Burosumab treatment in adults with X-linked hypophosphataemia: 96-week patient-reported outcomes and ambulatory function from a randomised phase 3 trial and open-label extension

Objectives To report the impact of burosumab on patient-reported outcomes (PROs) and ambulatory function in adults with X-linked hypophosphataemia (XLH) through 96 weeks. Methods Adults diagnosed with XLH were randomised 1:1 in a double-blinded trial to receive subcutaneous burosumab 1 mg/kg or placebo every 4 weeks for 24 weeks (NCT02526160). Thereafter, all subjects received burosumab every 4 weeks until week 96. PROs were measured using the Western Ontario and the McMaster Universities Osteoarthritis Index (WOMAC), Brief Pain Inventory-Short Form (BPI-SF) and Brief Fatigue Inventory (BFI), and ambulatory function was measured with the 6 min walk test (6MWT). Results Subjects (N=134) were randomised to burosumab (n=68) or placebo (n=66) for 24 weeks. At baseline, subjects experienced pain, stiffness, and impaired physical and ambulatory function. At week 24, subjects receiving burosumab achieved statistically significant improvement in some BPI-SF scores, BFI worst fatigue (average and greatest) and WOMAC stiffness. At week 48, all WOMAC and BPI-SF scores achieved statistically significant improvement, with some WOMAC and BFI scores achieving meaningful and significant change from baseline. At week 96, all WOMAC, BPI-SF and BFI achieved statistically significant improvement, with selected scores in all measures also achieving meaningful change. Improvement in 6MWT distance and percent predicted were statistically significant at all time points from 24 weeks. Conclusions Adults with XLH have substantial burden of disease as assessed by PROs and 6MWT. Burosumab treatment improved phosphate homoeostasis and was associated with a steady and consistent improvement in PROs and ambulatory function. Trial registration number NCT02526160

Fluvial system response to Late Devensian (Weichselian) aridity, Baston, Lincolnshire, England

Little is known about the impact of Late Devensian (Weichselian) aridity on lowland British landscapes, largely because they lack the widespread coversand deposits of the adjacent continent. The concentration of large interformational ice-wedge casts in the upper part of many Devensian fluvial sequences suggests that fluvial activity may have decreased considerably during this time. The development of optically stimulated luminescence (OSL) dating enables this period of ice-wedge cast formation to be constrained for the first time in eastern England, where a marked horizon of ice-wedge casts is found between two distinctive dateable facies associations. Contrasts between this horizon and adjacent sediments show clear changes in environment and fluvial system behaviour in response to changing water supply, in line with palaeontological evidence. In addition to providing chronological control on the period of ice-wedge formation, the study shows good agreement of the radiocarbon and OSL dating techniques during the Middle and Late Devensian, with direct comparison of these techniques beyond 15 000 yr for the first time in Britain. It is suggested that aridity during the Late Devensian forced a significant decrease in fluvial activity compared with preceding and following periods, initiating a system with low peak flows and widespread permafrost development

Sedimentology, palaeontology and archaeology of late Middle Pleistocene River Thames terrace deposits at Purfleet, Essex, UK

Middle Pleistocene fluvial deposits of the Corbets Tey Formation at Purfleet, Essex, provide evidence of an un-named and previously poorly recognized interglacial, thought to corrrelate with Oxygen Isotope Stage (OIS) 9. Previous attributions of the sediments to the Ipswichian (Last Interglacial) Stage are refuted. New investigations have yielded rich molluscan, mammalian and ostracod assemblages that indicate fully temperate conditions and the distal influence of marine transgression. Pollen analyses suggest a previously unrecorded phase of interglacial vegetational development. Clast composition, geomorphological evidence and the occurrence of molluscs that favour large rivers all point to deposition by the Thames, rather than in a minor tributary, as suggested previously. Three separate Palaeolithic industries in stratigraphical superposition are recognized at Purfleet, these being Clactonian, Acheulean and Levallois. Purfleet is therefore a key locality in the understanding of the early human occupation and exploitation of southern Britain, as well as for the interpretation and correlation of the terrace sequence in the Thames Valley

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.L. L. Laslett, B. Antony, A. E. Wluka, C. Hill, L. March, H. I. Keen, P. Otahal, F. M. Cicuttini and G. Jone

Methotrexate to treat hand osteoarthritis with synovitis (METHODS): an Australian, multisite, parallel-group, double-blind, randomised, placebo-controlled trial

