as interpersonal violence, suicide, liver cancer, diabetes, cirrhosis, Chagas disease, African trypanosomiasis, melanoma, and others. Regional heterogeneity highlights the importance of sound epidemiological assessments of the causes of death on a regular basis. FUNDING: Bill & Melinda Gates Foundation.

Summary Objective To assess the efficacy of thrice daily topical 4Jointz utilizing Acteev technology (a combination of a standardized comfrey extract and a pharmaceutical grade tannic acid, 3.5 g/day) on osteoarthritic knee pain, markers of inflammation and cartilage breakdown over 12 weeks. Patients and methods Adults aged 50–80 years ( n = 133) with clinical knee OA were randomised to receive 4Jointz or placebo in addition to existing medications. Pain and function were measured using a visual analogue scale (VAS) and the Knee Injury and Osteoarthritis Outcome Score (KOOS) scale at baseline, 4, 8 and 12 weeks. Inflammation was measured analysing IL-6 expression and CTX-2 presence as representative for cartilage breakdown using ELISA, at baseline and 12 weeks. Results Pain scores significantly reduced in the group who received 4Jointz compared to the group who received placebo after 12 weeks using both the VAS (−9.9 mm, P = 0.034) and the KOOS pain scale (+5.7, P = 0.047). Changes in IL-6 and CTX-2 were not significant (−0.04, P = 0.5; −0.01, P = 0.68). Post-hoc analyses suggested that treatment may be most effective in women (VAS −16.8 mm, P = 0.008) and those with milder radiographic osteoarthritis (OA) (VAS −16.1 mm, P = 0.009). Rates of adverse events were similar in both groups, excepting local rash that was more common amongst participants receiving 4Jointz (21% vs 1.6%, IRR 13.2, P = 0.013), but only 26% ( n = 4) of participants with rashes discontinued treatment. There were no changes in systemic blood results. Conclusions Topical treatment using 4Jointz reduced pain but had no effect on inflammation or cartilage breakdown over 12 weeks of treatment. Trial registration: Australia and New Zealand Clinical Trials registry ACTRN12610000877088.

Objective In the course of performing systematic reviews on the prevalence of low back and neck pain, we required a tool to assess the risk of study bias. Our objectives were to (1) modify an existing checklist and (2) test the final tool for interrater agreement. Study Design and Setting The final tool consists of 10 items addressing four domains of bias plus a summary risk of bias assessment. Two researchers tested the interrater agreement of the tool by independently assessing 54 randomly selected studies. Interrater agreement overall and for each individual item was assessed using the proportion of agreement and Kappa statistic. Results Raters found the tool easy to use, and there was high interrater agreement: overall agreement was 91% and the Kappa statistic was 0.82 (95% confidence interval: 0.76, 0.86). Agreement was almost perfect for the individual items on the tool and moderate for the summary assessment. Conclusion We have addressed a research gap by modifying and testing a tool to assess risk of study bias. Further research may be useful for assessing the applicability of the tool across different conditions.

The Drug Burden Index (DBI), a measure of an individual's exposure to anticholinergic and sedative medications, is associated with functional impairment in community-dwelling, older people. In people from residential aged care facilities (RACFs), DBI score does not appear to be associated with functional impairment, but is associated with an increased risk of falls.We investigated the associations between increasing DBI score and mortality in older adults living in RACFs.Study participants (n = 602; 70.9% female), recruited from 51 RACFs in Sydney, Australia, had a mean ± standard deviation (SD) age of 85.7 ± 6.4 years and a mean ± SD DBI score of 0.58 ± 0.64.Exposure to anticholinergic medication was 33.6% and sedative medications 41.9%. All-cause mortality after a variable follow-up time (774-1269 days) was 36.2% (n = 218), with the leading causes of death classified as stroke (n = 46; 21.1%), ischaemic heart disease/cardiovascular system (n = 44; 20.2%) and pneumonia (n = 31; 14.2%). One-year mortality multivariate models showed that the DBI categories low (n = 260; hazard ratio [HR] 1.13; 95% CI 0.82, 1.57) and high (n = 153; HR 1.19; 95% CI 0.82, 1.74) were not associated with mortality. This lack of a significant association remained after dichotomization into the anticholinergic and sedative components of the DBI.We found that with high exposure to anticholinergic and sedative medications, there was no significant association between increasing DBI score and all-cause mortality in old individuals living in RACFs. Further research into the adverse effects of medication use on the mortality of institutionalized older individuals is needed.

