Precision Medicine With Leflunomide: Consideration of the DHODH Haplotype and Plasma Teriflunomide Concentration and Modification of Outcomes in Patients With Rheumatoid Arthritis.

OBJECTIVE: Leflunomide is a commonly used disease-modifying drug in the treatment of rheumatoid arthritis (RA). Its effects are mediated via inhibition of dihydroorotate dehydrogenase (DHODH) by its active metabolite teriflunomide, and the pharmacokinetics of teriflunomide are highly variable. Our objective was to examine the association between the DHODH haplotype and plasma teriflunomide concentration with response to leflunomide in patients with RA where leflunomide was added to an existing disease-modifying drug regimen after failure to achieve an adequate response with conventional triple therapy. METHODS: Patients with RA who were taking, or were about to initiate, leflunomide were included. Participant characteristics, including the DHODH haplotype, were determined. Up to 5 plasma samples were collected after leflunomide was initiated for assays of total and free teriflunomide concentration. Disease activity was determined via the 28-joint Disease Activity Score (DAS28). The association between DAS28 scores and patient covariates was determined by linear mixed-effects modeling. RESULTS: A total of 67 patients were included in the study. The DAS28 score after initiation of leflunomide was associated with the baseline DAS28 score (ß = 0.70, P < 0.001) and was higher in those who carried the DHODH haplotype 2 (ß = 0.56. P = 0.01) and did not carry the shared epitope (ß = 0.56, P = 0.013). As total and free plasma teriflunomide concentration increased, the DAS28 score was significantly lower (P < 0.001 and P = 0.001, respectively). When considering threshold concentrations, teriflunomide concentrations >16 mg/liter were associated with a DAS28 score that was 0.33 lower, and when free teriflunomide concentration was >35 µg/liter, the DAS28 score was 0.32 lower. CONCLUSION: Teriflunomide concentration and carriage of the DHODH haplotype 2 are associated with response to leflunomide in patients with RA, and a total plasma teriflunomide concentration of at least 16 mg/liter is needed to maximize the likelihood of response.

Disease activity trajectories in early rheumatoid arthritis following intensive DMARD therapy over 3 years: association with persistence to therapy.

OBJECTIVE: To identify the disease activity trajectories during intensive triple disease modifying anti-rheumatic drug (DMARD) therapy over 3 years in rheumatoid arthritis (RA) patients and to evaluate the association with treatment persistence. METHODS: Disease Activity Score in 28 joints, baseline risk factors and medication usage were obtained from a longitudinal observational cohort of early RA patients, most of whom were treated with combination DMARD therapy consisting of methotrexate, sulfasalazine and hydroxychloroquine. Persistence of each DMARD was defined as the duration of time from initiation to cessation. A group-based trajectory modelling technique was used to identify disease activity trajectories. RESULT: Three disease activity trajectories (good [43.8%], moderate [39.7%] and poor [16.5%]) were identified in a cohort of 297 patients. Most baseline risk factors, medication usage, the rate of treatment persistence and the effect of persistence on disease activity differed among patients in each of the three trajectories. Although the rate of persistence was higher in the trajectory with a good outcome, the association with persistence was more pronounced among patients who were in the poor outcome trajectory. Persistence with at least two or all three baseline DMARDs was associated with a decrease in disease activity to a broadly similar degree in all trajectories. CONCLUSION: After correction for other baseline prognostic factors, persistence with initial DMARDs contributes to heterogeneity in disease activity trajectory and there was an association between persistence with initial DMARD therapy and lower long-term disease activity.

The PTPN22 gene is associated with idiopathic inflammatory myopathy.

