The gut microbiome is associated with bone mass acquisition, yet evidence in childhood remains limited. Given that lower peak bone mass predicts osteoporosis in later life, understanding early influences is important. This analysis explores the association between the early life gut microbiome and bone health in later childhood. Data were obtained from 700 children recruited in pregnancy and followed prospectively within the Copenhagen Prospective Studies on Asthma in Childhood2010 cohort, a population-based mother-child cohort. The infant gut microbiome was measured at 1 wk (n = 445), 1 mo (n = 492), 1 yr (n = 508), 4 yr (n = 350), and 6 yr (n = 327) of age by 16S ribosomal ribonucleic acid amplicon sequencing targeting the fourth variable region. Total body less head BMD and area-adjusted BMC were measured by DXA at 6 yr of age. Associations were investigated by multiple linear regression, permutational analysis of variance, differential abundance analysis, and Random Forest machine learning. There were few associations between the early-life gut microbiome and bone health outcomes at age 6. We found negative associations between alpha (within-sample) diversity and area-adjusted BMC at 4 yr. Beta (between-sample) diversity of the gut microbiome at 6 yr was associated with concurrent BMD. Escherichia-Shigella abundance at 1 mo of age was associated with lower BMD. Sutterella abundance at 1 yr was associated with lower BMD and area-adjusted BMC at 6 yr. There were no other associations between the gut microbiome and bone outcome measures at any time point. In a well-powered unselected cohort study with longitudinal sampling of the gut microbiome, there were some suggestive but no consistent associations between the early gut microbiome and bone health outcomes at 6 yr of age.

Background: To compare persistence of disease-modifying antirheumatic (DMARDs), with a focus on Janus kinase (JAK) inhibitors in Australian rheumatoid arthritis (RA) patients.Methods: A retrospective observational study was conducted among 4,521 RA patients (females n=3,181 [70.4%]), using data from the Services Australia 10% Pharmaceuticals Benefits Scheme (PBS) dataset, aged >= 18 years and initiating a DMARD between 2011 to 2021. Kaplan-Meier analysis was used to estimate persistence rates, defined as occurrence of 6 months gap after the end of a drug dispensing. Results: Twelve-month persistence rates were 72% for upadacitinib, 61% for baricitinib, 58% for subcutaneous tumor necrosis factor-alpha inhibitors (TNFi), 55% for tocilizumab, 53% for tofacitinib, and 49% for abatacept. Median treatment persistence was not reached for upadacitinib (n=574) and baricitinib (n=553); and was 15.0 months for tofacitinib (95% CI 13.5-19.5), 20.5 months for TNFi (95% CI 19.0-22.4), 19.1 months for tocilizumab (95% CI 17.9-23.6), and 12.5 months for abatacept (95% CI 10.4-14.9). Persistence rates on first-line JAK inhibitors were 68% for upadacitinib and baricitinib and 55% for tofacitinib, and 49% for TNFi, 55% for abatacept, and 57% for tocilizumab; rates were sustained for upadacitinib, TNFi, and tocilizumab but dropped to 59% for baricitinib and 47% for abatacept in the second-line treatment. For each b/tsDMARD, persistence rates were higher when combined with methotrexate or other conventional synthetic DMARDs. The median oral glucocorticoid dose decreased from 4.3 mg/day (range:0-40) to 2.3 mg/day (range:0-22) over 2 years. Changes were significant for all RA DMARDs, tofacitinib and baricitinib combined (1-2 years post initiation only), TNFi, abatacept, and tocilizumab.Conclusions: In a real-world setting, we showed highest persistence rates on upadacitinib, followed by baricitinib and then TNFi therapy and was improved by co-therapy. All agents appeared to be corticosteroid sparing.

