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Evidence for the utility of medications in settings lacking randomized trial data can come from studies of treatment persistence. The present study was undertaken to examine patterns of medication use in systemic lupus erythematosus (SLE) using data from a large multicenter longitudinal cohort.Prospectively collected data from the Asia Pacific Lupus Collaboration cohort including disease activity (SLE Disease Activity Index 2000 [SLEDAI-2K]) and medication details, captured at every visit from 2013-2018, were used. Medications were categorized as glucocorticoids (GCs), antimalarials (AM), and immunosuppressants (IS). Cox regression analyses were performed to determine the time-to-discontinuation of medications, stratified by SLE disease activity.Data from 19,804 visits of 2,860 patients were analyzed. Eight medication categories were observed: no treatment; GC, AM, or IS only; GC plus AM; GC plus IS; AM plus IS; and GC plus AM plus IS (triple therapy). Triple therapy was the most frequent pattern (31.4% of visits); single agents were used in 21% of visits, and biologics in only 3%. Time-to-discontinuation analysis indicated that medication persistence varied widely, with the highest treatment persistence for AM and lowest for IS. Patients with a time-adjusted mean SLEDAI-2K score of ≥10 had lower discontinuation of GCs and higher discontinuation of IS.Most patients received combination treatment. GC persistence was high, while IS persistence was low. Patients with high disease activity received more medication combinations but had reduced IS persistence, consistent with limited utility. These data confirm unmet need for improved SLE treatments.

In trials of systemic lupus erythematosus (SLE), the SLE Responder Index (SRI) is the most commonly used primary efficacy end point but has limited validation against long-term outcomes. We aimed to investigate associations of attainment of a modified version of the SRI (mSRI) with key clinical outcomes in SLE patients with up to 5 years of follow-up.We used data from a large multicenter, longitudinal SLE cohort in which patients received standard of care. The first visit with active disease (defined as SLE Disease Activity Index 2000 [SLEDAI-2K] score ≥6) was designated as baseline, and mSRI attainment (defined as a reduction in SLEDAI-2K ≥4 points with no worsening in physician global assessment ≥0.3 points) was determined at annual intervals from baseline up to 5 years. Associations between mSRI attainment and outcomes including disease activity, glucocorticoid dose, flare, damage accrual, Lupus Low Disease Activity State (LLDAS), and remission were studied.We included 2,060 patients, with a median baseline SLEDAI-2K score of 8. An mSRI response was attained by 56% of patients at 1 year, with similar responder rates seen at subsequent annual time points. Compared to nonresponders, mSRI responders had significantly lower disease activity and prednisolone dose and higher proportions of LLDAS and remission attainment at each year, and less damage accrual at years 2 and 3. Furthermore, mSRI responder status at 1 year predicted clinical benefit at subsequent years across most outcomes, including damage accrual (odds ratio [OR] range 0.58-0.69, P 0.05 for damage accrual ORs at all time points).In SLE patients with active disease receiving standard of care, mSRI attainment predicts favorable outcomes over long-term follow-up, supporting the clinical meaningfulness of SRI attainment as an SLE trial end point.

Objective The prevalence and associations of leucopenia in SLE remain incompletely understood. We evaluated associations of disease activity and medication use with leucopenia (lymphopenia and neutropenia) in a multinational, prospectively followed SLE cohort. Methods Data from the Asia Pacific Lupus Collaboration cohort, in which disease activity and medications were prospectively captured from 2013 to 2018, were used. Predictors of lymphopenia (lymphocyte count Results Data from 2330 patients and 18 287 visits were analysed. One thousand and eighteen patients (43.7%) had at least one episode of leucopenia; 867 patients (37.2%) had lymphopenia, observed in 3065 (16.8%) visits, and 292 (12.5%) patients had neutropenia, in 622 (3.4%) visits. After multivariable analyses, lymphopenia was associated with overall disease activity, ESR, serology, prednisolone, AZA, MTX, tacrolimus, CYC and rituximab use. MTX and ciclosporin were negatively associated with neutropenia. Lupus low disease activity state was negatively associated with both lymphopenia and neutropenia. Conclusion Both lymphopenia and neutropenia were common in SLE patients but were differentially associated with disease and treatment variables. Lymphopenia and neutropenia should be considered independently in studies in SLE.

Summary Background Evaluating the contribution of glucocorticoid use to organ damage in systemic lupus erythematosus is confounded by glucocorticoid use in active disease. We sought to determine the independence of the contribution of glucocorticoid use to damage accrual from associations with disease activity by analysing patients without measurable disease activity. Methods Patients (age >18 years) who met the criteria for systemic lupus erythematosus were recruited from 13 centres in Australia, Indonesia, Japan, Malaysia, the Philippines, Singapore, Taiwan, and Thailand, and followed longitudinally. Disease activity (Systemic Lupus Erythematosus Disease Activity Index 2000 [SLEDAI-2K] and Physician Global Assessment [PGA] scores) and treatment details were recorded at each visit (at least once every 6 months), and organ damage measured annually according to the Systemic Lupus International Collaborating Clinics Damage Index (SDI). Glucocorticoid use during the study period was recorded as any exposure to prednisolone, cumulative prednisolone exposure, and time-adjusted mean daily prednisolone dose. Multivariate survival analyses were used to examine time-dependent associations of glucocorticoid use with damage accrual (defined as an increase of ≥1 on SDI). A SLEDAI-2K score of 0 was taken to indicate the absence of clinical and serological disease activity; a subset of patients without disease activity during the study were defined by a time-adjusted mean SLEDAI-2K (AMS) score of 0. Findings Between May 1, 2013, and Dec 31, 2016, 1707 patients were recruited. Over a median observation period of 2·2 years (IQR 1·5–3·0), damage accrual events were observed in 255 (14·9%) patients. 1405 (82·3%) of patients were exposed to prednisolone, with a median time-adjusted mean prednisolone dose of 5·0 mg/day (IQR 1·9–8·8). As SLEDAI-2K and PGA scores were highly correlated, two multivariable models were set, each including one of these two variables. In the model including AMS score, baseline SDI damage (SDI >0) was independently associated with damage accrual (HR 1·32 [95% CI 1·01–1·73], p=0·0427). In the other model, time-adjusted mean PGA score was independently associated with damage accrual (1·05 [1·02–1·08], p=0·0012). In both models, factors independently associated with damage accrual included time-adjusted mean prednisolone dose, age at enrolment, and ethnicity (Asian vs non-Asians). 157 (9·2%) patients had an AMS score of 0 (no disease activity), among whom 103 (65·6%) had glucocorticoid exposure and the median time-adjusted mean prednisolone dose was 2·0 mg/day (IQR 0·0–5·0). Accrual of irreversible organ damage occurred in 21 (13·4%) of these patients and was independently associated with time-adjusted mean prednisolone dose (HR 1·14 [95% CI 1·03–1·26], p=0·0117), time-adjusted mean PGA score (1·13 [1·03–1·23], p=0·0144), and age at enrolment (1·04 [1·01–1·07], p=0·0061), but not baseline SDI damage (0·94 [0·43–2·06], p=0·8675). Interpretation Glucocorticoid use contributes to damage accrual in systemic lupus erythematosus independently of the presence of clinical or serological disease activity. Funding UCB Pharma, GlaxoSmithKline, Janssen, Bristol-Myers Squibb, and AstraZeneca (to the Asia-Pacific Lupus Collaboration).

Objective To examine longitudinal associations of active lupus nephritis with organ damage accrual in patients with systemic lupus erythematosus (SLE). Methods This study was performed using data from a large multinational prospective cohort. Active lupus nephritis at any visit was defined by the presence of urinary casts, proteinuria, haematuria or pyuria, as indicated by the cut-offs in the SLE Disease Activity Index (SLEDAI)-2K, collected at each visit. Organ damage accrual was defined as a change of SLICC-ACR Damage Index (SDI) score >0 units between baseline and final annual visits. Renal damage accrual was defined if there was new damage recorded in renal SDI domains (estimated glomerular filtration rate 3.5 g per 24 h/end-stage kidney disease). Time-dependent hazard regression analyses were used to examine the associations between active lupus nephritis and damage accrual. Results Patients ( N = 1735) were studied during 12,717 visits for a median (inter-quartile range) follow-up period of 795 (532, 1087) days. Forty per cent of patients had evidence of active lupus nephritis at least once during the study period, and active lupus nephritis was observed in 3030 (24%) visits. Forty-eight per cent of patients had organ damage at baseline and 14% accrued organ damage. Patients with active lupus nephritis were 52% more likely to accrue any organ damage compared with those without active lupus nephritis (adjusted hazard ratio = 1.52 (95% confidence interval (CI): 1.16, 1.97), p Conclusion Active lupus nephritis measured using the SLEDAI-2K domain cut-offs is associated with renal, but not non-renal, damage accrual in SLE.

