Fragmentation landscape of cell-free DNA revealed by deconvolutional analysis of end motifs.

Cell-free DNA (cfDNA) fragmentation is nonrandom, at least partially mediated by various DNA nucleases, forming characteristic cfDNA end motifs. However, there is a paucity of tools for deciphering the relative contributions of cfDNA cleavage patterns related to underlying fragmentation factors. In this study, through non-negative matrix factorization algorithm, we used 256 5' 4-mer end motifs to identify distinct types of cfDNA cleavage patterns, referred to as "founder" end-motif profiles (F-profiles). F-profiles were associated with different DNA nucleases based on whether such patterns were disrupted in nuclease-knockout mouse models. Contributions of individual F-profiles in a cfDNA sample could be determined by deconvolutional analysis. We analyzed 93 murine cfDNA samples of different nuclease-deficient mice and identified six types of F-profiles. F-profiles I, II, and III were linked to deoxyribonuclease 1 like 3 (DNASE1L3), deoxyribonuclease 1 (DNASE1), and DNA fragmentation factor subunit beta (DFFB), respectively. We revealed that 42.9% of plasma cfDNA molecules were attributed to DNASE1L3-mediated fragmentation, whereas 43.4% of urinary cfDNA molecules involved DNASE1-mediated fragmentation. We further demonstrated that the relative contributions of F-profiles were useful to inform pathological states, such as autoimmune disorders and cancer. Among the six F-profiles, the use of F-profile I could inform the human patients with systemic lupus erythematosus. F-profile VI could be used to detect individuals with hepatocellular carcinoma, with an area under the receiver operating characteristic curve of 0.97. F-profile VI was more prominent in patients with nasopharyngeal carcinoma undergoing chemoradiotherapy. We proposed that this profile might be related to oxidative stress.

Fragmentomics of urinary cell-free DNA in nuclease knockout mouse models.

Urinary cell-free DNA (ucfDNA) is a potential biomarker for bladder cancer detection. However, the biological characteristics of ucfDNA are not well understood. We explored the roles of deoxyribonuclease 1 (DNASE1) and deoxyribonuclease 1-like 3 (DNASE1L3) in the fragmentation of ucfDNA using mouse models. The deletion of Dnase1 in mice (Dnase1-/-) caused aberrations in ucfDNA fragmentation, including a 24-fold increase in DNA concentration, and a 3-fold enrichment of long DNA molecules, with a relative decrease of fragments with thymine ends and reduction of jaggedness (i.e., the presence of single-stranded protruding ends). In contrast, such changes were not observed in mice with Dnase1l3 deletion (Dnase1l3-/-). These results suggested that DNASE1 was an important nuclease contributing to the ucfDNA fragmentation. Western blot analysis revealed that the concentration of DNASE1 protein was higher in urine than DNASE1L3. The native-polyacrylamide gel electrophoresis zymogram showed that DNASE1 activity in urine was higher than that in plasma. Furthermore, the proportion of ucfDNA fragment ends within DNase I hypersensitive sites (DHSs) was significantly increased in Dnase1-deficient mice. In humans, patients with bladder cancer had lower proportions of ucfDNA fragment ends within the DHSs when compared with participants without bladder cancer. The area under the curve (AUC) for differentiating patients with and without bladder cancer was 0.83, suggesting the analysis of ucfDNA fragmentation in the DHSs may have potential for bladder cancer detection. This work revealed the intrinsic links between the nucleases in urine and ucfDNA fragmentomics.

Evaluation of a multidisciplinary care model to improve quality of life in rheumatoid arthritis: a randomised controlled trial.