Objective To investigate whether protease-activated receptor 1 (PAR-1) and/or PAR-2 promotes the invasiveness/proliferation of synovial fibroblasts (SFs) and to determine the signaling mechanisms of these pathways. Methods SFs were isolated from the synovial tissue of patients with rheumatoid arthritis (RA), patients with osteoarthritis (OA), and PAR-1– or PAR-2–knockout (KO) mice. Expression of PAR-1 and PAR-2 was detected by immunofluorescence and Western blotting. The invasion and proliferation of SFs were measured by invasion assay and MTT assay, respectively. Matrix metalloproteinase 2 (MMP-2) and MMP-9 were detected by zymography, and cytokines were measured by enzyme-linked immunosorbent assay. Results PAR-1 and PAR-2 were colocalized with SFs in RA and OA synovium and, to a considerably lesser extent, in normal synovium. Inhibition of PAR-2 by small interfering RNA (siRNA) inhibited RASF invasion and proliferation, whereas blocking of PAR-1 by siRNA had the reverse effects. SFs from PAR-2–KO mice exhibited slower rates of proliferation and invasion. SFs from PAR-1–KO mice produced less MMP-2 and, in response to tumor necrosis factor α (TNFα) stimulation, had increased MMP-9 secretion when compared to SFs from wild-type and PAR-2–KO mice. Inhibition of PAR-1, but not PAR-2, stimulated the secretion of interleukin-17 (IL-17) and TNFα by RASFs. Furthermore, PAR-1 and PAR-2 had opposing effects on the activation of ERK, p38, and NF-κB. Conclusion Activation of PAR-1 stimulates MMP-2 secretion, inhibits RASF growth and invasion, and decreases production of IL-17 and TNFα by RASFs, whereas activation of PAR-2 stimulates RASF growth and invasion and increases production of TNFα. Thus, although PAR-1 and PAR-2 are coexpressed by RASFs, PAR-2 alone appears to be responsible for the aggressive properties of RASFs and is likely to contribute to the pathologic progression of RA.

Activated protein C (APC) is a natural anticoagulant that exerts anti-inflammatory and cytoprotective properties mediated through the protease activated receptor (PAR)-1. APC can also proteolytically cleave PAR-2, although subsequent function is unknown. On the basis of recent evidence that APC promotes wound healing, the aim of this study was to determine whether APC acts through PARs to heal murine excisional wounds or to regulate human cultured keratinocyte function and to determine the signaling mechanisms. Topical administration of APC accelerated wound healing in wild-type mice and, unexpectedly, in PAR-1 knockout mice. PAR-2 knockout mice healed significantly slower than wild-type mice, and healing was not altered by adding APC, indicating that APC acts through PAR-2 to heal wounds. In cultured human primary keratinocytes, APC enhanced PAR-2, stimulated proliferation, activated phosphatidylinositol 3-kinase/Src/Akt, and inhibited phosphorylated (P)-p38. Inhibiting PAR-1 or PAR-2, by small-interfering RNA or blocking antibody, reversed APC-induced keratinocyte proliferation and Akt activation. Blocking PAR-2, but not PAR-1, reversed the inhibition of P-p38 by APC. Furthermore, inhibition of P-p38 accelerated wound healing in wild-type mice. In summary, although APC acts through both PAR-1 and PAR-2 to activate Akt and to increase keratinocyte proliferation, APC-induced murine wound healing depends on PAR-2 activity and inhibition of P-p38.

Objective. People with RA have episodes of worsening disease activity (flares) that prompt them to seek clinical review or medication change. This study explored patients’ perspectives of flare that prompts them to seek medication review. Methods. Fourteen focus groups across five countries comprised 67 RA patients. Transcripts were analysed by several researchers and a patient, using inductive thematic analysis. Results. Patients use flare for five different scenarios, including flare that prompts medical help-seeking, where six themes were identified. In ‘Symptoms and early warnings’, pain is intense (wanting to die), constant and persistent and considered a key feature. Systemic features predominate, including fatigue, feeling generally ill (flu-like), physical and cognitive shut-down and social withdrawal. Warning signs (prodrome) comprise fatigue and flu-like symptoms. ‘Self-management of intensifying symptoms’ includes pacing, heat/cold, rest and increasing medication, often without medical advice. Patients ‘Define this as uncontrollable flare’ when clusters of unprovoked, persistent symptoms halt their ability to run daily life, until prompted into ‘Seeking help when symptoms can’t be contained’. Underpinning themes are ‘Individual context’ (e.g. different symptom clusters) and ‘Uncertainty’ (e.g. when to seek help). Patients report that the current patient global visual analogue scale (VAS) does not capture flare. Conclusion. Patients use flare for multiple events and seek help for complex clusterings of intense, unprovoked symptoms that defy self-management, not necessarily captured in joint counts or global VAS. Flare terminology and definition have implications for clinical practice and trials, therefore further research should establish a professional/patient consensus.