Histochemical detection of tartrate-resistant acid phosphatase (TRAP) activity is a fundamental technique for visualizing osteoclastic bone resorption and assessing osteoclast activity status in tissues. This approach has mostly employed colorimetric detection, which has limited quantification of activity in situ and co-labelling with other skeletal markers. Here we report simple colorimetric and fluorescent TRAP assays in zebrafish and medaka, two important model organisms for investigating the pathogenesis of bone disorders. We show fluorescent TRAP staining, utilising the ELF97 substrate, is a rapid, robust and stable system to visualise and quantify osteoclast activity in zebrafish, and is compatible with other fluorescence stains, transgenic lines and antibody approaches. Using this approach, we show that TRAP activity is predominantly found around the base of the zebrafish pharyngeal teeth, where osteoclast activity state appears to be heterogeneous. Published version

Summary Background Treat-to-target strategies have improved outcomes in single-organ diseases with simple clinical or laboratory endpoints. A lack of validated endpoints has prevented adoption of treat to target for complex multiorgan conditions, such as systemic lupus erythematosus (SLE). We report the first prospective study undertaken to specifically validate a treat-to-target endpoint for SLE. Methods In this prospective cohort study, patients aged 18 years or older with SLE were recruited from 13 centres in eight countries and followed prospectively. Patients with at least two visits over the study period no more than 6 months apart were included in the longitudinal analysis. Patients with no visits in the final year of the study were censored from their last visit. Attainment of the lupus low disease activity state (LLDAS) was assessed at each visit. The primary outcome measure was accrual of irreversible end-organ damage, defined as at least a 1-point increase in the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index. We used time-dependent hazard regression models and generalised linear models to measure the association between LLDAS (attainment at any timepoint, cumulative time in LLDAS, and sustained LLDAS) with accrual of irreversible end-organ damage or flare (key secondary outcome). This study is registered with ClinicalTrials.gov , NCT03138941 . Findings Between May 1, 2013, and Dec 31, 2016, 1707 patients were recruited and followed for a mean of 2·2 years (SD 0·9), totalling 12 689 visits. Attainment of LLDAS at any timepoint was associated with reduction in damage accrual (hazard ratio 0·59, 0·45–0·76; p Interpretation LLDAS attainment is associated with significant protection against flare and damage accrual in SLE. These findings validate LLDAS as an endpoint for clinical studies in SLE. Funding The Asia Pacific Lupus Collaboration received project support grants from UCB Pharma, GlaxoSmithKline, Janssen, Bristol-Myers Squibb, and AstraZeneca.

Summary Background Validated outcome measures are needed from which to derive treatment strategies for systemic lupus erythematosus (SLE). However, no definition of remission for SLE has been widely adopted. The Definitions of Remission in Systemic Lupus Erythematosus (DORIS) group has proposed a framework with multiple potential definitions of remission. In this study, we aimed to assess the attainability and effect on disease outcomes of the DORIS definitions of remission, compared with the lupus low disease activity state (LLDAS), in patients with SLE. Methods In this prospective cohort study, we enrolled patients with SLE from 13 international centres that are part of the Asia Pacific Lupus Collaboration. Eligible patients were older than 18 years and fulfilled one of two classification criteria for SLE (1997 American College of Rheumatology criteria or the 2012 Systemic Lupus International Collaborating Clinics criteria). Visits were according to clinical need, with a minimum frequency of one visit per 6 months. We assessed attainment of remission on the basis of the eight DORIS definitions of remission, which varied in terms of serological activity, glucocorticoid use, and use of immunosuppresive agents; attainment of LLDAS; and disease flares at each visit. Irreversible organ damage accrual was recorded annually. Our primary aim was to assess exposure of patients to each of the remission definitions or LLDAS, and the respective association of these states with accrual of irreversible organ damage as the primary outcome measure. Occurrence of disease flares was the key secondary outcome. We used time-dependent Cox proportional hazards models and generalised linear models to assess DORIS definitions of remission and LLDAS in terms of their association with damage accrual and disease flares. Findings Between May 1, 2013, and Dec 31, 2016, 1707 patients with SLE were recruited and followed for a mean of 2·2 years (SD 0·9), totalling 12 689 visits. Remission, depending on DORIS definition, was achieved in 581 (4·6%) to 4546 (35·8%) of 12 689 visits. Spending 50% or more of observed time in any remission state was associated with a significant reduction in damage accrual, except for the two most stringent remission definitions, for which the frequency of attainment was lowest. Remission definitions disallowing serological activity were associated with the greatest reductions in disease flares. LLDAS was more attainable than any remission definition and was associated with a similar magnitude of protection from damage accrual and disease flares. Sustained remission and LLDAS were associated with a wider spread of effect sizes for reduction in risk of damage. By analysing patients who met the definition for LLDAS but not remission, we found that LLDAS was significantly associated with reduction in damage accrual, independent of all definitions of remission, except the least stringent. Interpretation Attainment of remission was associated with significant reductions in damage accrual and disease flares. LLDAS was more achievable than remission based on the DORIS criteria, but was similarly protective. Remission definitions with less stringency might be insufficiently distinct from LLDAS to substantially affect outcome measures, and further studies are needed to distinguish the protective effects of the various remission definitions. Funding UCB, GlaxoSmithKline, Janssen, Bristol-Myers Squibb, and AstraZeneca.