INTRODUCTION: The aim of this study was to determine whether a single-nucleotide polymorphism (SNP; 1858CT, R620W) in the protein tyrosine phosphatase N22 (PTPN22) gene confers susceptibility to idiopathic inflammatory myopathy (IIM) in South Australian patients with IIM. METHODS: Genotyping was performed on stored DNA from 199 patients with histologically confirmed polymyositis (PM), dermatomyositis (DM), and inclusion body myositis (IBM), and then compared with 455 matched controls. Associations with the 8.1 ancestral haplotype (AH), and myositis-specific (MSA) and myositis-associated (MAA) autoantibodies were investigated. RESULTS: The PTPN22 R620W minor allele frequency was increased in IIM patients (50 of 398, 12.6%) compared with controls (75 of 910, 8.2%) (odds ratio 1.6, 95% confidence interval 1.1-2.3, P = 0.016). In IIM patients, there was no association between the R620W minor allele and detection of any MSA/MAA (P = 0.70), nor any evidence of epistasis with the 8.1 AH (P = 0.69). CONCLUSIONS: The PTPN22 R620W minor allele is associated with susceptibility to IIM in SA patients, independent of the 8.1 AH. Muscle Nerve, 2016 Muscle Nerve 55: 270-273, 2017.

Determining the acceptable level of physician compliance with a treat-to-target strategy in early rheumatoid arthritis.

OBJECTIVE: To determine the minimum cut-points for rate of physician compliance with a treat-to-target (T2T) strategy needed to achieve optimal rates of remission or low disease activity (LDA). METHOD: In this analysis of longitudinal observational data from patients with early RA, physician compliance with a T2T treatment protocol was determined for each clinic visit over 3 years. Remission and LDA were measured by Disease Activity Score in 28 joints (DAS28), simplified disease activity index (SDAI) and clinical disease activity index (CDAI). The minimum physician compliance rates for predicting these outcomes were calculated using receiver operating characteristic (ROC) curves. RESULT: Overall, 149 patients completed 3078 clinic visits over 3 years of follow-up. Treatment decisions complied with the T2T protocol in 2343 of these visits (76.1%). The minimum cut-points for physician compliance rates that predicted remission and LDA according to DAS28 were 81.1% and 70.7%, respectively, and to predict remission and LDA according to SDAI, the respective cut-points were 92.7% and 77.4%. Based on these cut-points, three categories of physician compliance with T2T were proposed: high (to maximize the likelihood of achieving remission, > 80% according to DAS28 or > 90% according to SDAI/CDAI); medium (the minimal physician compliance to achieve LDA, 70-79% according to DAS28 or 75-89% for SDAI/CDAI); and low (< 70% for DAS28 and < 75% for SDAI/CDAI), where remission and LDA are unlikely). When patients were stratified by baseline disease activity, the physician compliance rate cut-points were similar for most outcomes at year 3. CONCLUSION: Using real-life clinical data, we determined the thresholds for physician compliance with a T2T strategy that stratified patients according to their disease outcomes and proposed a system for classifying physician compliance as high, medium and low.

Effect of Adherence to Protocolized Targeted Intensifications of Disease-modifying Antirheumatic Drugs on Treatment Outcomes in Rheumatoid Arthritis: Results from an Australian Early Arthritis Cohort.

OBJECTIVE: To investigate the association between adherence to treat-to-target (T2T) protocol and disease activity, functional outcomes, and radiographic outcomes in early rheumatoid arthritis (RA). METHODS: Data from a longitudinal cohort of patients with early RA were used. Adherence was determined at each followup visit over 3 years according to predefined criteria. The primary endpoint was remission according to Disease Activity Score in 28 joints (DAS28) and Simplified Disease Activity Index (SDAI) criteria. Functional and radiographic outcomes measured by modified Health Assessment Questionnaire and modified total Sharp score, respectively, were secondary endpoints. RESULTS: A total of 198 patients with 3078 clinic visits over 3 years were included in this analysis. After adjusting for relevant variables, although there was no significant association between adherence to T2T and remission rate after 1 year, the associations reached significance after 3 years for both DAS28 (OR 1.71, 95% CI 1.16-2.50; p = 0.006) and SDAI criteria (OR 1.94, 95% CI 1.06-3.56; p = 0.033). After 3 years, adherence was also associated with improvement in physical function (ß=0.12, 95% CI 0.06-0.18; p < 0.0001). None of the radiographic outcomes were associated with adherence after either 1 or 3 years, although there was a trend for higher adherence to be associated with less radiographic progression at the end of the study (p = 0.061). CONCLUSION: Increased adherence to T2T was associated with better longterm disease activity and functional outcomes, which suggests that the benefit of a T2T protocol may be enhanced by ensuring adequate adherence.