BACKGROUND AND PURPOSE: Health-Related Quality of Life (HR-QOL) is an important patient-reported domain in patients with rheumatoid arthritis (RA). The uptake of multidisciplinary team (MDT) care in RA is generally low, due to initial high demand for resources. We hypothesised that whilst pharmacological treatments are effective in controlling disease activity, a multipronged intervention in an MDT may have a positive impact on HR-QOL. METHODS: This was a single-centre randomized parallel group, single-blind controlled trial of MDT vs. usual care in an established RA clinic. Data were collected through face-to-face questionnaires, medical records review, and joint counts by a blinded assessor at 0, 3 and 6 months. Adult RA patients were randomly assigned in a single visit to a 6-member MDT (rheumatologist, nurse, social worker, physiotherapist, occupational therapist, and podiatrist) or usual care. MDT providers prescribed medications and counselled patients on managing flares, medication adherence, coping, joint protection, exercise, footwear. The primary outcome was minimal clinically important difference (MCID) in HR-QOL (increase in European QOL-5-Dimension-3-Level, EQ-5D-3L by 0.1) at six months. RESULTS: 140 patients (86.3% female, 53.4% Chinese, median (IQR) age 56.6 (46.7, 62.4) years); 70 were randomized to each arm. Median (IQR) disease duration was 5.5 (2.4, 11.0) years and disease activity in 28 joints (DAS28) was 2.87 (2.08, 3.66). 123 patients completed the study. Twenty-six (40.6%) MDT vs. 23 (34.3%) usual care patients achieved an MCID in EQ-5D-3L, OR 1.3 (0.6, 2.7). In multivariable logistic regression, baseline EQ-5D-3L was the only predictor of achieving MCID. There was more disease modifying anti-rheumatic drug escalation in MDT (34.4% vs. 19.4%). Patients with high disease activity were more likely to achieve MCID in the MDT arm. CONCLUSIONS: A single visit by stable patients with low disease activity to an MDT failed to achieve MCID in the EQ-5D-3L; however, did achieve small but significant improvements in the EQ-5D-3L, DAS28, pain, coping and self-efficacy. To be sustainable, MDT care should be targeted at patients with high disease activity or those with a new diagnosis of RA. TRIAL REGISTRATION: The study is registered on ClinicalTrials.gov, identifier: NCT03099668.

Burden and management of gout in a multi-ethnic Asian cohort.

Gout has significant impact on the quality of life with over-utilisation of health resources. While lowering serum urate (SU) to ≤ 360 µmol/L improves clinical outcomes, this is usually not achieved. We describe the burden of gout and determine predictors of achieving SU target in gout patients in Singapore. This was a cross-sectional study of 282 gout patients from a Singapore hospital rheumatology service. Sociodemographic and lifestyle factors, co-existing medical conditions and medications, gout history and severity, SU levels and treatment were obtained. Patients with SU ≤ 360 µmol/L were compared with those > 360 µmol/L to determine factors associated with achieving SU target. Descriptive statistics and multivariate model were used. Severe disease was reported in 50%, with emergency attendances and hospitalisations in 33% and 19% respectively, and unemployment in 32%. Only 22% were at SU target and 67% on urate-lowering therapy (ULT) at recruitment. Hypertension, dyslipidaemia, chronic kidney disease and diabetes were prevalent in 56.7%, 48.2%, 32.3% and 18.8%, respectively. Malays had more comorbidities compared to Chinese participants. In multivariate analysis, ULT prescription and ≥ 2 comorbidities were associated with reaching SU target with odds ratios of 3.92 [95% confidence interval (CI) (1.75-8.71)] and 2.65 [95% CI (1.59-4.43)] respectively, independent of age, tophi, disease duration, body mass index, alcohol and diuretic use. Patients with gout have high disease burden resulting in significant healthcare utilisation. SU control is sub-optimal hence the use of ULT remains key in achieving SU target. Patients with other comorbidities are more likely to reach target than those with only gout as a single diagnosis.

Transmission of H7N9 Influenza Viruses with a Polymorphism at PB2 Residue 627 in Chickens and Ferrets.

UNLABELLED: Poultry exposure is a major risk factor for human H7N9 zoonotic infections, for which the mode of transmission remains unclear. We studied the transmission of genetically related poultry and human H7N9 influenza viruses differing by four amino acids, including the host determinant PB2 residue 627. A/Silkie chicken/HK/1772/2014 (SCk1772) and A/HK/3263/14 (HK3263) replicated to comparable titers in chickens, with superior oropharyngeal over cloacal shedding; both viruses transmitted efficiently among chickens via direct contact but inefficiently via the airborne route. Interspecies transmission via the airborne route was observed for ferrets exposed to the SCk1772- or HK3263-infected chickens, while low numbers of copies of influenza viral genome were detected in the air, predominantly at particle sizes larger than 4 µm. In ferrets, the human isolate HK3263 replicated to higher titers and transmitted more efficiently via direct contact than SCk1772. We monitored "intrahost" and "interhost" adaptive changes at PB2 residue 627 during infection and transmission of the Sck1772 that carried E627 and HK3263 that carried V/K/E polymorphism at 60%, 20%, and 20%, respectively. For SCk1772, positive selection for K627 over E627 was observed in ferrets during the chicken-to-ferret or ferret-to-ferret transmission. For HK3263 that contained V/K/E polymorphism, mixed V627 and E627 genotypes were transmitted among chickens while either V627 or K627 was transmitted to ferrets with a narrow transmission bottleneck. Overall, our results suggest direct contact as the main mode for H7N9 transmission and identify the PB2-V627 genotype with uncompromised fitness and transmissibility in both avian and mammalian species. IMPORTANCE: We studied the modes of H7N9 transmission, as this information is crucial for developing effective control measures for prevention. Using chicken (SCk1772) and human (HK3263) H7N9 isolates that differed by four amino acids, including the host determinant PB2 residue 627, we observed that both viruses transmitted efficiently among chickens via direct contact but inefficiently via the airborne route. Chicken-to-ferret transmission via the airborne route was observed, along with the detection of viral genome in the air at low copy numbers. In ferrets, HK3263 transmitted more efficiently than SCk1772 via direct contact. During the transmission of SCk1772 that contained E and HK3263 that contained V/K/E polymorphism at PB2 residue 627, positive selections of E627 and K627 were observed in chickens and ferrets, respectively. In addition, PB2-V627 was transmitted and stably maintained in both avian and mammalian species. Our results support applying intervention strategies that minimize direct and indirect contact at the poultry markets during epidemics.