Background:The recent prospectively validated definition of the lupus low disease activity state (LLDAS) allows characterisation of patients not achieving a treatment goal, providing impetus for an analysis of unmet needs in SLE using formal definitions. Other recently described definitions of high disease burden include disease activity over time, high disease activity status (HDAS) episodes, and the combination of high disease activity, serological activity and glucocorticoid (GC) use (HDAS+SA+GC).Objectives:To determine the prevalence of formal categories of unmet need, and the association of these with adverse outcomes, in SLE.Methods:Data from a 13-country longitudinal SLE cohort (ACR/SLICC criteria) were collected between 2013 and 19 using standard templates. Unmet need was defined as (i) patients never attaining LLDAS defined as in Golder et al., 2019 [1], (ii) having persistently active disease (time adjusted mean SLEDAI-2K (AMS) > 4), (iii) ever exhibiting high disease activity status (HDAS; SLEDAI-2K ≥10[2]), or (iv) ever exhibiting all of SLEDAI≥10, serological activity, and glucocorticoid use (HDAS+SA+GC)[3]. Health-related quality of life (HRQoL) was assessed using SF36 (v2) surveys and damage accrual using SLE Damage Index (SDI).Results:3,384 SLE patients were followed for 30,313 visits over median [IQR] 2.4 [0.4, 4.3] years. 53% of all visits were not in LLDAS; 813 patients (24%) never achieved LLDAS during observation. Median AMS was 3.0 [1.4, 4.9] and 34% of patients had AMS > 4 throughout the study. 25% of patients had at least one episode of HDAS, representing 8% of visits. 702 patients (21%) had at least one episode of HDAS+SA+GC, representing 8% of visits. Each of never-LLDAS, AMS>4, ever-HDAS, and ever-HDAS+SA+GC were associated with significantly greater number of physician visits, higher mean glucocorticoid dose, lower HRQoL and higher mortality. 31%, 58% and 83% of never-LLDAS, AMS>4, and ever-HDAS patients respectively were also HDAS+SA+GC on at least one occasion.Conclusion:Data from a multinational longitudinal SLE cohort indicate that unmet need, defined by LLDAS-never, AMS>4, HDAS, or HDAS+SA+GC, is prevalent in SLE, and that these definitions are associated with poor outcomes.References:[1]Golder, V., et al., Lupus low disease activity state as a treatment endpoint for systemic lupus erythematosus: a prospective validation study. The Lancet Rheumatology, 2019. 1(2): p. e95-e102.[2]Koelmeyer, R., et al., High disease activity status suggests more severe disease and damage accrual in systemic lupus erythematosus. Lupus Sci Med, 2020. 7(1).[3]van Vollenhoven, R.F., et al., Belimumab in the treatment of systemic lupus erythematosus: high disease activity predictors of response. Annals of the Rheumatic Diseases, 2012. 71(8): p. 1343-1349.Acknowledgements:The APLC acknowledges all the Data Collectors and Patients for their valuable contributions to research.Disclosure of Interests:Rangi Kandane-Rathnayake: None declared, Worawit Louthrenoo: None declared, Alberta Hoi Consultant of: Abbvie and GSK, Grant/research support from: AstraZeneca, GSK, BMS, Janssen, and Merck Serono, Vera Golder: None declared, Yi-Hsing Chen Speakers bureau: Pfizer, Novartis, Abbvie, Johnson & Johnson, BMS, Roche, Lilly, AstraZeneca, Sanofi, MSD, Guigai, Astellas, Inova Diagnostics, UCB, Agnitio Science Technology, United Biopharma, Thermo Fisher, Consultant of: Pfizer, Novartis, Abbvie, Johnson & Johnson, BMS, Roche, Lilly, AstraZeneca, Sanofi, MSD, Guigai, Astellas, Inova Diagnostics, UCB, Agnitio Science Technology, United Biopharma, Thermo Fisher, Gilead, Grant/research support from: Pfizer, Norvatis, BMS, Abbevie, Johnson & Johnson, Roche, Sanofi, Guigai, Roche, Boehringer Ingelheim, UCB, MSD, Astra-Zeneca, Astellas, Gilead, Shue Fen Luo: None declared, Yeong-Jian Jan Wu Speakers bureau: Pfizer, Lilly, Novartis, Abbvie, Aisha Lateef: None declared, Jiacai Cho: None declared, Laniyati Hamijoyo Speakers bureau: Pfizer, Novartis, Abbot, Chak Sing Lau Shareholder of: Pfizer, Sanofi, and Janssen, Sandra Navarra Speakers bureau: Pfizer, Johnson & Johnson, Novartis, Astellas, Grant/research support from: Astellas, Johnson & Johnson, Leonid Zamora: None declared, Zhanguo Li Speakers bureau: Eli, Lilly, Novartis, GSK, AbbVie, Paid instructor for: Pfizer, Roche, Johnson., Consultant of: Lilly, Pfizer, Grant/research support from: Pfizer, Yuan An: None declared, Sargunan Sockalingam Speakers bureau: Pfizer, Roche, Novartis, Grant/research support from: Roche and Novartis, Yasuhiro Katsumata Speakers bureau: Chugai Pharmaceutical Co., Ltd., Glaxo-Smithkline K.K., and Sanofi K.K., masayoshi harigai Speakers bureau: AbbVie Japan GK, Ayumi Pharmaceutical Co., Boehringer Ingelheim Japan, Inc.,Bristol Myers Squibb Co., Ltd., Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., Eli Lilly Japan K.K., GlaxoSmithKline K.K., Kissei Pharmaceutical Co., Ltd., Pfizer Japan Inc., Takeda Pharmaceutical Co., Ltd., and Teijin Pharma Ltd., Consultant of: AbbVie, Boehringer-ingelheim, Bristol Myers Squibb Co., Kissei Pharmaceutical Co.,Ltd. and Teijin Pharma., Grant/research support from: AbbVie Japan GK, Asahi Kasei Corp., Astellas Pharma Inc., Ayumi Pharmaceutical Co., Bristol Myers Squibb Co., Ltd., Chugai Pharmaceutical Co., Daiichi-Sankyo, Inc.,Eisai Co., Ltd., Kissei Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Co., Nippon Kayaku Co., Ltd., Sekiui Medical, Shionogi & Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., and Teijin Pharma Ltd., Yanjie Hao: None declared, Zhuoli Zhang Speakers bureau: Norvatis, GSK, Pfizer, Jun Kikuchi: None declared, Tsutomu Takeuchi Speakers bureau: AbbVie AYUMI Pharmaceutical Corp. Bristol-Myers Squibb Chugai Pharmaceutical Co, Ltd. Daiichi Sankyo Co., Ltd. Eisai Co., Ltd. Eli Lilly Japan, Gilead Sciences, Inc. Mitsubishi-Tanabe Pharma Corp. Pfizer Japan Inc. Sanofi K.K., Consultant of: Astellas Pharma, Inc. Chugai Pharmaceutical Co, Ltd. Eli Lilly Japan, Mitsubishi-Tanabe Pharma Corp., Grant/research support from: AbbVie, Asahikasei Pharma Corp. Chugai Pharmaceutical Co, Ltd. Mitsubishi-Tanabe Pharma Corp. Sanofi K.K., BMDB Basnayake: None declared, Fiona Goldblatt: None declared, Madelynn Chan Speakers bureau: AbbVie, Novartis, Consultant of: Pfizer, Eli-Lilly, Kristine Ng Speakers bureau: Abbvie, Novartis, Janssen, Sang-Cheol Bae: None declared, Shereen Oon: None declared, Sean O’Neill Consultant of: GSK, Kathryn Gibson Speakers bureau: UCB, Consultant of: Novartis, Janssen, Grant/research support from: Novartis, Sunil Kumar: None declared, Nicola Tugnet: None declared, Yoshiya Tanaka Speakers bureau: Daiichi-Sankyo, Eli Lilly, Novartis, YL Biologics, Bristol-Myers, Eisai, Chugai, Abbvie, Astellas, Pfizer, Sanofi, Asahi-kasei, GSK, Mitsubishi-Tanabe, Gilead, Janssen, Grant/research support from: Abbvie, Mitsubishi-Tanabe, Chugai, Asahi-Kasei, Eisai, Takeda, Daiichi-Sankyo, Mandana Nikpour Speakers bureau: Actelion, GSK, Janssen, Pfizer, UCB, Paid instructor for: UCB, Consultant of: Actelion, Boehringer Ingelheim, Certa Therapeutics, Eli Lilly, GSK, Janssen, Pfizer, UCB, Grant/research support from: Actelion, Astra Zeneca, BMS, GSK, Janssen, UCB, Eric F. Morand Speakers bureau: AstraZeneca, Paid instructor for: Eli Lilly, Consultant of: AstraZeneca, Amgen, Biogen, BristolMyersSquibb, Eli Lilly, EMD Serono, Genentech, Janssen, Grant/research support from: AstraZeneca, BristolMyersSquibb, Eli Lilly, EMD Serono, Janssen.