Specialised pro-resolving mediators of inflammation in inflammatory arthritis.

INTRODUCTION: Specialised pro-resolving mediators (SPM) are derived from n-3 long chain polyunsaturated fatty acids (n-3FA). They promote resolution of inflammation and may contribute to the beneficial effects of n-3FA in patients with arthritis. This study compared SPM in knee effusions and plasma of patients with arthritis taking n-3FA, and plasma of healthy volunteers taking n-3FA. METHODS: Thirty six patients taking n-3FA undergoing arthrocentesis for an inflammatory knee effusion and 36 healthy volunteers who had taken n-3FA (2.4g/day) for 4 weeks were studied. SPM in synovial fluid and plasma were measured by liquid chromatography-tandem mass spectrometry included 18-hydroxyeicosapentaenoic acid (18-HEPE), the precursor of the E-series SPM (RvE1, RvE2, RvE3, 18R-RvE3), and 17-hydroxydocosahexaenoic acid (17-HDHA), the precursor of the D-series SPM (RvD1, 17R-RvD1, RvD2). Other SPM included protectin D1 (PD1), 10S,17S-dihydroxydocosahexaenoic acid (10,17S-DHDHA), maresin-1 (MaR-1) and 14-hydroxydocosahexaenoic acid (14-HDHA) derived from docosahexaenoic acid (DHA). RESULTS: E- and D-series SPM and the precursors 18-HEPE and 17-HDHA were present in synovial fluid and plasma of the patients with inflammatory arthritis. Plasma SPM were negatively related to erythrocyte sedimentation rate in arthritis patients (P<0.01) and synovial fluid RvE2 was negatively associated with pain score (P=0.02). Conversion from 18-HEPE and 17-HDHA to E- and D-series SPM was greater in synovial fluid (P<0.01). Most plasma SPM in arthritis patients were elevated (P<0.05) compared with healthy volunteers, and conversion to E- and D-series SPM was greater (P<0.01). CONCLUSIONS: SPM are present in chronic knee effusions and although the levels are lower than in plasma, the association between synovial fluid RvE2 and reduced pain scores suggests that synthesis of SPM at the site of inflammation is a relevant mechanism by which n-3FA alleviate the symptoms of arthritis.

Ten years of publicly funded biological disease-modifying antirheumatic drugs in Australia.

Biological disease-modifying antirheumatic drugs (bDMARDs) for rheumatoid arthritis (RA) treatment were among the first high-cost medicines to be subsidised in Australia. High-cost medicines pose several challenges to the Australian National Medicines Policy, which aims to provide timely access to effective medicines at a cost individuals and the community can afford. Thus, novel restriction criteria were developed to encourage cost-effective use of bDMARDs. Government expenditure on bDMARD subsidies for RA treatment grew to about $383 million in 2014. Evidence that initiation and continuation criteria for bDMARDs meet usually applied cost-benefit criteria is lacking. The combined expenditure on tocilizumab, certolizumab pegol and golimumab (added to the Australian Government's Pharmaceutical Benefits Scheme in 2010) was $93 million in 2014, which is 210% over the initial estimate. Present and future challenges with regard to bDMARDs for RA and other high-cost drugs include improved expenditure predictions, monitoring of cost-effectiveness in relation to actual use and strategic development, regulation and use of biosimilars. Ten years of documentation on clinical and laboratory findings indicating eligibility to initiate and continue on bDMARDs remains un-used. These data represent an untapped opportunity to promote quality of use of bDMARDs and biosimilars and to improve cost predictions for high-cost drugs.

