Zoledronic acid does not slow spinal radiographic progression of osteoarthritis in postmenopausal women with osteoporosis and radiographic osteoarthritis.

Introduction: Post hoc analyses of osteoporosis trials have suggested that alendronate and strontium ranelate may be associated with a reduction in the progression of spinal radiographic osteoarthritis (OA). We performed an analysis on a subgroup of participants in the horizon PFT trial (a 3-year randomized controlled trial (RCT) of yearly zoledronic acid (ZA) in postmenopausal women with osteoporosis), to evaluate the effect of ZA on the structural progression of spinal osteophytes (OPh) and disk space narrowing (DN). Methods: Paired lateral spinal X-rays (baseline and 36 months) were selected from the horizon PFT trial records restricted to those with radiographic OA at baseline. The X-rays were analyzed by two readers blinded to the treatment allocation. OPh and DN were scored separately using the Lane atlas (0-3 for increasing severity at each vertebral level) at all evaluable levels from T4-12 and L1-5. Results: A total of 504 sets of paired radiographs were included in the analysis, 245 in the ZA group and 259 in the placebo group. Overall, the rates of change of OPh and DN scores were low, and they were not statistically different between the groups (change in the whole spine OPh ZA 1.0 ± 1.6, placebo 0.8 ± 1.3, p = 0.1; DN ZA 0.3 ± 1.0, placebo 0.3 ± 0.8, p = 0.7). Conclusion: Yearly ZA for 3 years was not associated with a slowing of progression of OPh or DN in the thoracolumbar spine in patients with pre-existing radiographic OA.

Accuracy of synovial fluid analysis compared to histology for the identification of calcium pyrophosphate crystals: an ancillary study of the OMERACT US Working Group - CPPD subgroup.

The aim of this study was to evaluate the accuracy of synovial fluid analysis in the identification of calcium pyrophosphate dihydrate crystals compared to microscopic analysis of joint tissues as the reference standard. This is an ancillary study of an international, multicentre cross-sectional study performed by the calcium pyrophosphate deposition disease (CPPD) subgroup of the OMERACT Ultrasound working group. Consecutive patients with knee osteoarthritis (OA) waiting for total knee replacement surgery were enrolled in the study from 2 participating centres in Mexico and Romania. During the surgical procedures, synovial fluid, menisci and hyaline cartilage were collected and analysed within 48 hours from surgery under transmitted light microscopy and compensated polarised light microscopy for the presence/absence of calcium pyrophosphate crystals. All slides were analysed by expert examiners on site, blinded to other findings. A dichotomic score (absence/ presence) was used for scoring both synovial fluid and tissues. Microscopic analysis of knee tissues was considered the gold standard. Sensitivity, specificity, accuracy, positive and negative predictive values of synovial fluid analysis in the identification of calcium pyrophosphate crystals were calculated. 15 patients (53% female, mean age 68 yo ± 8.4) with OA of grade 3 or 4 according to Kellgren-Lawrence scoring were enrolled. 12 patients (80%) were positive for calcium pyrophosphate crystals at the synovial fluid analysis and 14 (93%) at the tissue microscopic analysis. The overall diagnostic accuracy of synovial fluid analysis compared with histology for CPPD was 87%, with a sensitivity of 86% and a specificity of 100%, the positive predictive value was 100% and the negative predictive value was 33%. In conclusion synovial fluid analysis proved to be an accurate test for the identification of calcium pyrophosphate dihydrate crystals in patients with advanced OA.

Structural damage in rheumatoid arthritis assessed by musculoskeletal ultrasound: A systematic literature review by the Structural Joint Damage Task Force of the OMERACT Ultrasound Working Group.

