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Background The unmet need in systemic lupus erythematosus (SLE) with the current standard of care is widely recognised, but few studies have quantified this. The recent definition of treat-to-target endpoints and other thresholds of uncontrolled disease activity provide an opportunity to formally define unmet need in SLE. In this study, we enumerated the prevalence of these states and examined their association with adverse outcomes. Methods Data were collected prospectively in a 13-country longitudinal SLE cohort between 2013 and 2019. Unmet need was defined as never attaining lupus low disease activity state (LLDAS), a time-adjusted mean SLEDAI-2K (AMS) > 4, or ever experiencing high disease activity status (HDAS; SLEDAI-2K ≥10). Health-related quality of life (HRQoL) was assessed using SF36 (v2) and damage accrual using the SLICC-ACR SLE Damage Index (SDI). Results A total of 3384 SLE patients were followed over 30,313 visits (median [IQR] follow-up 2.4 [0.4, 4.3] years). Eight hundred thirteen patients (24%) never achieved LLDAS. Median AMS was 3.0 [1.4, 4.9]; 34% of patients had AMS > 4. Twenty-five per cent of patients had episodes of HDAS. Each of LLDAS-never, AMS>4, and HDAS-ever was strongly associated with damage accrual, higher glucocorticoid use, and worse HRQoL. Mortality was significantly increased in LLDAS-never (adjusted HR [95% CI ] = 4.98 [2.07, 12.0], p <0.001) and HDAS-ever (adjusted hazard ratio (HR) [95% CI ] = 5.45 [2.75, 10.8], p <0.001) patients. Conclusion Failure to achieve LLDAS, high average disease activity, and episodes of HDAS were prevalent in SLE and were significantly associated with poor outcomes including organ damage, glucocorticoid exposure, poor quality of life, and mortality.

Introduction Over-expression of common inflammatory mediators in the metabolic syndrome (MetS) and in rheumatoid arthritis (RA) may lead to mutually adverse outcomes. Aim We investigate the prevalence of MetS in a multi-ethnic population of RA patients and its effect on clinical and patient-reported outcomes. Method Six hundred sixty RA (561 women) patients from a public-sector specialist clinic in a hospital in Singapore were assessed for MetS according to the 2009 Joint Consensus (JC) and the 2004 National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) definitions. Univariable and multivariable regression modelling were used to investigate the associations between patients’ demographics with MetS and MetS with RA outcomes. Results The prevalence of MetS in our RA cohort was 49.4% and 44.9% according to the JC and NCEP ATP III definitions, respectively. The diagnosis of MetS was largely due to hypertriglyceridemia, hypertension, and obesity. MetS was associated with older age (OR 1.06 [95% CI 1.04–1.08]), Malay ethnicity (OR 1.78 [95% CI 1.02–3.09]), or Indian ethnicity (OR 3.07 [95% CI 1.68–5.59]). No significant associations between MetS and RA outcomes were observed. RA patients with MetS are more likely to suffer from stroke and ischemic heart disease. Conclusion The prevalence of MetS in RA patients in Singapore was almost double that in the general population. MetS does not adversely affect RA outcomes but raises the risks of stroke and heart disease. RA patients, especially those older and of Indian and Malay ethnicities, should be routinely screened for MetS. Any MetS-defining condition should be actively controlled. Key Points • Approximately half of the RA sample from the Singapore RA population can be diagnosed with MetS. • Older patients, and patients of Malay and Indian ethnicities have higher odds of MetS. • MetS does not adversely affect RA outcomes but raises the risks of stroke and heart disease.