Importance Knee osteoarthritis is disabling, with few effective treatments. Preliminary evidence suggested that krill oil supplementation improved knee pain, but effects on knee osteoarthritis remain unclear. Objective To evaluate efficacy of krill oil supplementation, compared with placebo, on knee pain in people with knee osteoarthritis who have significant knee pain and effusion-synovitis. Design, Setting, and Participants Multicenter, randomized, double-blind, placebo-controlled clinical trial in 5 Australian cities. Participants with clinical knee osteoarthritis, significant knee pain, and effusion-synovitis on magnetic resonance imaging were enrolled from December 2016 to June 2019; final follow-up occurred on February 7, 2020. Interventions Participants were randomized to 2 g/d of krill oil (n = 130) or matching placebo (n = 132) for 24 weeks. Main Outcomes and Measures The primary outcome was change in knee pain as assessed by visual analog scale (range, 0-100; 0 indicating least pain; minimum clinically important improvement = 15) over 24 weeks. Results Of 262 participants randomized (mean age, 61.6 [SD, 9.6] years; 53% women), 222 (85%) completed the trial. Krill oil did not improve knee pain compared with placebo (mean change in VAS score, −19.9 [krill oil] vs −20.2 [placebo]; between-group mean difference, −0.3; 95% CI, −6.9 to 6.4) over 24 weeks. One or more adverse events was reported by 51% in the krill oil group (67/130) and by 54% in the placebo group (71/132). The most common adverse events were musculoskeletal and connective tissue disorders, which occurred 32 times in the krill oil group and 42 times in the placebo group, including knee pain (n = 10 with krill oil; n = 9 with placebo), lower extremity pain (n = 1 with krill oil; n = 5 with placebo), and hip pain (n = 3 with krill oil; n = 2 with placebo). Conclusions and Relevance Among people with knee osteoarthritis who have significant knee pain and effusion-synovitis on magnetic resonance imaging, 2 g/d of daily krill oil supplementation did not improve knee pain over 24 weeks compared with placebo. These findings do not support krill oil for treating knee pain in this population. Trial Registration Australian New Zealand Clinical Trials Registry Identifier: ACTRN12616000726459 ; Universal Trial Number: U1111-1181-7087

IMPORTANCE Knee osteoarthritis is disabling, with few effective treatments. Preliminary evidence suggested that krill oil supplementation improved knee pain, but effects on knee osteoarthritis remain unclear. OBJECTIVE To evaluate efficacy of krill oil supplementation, compared with placebo, on knee pain in people with knee osteoarthritis who have significant knee pain and effusion-synovitis. DESIGN, SETTING, AND PARTICIPANTS Multicenter, randomized, double-blind, placebo-controlled clinical trial in 5 Australian cities. Participants with clinical knee osteoarthritis, significant knee pain, and effusion-synovitis on magnetic resonance imaging were enrolled from December 2016 to June 2019; final follow-up occurred on February 7, 2020. INTERVENTIONS Participants were randomized to 2 g/d of krill oil (n = 130) or matching placebo (n = 132) for 24 weeks. MAIN OUTCOMES AND MEASURES The primary outcome was change in knee pain as assessed by visual analog scale (range, 0-100; 0 indicating least pain; minimum clinically important improvement = 15) over 24 weeks. RESULTS Of 262 participants randomized (mean age, 61.6 [SD, 9.6] years; 53% women), 222 (85%) completed the trial. Krill oil did not improve knee pain compared with placebo (mean change in VAS score, -19.9 [krill oil] vs -20.2 [placebo]; between-group mean difference, -0.3; 95% CI, -6.9 to 6.4) over 24 weeks. One or more adverse events was reported by 51% in the krill oil group (67/130) and by 54% in the placebo group (71/132). The most common adverse events were musculoskeletal and connective tissue disorders, which occurred 32 times in the krill oil group and 42 times in the placebo group, including knee pain (n = 10 with krill oil; n = 9 with placebo), lower extremity pain (n = 1 with krill oil; n = 5 with placebo), and hip pain (n = 3 with krill oil; n = 2 with placebo). CONCLUSIONS AND RELEVANCE Among people with knee osteoarthritis who have significant knee pain and effusion-synovitis on magnetic resonance imaging, 2 g/d of daily krill oil supplementation did not improve knee pain over 24 weeks compared with placebo. These findings do not support krill oil for treating knee pain in this population. TRIAL REGISTRATION Australian New Zealand Clinical Trials Registry Identifier: ACTRN12616000726459; Universal Trial Number: U1111-1181-7087

Objectives: Exploring (1) pre-exercise and acute movement-evoked pain (AMEP) during an outdoor walking program in individuals with knee osteoarthritis (OA); and (2) comparing baseline physical performance and AMEP flares initiated by walking between participants with either a higher or lower attendance rate. Methods: Individuals with knee OA were prescribed a 24-week walking program, including one unsupervised walk and two supervised walk classes per week. Participants self-reported knee pain on a numerical rating scale (NRS; 0-10) before and after each supervised class. Mixed-effects models were used to investigate trajectories over time for pre-exercise pain and AMEP change (post-minus pre-exercise pain; positive value indicates flare-up). Baseline physical performance (6 tests) and AMEP flares were compared between participants with higher (attending >_70% of supervised classes) and lower attendance rates. Results: Of 24 participants commencing the program, 7 (29%) withdrew. Over 24 weeks, pre-exercise pain improved by 1.20 NRS (95% CI-1.41 to-0.99), with estimated largest per class improvements during the first 8 weeks (-0.05 (-0.06 to-0.03) and plateauing around 20-weeks. The AMEP was estimated to improve by 0.19 NRS (95% CI-0.38 to-0.004) over 24-weeks, with improvements plateauing around 12-weeks. Participants with lower attendance (n = 11) scored poorer on all physical performance tests and experienced a slight increase in AMEP during the first two weeks of the program. Conclusions: Participants improved in pre-exercise pain and AMEP in the first 20 and 12 weeks, respectively. Despite supervision, physical performance and AMEP flares may have contributed to lower attendance. Trial registration number: 12618001097235.