OBJECTIVES: To identify and synthesize the evidence for the use and measurement properties of musculoskeletal ultrasound in assessing structural joint damage in patients with rheumatoid arthritis (RA). METHODS: A systematic literature search (SLR) of the PubMed, Embase and Cochrane Library was performed. Original articles were included published in English reporting on ultrasound of bone erosion, cartilage damage and the measurement properties of ultrasound according to the OMERACT filter 2.1. RESULTS: Of the 1.495 identified articles 149 were included in the final review, most of which reported on cross-sectional studies and used the OMERACT definitions for ultrasonographic pathology. Among these, bone erosions were assessed in 139 (93.3%), cartilage damage in 24 (16.1%), enthesophytes in 8 (5.4%), osteophytes in 15 (10.1%) and malalignment and ankylosis in a single (0.9%) study, respectively. Most studies (126/149, 84.6%) assessed the joints of the hands. The overwhelming majority of studies (127/149, 85.2%) assessed structural joint damage bilaterally. Validity, reliability and responsiveness were assessed in 21 (14.1%), 34 (22.8%) and 17 (11.4%) studies, respectively. CONCLUSION: While the results of this SLR suggest that ultrasound is a sensitive, reliable and feasible tool to detect damage in RA, they also highlight the need for further research and validation. Findings of this SLR will inform the next steps of the OMERACT Ultrasound Working Group in developing an ultrasound score for assessing structural joint damage in patients with RA.

The prevalence of gout and hyperuricaemia in Australia: An updated systematic review.

BACKGROUND: Gout continues to increase in prevalence in developed countries with Oceanic countries particularly affected. Both gout and hyperuricaemia are associated with the metabolic syndrome and its sequelae. Recently, the Australian Institute for Health and Welfare (AIHW) reported a prevalence rate of 0.8% which appeared incongruous with other published research. Thus, an updated systematic review was undertaken to review the literature on the prevalence of gout and hyperuricaemia in Australia from data published after 2011. METHODS: A comprehensive, systematic search was conducted in MEDLINE, Embase and Web of Science in addition to relevant websites to identify research reporting the prevalence of gout and/or hyperuricaemia in Australia from May 2011 until June 2020. Crude gout and hyperuricaemia prevalence data was obtained and presented alongside case ascertainment, time-period, age range and stratified by gender if available. RESULTS: 118 full text articles were screened. 12 articles were included for analysis of gout prevalence. 4 articles were identified for the hyperuricaemia analysis. Wide variation in prevalence figures exist largely due study design and sample age range. Studies using a case definition of self-reported diagnosis of gout reported prevalence rates between 4.5% and 6.8%. The remaining studies used either electronic coding data from general practitioners or wastewater estimation of allopurinol consumption and documented adult prevalence rates between 1.5% and 2.9%. Prevalence increases with age, male sex and over time in keeping with global data. Hyperuricaemia prevalence ranged between 10.5% and 16.6% in Caucasian or an Australian representative population. AIHW estimates applied a chronic condition status, defined as current and lasted or expected to last more than six months, to cases of gout in the Australian National Health Survey. This likely results in an under-estimation in reported Australian gout prevalence rates. CONCLUSIONS: Gout is highly prevalent in Australia compared to global comparisons and continues to increase over time. Hyperuricaemia prevalence is also high although contemporary data is limited.

Once-yearly zoledronic acid and change in abdominal aortic calcification over 3 years in postmenopausal women with osteoporosis: results from the HORIZON Pivotal Fracture Trial.

This study evaluated whether zoledronic acid (ZA) inhibited the progression of abdominal aortic calcification (AAC) over 3 years in 502 postmenopausal women with osteoporosis. AAC progressed in a similar proportion of participants in the ZA (29%) and placebo (31%) groups, suggesting no effect of ZA on AAC progression. INTRODUCTION: Bisphosphonate use is associated with reduced risk of all-cause mortality and cardiovascular events. The underlying mechanisms are uncertain but may include effects on vascular calcification. This study aimed to evaluate the effect of zoledronic acid (ZA) on abdominal aortic calcification (AAC) in postmenopausal women with osteoporosis. METHODS: This was a post hoc analysis of the HORIZON Pivotal Fracture Trial that included 502 postmenopausal women (mean age 72.5 years) with osteoporosis (234 received ZA and 268 placebo). AAC scores (range, 0-8) were assessed from paired spine X-rays at baseline and after 3 years. Progression of AAC was defined as any increase in AAC score. The association between change in hip and femoral neck bone mineral density and change in AAC score was also assessed. RESULTS: At baseline, 292 (58.2%) participants had AAC (i.e., AAC score > 0), with AAC scores similar in the two intervention groups (median [interquartile range], 1 [0 to 2] for both; p = 0.98). Over 3 years, AAC progressed in a similar proportion of participants in both groups (ZA 29% and placebo 31%; p = 0.64). Change in bone mineral density and change in AAC score were not correlated. CONCLUSION: Once-yearly zoledronic acid did not affect progression of AAC over 3 years in postmenopausal women with osteoporosis. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00049829.