Background Emerging therapies have the potential to be used in patients with severe refractory systemic lupus erythematosus (srSLE), but no agreed definition of srSLE exists. We evaluated a pilot srSLE definition to assess whether a set of disease activity and treatment thresholds could identify patients with poor outcomes. Methods Data from a 13-country longitudinal SLE cohort, collected prospectively between 2013 and 2020 were analysed. srSLE was defined if a patient was in high disease activity (SLEDAI-2K ≥ 10) despite combination use of at least glucocorticoids (GC) and immunosuppressants (IS) at both the index and preceding visit. Synchronised to the index srSLE visit, we assessed disease activity, medication use and treat-to-target (T2T) endpoint attainment over 12 months (m). Results Of 3,744 patients studied, 578 (14%) had srSLE, in 1,810 visits. The median [IQR] SLEDAI-2K at the srSLE index visit was 12 [10, 14], which decreased to 6 [4, 10] at 6m and 12m. Most patients remained on combination anti-malarial, GC, and IS at all follow-up time points. The median [IQR] GC dose at the index visit was 10 [5, 20] mg/day; this reduced to 8 mg [5.0, 12.9] at 6m and 5 mg [5.0, 10.0] at 12m. Less than a quarter of patients attained LLDAS and only 1% attained GC-free remission over 12 months. Conclusions A draft definition of srSLE was clearly associated with poor outcomes. Work to evaluate multiple thresholds with which to define srSLE, and their outcomes, is warranted.

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.

Background The popular statistics-based Genome-wide association studies (GWAS) have provided deep insights into the field of complex disorder genetics. However, its clinical applicability to predict disease/trait outcomes remains unclear as statistical models are not designed to make predictions. This study employs statistics-free machine-learning (ML)-optimized polygenic risk score (PRS) to complement existing GWAS and bring the prediction of disease/trait outcomes closer to clinical application. Rheumatoid Arthritis (RA) was selected as a model disease to demonstrate the robustness of ML in disease prediction as RA is a prevalent chronic inflammatory joint disease with high mortality rates, affecting adults at the economic prime. Early identification of at-risk individuals may facilitate measures to mitigate the effects of the disease. Methods This study employs a robust ML feature selection algorithm to identify single nucleotide polymorphisms (SNPs) that can predict RA from a set of training data comprising RA patients and population control samples. Thereafter, selected SNPs were evaluated for their predictive performances across 3 independent, unseen test datasets. The selected SNPs were subsequently used to generate PRS which was also evaluated for its predictive capacity as a sole feature. Results Through robust ML feature selection, 9 SNPs were found to be the minimum number of features for excellent predictive performance (AUC > 0.9) in 3 independent, unseen test datasets. PRS based on these 9 SNPs was significantly associated with (P < 1 × 10 –16 ) and predictive (AUC > 0.9) of RA in the 3 unseen datasets. A RA ML-PRS calculator of these 9 SNPs was developed ( https://xistance.shinyapps.io/prs-ra/ ) to facilitate individualized clinical applicability. The majority of the predictive SNPs are protective, reside in non-coding regions, and are either predicted to be potentially functional SNPs (pfSNPs) or in high linkage disequilibrium (r2 > 0.8) with un-interrogated pfSNPs. Conclusions These findings highlight the promise of this ML strategy to identify useful genetic features that can robustly predict disease and amenable to translation for clinical application.

ObjectivesThis study examined if lowering the glucocorticoid (GC) ceiling in the definition of lupus low disease activity state (LLDAS) from 7.5 mg/day to 5 mg/day (LLDAS-5) was associated with better outcomes in patients with systemic lupus erythematosus (SLE).MethodsData from a 13-country longitudinal SLE cohort (American College of Rheumatology/Systemic Lupus International Collaborating Clinics criteria), collected prospectively between 2013 and 2020, were analysed. Survival analyses were used to examine the longitudinal associations of LLDAS definitions with flare, organ damage accrual (frailty models) and mortality (Cox regression models).Results3801 patients with ≥2 visits were studied, with a median of 2.8 years (IQR: 1.0–5.4) of follow-up data (total visits: 40 949). 2141 (56.3%) patients experienced mild–moderate/severe flares; 717 (20.8%) accrued organ damage, and 80 (2.1%) died. 3072 (80%) patients attained LLDAS in 19 293 (47%) visits, while 2858 (75%) patients attained LLDAS-5 in 17 403 (42%) visits. Most patients in LLDAS were also in LLDAS-5; 214 patients (5.6%) attained LLDAS on at least one occasion, but never attained LLDAS-5. The magnitude of protection provided by LLDAS attainment against flare, irreversible organ damage accrual and mortality was similar with both GC thresholds. HRs (95% CIs) of damage accrual subsequent to spending 12 months in sustained LLDAS and LLDAS-5 were 0.42 (0.33 to 0.54, p<0.0001) and 0.43 (0.34 to 0.55, p<0.001), respectively. Likewise, HRs of flare and mortality corresponding to 12 months in LLDAS and LLDAS-5 were similar.ConclusionsNo evidence was found to support revising the GC dose threshold of the LLDAS definition. Regardless, minimising GC exposure remains a key goal of SLE management.Trial registration numberNCT03138941.