Background:In the absence of evidence-based treatment guidelines, medication use in SLE is highly variable. Low rates of remission and lupus low disease activity state (LLDAS) suggest that suboptimal responses to standard medications, which include glucocorticoids (GC), anti-malarial (AM) drugs and immunosuppressive (IS) agents, are common. Understanding the utility of current medications will facilitate the selection of patients for advanced therapies as they emerge.Objectives:To examine medication use patterns in a large multicentre SLE cohort.Methods:We used 2013-18 data from the Asia Pacific Lupus Collaboration (APLC) cohort in which disease activity (SLEDAI-2K) and medication details were captured at every visit. LLDAS was defined as in Golderet al., 2019 (1). We examined the use of medication (med) categories (GC &/or AM &/or IS) by SLE disease activity and LLDAS at the visit level. Additionally, we performed Cox regression analyses to determine the time-to-discontinuation of meds stratified by SLE disease activity, ranked by time-adjusted mean SLEDAI-2K, and by percent-time spent in LLDAS.Results:We analysed data from 19,804 visits of 2,860 patients. We observed 8 med categories: no meds; GC, AM or IS only; GC+AM; GC+IS; AM+IS and GC+AM+IS (triple therapy). Triple therapy was the most frequent med pattern (32%); single agents were used in 21% of visits and biologicals in only 3%. Among visits where SLEDAI-2K was ≥10, triple therapy was used in 46%, with median [IQR] GC dose 10 [6, 24] mg/day; in contrast, among visits with SLEDAI-2K≤4 triple therapy was used in 28% (pMed persistence (survival analysis) varied widely, with lowest survivals for IS. Patients with time-adjusted mean SLEDAI-2K ≥10 had lower discontinuation of GC and higher discontinuation of IS including azathioprine, leflunomide and cyclosporine (Table 1). In contrast, increased time in LLDAS was associated with reduced discontinuation of AM and azathioprine.GCAMISMPhMPhAAZAMTXCyALEFOverall med survival, days to 25% discontinuation (95%CI)1048(938, 1197)1267(1113, 1428)175(175, 182)387(252, 756)409(350, 476)525(219, 686)268(182, 350)329(190, 524)Univariable associations,HR (95% CI) p-valueDisease activity≤41.001.001.001.001.001.001.001.00>4 & 0.69 (0.56,0.84)p1.15 (0.92,1.44)0.20.92 (0.80,1.05)0.21.37 (0.78,2.42)0.31.16 (0.97,1.39)0.111.11 (0.72,1.71)0.61.26 (0.90,1.77) 0.181.88 (1.07,3.30) 0.03≥100.65 (0.35,1.21) 0.181.56 (0.94,2.59) 0.080.84 (0.45,1.57)0.61.92 (0.80,4.63)0.142.69 (1.86,3.91) p1.85 (0.92,3.71) 0.082.66 (1.36,5.21) 0.0041.62 (1.13,2.32)0.009LLDAS1.001.001.001.001.001.001.001.00≥50%1.30 (1.09, 1.55)0.0030.67 (0.54, 0.84)1.22 (1.08, 1.40)0.0020.83 (0.44,1.57)0.60.83 (0.69, 1.00)0.0540.70 (0.46, 1.07)0.101.29 (0.92, 1.83)0.140.43 (1.5, 1.25)0.12Conclusion:In a large multicentre SLE cohort, most patients were receiving combination treatment. AM treatment survival was high and associated with low disease activity, GC survival was high and associated with high disease activity, while IS survival was low. Patients with high disease activity received more medication combinations but had reduced IS survival. These data suggest ongoing unmet need for improved medications for treatment of SLE.Reference:Golder, V., et al Lancet Rheum. 2019 1(2):e95-102Disclosure of Interests:Rangi Kandane-Rathnayake Grant/research support from: The APLC has received financial (non-restricted educational) grants from AstraZeneca, Bristol Myers Squibb, GlaxoSmithKline, Janssen, EMD Serono, Eli Lilly and UCB for the LLDAS Validation Study., Worawit Louthrenoo: None declared, Shue Fen Luo: None declared, Yeong-Jian Wu Consultant of: Pfizer, Lilly, Novartis, Abbvie, Roche, Speakers bureau: Lilly, Novartis, Yi-Hsing Chen Grant/research support from: Taiwan Ministry of Science and Technology, Taiwan Department of Health, Taichung Veterans General Hospital, National Yang-Ming University, GSK, Pfizer, BMS., Consultant of: Pfizer, Novartis, Abbvie, Johnson & Johnson, BMS, Roche, Lilly, GSK, Astra& Zeneca, Sanofi, MSD, Guigai, Astellas, Inova Diagnostics, UCB, Agnitio Science Technology, United Biopharma, Thermo Fisher, Gilead., Paid instructor for: Pfizer, Novartis, Johnson & Johnson, Roche, Lilly, Astra& Zeneca, Sanofi, Astellas, Agnitio Science Technology, United Biopharma., Speakers bureau: Pfizer, Novartis, Abbvie, Johnson & Johnson, BMS, Roche, Lilly, GSK, Astra& Zeneca, Sanofi, MSD, Guigai, Astellas, Inova Diagnostics, UCB, Agnitio Science Technology, United Biopharma, Thermo Fisher, Gilead., Vera Golder: None declared, Aisha Lateef: None declared, Jiacai Cho: None declared, Sandra Navarra Speakers bureau: Astellas, Novartis, Pfizer, Johnson & Johnson, Abbvie, Leonid Zamora: None declared, Laniyati Hamijoyo Speakers bureau: Pfizer, Novartis, Tanabe, Abbot, Dexa Medica, Roche, Sargunan Sockalingam: None declared, Yuan An: None declared, Zhanguo Li: None declared, Yasuhiro Katsumata: None declared, masayoshi harigai Grant/research support from: AbbVie Japan GK, Ayumi Pharmaceutical Co., Bristol Myers Squibb Co., Ltd., Eisai Co., Ltd., Mitsubishi Tanabe Pharma Co., Nippon Kayaku Co., Ltd., and Teijin Pharma Ltd. MH has received speaker’s fee from AbbVie Japan GK, Ayumi Pharmaceutical Co., Boehringer Ingelheim Japan, Inc., Bristol Myers Squibb Co., Ltd., Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., Eli Lilly Japan K.K., GlaxoSmithKline K.K., Kissei Pharmaceutical Co., Ltd., Oxford Immuotec, Pfizer Japan Inc., and Teijin Pharma Ltd. MH is a consultant for AbbVie, Boehringer-ingelheim, Kissei Pharmaceutical Co., Ltd. and Teijin Pharma., Yanjie Hao: None declared, Zhuoli Zhang: None declared, Madelynn Chan: None declared, Jun Kikuchi: None declared, Tsutomu Takeuchi Grant/research support from: Eisai Co., Ltd, Astellas Pharma Inc., AbbVie GK, Asahi Kasei Pharma Corporation, Nippon Kayaku Co., Ltd, Takeda Pharmaceutical Company Ltd, UCB Pharma, Shionogi & Co., Ltd., Mitsubishi-Tanabe Pharma Corp., Daiichi Sankyo Co., Ltd., Chugai Pharmaceutical Co. Ltd., Consultant of: Chugai Pharmaceutical Co Ltd, Astellas Pharma Inc., Eli Lilly Japan KK, Speakers bureau: AbbVie GK, Eisai Co., Ltd, Mitsubishi-Tanabe Pharma Corporation, Chugai Pharmaceutical Co Ltd, Bristol-Myers Squibb Company, AYUMI Pharmaceutical Corp., Eisai Co., Ltd, Daiichi Sankyo Co., Ltd., Gilead Sciences, Inc., Novartis Pharma K.K., Pfizer Japan Inc., Sanofi K.K., Dainippon Sumitomo Co., Ltd., Fiona Goldblatt: None declared, Sean O’Neill: None declared, Chetan Karyekar Shareholder of: Johnson & Johnson, Consultant of: Janssen, Employee of: Janssen Global Services, LLC. Previously, Novartis, Bristol-Myers Squibb, and Abbott Labs., Jennifer H. Lofland Employee of: Janssen, Sang-Cheol Bae: None declared, Chak Sing Lau: None declared, Alberta Hoi: None declared, Mandana Nikpour: None declared, Eric F. Morand Grant/research support from: AstraZeneca, Consultant of: AstraZeneca, Speakers bureau: AstraZeneca