Background Janus Kinase inhibitors (JAKi) and biologic disease modifying anti-rheumatic drugs (bDMARDs) are routinely used in the management of rheumatoid arthritis (RA) patients for whom conventional (c)DMARDs have failed. The usage of glucocorticoids after DMARD initiation and the influence of comedication on treatment persistence, used as a surrogate for treatment effectiveness, remains unkown. Objectives To assess glucocorticoids usage after treatment initiation and to compare the impact of comedication on the persistence of JAKi and bDMARDs in Australian RA patients. Methods A retrospective observational study was conducted among 4,521 RA patients in the Australian Medicare Database (from 2011 to 2022), aged ≥18 and for whom a JAKi or bDMARDs were dispensed. A deidentified 10% sample of the database was taken as a random representation of RA patients in Australia. Kaplan-Meier analysis was used to calculate drug persistence rates, defined as the time from treatment initiation until the date of the last dose when there had not been a script dispensed for 6 months. Wilcoxon Singed Rank test was used to compare glucocorticoid dose changes from 1-year prior to 1 and 1 – 2 years after initiation of the DMARDs. Only patients who had persisted on DMARDs for 2 years were included for analysis. Log-rank test was used to compare time on a particular DMARDs treatment between the following sub-groups: (a) monotherapy; (b) combination MTX; and (c) combination cDMARDs. Results A total of 634 met the inclusion criteria for the glucocorticoids analyses, average dose of glucocorticoids decreased from 4.1 mg/day at 1 year prior to initiation of DMARD, to 2.9 mg/day and 2.0 mg/ day at 1- and 1–2-years post-initiation, respectively (Figure 1). Daily dose changes were statistically significant for all RA DMARDs combined, tofacitinib and baricitinib combined (1–2 years post initiation only), TNFi, abatacept, and tocilizumab. The proportion of patients with a decrease in glucocorticoids dose from 1 year prior to 1 and 1–2 years after DMARD initiation was 62% and 70% for ‘all DMARDs’ (n=634), 35% and 52% for baricitinib (n=23), 58% and 63% for tofacitinib, 59% and 61% for abatacept (n=87), 65% and 78% for tocilizumab (n=148), and 62% and 70% for TNFi (n=387), respectively. For each drug individually, treatment persistence rates were higher in combination with MTX and in combination with other cDMARDs, compared to monotherapy (Table 1). Statistical significance was only reached when comparing baricitinib combined with cDMARD to monotherapy baricitinib (65% [p=0.04] vs 52%), tofacitinib combined with MTX and combined with other cDMARDs to monotherapy tofacitinib (56% [p=<0.01] and 55% [p=<0.01] vs. 45%); and TNFi combined with MTX and combined with other cDMARDs to monotherapy TNFi (63% [p=<0.0001] and 65% [p=<0.0001] vs. 43%). Conclusion This real-world data showed that among Australian RA patients glucocorticoids dosage decreased with JAKi and bDMARD use. When treatment was combined with MTX or other cDMARDs persistence rates were not sig. different when comparing upadacitinib, baricitinib and TNFi. Tofacitinib had similar persistence rates to TNFi. Average daily glucocorticoids usage. Acknowledgements L. Scheepers receives funding from The Farrell Family Foundation. Disclosure of Interests Lieke Scheepers Grant/research support from: ASPIRE Grant 2020, Pfizer, Employee of: AstraZeneca 2017 till 2020, Yifei Yang: None declared, Yi Chen: None declared, Graeme Jones: None declared.

Exercise therapy is recommended as first line treatment for knee osteoarthritis (OA), but it remains to be sub-optimally applied (1). Movement-evoked pain is a potential barrier to exercise adherence, but recent evidence suggests that such pain can be improved by training (2). Walking programs are low-cost, easily adopted and can be performed outdoors which can minimize the risk of SARS-CoV-2 transmission when in a group (3).To explore the acute pain trajectories of individuals with knee OA during a 24-week outdoor walking intervention. In addition, to explore the effect of pain trajectories and/or baseline characteristics on retention and adherence.Individuals with clinical knee OA and bone marrow lesions (BMLs) on magnetic resonance imaging (MRI) were asked to follow a 24-week walking program. Every week consisted of two one hour supervised group sessions at various outdoor locations and one unsupervised session. At the start and end of every supervised group walk, knee pain was self-reported by participants to their trainer using a numerical rating scale (NRS) (0-10). The difference between the NRS pain values was considered as an acute pain change evoked by that walk. At baseline, the most affected knee of each participant was assessed using the Visual Analogue Scale (VAS) pain, the Western Ontario and McMasters Universities Osteoarthritis Index (WOMAC) pain, stiffness and function, wellbeing (3 questionnaires) and the Osteoarthritis Research Society International (OARSI) recommended strength and performance measures.In total, N = 24 participants started the program of whom N = 7 (29%) withdrew. Pain at the start of each walk decreased from NRS 2.5 (SD 1.6) at the first walk (N = 24) to NRS 0.9 (SD 0.8) at the final walk (N = 17). This pain was estimated to decrease on NRS by -0.04 (95% CI -0.05 to -0.02) per supervised session, p < 0.001 during the first 12 weeks and -0.01 (95% CI -0.02 to -0.004), p = 0.004 during the second twelve weeks of the program. The number (%) of participants who experienced an acute increase in pain decreased from 11 (45.8%) at the first walk to 4 (23.5%) at the last walk.At baseline, non-adherent participants (<70% of group sessions) (N = 11) had lower physical performance scores, including the 30s Chair Stand Test (mean 10 (SD 1.7) stands versus mean 12.0 (SD 1.7) stands, p = 0.011), Fast Past Walk Test (1.23 (SD 0.14) meter per seconds (m/s) vs 1.50 (SD 0.20) m/s, p = 0.001), Six Minute Walk Test (418.8 (SD 75.9) m vs 529 (SD 72.6) m, p = 0.002), compared to adherent participants (N = 13). Non-adherent participants also had less severe self-reported symptoms including WOMAC stiffness (90.7 (SD 44.5) mm vs 121.5 (SD 17.0) mm, p = 0.031), compared to adherent participants. During the first two weeks of walking, acute increases in pain on average (mean ≥0.5 NRS) were reported by a greater number of non-adherent (N = 5 (45.5%)) than adherent participants (n = 4 (30.8%)).This was an exploratory study and results need to be interpreted with caution due to the small sample size. The walking program resulted in clinically important improvements (MCIIs) (≥ 1 on NRS) (4) in start pain and acute pain changes. Improvements in start pain during the first 12-weeks were comparable to improvements measured in the NEMEX program (2) and may suggest that 12 weeks of exercise is sufficient to achieve MCIIs in pain. Improvements in acute changes in pain were smaller, which may have been related to a floor effect (5). Lower physical performance scores at baseline and more acute increases in pain during the first two weeks was associated with non-adherence. Participants with these characteristics may benefit from a lighter introduction to exercise.[1]Bennell KL, et al. The Lancet Regional Health-Western Pacific. 2021;12:100187.[2]Sandal LF, et al. Osteoarthritis and cartilage. 2016;24(4):589-92.[3]Bulfone TC, et al. The Journal of infectious diseases. 2021;223(4):550-61.[4]Perrot S, et al. Pain. 2013;154(2):248-56.[5]McHorney CA, et al. Quality of life research. 1995;4(4):293-307.We thank the participants who made this study possible. We would like to acknowledge the research staff, Kate Probert, Lizzy Reid, Simone Fitzgerald, Claire Roberts, Jasmin Ritchie, Dawn Simpson, and Tim Albion. We also thank Hamish Newsham-West for his contribution to the study design.Stan Drummen: None declared, Saliu Balogun: None declared, Lieke Scheepers Grant/research support from: Competitive Grant Program Inflammation ASPIRE 2020 Rheumatology International Developed Markets from Pfizer, Employee of: previously worked as an Associate Director Epidemiology at the Medical Evidence Observational Research Department at AstraZeneca., Ishanka Munugoda: None declared, aroub lahham: None declared, Kim Bennell: None declared, Rana Hinman: None declared, Michele Callisaya: None declared, Guoqi Cai: None declared, Petr Otahal: None declared, Tania Winzenberg Consultant of: received payment to create educational material by AMGEN, Zhiqiang Wang: None declared, Benny Antony: None declared, Johanne Martel-Pelletier Shareholder of: ArthroLab Inc., Jean-Pierre Pelletier Shareholder of: ArthroLab Inc., François Abram Consultant of: ArthroLab Inc., Employee of: Arthrolab Inc., Graeme Jones Speakers bureau: received payment for a speakers bureau from Novartis, Dawn Aitken: None declared

BackgroundIn rheumatoid arthritis (RA) persistence on disease modifying anti-rheumatic drugs (DMARDs) can be interpreted as a composite measure of effectiveness, safety, and tolerability. There is limited data available on real-life use of the newest class of drugs, the Janus Kinase (JAK) inhibitors. JAK inhibitors are small-molecule treatments which are administered orally on a daily basis and offer a long-term option in RA treatment.ObjectivesTo compare drug persistence on JAK inhibitors tofacitinib, baricitinib and upadacitinib to tumor necrosis factor-α (TNF) inhibitors and other DMARDs in RA patients in Australia.MethodsA retrospective observational study was conducted among RA patients in the Australian Medicare Database (from January 2006 till October 2021), aged ≥18 and for whom a JAK inhibitor or biologic DMARDs were dispensed. Data were provided by the Australian Department of Health and Aging through PROSPECTION, an Australian healthcare consulting company. A deidentified 10% sample of the database was taken as a random representation of RA patients in Australia.Kaplan-Meier analysis was used to calculate drug persistence rates, defined as the time from treatment initiation until the date of the last dose when there had not been a script dispensed for 6 months; except for rituximab, where a 12-month gap was applied.ResultsData from 5,455 patients were analysed. For all patients the 12-month persistence rates were 61% for JAK inhibitors (baricitinib, tofacitinib, upadacitinib), 62% for tocilizumab, 52% for TNF inhibitors (adalimumab, certolizumab, etanercept, golimumab, infliximab), and 51% for abatacept. The JAK inhibitors baricitinib (64%) and upadacitinib (78%) were superior to tofacitinib (54%). Median treatment persistence for upadacitinib was not reached (n = 430); was 27.1 months for baricitinib and 15.2 months for tofacitinib. For TNF inhibitors, treatment persistence was 15.1 months for adalimumab, 14.1 months for certolizumab, 14.0 months for etanercept, 11.1 months for