Fish oil in knee osteoarthritis: a randomised clinical trial of low dose versus high dose.

OBJECTIVES: To determine whether high-dose fish oil is superior to low-dose supplementation for symptomatic and structural outcomes in knee osteoarthritis (OA). METHODS: A randomised, double-blind, multicentre trial enrolled 202 patients with knee OA and regular knee pain. They were randomised 1:1 to high-dose fish oil (4.5 g omega-3 fatty acids) 15 mL/day or (2) low-dose fish oil (blend of fish oil and sunola oil; ratio of 1:9, 0.45 g omega-3 fatty acids) 15 mL/day. The primary endpoints were Western Ontario and McMaster Universities Arthritis Index (WOMAC) pain score at 3, 6, 12 and 24 months, and change in cartilage volume at 24 months. Secondary outcomes included WOMAC function, quality of life, analgesic and non-steroidal anti-inflammatory drug use and bone marrow lesion score. RESULTS: Although there was improvement in both groups, the low-dose fish oil group had greater improvement in WOMAC pain and function scores at 2 years compared with the high-dose group, whereas between-group differences at 1 year did not reach statistical significance. There was no difference between the two groups in cartilage volume loss at 2 years. For other secondary endpoints, there was no difference between the two groups at 2 years. CONCLUSIONS: In people with symptomatic knee OA, there was no additional benefit of a high-dose fish oil compared with low-dose fish oil. The combination comparator oil appeared to have better efficacy in reducing pain at 2 years, suggesting that this requires further investigation. TRIAL REGISTRATION NUMBER: Australian New Zealand Clinical Trials Registry (ACTRN 12607000415404).

Plasma n-3 fatty acids and clinical outcomes in recent-onset rheumatoid arthritis.

A randomised controlled trial (RCT) of high-dose v. low-dose fish oil in recent-onset rheumatoid arthritis (RA) demonstrated that the group allocated to high-dose fish oil had increased remission and decreased failure of disease-modifying anti-rheumatic drug (DMARD) therapy. This study examines the relationships between plasma phospholipid levels of the n-3 fatty acids in fish oil, EPA and DHA, and remission and DMARD use in recent-onset RA. EPA and DHA were measured in blood samples from both groups of the RCT. The data were analysed as a single cohort, and Cox proportional hazards models were used to examine relationships between plasma phospholipid (PL) EPA and DHA and various outcome measures. When analysed as a single cohort, plasma PL EPA was related to time to remission, with a one unit increase in EPA (1% total fatty acids) associated with a 12% increase in the probability of remission at any time during the study period (hazard ratio (HR)=1.12; 95% CI 1.02, 1.23; P=0.02). Adjustment for smoking, anti-cyclic citrullinated peptide antibodies and 'shared epitope' HLA-DR allele status did not change the HR. Plasma PL EPA, adjusted for the same variables, was negatively related to time to DMARD failure (HR=0.85; 95% CI 0.72, 0.99; P=0.047). The HR for DHA and time to remission or DMARD failure were similar in magnitude to those for EPA, but not statistically significant. Biomarkers of n-3 status, such as plasma PL EPA, have the potential to predict clinical outcomes relevant to standard drug treatment of RA patients.

Characterising deviation from treat-to-target strategies for early rheumatoid arthritis: the first three years.