Background The Definitions of Remission in SLE (DORIS) group has proposed multiple definitions of remission, but these are infrequently attained and have not been prospectively evaluated in relation to protection from damage accrual. In contrast, the Lupus Low Disease Activity State (LLDAS) is more attainable, and has been shown to be associated with improved patient outcomes. Objectives To compare the attainability, and association with outcomes, of LLDAS and remission in a prospective multicentre study. Methods A prospective multinational cohort study was undertaken in 13 centres between 2013-2017. Time dependent Cox proportional hazards models were used to compare LLDAS and DORIS definitions of remission in terms of impact on disease flares and damage accrual. Results 1735 SLE patients were recruited, and followed for (mean±SD) 2.2±0.9 years, totalling 12,717 visits. LLDAS was achieved in 47.2% of observed visits. In contrast, remission was achieved in 1.1%-15.4% of visits depending on the stringency of remission definition. LLDAS attainment at any visit was associated with significantly reduced subsequent flare (HR 0.65, 95%CI 0.56-0.75, p Conclusion LLDAS was more attainable than any remission definition, whilst still conferring significant reduction in flares and damage accrual. Only the least stringent remission definitions could be shown to be associated with significantly lower damage accrual, likely reflecting a low frequency of remission attainment overall. LLDAS is a valid treatment target for SLE and is more achievable than remission. Disclosure of Interests Vera Golder: None declared, Eric F. Morand Grant/research support from: AstraZeneca, Bristol Myers Squibb, Janssen, Merck Serono, and UCB, Consultant for: AstraZeneca, Eli Lilly, Janssen, and Merck Serono, Speakers bureau: AstraZeneca, Rangi Kandane-Rathnayake: None declared, Molla Huq: None declared, Worawit Louthrenoo: None declared, Shue Fen Luo: None declared, Yeong-Jian Wu: None declared, Aisha Lateef : None declared, Sargunan Sockalingam: None declared, Sandra Navarra: None declared, Leonid Zamora: None declared, Laniyati Hamijoyo: None declared, Yasuhiro Katsumata: None declared, masayoshi harigai Grant/research support from: Tokyo Women’s Medical University (TWMU) has received unrestricted research grants for Division of Epidemiology and Pharmacoepidemiology of Rheumatic Diseases from Ayumi Pharmaceutical Co. Ltd., Bristol Meyers Squib, Chugai Pharmaceutical Co. Ltd., Nippon Kayaku Co. Ltd., Taisho Toyama Pharmaceutical Co. Ltd., Mitsubishi Tanabe Pharma Corp., and with which TWMU paid the salary of MH. MH has also received research grants from AbbVie Japan GK, Eisai Co. Ltd., Takeda Pharmaceutical Co., Ltd., and Teijin Pharma Ltd., Madelynn Chan: None declared, Sean O’Neill: None declared, Fiona Goldblatt: None declared, Chak Sing Lau: None declared, Zhanguo Li: None declared, Alberta Hoi Grant/research support from: GSK, AstraZeneca, UCB and Merck Serono, Consultant for: Janssen Steering Committee, Speakers bureau: Novartis, Mandana Nikpour: None declared

Background The recently validated Lupus Low Disease Activity State (LLDAS) definition has been shown to have utility as a treat to target endpoint in SLE, whereby LLDAS attainment is associated with reduction in permanent damage accrual. Robust evaluation is required to ensure this protective association is not simply reflective of milder disease phenotypes being over-represented among LLDAS attainers. Objectives To assess the effect of attainment of LLDAS on damage accrual in patients with active disease at baseline. SLEDAI-2K≥6 was chosen as this reflects clinical trial entry criteria. Methods A prospective multinational cohort study was undertaken in 13 centres between 2013-2017. Patients with SLE were recruited, SLEDAI-2k, SELENA flare index, PGA, and medication data collected at every visit, and damage score (SLICC-ACR damage index (SDI)) collected annually. Subgroup analyses were performed to assess the effect of LLDAS on damage accrual in patients who had active disease at baseline (SLEDAI-2K≥6). Time-dependent hazards regression models were used to assess the association of attainment of LLDAS at any time point, and proportion of time in LLDAS at the 50% observed time cut-off, with accrual of irreversible end-organ damage. Results 1,735 patients were followed for (mean ± SD) 2.2 ± 0.9 years, totalling 12,717 visits. LLDAS attainment was less frequent in patients with active disease at baseline (901 of 3835 visits in LLDAS, 23.5%), compared to patients with SLEDAI2-K Conclusion Despite lower attainment of LLDAS in patients with higher disease activity at baseline, the magnitude of association of LLDAS attainment with lower damage accrual was greater in this subgroup of patients compared to those less active baseline disease. This supports the validity of LLDAS as an outcome measure, in a population similar to that typically selected into clinical trials, and further highlights the potential impact of achieving a target outcome in SLE patients with active disease. Disclosure of Interests Vera Golder: None declared, Eric F. Morand Grant/research support from: AstraZeneca, Bristol Myers Squibb, Janssen, Merck Serono, and UCB, Consultant for: AstraZeneca, Eli Lilly, Janssen, and Merck Serono, Speakers bureau: AstraZeneca, Rangi Kandane-Rathnayake: None declared, Molla Huq: None declared, Hieu Nim: None declared, Worawit Louthrenoo: None declared, Shue Fen Luo: None declared, Yeong-Jian Wu: None declared, Aisha Lateef : None declared, Sargunan Sockalingam: None declared, Sandra Navarra: None declared, Leonid Zamora: None declared, Laniyati Hamijoyo: None declared, Yasuhiro Katsumata: None declared, masayoshi harigai Grant/research support from: Tokyo Women’s Medical University (TWMU) has received unrestricted research grants for Division of Epidemiology and Pharmacoepidemiology of Rheumatic Diseases from Ayumi Pharmaceutical Co. Ltd., Bristol Meyers Squib, Chugai Pharmaceutical Co. Ltd., Nippon Kayaku Co. Ltd., Taisho Toyama Pharmaceutical Co. Ltd., Mitsubishi Tanabe Pharma Corp., and with which TWMU paid the salary of MH. MH has also received research grants from AbbVie Japan GK, Eisai Co. Ltd., Takeda Pharmaceutical Co., Ltd., and Teijin Pharma Ltd., Madelynn Chan: None declared, Sean O’Neill: None declared, Fiona Goldblatt: None declared, Chak Sing Lau: None declared, Zhanguo Li: None declared, Alberta Hoi Grant/research support from: GSK, AstraZeneca, UCB and Merck Serono, Consultant for: Janssen Steering Committee, Speakers bureau: Novartis, Mandana Nikpour: None declared

Background The Definitions of Remission in SLE (DORIS) group has proposed multiple definitions of remission, but these are infrequently attained and have not previously been evaluated in relation to protection from damage accrual. In contrast, the Lupus Low Disease Activity State (LLDAS) is more attainable, and has been shown to be associated with improved patient outcomes. The objective of this study was to compare the attainability and effect of LLDAS and remission on outcomes in a prospective multicenter study. Methods A prospective multinational cohort study was undertaken in 13 centres between 2013–2017. Time dependent Cox proportional hazards models were used to compare LLDAS and DORIS definitions of remission in terms of impact on disease flares and damage accrual. Results 1735 SLE patients were recruited, and followed for (mean ±SD) 2.2±0.9 years. LLDAS was achieved in 6922 visits (54.6%). In contrast, remission was achieved in 1.1%–15.4% of visits. LLDAS attainment at any visit was associated with significantly reduced subsequent flare (HR 0.65, 95% CI 0.56–0.76, p Conclusions LLDAS was markedly more attainable than any remission definition, whilst still conferring significant protection against flares and damage accrual. Only the least stringent remission definitions could be shown to be associated with significant reduction in damage accrual, likely reflecting a low frequency of remission attainment overall; and normal serology was required for protection from flare. LLDAS is a valid treatment target for SLE and is more achievable than remission. Funding Source(s): The Asia Pacific Lupus Collaboration receives project support grants from UCB, GlaxoSmithKline, Janssen, Bristo-Myers Squibb, and AstraZeneca.

Background Adoption of treat to target approaches for Systemic Lupus Erythematosus (SLE) requires the definition of a target state validated for improved patient outcomes. The Lupus Low Disease Activity State (LLDAS) has been shown in multiple retrospective and cross-sectional studies to have face, content, construct and criterion validity and be associated with better quality of life. We report on a multinational prospective study undertaken to determine whether LLDAS attainment is associated with protection from flare and damage accrual. Methods A prospective multinational cohort study was undertaken in 13 centres between 2013–2017. Patients with SLE were recruited, SLEDAI-2k, SELENA flare index, PGA, and medication data collected at every visit, and damage (SLICC-ACR damage index (SDI)) collected annually. Time-dependent Cox proportional hazards models were used to assess the association of LLDAS at any time point, as well as the effect of the proportion of time spent in LLDAS, with disease flare and damage accrual (increase in SDI). Results 1735 patients were followed for (mean ±SD) 2.2±0.9 years, totalling 12 717 visits. LLDAS was achieved in 54.6% of visits. Attainment of LLDAS at any timepoint was associated with reduction in subsequent flare (HR 0.65, 95% CI 0.56–0.76, p 6) or pre-existing damage (SDI>0). Conclusions LLDAS attainment provides significant protection against disease flare and damage accrual thereby supporting its use as a treatment target in SLE, and as an outcome measure for clinical trials and treat-to-target strategies. Funding Source(s): The Asia Pacific Lupus Collaboration receives project support grants from UCB, GlaxoSmithKline, Janssen, Bristo-Myers Squibb, and AstraZeneca.