ObjectiveTo estimate the prevalence of organ damage (damage) and flare and to examine longitudinal associations between flares and subsequent damage accrual, in patients with systemic lupus erythematosus (SLE).MethodsPatients enrolled in the Asia Pacific Lupus Collaboration cohort with ≥3 years of prospectively captured data were studied. Flares were assessed at routine visits, while damage ((Systemic Lupus International Collaborating Clinics/American College of Rheumatology) Damage Index) was assessed annually. Multivariable, multifailure survival analyses were carried out to quantify the association between flares and damage accrual.Results1556 patients with SLE with a median (IQR) of 5.7 (3.9, 7.0) years of follow-up were studied. 39.5% (n=614) of patients had damage at enrolment, and 31.9% (n=496) accrued damage during the study observation period. The incidence of damage accrual during observation was ~58/1000 person-years. Overall, 74.1% (n=1153) of patients experienced a flare of any severity (mild/moderate or severe) at least once; 56.9% (n=885) experienced recurrent (≥2) flares. The risk of subsequent damage accrual in patients who experienced mild-to-moderate flare, after controlling for confounders, was 32% greater than in patients without flares (adjusted HR) (95% CI 1.32 (1.17 to 1.72)). The risk of damage accrual was greater if patients had severe flares (HR (95% CI) 1.58 (1.18 to 2.11)). For each additional flare, the risk of damage accrual increased by 7% (HR (95% CI) 1.07 (1.02 to 1.13)).ConclusionsFlares independently increased the risk of damage accrual. Prevention of flares should be considered a necessary goal of SLE disease management to minimise permanent damage.

ObjectiveTo report the prevalence of disease activity in individual SLE organ domains, including prevalence stratified by the most common disease activity cut-off score for clinical trial eligibility (SLE Disease Activity Index 2000; SLEDAI-2K ≥6).MethodsWe used data from a multinational longitudinal SLE cohort, prospectively collected between 2013 and 2020. Disease activity was categorised by the SLEDAI-2K into nine organ systems. We calculated proportions of organ-specific disease activity in the overall cohort and stratified by SLEDAI-2K ≥6 or <6, on both a per-patient and per-visit level.ResultsWe included 4102 patients (92.0% female, 88.9% Asian) contributing 42 345 eligible visits. Serological disease activity was most prevalent, affecting 75.5% of patients at least once during follow-up, followed by renal (41.6%), cutaneous (36.5%), musculoskeletal (20.1%) and haematological (19.1%) activity. Serositis (3.4%), vasculitis (3.4%), central nervous system activity (3.0%) and fever (2.9%) occurred infrequently. In patient visits with an SLEDAI-2K ≥6 (n=10 031), the most common active manifestations were serological (89.8%), renal (72.9%), cutaneous (26.4%) and musculoskeletal (14.3%). In patient visits with an SLEDAI-2K <6 (n=32 314), renal (7.3%), cutaneous (6.7%), haematological (5.8%) and musculoskeletal (1.3%) disease activity were still present.ConclusionSerological, renal, cutaneous, musculoskeletal and haematological manifestations predominate in patients with active SLE; other organs are affected infrequently. Trial outcome measures could focus on measuring change in these systems and omit detailed analysis of rare events. Conversely, some patients with active disease in common domains would be ineligible for clinical trials based on an SLEDAI-2K <6. Use of organ-specific activity measures and inclusion criteria may overcome this limitation.