KARAOKE: Krill oil versus placebo in the treatment of knee osteoarthritis: protocol for a randomised controlled trial.

BACKGROUND: Knee osteoarthritis (OA) is a common and important cause of pain and disability, but interventions aimed at modifying structures visible on imaging have been disappointing. While OA affects the whole joint, synovitis and effusion have been recognised as having a role in the pathogenesis of OA. Krill oil reduces knee pain and systemic inflammation and could be used for targeting inflammatory mechanisms of OA. METHODS/DESIGN: We will recruit 260 patients with clinical knee OA, significant knee pain and effusion-synovitis present on MRI in five Australian cities (Hobart, Melbourne, Sydney, Adelaide and Perth). These patients will be randomly allocated to the two arms of the study, receiving 2 g/day krill oil or inert placebo daily for 6 months. MRI of the study knee will be performed at screening and after 6 months. Knee symptoms, function and MRI structural abnormalities will be assessed using validated methods. Safety data will be recorded. Primary outcomes are absolute change in knee pain (assessed by visual analog score) and change in size of knee effusion-synovitis over 24 weeks. Secondary outcomes include improvement in knee pain over 4, 8, 12, 16 and 20 weeks. The primary analyses will be intention-to-treat analyses of primary and secondary outcomes. Per protocol analyses adjusting for missing data and for treatment compliance will be performed as the secondary analyses. DISCUSSION: This study will provide high-quality evidence to assess whether krill oil 2 g/day reduces pain and effusion-synovitis size in older adults with clinical knee OA and knee effusion-synovitis. If krill oil is effective and confirmed to be safe, we will provide compelling evidence that krill oil improves pain and function, changes disease trajectory and slows disease progression in OA. Given the lack of approved therapies for slowing disease progression in OA, and moderate cost of krill oil, these findings will be readily translated into clinical practice. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry, ACTRN12616000726459. Registered on 02 June 2016. Universal Trial Number (UTN) U1111-1181-7087.

Clinimetrics of ultrasound pathologies in osteoarthritis: systematic literature review and meta-analysis.

OBJECTIVE: The aims of this study were to systematically review clinimetrics of commonly assessed ultrasound pathologies in knee, hip and hand osteoarthritis (OA), and to conduct a meta-analysis for each clinimetric. METHODS: Medline, Embase, and Cochrane Library databases were searched from their inceptions to September 2016. According to the Outcome Measures in Rheumatology (OMERACT) Instrument Selection Algorithm, data extraction focused on ultrasound technical features and performance metrics. Methodological quality was assessed with modified 19-item Downs and Black score and 11-item Quality Appraisal of Diagnostic Reliability (QAREL) score. Separate meta-analyses were performed for clinimetrics: (1) inter-rater/intra-rater reliability; (2) construct validity; (3) criteria validity; and (4) internal/external responsiveness. Statistical Package for the Social Sciences (SPSS), Excel and Comprehensive Meta-analysis were used. RESULT: Our search identified 1126 records; of these, 100 were eligible, including a total of 8542 patients and 32,373 joints. The average Downs and Black score was 13.01, and average QAREL was 5.93. The stratified meta-analysis was performed only for knee OA, which demonstrated moderate to substantial reliability [minimum kappa > 0.44(0.15,0.74), minimum intraclass correlation coefficient (ICC) > 0.82(0.73-0.89)], weak construct validity against pain (r = 0.12 to 0.27), function (r = 0.15 to 0.23), and blood biomarkers (r = 0.01 to 0.21), but weak to strong correlation with plain radiography (r = 0.13 to 0.60), strong association with Magnetic Resonance Imaging (MRI) [minimum r = 0.60(0.52,0.67)] and strong discrimination against symptomatic patients (OR = 3.08 to 7.46). There was strong criterion validity against cartilage histology [r = 0.66(-0.05,0.93)], and small to moderate internal [standardized mean difference(SMD) = 0.20 to 0.58] and external (r = 0.35 to 0.43) responsiveness to interventions. CONCLUSION: Ultrasound demonstrated strong criterion validity with cartilage histology, poor to strong correlation with patient findings and MRI, moderate reliability, and low responsiveness to interventions. PROSPERO REGISTRATION NO: CRD42016039954.