Models of Care (MoCs) are increasingly recognised as a system-level enabler to translate evidence for ‘what works' into policy and, ultimately, clinical practice. MoCs provide a platform for a reform agenda in health systems by describing not only what care to deliver but also how to deliver it. Given the enormous burden of disease associated with musculoskeletal (MSK) conditions, system-level (macro) reform is needed to drive downstream improvements in MSK healthcare – at the health service (meso) level and at the clinical interface (micro) level. A key challenge in achieving improvements in MSK healthcare is sustainable implementation of reform initiatives, whether they be macro, meso or micro level in scope. In this chapter, we introduce the special issue of the Journal dedicated to implementation of MSK MoCs. We provide a contextual background on MoCs, a synthesis of implementation approaches across care settings covered across the chapters in this themed issued, and perspectives on the evaluation of MoCs.

Background Lupus nephritis (LN) is a common feature of systemic lupus erythematosus (SLE). While LN is considered a contributor to irreversible organ damage in SLE, the magnitude of impact of active renal disease relative to other contributors to damage accrual is unknown. Objectives To determine the time-dependent association of active lupus nephritis (LN) with organ damage accrual in SLE. Methods This study was performed on patients from the Asia Pacific Lupus Collaboration (APLC) cohort. SLE Disease Activity Index-2000 (SLEDAI-2k) is collected per-visit and SLICC-ACR Damage Index (SDI) annually. Analysis was restricted to patients with ≥2 SDI scores. Active LN was defined if patients had urinary casts, proteinuria, haematuria or pyuria as indicated in the SLEDAI-2k descriptor. Organ damage accrual was defined as a change of SDI (ΔSDI>0) between baseline and final visit. Glucocorticoid (GC) categories were defined according to cumulative GC exposure at each visit as either no GC (cum.GC=0); low GC (cum.GC ≤median) or high GC (cum.GC >median). Cox regression analyses were performed. Results 1735 patients and 5593 visits were included in the analysis. 93% of patients was female with a median ([inter-quartile range (IQR), (range)] age of 40 years.31, 51 18, 77 Median study observation period was 853 days [621, 1094].98, 1443 36% were Chinese; 20% Thai and 10% Caucasian ethnicity. 82% of patients were exposed to glucocorticoids. 40% had active renal disease at least once during the study period, and active renal disease was observed in 22% of visits (n=1238 visits). 41% of patients had organ damage at baseline and 14% accrued organ damage (272 damage accrual episodes in 250 patients). Active renal disease was significantly associated with damage accrual; after adjusting for confounders, patients with active renal disease were 66% more likely to accrue organ damage compared to those without active renal disease (adjusted hazard ratio=1.66 (95% CI: 1.26, 2.19), p-value Conclusions Active LN is an independent risk factor for damage accrual in SLE. The concomitant independent association of GC exposure with damage accrual suggests non-GC treatments to reduce active LN are needed to reduce damage burden in SLE. Disclosure of Interest None declared

Aim The aim of this manuscript is to describe the development of the Asia Pacific Lupus Collaboration (APLC) cohort. Method The APLC cohort is an ongoing, prospective longitudinal cohort. Adult patients who meet either the American College of Rheumatology (ACR) Modified Classification Criteria for systemic lupus erythematosus (SLE), or the Systemic Lupus International Collaborating Clinics (SLICC) Classification Criteria, and provide informed consent are recruited into the cohort. Patients are routinely followed up at 3- to 6-monthly intervals. Information on demographics, clinical manifestations, treatment, pathology results, outcomes, and patient-reported quality of life (Short-form 36 version 2) are collected using a standardized case report form. Each site is responsible for obtaining local ethics and governance approval, patient recruitment, data collection, and data transfer into a centralized APLC database. Results The latest APLC cohort comprises 2160 patients with >12 000 visits from Australia, China, Hong Kong, Indonesia, Japan, Malaysia, Philippines, Singapore, Taiwan and Thailand. The APLC has proposed the Lupus Low Disease Activity State (LLDAS) as a treat-to-target (T2T) endpoint, and reported several retrospective and cross-sectional analyses consistent with the validity of LLDAS. Longitudinal validation of LLDAS as a T2T endpoint is currently underway. Conclusion The APLC cohort is one of the largest contemporary SLE patient cohorts in the world. It is the only cohort with substantial representation of Asian patients. This cohort represents a unique resource for future clinical research including evaluation of other endpoints and quality of care.

Background and Aims Systemic lupus erythematosus (SLE) is associated with significant impairment of health-related quality of life (HR-QoL). The Lupus Low Disease Activity State (LLDAS) definition has not been previously evaluated for association with patient reported outcomes. The objective of this study was to determine whether LLDAS was associated with better HR-QoL, and examine predictors of HR-QoL, in a large multiethnic, multinational cohort of SLE patients. Methods HR-QoL was measured using the Medical Outcomes Study 36-item Short Form Health Survey (SF-36v2) in a prospective study of 1422 patients. Disease status was measured using SLE disease activity index (SLEDAI-2K), physician global assessment (PGA) and LLDAS. Results Significant differences in SF-36 domain scores were found between patients stratified by ethnic group, education level, damage score, and with the presence of active musculoskeletal or cutaneous manifestations. In multiple linear regression analysis, Asian ethnicity (p Conclusions Ethnicity, education, disease damage, and specific organ involvement impacts on HR-QoL in SLE. Attainment of LLDAS is associated with better HR-QoL.

Background The Integrin-alpha-M (ITGAM) rs1143679 SNP has been associated with susceptibility to SLE and lupus nephritis (LN) in oriental Chinese and Thai populations. We previously found 13 ITGAM SNPs in linkage disequilibrium (LD) that were associated with susceptibility to SLE, but found no association with rs1143679. Aim To determine associations of ITGAM SNPs with SLE subphenotypes and autoantibodies. Methods We studied 248 patients fulfilling the 1997 ACR revised criteria for SLE. SLE-associated ITGAM SNP alleles were identified using custom-designed Immunochip arrays and gPLINK 1.062 software, with Bonferroni corrections for multiple comparisons. Associations of SLE-related ITGAM SNPs with SLE subphenotypes (malar or discoid rash, serositis, mouth ulcers, arthritis, haematological, renal or neurological involvement) and autoantibodies to dsDNA, Ro, RNP or Sm were determined with chi-square and Fisher’s tests and logistic regression. Results All 13 SLE susceptibility ITGAM SNPs as well as the uncommon rs1143679 SNP (n=11) were associated with LN (Table 1). The strongest association was with rs2359661 (p=0.002, uncorrected). Subjects with these SNPs were less likely to have discoid rash. There was a trend towards an association with anti-Sm. Logistic regression models for 11 SNPs retained the factors LN, discoid rash and anti-Sm, suggesting strong LD for these SNPs. Conclusions This study demonstrated novel ITGAM SNP associations with LN and confirmed the association of rs1143679 with LN. Most associated SNPs were in the regulatory region of ITGAM bearing promoter/enhancer histone marks and have been associated with expression levels in several cell types, suggesting modulation of levels of ITGAM expression to impact these subphenotypes.