golimumab and 4.5 months for infliximab.Persistence rates on first-line JAK inhibitors were 70% for baricitinib and 57% for tofacitinib; persistence rates dropped to 63% for baricitinib and 47% for tofacitinib in the second-line setting. First-line persistence rates were 54% for TNF inhibitors and 65% for tocilizumab, rates were sustained for tocilizumab, but dropped to 48% for TNF inhibitors in the second-line setting.ConclusionThis real-world data highlights that in an Australian clinical practice setting treatment persistence rates on 12 months on JAK inhibitors, in particular baricitinib and upadacitinib, were superior to TNF inhibitors, but not to tocilizumab. Suggesting that persistence rates might differ according to biologics mode of action and line of treatment.Table 1.Persistence rates at 12 months post treatment initiationAll patientsFirst lineSecond lineJAK inhibitorsOverall61% (2155)60% (616)60% (554)Baricitinib64% (537)70% (158)63% (124)Tofacitinib54% (1188)57% (441)47% (294)Upadacitinib78% (430)28% (17)84% (136)TNF inhibitorsOverall52% (6339)54% (4227)48% (1561)Adalimumab55% (2710)56% (2030)48% (590)Certolizumab51% (593)54% (251)47% (147)Etanercept52% (2079)55% (1354)47% (623)Golimumab49% (814)49% (506)47% (174)Infliximab35% (143)23% (86)53% (27)Other DMARDsAbatacept51% (952)56% (263)46% (310)Rituximab49% (284)41% (70)65% (79)Tocilizumab62% (1156)65% (279)65% (351)In brackets are number of patients.References[1]Hetland, M.L., et al., Direct comparison of treatment responses, remission rates, and drug adherence in patients with rheumatoid arthritis treated with adalimumab, etanercept, or infliximab: results from eight years of surveillance of clinical practice in the nationwide Danish DANBIO registry. Arthritis Rheum, 2010[2]Jones, G., et al., A retrospective review of the persistence on bDMARDs prescribed for the treatment of rheumatoid arthritis in the Australian population. Int J Rheum Dis, 2018AcknowledgementsL. Scheepers receives funding from The Farrell Family Foundation.Disclosure of InterestsLieke Scheepers Grant/research support from: received the Competitive Grant Program InflammationASPIRE 2020 Rheumatology International Developed Markets from Pfizer, Employee of: worked as an Associate Director Epidemiology at the Medical Evidence Observational Research Department at AstraZeneca., Graeme Jones Speakers bureau: Received payment for a speakers bureau from Novartis

Background: Elevated levels of systemic inflammation are common in people with osteoarthritis and predict both pain and structural outcomes. Krill oil has anti-inflammatory properties and reduces severity of inflammatory arthritis in mice by 50% compared to controls. 1 In humans, krill oil reduced knee pain and function in two short, moderate quality randomised controlled trials (RCTs) in people with osteoarthritis. However, evidence from longer trials with imaging data is lacking. Objectives: The aim of this study was to compare the efficacy of krill oil (2g / day) vs. placebo for treating knee pain in patient with clinical knee osteoarthritis who have significant knee pain and effusion-synovitis. Methods: KARAOKE was a 24-week multicentre, randomised, double-blind, placebo-controlled trial conducted at five Australian sites. Participants aged ≥40 years with symptomatic knee OA (according to ACR criteria), significant knee pain (pain score ≥40mm on a 100mm visual analogue scale [VAS]), and effusion-synovitis present on MRI (grade ≥1 according to modified Whole-Organ Magnetic Resonance Imaging Score (WORMS) scoring) were eligible. The study protocol has been published previously. 2 Participants were randomised to receive 2g/day of krill oil, (350 mg/g omega-3 content, 12 mg/g total omega-6 content) or inert placebo (vegetable oil, no EPA or DHA, <5 mg/g (0.05%) other omega-3s). The primary outcome was absolute change in knee pain assessed using a VAS [0-100mm] after 24 weeks. Secondary outcomes were: change in knee pain and function assessed using Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score [0-500mm]), change in back and hand pain assessed using a VAS [0-100mm], change in lower limb leg strength assessed using a dynamometer, and change in blood parameters (including CRP, triglycerides, fasting glucose and total, HDL, LDL cholesterol), after 24 weeks. Linear mixed-models were used, using patient identification as random intercepts and trial centre and treatment month as random effect to adjust for correlated data within trial centres and repeated measures and to allow different treatment effects among patients over time, respectively. Results: 262 participants were randomised (mean age 61.5 years, 53% females) to receive krill oil (n=130) or placebo (n=132). A total of 85% completed the trial. Knee pain improved in both groups over 24 weeks, but with no between-group difference (krill oil, -20.1mm; placebo, -19.3mm, p=0.81). Secondary outcomes: knee pain and function score improved in both groups, but with no between-group difference (WOMAC pain: krill oil, -86.7; placebo, -82.5mm, p=0.81; WOMAC function: krill oil, -245.3; placebo, -184.3, p=0.14 at 24 weeks). The same applies for hand pain and back pain. No significant changes were seen in leg strength or any of the blood parameters at 24 weeks). Incidence of one or more adverse events was 50% in the krill oil group (n=66) and 55% in the placebo group (n=71). There were 8 serious adverse events in the krill oil