Optimising ultrasonography in rheumatology.

Ultrasonography is an imaging modality that has been utilised in clinical medicine since the 1950s. However, application to joints and rheumatic disease was delayed until appropriate advances in technology made it feasible. Since the 1990s, rheumatologists have embraced ultrasonography as a useful clinical tool and it has increasingly been applied in routine practice. Initial criticism correctly focused on a lack of validity data, recognition that this modality is highly user-dependent and that reliability was not established. In response, the rheumatological community identified relevant pathologies to study, starting with synovitis in rheumatoid arthritis, and set about defining the ultrasound abnormalities, followed by demonstrating the validity, reproducibility and responsiveness of these measures. Much work is now ongoing in the areas of enthesitis, gout and osteoarthritis. Additionally, the evidence base for ultrasonography in clinical practice is being investigated, in order to understand its appropriate place. Given the sensitivity of ultrasonography over clinical examination for detection of inflammation, this work will focus on its role in optimising diagnosis, directing therapy through accurate assessment of disease activity and understanding the optimal selection of joints for feasible disease monitoring. This review summarises the work undertaken to date, ongoing work and future challenges of optimising the role of ultrasonography in rheumatology.

Remission induction comparing infliximab and high-dose intravenous steroid, followed by treat-to-target: a double-blind, randomised, controlled trial in new-onset, treatment-naive, rheumatoid arthritis (the IDEA study).

OBJECTIVES: In disease modifying antirheumatic drug (DMARD)-naive early rheumatoid arthritis (RA), to compare the efficacy of methotrexate (MTX) and infliximab (IFX) with MTX and intravenous corticosteroid for remission induction. METHODS: In a 78-week multicentre randomised controlled trial, double-blinded to week 26, 112 treatment-naive RA patients (1987 American College of Rheumatology classification criteria) with disease activity score 44 (DAS44)>2.4 were randomised to MTX + IFX or MTX + single dose intravenous methylprednisolone 250 mg. A treat-to-target approach was used with treatment escalation if DAS44>2.4. In the IFX group, IFX was discontinued for sustained remission (DAS44<1.6 for 6 months). The primary outcome was change in modified total Sharp-van der Heijde score (mTSS) at week 50. RESULTS: The mean changes in mTSS score at week 50 in the IFX and intravenous steroid groups were 1.20 units and 2.81 units, respectively (adjusted difference (95% CI) -1.45 (-3.35 to 0.45); p=0.132). Radiographic non-progression (mTSS<2.0) occurred in 81% vs 71% (OR 1.77 (0.56 to 5.61); p=0.328). DAS44 remission was achieved at week 50 in 49% and 36% (OR 2.13 (0.91 to 5.00); p=0.082), and at week 78 in 48% and 50% (OR 1.12 (0.47 to 2.68); p=0.792). Exploratory analyses suggested higher DAS28 remission at week 6 and less ultrasound synovitis at week 50 in the IFX group. Of the IFX group, 25% (14/55) achieved sustained remission and stopped IFX. No substantive differences in adverse events were seen. CONCLUSIONS: In DMARD-naive early RA patients, initial therapy with MTX+high-dose intravenous steroid resulted in good disease control with little structural damage. MTX+IFX was not statistically superior to MTX+intravenous steroid when combined with a treat-to-target approach.

A systematic review of ultrasonography in osteoarthritis.