The prevalence of non-alcoholic fatty liver disease (NAFLD) in children is increasing. This study evaluated the efficacy of a dietitian-led lifestyle modification programme (D-LMP) to reduce NAFLD in obese adolescents. Subjects with intra-hepatic triglyceride content (IHTC) equal to or greater than 5% diagnosed by proton-magnetic resonance spectroscopy (1H-MRS) were enroled and randomly assigned to either the D-LMP intervention or conventional paediatrician-led consultation (P-CON) group. Subjects in the P-CON group received usual care consisting of a consultation by a paediatrician with the child and parents every 16 weeks. Intention-to-treat analysis was used for data analysis. Fifty-two subjects were recruited, with 26 in each group. After the initiation phase (at week-16), there was a greater difference in the change in the IHTC and BMI z-score in the D-LMP group (P = 0.029 and

Background Systemic lupus erythematosus (SLE) is associated with significant impairment of health-related quality of life (HR-QoL). Recently, meeting a definition of a lupus low disease activity state (LLDAS), analogous to low disease activity in rheumatoid arthritis, was preliminarily validated as associated with protection from damage accrual. The LLDAS definition has not been previously evaluated for association with patient-reported outcomes. The objective of this study was to determine whether LLDAS is associated with better HR-QoL, and examine predictors of HR-QoL, in a large multiethnic, multinational cohort of patients with SLE. Methods HR-QoL was measured using the Medical Outcomes Study 36-item short form health survey (SF-36v2) in a prospective study of 1422 patients. Disease status was measured using the SLE disease activity index (SLEDAI-2 K), physician global assessment (PGA) and LLDAS. Results Significant differences in SF-36 domain scores were found between patients stratified by ethnic group, education level and damage score, and with the presence of active musculoskeletal or cutaneous manifestations. In multiple linear regression analysis, Asian ethnicity (p

This case report describes a patient who presented with cervical spinal pain and headaches associated with atlanto-axial subluxation (AAS) secondary to rheumatoid arthritis (RA). For physiotherapists, especially less experienced clinicians, the significant risks associated with using manual assessment and treatment techniques in such a patient require careful consideration right at the start of a consultation. The focus of the case is therefore on the recognition of AAS in this patient with RA, highlighting the clinical findings that alert clinicians to this possibility and explaining the requisite knowledge and skills required to safely and effectively manage this patient. The use of screening tools to help clinicians identify possible RA in its pre-diagnosis stage and the clinical signs and symptoms that raise the index of suspicion for AAS, are discussed. The relevant contraindications and precautions associated with manual treatments directed at the upper cervical spine, and which may have potentially serious negative consequences, including quadriplegia and mortality, are addressed. Finally, the implications for the use of manual assessment and treatment of patients with RA and co-morbid AAS are addressed.

Rheumatoid arthritis (RA) is a chronic, systemic, autoimmune disease. Physiotherapy interventions for people with RA are predominantly targeted at ameliorating disability resulting from articular and peri-articular manifestations of the disease and providing advice and education to improve functional capacity and quality of life. To ensure safe and effective care, it is critical that physiotherapists are able to identify potentially serious articular and peri-articular manifestations of RA, such as instability of the cervical spine. Additionally, as primary contact professionals, it is essential that physiotherapists are aware of the potentially serious extra-articular manifestations of RA. This paper provides an overview of the practice-relevant manifestations associated with RA that might warrant further investigation by a medical practitioner (red flags), their relevance to physiotherapy practice, and recommended management pathways.

This chapter discusses the challenges faced in the development and implementation of musculoskeletal (MSK) Models of Care (MoCs) in middle-income and low-income countries in Asia and outlines the components of an effective MoC for MSK conditions. Case studies of four such countries (The Philippines, Malaysia, Bangladesh and Myanmar) are presented, and their unique implementation issues are discussed. The success experienced in one high-income country (Singapore) is also described as a comparison. The Community Oriented Program for Control of Rheumatic Diseases (COPCORD) project and the role of Asia Pacific League of Associations for Rheumatology (APLAR), a professional body supporting MoC initiatives in this region, are also discussed. The experience and lessons learned from these case studies can provide useful information to guide the implementation of future MSK MoC initiatives in other middle-income and low-income countries.

Background Systemic lupus erythematosus (SLE) is a chronic heterogeneous disease with considerable burden from disease activity and damage. A novel clinical treatment target in the form of the lupus low disease activity state (LLDAS) has been recently reported, with retrospective validation showing that time spent in LLDAS translates to reduced damage accrual. The objectives of this study were to describe the frequency and identify the predictors of attaining LLDAS in a large multinational cohort of patients with SLE. Methods Data were collected at the recruitment visit in patients with SLE enrolled in a longitudinal study in nine countries. Data were analysed cross-sectionally against the recently published definition of LLDAS, and the frequency and characteristics associated with presence of LLDAS were determined. Stepwise multivariable logistic regression was used to determine predictors of LLDAS. Results Of the 1846 patients assessed, criteria for LLDAS were met by 44 %. Patients with shorter disease duration were less likely to be in LLDAS (OR 0.31, 95 % CI 0.19–0.49, p

Gout affecting the axial joints is uncommon; however, its involvement may be complicated by neurological symptoms associated with spinal compression at the affected level. Specific involvement of the odontoid process is even rarer. We report the first case of gout involving the odontoid process with resultant glossopharyngeal (CN IX), vagus (CN X) and hypoglossal (CN XII) nerve palsies.

Background Prompt utilization of health services on detecting breast symptoms can improve breast cancer (BC) survival. Little is known about Chinese women’s help-seeking behaviour. Our aim was to determine patterns of self-referral among Hong Kong Chinese women with selfdetected breast symptoms. Methods We recruited 37 women awaiting their first consultation at public hospitals for breast symptoms. Interviews were transcribed and analysed based on the grounded theory approaches. Results A two-stage help-seeking model provided the best interpretation of the data. Symptom recognition was triggered by symptom interpretation, symptom progression and social messages. Painful lumps were seen as symptomatic, but atypical symptoms were often dismissed as benign as they responded to dietary change. Symptom intensification and discussions with someone who had faced BC prompted consultation. Service utilization involved fear of consequences, confirmation need, symptom distress, lay referral, media prompts and opportunistic presentation. Fearing cancer as incurable delayed consultation. Utilization barriers included cost, uncertainty about referral pathways, competing priorities and embarrassment. Conclusions Atypical and painless presentation was more common among women delaying presentation. Barriers included cost, access, time and embarrassment. Education should emphasize atypical symptoms, the high-cure rate and the need for early presentation. Reduced cost and improved access to clinics would enhance early consultation.

Background Nonmelanoma skin cancer (NMSC) comprises a heterogeneous group of cancers. A comprehensive review of NMSC mortality has not been performed previously in this region. Objective We sought to document the population affected by lethal NMSC, the types of tumors involved, and their histopathologic features. Methods Death certificates of all patients who died from NMSC were examined. Histology of the primary lesion was reviewed in cases when the primary lesion was identified and sections were available. Results A total of 120 NMSC deaths occurred, including 89 caused by squamous cell carcinoma, 22 by Merkel cell carcinoma, and 9 others. The median age at death was 79 years, unless the patients were immune deficient (68 years). When the primary lesion was identified (n=45), the median survival after diagnosis was 17 months; 75% of patients died within 3 years. Lethal neoplasms were deeply invasive and infiltrated into the reticular dermis and beyond. Three squamous cell carcinomas were reclassified as adenosquamous carcinoma. Conclusion Lethal NMSC occurs in the elderly and consists mainly of 3 types of deeply invasive cancers.