ObjectiveDisease activity both between and within patients with SLE is highly variable, yet factors driving this variability remain unclear. This study aimed to identify predictors of variability in SLE disease activity over time.MethodsWe analysed data from 2930 patients with SLE across 13 countries, collected over 38 754 clinic visits between 2013 and 2020. Clinic visit records were converted to panel data with 1-year intervals. The time-adjusted mean disease activity, termed AMS, was calculated. The yearly change in AMS , denoted as ΔAMSt , was regressed onto AMSt−1 and other potential predictors using random-effects models. Some variables were split into a person-mean component to assess between-patient differences and a demeaned component to assess within-patient variability.ResultsOverall, variability in SLE disease activity exhibited stabilisation over time. A significant inverse relationship emerged between a patient’s disease activity in a given year and variability in disease activity in the subsequent year: a 1-point increase in person-mean disease activity was associated with a 0.27-point decrease (95% CI −0.29 to –0.26, p<0.001) in subsequent variability. Additionally, a 1-point increase in within-patient disease activity variability was associated with a 0.56-point decrease (95% CI −0.57 to –0.55, p<0.001) in the subsequent year. Furthermore, each 1-point increase in the annual average time-adjusted mean Physician Global Assessment was associated with a 0.08-point decrease (90% CI −0.13 to –0.03, p=0.002) in disease activity variability for the following year. Prednisolone dose and the duration of activity in specific organ systems exhibited negative and positive associations, respectively, with disease activity variability in the subsequent year. Patients from less affluent countries displayed greater disease activity variability compared with those from wealthier nations.ConclusionDisease activity tends to be less variable among patients with higher or more variable disease activity in the previous year. Within-patient variability in disease activity has a stronger impact on subsequent fluctuations than differences between individual patients.

BackgroundThis study examines the association of standard-of-care systemic lupus erythematosus (SLE) medications with key outcomes such as low disease activity attainment, flares, damage accrual, and steroid-sparing, for which there is current paucity of data.MethodsThe Asia Pacific Lupus Collaboration (APLC) prospectively collects data across numerous sites regarding demographic and disease characteristics, medication use, and lupus outcomes. Using propensity score methods and panel logistic regression models, we determined the association between lupus medications and outcomes.ResultsAmong 1707 patients followed over 12,689 visits for a median of 2.19 years, 1332 (78.03%) patients achieved the Lupus Low Disease Activity State (LLDAS), 976 (57.18%) experienced flares, and on most visits patients were taking an anti-malarial (69.86%) or immunosuppressive drug (76.37%). Prednisolone, hydroxychloroquine and azathioprine were utilised with similar frequency across all organ domains; methotrexate for musculoskeletal activity. There were differences in medication utilisation between countries, with hydroxychloroquine less frequently, and calcineurin inhibitors more frequently, used in Japan. More patients taking leflunomide, methotrexate, chloroquine/hydroxychloroquine, azathioprine, and mycophenolate mofetil/mycophenolic acid were taking ≤ 7.5 mg/day of prednisolone (compared to > 7.5 mg/day) suggesting a steroid-sparing effect. Patients taking tacrolimus were more likely (Odds Ratio [95% Confidence Interval] 13.58 [2.23–82.78], p = 0.005) to attain LLDAS. Patients taking azathioprine (OR 0.67 [0.53–0.86], p = 0.001) and methotrexate (OR 0.68 [0.47–0.98], p = 0.038) were less likely to attain LLDAS. Patients taking mycophenolate mofetil were less likely to experience a flare (OR 0.79 [0.64–0.97], p = 0.025). None of the drugs was associated with a reduction in damage accrual.ConclusionsThis study suggests a steroid-sparing benefit for most commonly used standard of care immunosuppressants used in SLE treatment, some of which were associated with an increased likelihood of attaining LLDAS, or reduced incidence of flares. It also highlights the unmet need for effective treatments in lupus.