INTRODUCTION: Treat-to-target (T2T) strategies using a protocol of pre-defined adjustments of disease-modifying anti-rheumatic drugs (DMARDs) according to disease activity improve outcomes for patients with rheumatoid arthritis (RA). However, successful implementation may be limited by deviations from the protocol. The aim of this study was to determine the prevalence of protocol deviation, explore the reasons and identify subsets of patients in whom treatment protocols are more difficult to follow. METHODS: In this retrospective cohort study, treatment-naïve patients with RA of less than one year's duration, attending a dedicated early arthritis clinic between 2001 and 2013, were followed for three years from initiation of combination therapy with conventional DMARDs which was subsequently modified according to a T2T protocol. At each clinic visit, whether deviation from the protocol occurred, the type of deviation and the reasons for deviation were assessed. The relationship between protocol deviations and baseline variables was determined using linear regression analysis. RESULTS: In total, 198 patients contributed 3,654 clinic visits. The prevalence of protocol deviations was 24.5% and deviation in at least at one clinic visit was experienced by 90.4% of patients. The median time to first deviation was 30 weeks. Continuing existing treatment rather than intensifying therapy was the most common type of deviation (59.9%). Patient and physician related factors were the most common reasons for deviation, each accounting for 24.7% of deviations, followed by toxicities (23.3%) and comorbidities (20.0%). The prevalence of protocol deviations was lower among patients who achieved remission after three years (13.1%; 162 deviations out of 1,228 visits) compared with those who were not in remission (30.9%; 523/1692) (P<0.0001). On multivariate analysis, only body mass index (P=0.003) and helplessness score (P=0.04) were independent predictors of protocol deviations although the predictive power of the model was not strong (R2=0.17). CONCLUSIONS: Deviation from a T2T protocol occurred in one quarter of visits, indicating that applying the T2T approach is feasible in clinical practice. Failure to escalate dose when indicated was commonly encountered, and just under half of the observed deviations were related to either toxicities or comorbidities and were therefore justifiable on clinical grounds.

Synovial fluid and plasma n3 long chain polyunsaturated fatty acids in patients with inflammatory arthritis.

Relationships between n-3 long chain polyunsaturated fatty acids (LC-PUFA) in plasma and synovial fluid (SF) were examined in 36 patients with knee effusion within the context of a variety of rheumatic diagnoses and various stated fish oil (FO) intakes (from 0 to 30mL of standard FO daily) of variable duration. In a sub-group of patients, correlations between PUFA in SF mononuclear cells (MNC) and cell-free supernatants of SF and between SF MNC and peripheral blood (PB) MNC were examined. Correlations were also sought between clinical data (stated FO intake, pain score) and n-3 LC-PUFA. Correlations between plasma n-3 LC-PUFA and SF n-3 LC-PUFA were very strong (r(2)>0.9, p<0.001). The LC-PUFA profiles of SF supernatants differed from those of MNC. PUFA profiles in PB MNC and SF MNC were similar, except for a higher proportion of DHA in the latter. Positive correlations were observed between stated intakes of FO and EPA in plasma and SF (for both r=0.37, p=0.02) and DHA in plasma (r=0.37, p=0.02) and SF (r=0.36, p=0.03). n-3 LC-PUFA in plasma and SF correlated inversely with pain score (plasma r(2)=0.16, p<0.02; SF r(2) 0.32, p=0.001). In conclusion, plasma n-3 LC-PUFA is a strong indicator of SF n-3 LC-PUFA status across a broad range of rheumatic diagnoses and FO intakes. Higher n-3 LC-PUFA in plasma and SF were associated with lesser pain experience.

Fish oil in recent onset rheumatoid arthritis: a randomised, double-blind controlled trial within algorithm-based drug use.