group 6 in the placebo group, all considered unrelated to treatment. Conclusion: Krill oil was safe and well tolerated, but did not significantly reduce knee pain in patients with clinical knee osteoarthritis, significant knee pain and effusion-synovitis after 24 weeks compared to placebo. These findings do not support use of krill oil for alleviating knee pain in clinical knee osteoarthritis. References: [1]Ierna M, et al. BMC Musculoskelet Disord 2010;11:136. [2]Laslett L, et al. Trials 2020;21:79 Outcomes Absolute between group difference at 24 weeks P value Primary Knee pain 0.8 (-5.6 to 7.2) 0.81 Secondary Knee pain (WOMAC) 4.2 (-29.1 to 37.5) 0.81 Knee function (WOMAC) 61 (-19.2 to 141.3) 0.14 Hand pain 2.8 (-2.6 to 8.3) 0.31 Back pain 1.9 (-3.9 to 7.8) 0.46 Leg strength -2.59 (-9.41 to 4.23) 0.52 Metabolic factors Total Cholesterol 0.09 (-0.1 to 0.29) 0.34 HDL Cholesterol -0.03 (-0.1 to 0.03) 0.35 LDL Cholesterol 0.05 (-0.12 to 0.22) 0.57 Triglycerides 0.12 (-0.09 to 0.33) 0.27 Fasting glucose 0.01 (-0.26 to 0.29) 0.93 hsCRP 0.64 (-0.56 to 1.84) 0.30 Disclosure of Interests: Laura Laslett Speakers bureau: once, several years ago, and unrelated to this topic, Grant/research support from: Yes, received funding from Aker Biomarine to conduct this trial, Lieke Scheepers Shareholder of: AstraZeneca, Grant/research support from: Pfizer, unrelated to this topic, Employee of: Previously employed by AstraZeneca, Benny Antony Speakers bureau: Zydus, Grant/research support from: Grant support for investigator-initiated trial from NR Ltd for unrelated research, Anita Wluka: None declared, Catherine Hill: None declared, Lyn March Speakers bureau: Speaker fees from Pfizer Australia Ltd, Bristol Myer Squibb Australia, Abbvie Australia, Grant/research support from: Grant support for my institution from Janssen for unrelated research, Helen Keen: None declared, Petr Otahal: None declared, Flavia Cicuttini: None declared, Graeme Jones: None declared

BackgroundFrequency of moderate and severe chronic obstructive pulmonary disease exacerbations is an important endpoint in clinical trials, but makes them large and lengthy when powered to evaluate it. We aimed to develop a composite endpoint (COPDCompEx) that could predict treatment effect on exacerbations, enabling the design of shorter early phase clinical trials requiring fewer patients.MethodsIn this post hoc analysis, data from 20 randomized controlled trials were used to develop and test COPDCompEx. Diary events were tested against predefined threshold values for peak expiratory flow, reliever medication use, and symptoms. A COPDCompEx event was defined as first occurrence of a diary event, a moderate or severe exacerbation, or a study dropout. Ratios of event frequency, treatment effect and future trial sample size were compared between COPDCompEx and moderate and severe exacerbations.FindingsAt 3 months, the proportion of patients experiencing COPDCompEx events increased over 3-fold versus exacerbations alone. All components contributed to COPDCompEx event rate. Treatment effects at 3 months were closely matched between COPDCompEx and exacerbations, and the large net gain in power substantially reduced the required sample size.InterpretationCOPDCompEx may be used to predict treatment effect on moderate and severe exacerbations of chronic obstructive pulmonary disease. This may enable the design of shorter Phase 2 clinical trials requiring fewer patients when compared with current exacerbation studies, with exacerbations as a key Phase 3 endpoint. This would, therefore, allow more efficient decision-making with reduced burden and risk to study participants.

Background CompEx Asthma, a novel composite end-point combining severe exacerbations (SevEx) with asthma-worsening events, was recently developed. Further characterisation of CompEx Asthma is needed to illustrate the applicability of this end-point. The objective was to evaluate CompEx Asthma as a rate end-point to determine how seasonal and geographical factors impact this novel outcome. Methods Seven 24–56-week randomised controlled trials of budesonide/formoterol (BUD/FORM) and benralizumab were analysed. Annualised event rates (AERs) and treatment effects (hazard ratio (HR)) were analysed with Poisson and Andersen–Gill models, respectively. Seasonality was analysed by month and five geographical regions were evaluated. Results The studies included 10 815 patients (63% female, mean age 42–49 years). CompEx Asthma AER mirrored seasonal variations in SevEx AER. CompEx Asthma AERs were higher versus SevEx in BUD/FORM and benralizumab trials (range 2.7–4.5-fold and 1.3–2.0-fold increase, respectively) and were less variable versus SevEx between regions (ratios of greatest:smallest AERs: 1.36 for CompEx versus 2.28 for SevEx (BUD/FORM); 1.81 for CompEx versus 2.22 for SevEx (benralizumab)). Treatment effects for CompEx Asthma and SevEx were generally similar across regions and months. However, in Eastern Europe, where SevEx rates were lowest, treatment effect was greater with CompEx Asthma versus SevEx, reaching statistical significance in the benralizumab studies (HR (95% CI): 0.67 (0.53–0.85) versus 0.87 (0.65–1.15)). Conclusion This study confirmed the reliability of CompEx Asthma as a rate end-point and allowed detection of variations in seasonal SevEx rates, reduction of variation in rates across regions and potential greater sensitivity to treatment effects.