BACKGROUND: Ultrasonography has been increasingly utilised to aid the understanding and management of rheumatic conditions. In recent years there has been a focus on the validity and utility of ultrasonography in demonstrating joint pathology, although this has largely focused on inflammatory arthritis. AIMS: To undertake a systematic review of the published literature evaluating ultrasonography as an assessment tool in osteoarthritis. METHODS: Medline and Pubmed were searched to identify original manuscripts, published before June 2008, utilising ultrasonography to assess the joints of cohorts of subjects with osteoarthritis. Data were extracted from manuscripts meeting the inclusion criteria, with a particular focus on the pathology imaged, the definitions used, scoring systems and their metric properties. RESULTS: Forty-seven studies were identified that utilised ultrasonography to assess structural pathology in osteoarthritis. Doppler function was only assessed in 10 studies and contrast agents in one. There was heterogeneity with regard to the pathology examined, the definition of pathology, quantification and the reporting of these factors. There was also a lack of construct and criterion validity and data demonstrating reliability and sensitivity to change. CONCLUSIONS: Whereas there is increasing evidence of the validity of ultrasonography in detecting structural pathology in inflammatory arthritis, more work is required to develop standardised definitions of pathology and to demonstrate the validity of ultrasonography in osteoarthritis.

The development of a preliminary ultrasonographic scoring system for features of hand osteoarthritis.

OBJECTIVES: Painful osteoarthritis (OA) of the hand is common and a validated ultrasound (US) scoring system would be valuable for epidemiological and therapeutic outcome studies. US is increasingly used to assess peripheral joints, though most of the US focus in rheumatic diseases has been on rheumatoid arthritis. We aimed to develop a preliminary US hand OA scoring system, initially focusing on relevant pathological features with potentially high reliability. METHODS: A group of experts in the fields of OA, US and novel tool development agreed on domains and suggested scaling of the items to be used in US hand OA scoring systems. A multi-observer reliability exercise was then performed to evaluate the draft items. RESULTS: Synovitis (grey scale and Power Doppler) and osteophytes (representing activity and damage domains) were included and evaluated as the initial components of the scoring system. All three features were evaluated for their presence/absence and if present were scored using a 1-3 scale. The reliability exercise demonstrated intra-reader kappa values of 0.444-1.0, 0.211-1.0 and 0.087-1.0 for grey scale synovitis, power Doppler and osteophytes respectively. Inter-reader reliability kappa values were 0.398, 0.327 and 0.530 grey-scale synovitis, power Doppler and osteophytes respectively. Without extensive standardisation, both intra- and inter-reader reliability were moderately good. CONCLUSIONS: The draft scoring system demonstrated substantive to almost perfect percentage exact agreement on the presence/absence of the selected OA features and moderate to substantive percentage exact agreement on semi-quantitative grading. This preliminary process provides a good basis from which to further develop an US outcome tool for hand OA that has the potential to be utilised in multicentre clinical trials.

Can ultrasonography improve on radiographic assessment in osteoarthritis of the hands? A comparison between radiographic and ultrasonographic detected pathology.

OBJECTIVES: Ultrasonography (US) is used in rheumatology to assess small joints in inflammatory arthritis. Recently there has been some investigation into the utility of US in osteoarthritis (OA), however there has been little comparison of US to other imaging modalities in OA. This study aimed to compare the detection of osteophytosis and joint space narrowing (JSN) by US and conventional radiography (CR) in OA of the hand. SUBJECTS: with OA of the hand underwent US and CR examination of the small joints of both hands to identify osteophytosis and joint space narrowing. RESULTS: 1106 joints of 37 patients were imaged with US and CR. US detected osteophytosis in 448 joints, compared to CR that detected osteophytosis in 228 joints (approximately 30% fewer joints). Where osteophytosis was detected by US but not CR, this was usually proximal to the joint line. Joint space narrowing was detected in 450 joints by US, but only 261 joints by CR. The distribution of US and CR detected osteoarthritis changes in this cohort was consistent with population studies of radiographic hand OA, although metacarpophalangeal (MCP) involvement was higher than might be expected CONCLUSIONS: US detected more osteophytosis and joint space narrowing than CR in OA of the hand. Involvement of MCP joints was more common than would be expected from population radiographic studies. The increased detection of OA structural pathology by US may make this a useful tool for hand OA research.