BACKGROUND: The effects of fish oil (FO) in rheumatoid arthritis (RA) have not been examined in the context of contemporary treatment of early RA. This study examined the effects of high versus low dose FO in early RA employing a 'treat-to-target' protocol of combination disease-modifying anti-rheumatic drugs (DMARDs). METHODS: Patients with RA <12 months' duration and who were DMARD-naïve were enrolled and randomised 2:1 to FO at a high dose or low dose (for masking). These groups, designated FO and control, were given 5.5 or 0.4 g/day, respectively, of the omega-3 fats, eicosapentaenoic acid + docosahexaenoic acid. All patients received methotrexate (MTX), sulphasalazine and hydroxychloroquine, and DMARD doses were adjusted according to an algorithm taking disease activity and toxicity into account. DAS28-erythrocyte sedimentation rate, modified Health Assessment Questionnaire (mHAQ) and remission were assessed three monthly. The primary outcome measure was failure of triple DMARD therapy. RESULTS: In the FO group, failure of triple DMARD therapy was lower (HR=0.28 (95% CI 0.12 to 0.63; p=0.002) unadjusted and 0.24 (95% CI 0.10 to 0.54; p=0.0006) following adjustment for smoking history, shared epitope and baseline anti-cyclic citrullinated peptide. The rate of first American College of Rheumatology (ACR) remission was significantly greater in the FO compared with the control group (HRs=2.17 (95% CI 1.07 to 4.42; p=0.03) unadjusted and 2.09 (95% CI 1.02 to 4.30; p=0.04) adjusted). There were no differences between groups in MTX dose, DAS28 or mHAQ scores, or adverse events. CONCLUSIONS: FO was associated with benefits additional to those achieved by combination 'treat-to-target' DMARDs with similar MTX use. These included reduced triple DMARD failure and a higher rate of ACR remission.

Synovial fluid myeloid dendritic cells display important differences compared to monocyte-derived dendritic cells prepared in vitro.

The object of this study was to characterise synovial fluid dendritic cells (SFDCs) with regard to morphology, phenotype and responses to 1,25hydroxy-cholecalciferol (1,25D) and lipopolysaccharide (LPS), and to compare these characteristics with those of peripheral blood (PB) monocyte-derived DCs (MDDCs). SF was aspirated from knees with inflammatory effusions. PB samples were obtained contemporaneously. SFDCs were separated by flow cytometry. Morphology was determined on cytosmears. Expression of accessory molecules, cytokines and prostaglandin synthases mRNA was quantified by reverse transcription PCR. Analyses were performed on freshly prepared DCs and after incubation with 1,25D and LPS, separately and in combination. SFDCs and MDDCs displayed broadly similar morphology. Expression of accessory molecules, cytokines, cyclooxygenase-2 (COX-2) and prostaglandin E-synthase (PGES) was similar. SFDCs, but not MDDCs, expressed prostaglandin D-synthase (PGDS). PGDS was lost on incubation with SFDCs, but was induced by 1,25D in MDDCs. LPS in the presence or absence of 1,25D, induced interleukin 23 (IL23), IL1ß and tumour necrosis factor-α in SFDCs and MDDCs, with SFDC showing stronger expression of these cytokines. 1,25D in combination with LPS induced PGES and enhanced LPS induction of IL6 in SFDCs and MDDCs. LPS reduced 1,25D-induced expression of PGDS in MDDCs. SFDCs and MDDCs display similar basal characteristics but differ in PGDS expression and responsiveness to LPS and 1,25D. MDDCs have limitations as a model of SFDCs which have differentiated in vivo.

Multicentric myofibroblastic sarcoma.

We report a case of synchronous, multicentric low-grade myofibroblastic sarcoma presenting in a 62-year-old man. He initially presented with inflammatory symmetric polyarthritis and adhesive capsulitis of his shoulder and hips bilaterally and did not respond to a trial of disease modifying antirheumatic drugs. Over a period of several years he developed progressive restriction of both knees and nodules on his hands, both knees and back. A biopsy of the nodule on his back was inconclusive and subsequent biopsies on his left and then right knee revealed a spindle cell neoplasm with an infiltrative growth pattern, mitotic figures, positive immunostaining for smooth muscle actin and focal myxoid change consistent with myofibroblastic sarcoma. While myofibroblastic sarcoma has been known to metastasise, to our knowledge, a multifocal presentation of this tumour has not been described previously.

Appendicular skeletal muscle in hospitalised hip-fracture patients: development and cross-validation of anthropometric prediction equations against dual-energy X-ray absorptiometry.