INTRODUCTION:Low serum urate (sU) has been suggested to increase the risk of dementia since a reduction might impair antioxidant capacity. On the other hand, high sU is associated with increased cardiovascular risk which might increase the risk of dementia, especially for vascular dementia.METHODS:In 1968-1969, a population-based sample of 1462 women aged 38 to 60 years was examined and were followed up over 44 years (mean 33.1 years). We examined whether sU (determined in 1968-1969 and 1992-1994) is associated with risk of late-life dementia.RESULTS:During 44 years of follow-up, a higher sU (per standard deviation of 76.5 μmol/L) was associated with lower risk for dementia (n = 320; hazard ratio [HR] 0.81; confidence interval [CI] 0.72-0.91), Alzheimer's disease (n = 152; HR 0.78; CI 0.66-0.91), and vascular dementia (n = 52; HR 0.66; CI 0.47-0.94).DISCUSSION:Our findings support the hypothesis that sU has a protective role in the development of dementia, regardless of dementia subtype. This may have important implications in the treatment of dementia and treatment goals for hyperuricemia in patients with gout.

Objectives When urate lowering therapy is indicated in patients with gout, medication adherence is essential. This study assesses non-persistence and non-adherence in patients with newly diagnosed gout, and identifies factors associated with poor medication adherence. Methods A retrospective data analysis was performed within the UK Clinical Practice Research Datalink (1987-2014) among incident gout patients, aged ⩾40 years and starting allopurinol (n = 48 280). The proportion of patients non-persistent (a first medication gap of ⩾90 days) after 1 and 5 years, and median time until a first 90-day gap was estimated using Kaplan-Meier statistics in those starting allopurinol and restarting after a first interruption. Non-adherence (proportion of days covered <80%) over the full observation period was calculated. Multivariable Cox- or logistic regressions assessed factors associated with non-persistence or non-adherence, respectively. Results Non-persistence increased from 38.5% (95% CI: 38.1, 38.9) to 56.9% (95% CI: 56.4, 57.4) after 1 and 5 years of initiation. Median time until a first 90-day gap was 1029 days (95% CI: 988, 1078) and 61% were non-adherent. After a first gap, 43.3% (95% CI: 42.7, 43.9) restarted therapy within 1 year, yet only 52.3% (95% CI: 51.4, 53.1) persisted for 1 year. Being female and a current smoker increased the risk for non-persistence and non-adherence, while older age, overweight, receiving anti-hypertensive medication or colchicine and suffering from dementia, diabetes or dyslipidaemia decreased the risk. Conclusion Medication adherence among gout patients starting allopurinol is poor, particularly among females and younger patients and patients with fewer comorbidities. Medication adherence remains low in those reinitiating after a first gap.

Background Gout is the most common inflammatory arthritis and relatively much is known regarding its pathogenesis. It is clear that life style factors play a significant role in developing and maintaining disease. Objectives This study aimed to analyse lifestyle factors in prevalent gout patients by sex compared to age matched controls from the general population. Methods All patients above 18 years of age with an ICD 10-diagnosis of gout from Jan 2015 through Feb 2017 listed at any of twelve randomly selected primary health care centres or the rheumatology department at Sahlgrenska University hospital in the Western Sweden Health Care Region (WSHCR) were identified. They were sent a questionnaire, regarding demographics, life style factors such as smoking status, alcohol consumption, physical activity, body mass index (BMI; categorised into 4 levels in the analyses) and comorbidities such as diabetes and hypertension. All responders aged 18–84 years were matched to five control individuals, without gout, by sex and age. Control individuals were selected from a random sample of 52 348 individuals aged 16–84 years who participated in the National Public Health survey in Sweden year 2015 This survey is a national study on health, lifestyle and living conditions. Alcohol consumption was categorised as none and any with/without binge drinking behaviour. Binge drinking was (liberally) defined as consuming more than four (women) or five glasses (men) on any occasion. Conditional logistic regression models were used to compare cases and controls with regard to lifestyle factors and comorbidities. Multivariate analyses were also performed, including BMI, smoking status, alcohol consumption, and physical activity. Results Of the 1589 invited gout patients, 868 responded and 79.7% were male. Non-responders were more often young men. Mean age was 69.3 (std:10.5) years for men and 71.8 (std: 9.9) years for women with gout. Male gout patients were in multivariate analyses more likely to be overweight (OR 1.67 (95% CI: 1.31–2.14)), obese (OR 2.20 (95% CI: 1.64–2.94)), have binge drink behaviour (OR 3.32 (95% CI: 2.39–4.62)), and had lower levels of physical activity compared to controls (table 1). Current smoking habits did not differ between male gout patients and controls. Female gout patients were in multivariate analyses more likely to be overweight (OR 1.87 (95% CI: 1.05–3.33)), obese (OR 3.62 (95% CI: 1.96–6.72)), and have binge drink behaviour (OR 4.28 (95% CI: 1.92–9.53)), but not did not differ with regard to current smoking habits or physical activity compared to controls. In bivariate analyses, comorbidities such as diabetes and hypertension, were significantly more common in gout patients among both sexes. Conclusions Compared to the general population, patients with gout were more often obese (in particular women) and had higher occurrence of binge drinking behaviour (in particular men). The lower level of physical activity (men) and normal frequency of smoking among gout patients may be a consequence of the high comorbidity rates. Disclosure of Interest None declared