OBJECTIVES: The aims of our study were: (1) to determine the prevalence of asymptomatic hepatic steatosis and presumed nonalcoholic steatohepatitis, in our local population of obese Chinese children referred for medical assessment; and (2) to assess the correlation between severity of ultrasonographic hepatic steatosis and degree of obesity, insulin resistance and serum biochemical abnormalities. DESIGN: Cross-sectional study. METHODS: In total, 84 obese children, 25 girls and 59 boys with median age and body mass index (BMI) of 12.0 years (interquartile range (IR): 9.5–14.0) and 30.3 kg/m2 (IR: 27.1–33.4), respectively, referred for medical assessment were studied. All subjects underwent physical examination, anthropometric and dual energy X-ray absorptiometry (DEXA) scan measurements and real-time ultrasonographic (US) examination of the liver. Fasting blood samples were collected for the measurement of liver function, hepatitis status, levels of serum glucose and insulin and lipid profile. Degree of fatty infiltration of the liver was graded according to ultrasonic appearance of liver echotexture, liver–diaphragm differentiation in echo amplitude, hepatic echo penetration and clarity of hepatic blood vessels. RESULTS: All recruited subjects had no history of alcohol abuse and tests for Hepatitis B or C virus were negative. Thorough examination showed all of them to be in general good health without signs of chronic liver disease. Hepatic steatosis identified by defined ultrasonic appearances was diagnosed in 65 subjects (77%); 17 girls and 48 boys. The severity of fatty liver was positively related to anthropometric measurements including BMI, waist and hip circumference, subscapular skinfold thickness; insulin resistance markers [QUICKI and homeostasis model assessment (HOMA)], and hypertriglyceridaemia. Multvariate ordinal regression analysis showed that BMI and raised alanine aminotransferase (ALT) were positively associated with fatty liver. Combination of hepatic steatosis with raised ALT (presumptive NASH) was found in 19 subjects (24%). This group of patients had significantly higher waist hip ratio and conicity index compared to those with isolated hepatic steatosis. Boys with presumed NASH were also found to have significantly higher insulin resistance. CONCLUSION: Nonalcoholic fatty liver disease (NAFLD) was common among our cohort of obese children referred for medical assessment. The prevalence of simple steatosis and presumed NASH was 77 and 24%, respectively. The severity of US steatosis was positively correlated with BMI, raised ALT, insulin resistance and hypertryglyceridaemia. Ultrasonography being noninvasive and readily available could be used for the monitoring of the progression of hepatic steatosis. Further longitudinal studies are required to determine the natural disease progression and the role of insulin resistance and other factors in the pathophysiology of NAFLD.

To examine the effectiveness of a physiotherapy-specific, web-based e-learning platform, "RAP-el," in best-practice management of rheumatoid arthritis (RA) using a single-blind, randomized controlled trial (RCT) and prospective cohort study.Australian-registered physiotherapists were electronically randomized into intervention and control groups. The intervention group accessed RAP-eL over 4 weeks. Change in self-reported confidence in knowledge and skills was compared between groups at the end of the RCT using linear regression conditioned for baseline scores by a blinded assessor, using intent-to-treat analysis. Secondary outcomes included physiotherapists' satisfaction with RA management and responses to RA-relevant clinical statements and practice-relevant vignettes. Retention was evaluated in a cohort study 8 weeks after the RCT.Eighty physiotherapists were randomized into the intervention and 79 into the control groups. Fifty-six and 48, respectively, provided baseline data. Significant between-group differences were observed for change in confidence in knowledge (mean difference 8.51; 95% confidence interval [95% CI] 6.29, 10.73; effect size 1.62) and skills (mean difference 7.26; 95% CI 5.1, 9.4; effect size 1.54), with the intervention group performing better. Satisfaction in ability to manage RA, 4 of the 6 clinical statements, and responses to vignettes demonstrated significant improvement in the intervention group. Although 8-week scores showed declines in most outcomes, their clinical significance remains uncertain.RAP-eL can improve self-reported confidence, likely practice behaviors and satisfaction in physiotherapists' ability to manage people with RA, and improve their clinical knowledge in several areas of best-practice RA management in the short term.

Background Systemic lupus erythematosus (SLE) is a heterogeneous disease characterised by fluctuating disease activity. A low disease activity endpoint, the Lupus Low Disease Activity State (LLDAS), was recently reported and retrospective validation showed that time spent in LLDAS translated into reduced damage accrual (Franklyn, Ann Rheum Dis, 2015). A large prospective study to validate LLDAS in a multiethnic cohort of lupus patients from the Asia Pacific Region is underway. Objectives To describe the frequency and identify the predictors of fulfilling criteria for LLDAS in baseline visit data from a large multinational multiethnic cohort of patients with SLE in nine Asia Pacific countries. Methods Prospectively collected baseline visit data from 1846 SLE patients enrolled in a longitudinal study were analysed cross sectionally against the recently published definition of LLDAS, and patient characteristics associated with LLDAS attainment determined. Results LLDAS criteria were met by 44% of patients at a single baseline visit. Stepwise multivariable logistic regression revealed that patients with shorter disease duration were less likely to be in LLDAS (OR 0.31, 95% CI 0.19–0.49, p Conclusions Low disease activity was observed in less than half of SLE patients at a single point in time. Disease duration and phenotype, as well as national social wealth, were predictive of LLDAS attainment. Disclosure of Interest None declared

Background While translation of evidence into health policy and practice is recognised as critical to optimising health system performance and health-related outcomes for consumers, mechanisms to effectively achieve these goals are neither well understood, nor widely communicated. Health Networks represent a framework which offers a possible solution to this dilemma, particularly in light of emerging evidence regarding the importance of establishing relationships between stakeholders and identifying clinical leaders to drive evidence integration and translation into policy. This is particularly important for service delivery related to chronic diseases. In Western Australia (WA), disease and population-specific Health Networks are comprised of cross-discipline stakeholders who work collaboratively to develop evidence-informed policies and drive their implementation. Since establishment of the Health Networks in WA, over 50 evidence-informed Models of Care (MoCs) have been produced across 18 condition or population-focused Networks. The aim of this paper is to provide an overview of the Health Network framework in facilitating the translation of evidence into policy and practice with a particular focus on musculoskeletal health. Case presentation A review of activities of the WA Musculoskeletal Health Network was undertaken, focussing on outcomes and the processes used to achieve them in the context of: development of policy, procurement of funding, stakeholder engagement, publications, and projects undertaken by the Network which aligned to implementation of MoCs. The Musculoskeletal Health Network has developed four MoCs which reflect Australian National Health Priority Areas. Establishment of community-based services for consumers with musculoskeletal health conditions is a key recommendation from these MoCs. Through mapping barriers and enablers to policy implementation, working groups, led by local clinical leaders and supported by the broader Network and government officers, have undertaken a range of integrated projects, such as the establishment of a community-based, multidisciplinary rheumatology service. The success of these projects has been contingent on developing relationships between key stakeholders across the health system. Conclusions In WA, Networks have provided a sustainable mechanism to meaningfully engage consumers, carers, clinicians and other stakeholders; provided a forum to exchange ideas, information and evidence; and collaboratively plan and deliver evidence-based and contextually-appropriate health system improvements for consumers.

Objective While strong evidence supports the role of physiotherapy in the co-management of patients with rheumatoid arthritis (RA), it remains unclear what constitutes the essential disease-specific knowledge and clinical skills required by community-based physiotherapists to effectively and safely deliver recommended care. This study aimed to identify essential disease-specific knowledge and skills, link these with evidence from clinical guidelines, and broadly determine the professional development (PD) needs and confidence related to the management of RA among physiotherapists. Methods An international Delphi panel of rheumatologists, physiotherapists, and consumers (n = 27) identified essential disease-specific knowledge and clinical skills over 3 rounds. Physiotherapy-relevant recommendations from high-quality, contemporary clinical guidelines were linked to Delphi responses. Finally, an e-survey of PD needs among registered physiotherapists (n = 285) was undertaken. Results Overarching themes identified by the Delphi panel across the RA disease stages included the need for excellent communication, the importance of a multidisciplinary team and early referral, adoption of chronic disease management principles, and disease monitoring. Of the essential Delphi themes, 86.7% aligned with clinical guideline recommendations. Up to 77.5% of physiotherapists reported not being confident in managing patients with RA. Across the range of essential knowledge and skills themes, 45.1–93.5% and 71.1–95.2% of respondents, respectively, indicated they would benefit from or definitely need PD. Conclusion To effectively manage RA, community-based physiotherapists require excellent communication skills and disease-specific knowledge, including understanding the role of the multidisciplinary team and the principles of early referral, chronic disease management, and monitoring. Physiotherapists identified a need for PD to develop these skills.

Gout affecting the axial joints is uncommon; however, its involvement may be complicated by neurological symptoms associated with spinal compression at the affected level. Specific involvement of the odontoid process is even rarer. We report the first case of gout involving the odontoid process with resultant glossopharyngeal (CN IX), vagus (CN X) and hypoglossal (CN XII) nerve palsies.