Background Hand osteoarthritis is a disabling condition with few effective therapies. Hand osteoarthritis with synovitis is a common inflammatory phenotype associated with pain. We aimed to examine the efficacy and safety of methotrexate at 6 months in participants with hand osteoarthritis and synovitis. Methods In this multisite, parallel-group, double-blind, randomised, placebo-controlled trial, participants (aged 40–75 years) with hand osteoarthritis (Kellgren and Lawrence grade ≥2 in at least one joint) and MRI-detected synovitis of grade 1 or more were recruited from the community in Melbourne, Hobart, Adelaide, and Perth, Australia. Participants were randomly assigned (1:1) using block randomisation, stratified by study site and self-reported sex, to receive methotrexate 20 mg or identical placebo orally once weekly for 6 months. The primary outcome was pain reduction (measured with a 100 mm visual analogue scale; VAS) in the study hand at 6 months assessed in the intention-to-treat population. Safety outcomes were assessed in all randomly assigned participants. This trial was registered with the Australian New Zealand Clinical Trials Registry (ACTRN12617000877381). Findings Between Nov 22, 2017, and Nov 8, 2021, of 202 participants who were assessed for eligibility, 97 (48%) were randomly assigned to receive methotrexate (n=50) or placebo (n=47). 68 (70%) of 97 participants were female and 29 (30%) were male. 42 (84%) of 50 participants in the methotrexate group and 40 (85%) of 47 in the placebo group provided primary outcome data. The mean change in VAS pain at 6 months was –15·2 mm (SD 24·0) in the methotrexate group and –7·7 mm (25·3) in the placebo group, with a mean between-group difference of –9·9 (95% CI –19·3 to –0·6; p=0·037) and an effect size (standardised mean difference) of 0·45 (0·03 to 0·87). Adverse events occurred in 31 (62%) of 50 participants in the methotrexate group and 28 (60%) of 47 participants in the placebo group. Interpretation Treatment of hand osteoarthritis and synovitis with 20 mg methotrexate for 6 months had a moderate but potentially clinically meaningful effect on reducing pain, providing proof of concept that methotrexate might have a role in the management of hand osteoarthritis with an inflammatory phenotype.Yuanyuan Wang, Graeme Jones, Helen I Keen, Catherine L Hill, Anita E Wluka, Jessica Kasza, Andrew J Teichtahl, Benny Antony, Richard O'Sullivan, Flavia M Cicuttin

2021 Asia‐Pacific League of Associations for Rheumatology clinical practice guideline for treatment of gout

Background Gout is the most prevalent inflammatory arthritis in the Asia-Pacific region and worldwide. This clinical practice guideline (CPG) aims to provide recommendations based on systematically obtained evidence and values and preferences tailored to the unique needs of patients with gout and hyperuricemia in Asia, Australasia, and the Middle East. The target users of these guidelines are general practitioners and specialists, including rheumatologists, in these regions. Methods Relevant clinical questions were formulated by the Steering Committee. Systematic reviews of evidence were done, and certainty of evidence was assessed using Grading of Recommendations Assessment, Development and Evaluation methodology. A multi-sectoral consensus panel formulated the final recommendations. Results The Asia-Pacific League of Associations for Rheumatology Task Force developed this CPG for treatment of gout with 3 overarching principles and 22 recommendation statements that covered the treatment of asymptomatic hyperuricemia (2 statements), treatment of acute gout (4 statements), prophylaxis against gout flare when initiating urate-lowering therapy (3 statements), urate-lowering therapy (3 statements), treatment of chronic tophaceous gout (2 statements), treatment of complicated gout and non-responders (2 statements), treatment of gout with moderate to severe renal impairment (1 statement), and non-pharmacologic interventions (5 statements). Conclusion Recommendations for clinically relevant scenarios in the management of gout were formulated to guide physicians in administering individualized care

Reliability and diagnostic accuracy of radiography for the diagnosis of calcium pyrophosphate deposition: performance of the novel definitions developed by an international multidisciplinary working group.

To assess the reliability and diagnostic accuracy of new radiographic definitions for calcium pyrophosphate deposition (CPPD) identification, developed by an international multidisciplinary working group. Patients with knee osteoarthritis scheduled for knee replacement were enrolled. Two radiologists and two rheumatologists assessed twice the images for presence/absence of CPPD on menisci, hyaline cartilage, tendons, joint capsule, synovial membrane, using the new definitions. In case of disagreement, a consensus decision was taken and considered for the assessment of diagnostic performance. Histological examination of specimens under compensated polarized light microscopy was the reference standard. Prevalence-adjusted bias-adjusted kappa (PABAK) was used to assess the reliability. Diagnostic performance statistics were calculated. Sixty-seven participants were enrolled for the reliability study. The inter-observer reliability was substantial in most of the assessed structures when considering all 4 readers (kappa range 0.59 - 0.90), substantial to almost perfect among radiologists (kappa range 0.70-0.91), and moderate to almost perfect among rheumatologists (kappa range 0.46 - 0.88). The intra-observer reliability was substantial to almost perfect for all the observers (kappa range 0.70 - 1). Fifty-one patients were enrolled for the accuracy study. Radiography demonstrated to be specific for CPPD (92%), but sensitivity remained low in all sites and in the overall diagnosis (54%). The new imaging definitions of CPPD are highly specific against the gold standard of histological diagnosis; when described findings are present these definitions allow for a definite diagnosis of CPPD, rather than other calcium-containing crystal depositions; instead a negative finding does not exclude the diagnosis