BACKGROUND: accurate and practical assessment methods for assessing appendicular skeletal muscle (ASM) is of clinical importance for the diagnosis of geriatric syndromes associated with skeletal muscle wasting. OBJECTIVES: the purpose of this study was to develop and cross-validate novel anthropometric prediction equations for the estimate of ASM in older adults post-surgical fixation for hip fracture, using dual-energy X-ray absorptiometry (DEXA) as the criterion measure. SUBJECTS: community-dwelling older adults (aged ≥65 years) recently hospitalised for hip fracture. SETTING: participants were recruited from hospital in the acute phase of recovery. DESIGN: validation measurement study. MEASUREMENTS: a total of 79 hip fracture patients were involved in the development of the regression models (MD group). A further 64 hip fracture patients also recruited in the early phase of recovery were used in the cross-validation of the regression models (CV group). Multiple linear regression analyses were undertaken in the MD group to identify the best performing prediction models. The linear coefficient of determination (R(2)) in addition to the standard error of the estimate (SEE) were calculated to determine the best performing model. Agreement between estimated ASM and ASMDEXA in the CV group was assessed using paired t-tests with the 95% limits of agreement (LOA) assessed using Bland-Altman analyses. RESULTS: the mean age of all the participants was 82.1 ± 7.3 years. The best two prediction models are presented as follows: ASMPRED-EQUATION_1: 22.28 - (0.069 * age) + (0.407 * weight) - (0.807 * BMI) - (0.222 * MAC) (adjusted R(2): 0.76; SEE: 1.80 kg); ASMPRED-EQUATION_2: 16.77 - (0.036 * age) + (0.385 * weight) - (0.873 * BMI) (adjusted R(2): 0.73; SEE: 1.90 kg). The mean bias from the CV group between ASMDEXA and the predictive equations is as follows: ASMDEXA - ASMPRED-EQUATION_1: 0.29 ± 2.6 kg (LOA: -4.80, 5.40 kg); ASMDEXA - ASMPRED-EQUATION_2: 0.13 ± 2.5 kg (LOA: -4.77, 5.0 kg). No significant difference was observed between measured ASMDEXA and estimated ASM (ASMDEXA: 16.4 ± 3.9 kg; ASMPRED-EQUATION_1: 16.7 ± 3.2 kg (P = 0.379); ASMPRED-EQUATION_2: 16.6 ± 3.2 kg (P = 0.670)). CONCLUSIONS: we have developed and cross-validated novel anthropometric prediction equations against DEXA for the estimate of ASM designed for application in older orthopaedic patients. Our equation may be of use as an alternative to DEXA in the diagnosis of skeletal muscle wasting syndromes. Further validation studies are required to determine the clinical utility of our equation across other settings, including hip fracture patients admitted from residential care, and also with a longer-term follow-up.

Pitfalls in the use of randomised controlled trials for fish oil studies with cardiac patients.

Randomised controlled trials (RCT) examining the effects of fish oil supplementation on cardiac outcomes have yielded varying results over time. Although RCT are placed at the top of the evidence hierarchy, this methodology arose in the framework of pharmaceutical development. RCT with pharmaceuticals differ in important ways from RCT involving fish oil interventions. In particular, in pharmaceutical RCT, the test agent is present only in the intervention group and not in the control group, whereas in fish oil RCT, n-3 fats are present in the diet and in the tissues of both groups. Also, early phase studies with pharmaceuticals determine pharmacokinetics and pharmacodynamics to design the dose of the RCT intervention so that it is in a predicted linear dose-response range. None of this happens in fish oil RCT, and there is evidence that both baseline n-3 intake and tissue levels may be sufficiently high in the dose-response range that it is not possible to demonstrate a clinical effect with a RCT. When these issues are considered, it is possible that the changing pattern of fish consumption and fish oil use over time, especially in cardiac patients, can explain the disparity where benefit was observed in the early fish oil trials but not in the more recent trials.