OBJECTIVES: To evaluate the association between the Drug Burden Index (DBI), a measure of a person's total exposure to anticholinergic and sedative medications that includes principles of dose-response and maximal effect and is associated with impaired physical function in community-dwelling older people, and falls in residents of residential aged care facilities (RACFs). DESIGN: Data were drawn from participants in a randomized controlled trial that investigated falls and fractures. SETTING: RACFs in Sydney, Australia. PARTICIPANTS: Study participants (N=602; 70.9% female) were recruited from 51 RACFs. Mean age was 85.7 ± 6.4, and mean DBI was 0.60 ± 0.66. MEASUREMENTS: Medication history was obtained on each participant. Drugs were classified as anticholinergic or sedative and a DBI was calculated. Falls were measured over a 12-month period. Comorbidity, cognitive impairment (Mini-Mental State Examination) and depression (Geriatric Depression Scale) were determined. RESULTS: There were 998 falls in 330 individuals during a follow-up period of 574.2 person-years, equating to an average rate of 1.74 falls per person-year. The univariate negative binomial regression model for falls showed incidence rate ratios of 1.69 (95% confidence interval (CI)=1.22-2.34) for low DBI ( Language: en

There is strong rationale for improving care for people with chronic conditions, including osteoarthritis (OA). Successful implementation of healthcare reform requires new concepts and directions that are strongly supported by policy, new models of care (service redesign) and changes in day-to-day practice (healthcare provider and patient practice). In this paper we discuss the extent to which policy about management of OA of the hip and knee has been translated into new service models in Australia. A structured search of government and other key health websites in Australia was performed to identify policy, funding initiatives and new services models for managing OA of the hip and knee. This search was supported by a literature review. Musculoskeletal conditions were designated a National Health Priority in Australia in 2002. Under the Better Arthritis and Osteoporosis Care initiative, Australia has developed a national policy for OA care and national evidence-based clinical practice guidelines for management of OA of the hip and knee. Only two well-described examples of new chronic disease management service models, the Osteoarthritis Clinical Pathway (OACP) model and the Osteoarthritis Hip and Knee Service (OAHKS) were identified. Primarily focused within acute care public hospital settings, these have been shown to be feasible and acceptable but have limited data on clinical impact and cost-effectiveness. While policy is extant, implementation has not been systematic and comprehensive. Clinicians have evidence-based recommendations for OA management but are poorly supported by service models to deliver these effectively and efficiently.

Worldwide, osteoarthritis (OA) is estimated to be the fourth leading cause of disability. Most of this disability burden is attributable to the involvement of the hips or the knees. OA is strongly associated with ageing and the Asian region is ageing rapidly. Further, OA has been associated with heavy physical occupational activity, a required livelihood for many people living in rural communities in developing countries. Unfortunately, joint replacement surgery, an effective intervention for people with severe OA involving the hips or knees, is inaccessible to most people in these regions. On the other hand, obesity, another major risk factor, may be less prevalent, although it is on the increase. Determining region-specific OA prevalence and risk factor profiles will provide important information for planning future cost-effective preventive strategies and health care services. An update of what is currently known about the prevalence of hip and knee OA from population-based studies conducted in the Asian region is presented in this review. Many of the recent studies have conducted comparisons between urban and rural areas and poor and affluent communities. The results of Asian-based studies evaluating risk factors from population-based cohorts or case–control studies, and the current evidence on OA morbidity burden in Asia is also outlined.

Background: The aim of this study was to compare the efficacy and safety of zoledronic acid (ZA) plus intravenous methylprednisolone (VOLT01) to ZA, and placebo for knee osteoarthritis. Methods: A single-center, double-blind, randomized controlled trial (RCT) was carried out. Adults (aged ⩾50 years) with knee osteoarthritis, significant knee pain [⩾40 mm on a 100 mm visual analog scale (VAS)], and magnetic resonance imaging-detected bone marrow lesion (BML) were randomized to receive a one-off administration of VOLT01, ZA, or placebo. The primary hypothesis was that VOLT01 was superior to ZA in having a lower incidence of acute phase responses (APRs) over 3 days. Secondary hypotheses were that VOLT01 was noninferior to ZA, and both treatments were superior to placebo in decreasing BML size over 6 months and in improving knee pain [Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and VAS] and function (WOMAC) over 3 and 6 months. Results: A total of 117 patients (62.2 ± 8.1 years, 63 women) were enrolled. The incidence of APRs was similar in the VOLT01 (90%) and ZA (87%) groups ( p = 0.74). VOLT01 was superior to ZA in improving knee pain and function after 6 months and noninferior to ZA in reducing BML size. However, BML size change was small in all groups and there were no between-group differences. Compared with placebo, VOLT01 but not ZA improved knee function and showed a trend toward improving knee pain after 6 months. Conclusions: Administering intravenous methylprednisolone with ZA did not reduce APRs or change knee BML size over 6 months, but in contrast to ZA or placebo, it may have a beneficial effect on symptoms in knee osteoarthritis. Trial registration: Australian New Zealand Clinical Trials Registry: ACTRN12613000039785.