Among patients with gout, the increased risk of hypertension and cardiovascular diseases has often been attributed to hyperuricemia (1). Further research confirmed that asymptomatic hyperuricemia, which has a prevalence of ;20% in China and the United States, is related to hypertension (2–4). Inhibitors of xanthine oxidase (XOR) and uricosurics are highly effective in reducing uric acid concentrations and have been the cornerstone of the clinical management of gout for decades (5). However, the role of these compounds to treat or prevent hypertension in persons with asymptomatic hyperuricemia is less obvious. This hesitation is not without reason, because the treatment of asymptomatic hyperuricemia comes with an increased risk of hypersensitivity reactions and hepatotoxicity (6, 7). Moreover, it is questionable whether such treatments have a relevant effect on blood pressure reduction and the prevention of cardiovascular events, thus outweighing the long-term use of these medications. However, there are other means to lower serum uric acid concentrations, which might be useful in the management of asymptomatic hyperuricemia. For example, folic acid and its derivatives are believed to inactivate the XOR enzyme, which is responsible for the oxidation of hypoxanthine to xanthine and xanthine to uric acid (8, 9). Folate and its oxidized form, folic acid, appear to inhibit XOR by slow binding with high affinity at the molybdenum site, the site of purine interaction. In so doing, folic acid interferes with the interaction of the enzyme with xanthine and hypoxanthine. Folic acid and a variety of folate derivatives, including methotrexate, have been reported to be potent competitive inhibitors of XOR, with apparent inhibition constants (K1) comparable to that of allopurinol (8, 9). In this issue of the Journal, Qin et al. (10) studied whether folic acid supplementation could reduce serum uric acid concentrations among hypertensive adults. A total of 15,364 hypertensive Chinese adults were randomly assigned to receive double-blind daily treatment with 10 mg enalapril and 0.8 mg folic acid (n1⁄4 7685) or to receive 10 mg enalapril alone (n 1⁄4 7679) and were followed for 4.5 y. The combined use of enalapril and folic acid, compared with enalapril alone, significantly reduced the magnitude of the increase in uric acid concentrations and decreased the incidence of new-onset hyperuricemia. Earlier studies showed that the administration of an XOR inhibitor led to a decrease in blood pressure (11, 12). Because folic acid and its derivatives are believed to be an XOR inhibitor, folic acid might be used to reduce blood pressure in patients with hyperuricemia. However, despite the significant decrease in serum uric acid concentrations, the intake of folic acid was not associated with a further reduction in blood pressure in the present study (10). There are some important considerations that might explain this incongruity between folic acid intake and blood pressure. First, participants received treatment with either a combination of the antihypertensive medication enalapril and folic acid or enalapril alone. For both treatment groups, systolic and diastolic blood pressure decreased by an average of 28 and 12 mm Hg, respectively, from baseline, which can be considered substantial from a clinical point of view. The additional effect of folic acid intake on blood pressure might therefore not be distinguished from this main background impact. Second, although the difference of 24 lmol in serum uric acid concentrations between the 2 treatment groups was significant, this is a small between-group difference and might not be sufficient to result in relevant differences in blood pressure. However, it should be noted that the studied population also included patients without hyperuricemia. In the subgroup of patients with hyperuricemia (n 1⁄4 1506), the mean group difference in serum uric acid was much higher (28.7 lmol). Unfortunately, the effect on blood pressure was not presented for this subgroup. Third, the mean age of the study population was 60 y, which is a relatively old population and the patients are likely to have more established hypertension. It is suggested that uric acid increases blood pressure by a 2-phase process (13). In the first phase, the generation of reactive oxygen species by XOR and increased renal renin cause vasoconstriction. This phase, also called “early” hypertension, is reversible and blood pressure can be reduced by lowering serum uric acid concentrations. In the second phase, which develops over time when hyperuricemia persists, the proliferation of vascular smooth muscle cells thickens the vessel wall and leads to a loss in vascular compliance. This phase is irreversible and blood pressure cannot be reduced by lowering serum uric acid concentrations (13). Overall, the current study showed a means to lower serum uric acid concentration without the use of chronic medication or drastic lifestyle changes. These results should lead to further discussion about the use of folic acid or folate supplementation in the prevention