Prevalence of comorbidities and evaluation of their screening in spondyloarthritis: results of the international cross-sectional ASAS-COMOSPA study.

BACKGROUND: Increased risk of some comorbidities has been reported in spondyloarthritis (SpA). Recommendations for detection/management of some of these comorbidities have been proposed, and it is known that a gap exists between these and their implementation in practice. OBJECTIVE: To evaluate (1) the prevalence of comorbidities and risk factors in different countries worldwide, (2) the gap between available recommendations and daily practice for management of these comorbidities and (3) the prevalence of previously unknown risk factors detected as a result of the present initiative. METHODS: Cross-sectional international study with 22 participating countries (from four continents), including 3984 patients with SpA according to the rheumatologist. STATISTICAL ANALYSIS: The prevalence of comorbidities (cardiovascular, infection, cancer, osteoporosis and gastrointestinal) and risk factors; percentage of patients optimally monitored for comorbidities according to available recommendations and percentage of patients for whom a risk factor was detected due to this study. RESULTS: The most frequent comorbidities were osteoporosis (13%) and gastroduodenal ulcer (11%). The most frequent risk factors were hypertension (34%), smoking (29%) and hypercholesterolaemia (27%). Substantial intercountry variability was observed for screening of comorbidities (eg, for LDL cholesterol measurement: from 8% (Taiwan) to 98% (Germany)). Systematic evaluation (eg, blood pressure (BP), cholesterol) during this study unveiled previously unknown risk factors (eg, elevated BP (14%)), emphasising the suboptimal monitoring of comorbidities. CONCLUSIONS: A high prevalence of comorbidities in SpA has been shown. Rigorous application of systematic evaluation of comorbidities may permit earlier detection, which may ultimately result in an improved outcome of patients with SpA.

Health-related quality of life and its predictors among patients with rheumatoid arthritis.

BACKGROUND: Limited studies have examined the predictors of HRQoL among patients with rheumatoid arthritis. This study helped to ascertain the predictors of HRQoL from the pool of influencing factors identified by previous studies. AIM: This study investigated the health-related quality of life (HRQoL) of adult patients with rheumatoid arthritis and its predictors. METHODS: Using a descriptive correlational design, this study explored the relationship between HRQoL and pain, functional disability, anxiety, depression, medication adherence and social support. Eligible outpatients (n=108) were recruited via their attending doctors who were co-investigators of this study. Informed consent forms were distributed and questionnaires administered in a teaching hub by the main researcher. RESULTS: Significant correlations were found between HRQoL and all of the study variables. Pain, functional disability and depression were main predictors of HRQoL. CONCLUSIONS: Future evidence-based interventions focusing on pain relief, delaying disability or improving functional ability and reducing depressive symptoms are required to enhance the HRQoL of patients with rheumatoid arthritis.

A randomized controlled trial for improving patient self-assessment of synovitis in rheumatoid arthritis with education by ultrasonography: the RAEUS Study.

OBJECTIVE: Patients can potentially monitor disease activity of RA through self-assessed swollen joints (clinical synovitis), but reliability is poor. The objective is to evaluate the use of education by US feedback on the ability of patients to assess for clinical synovitis in RA. METHODS: We performed a 6 month, single-centre, randomized controlled trial on patients with established RA to study the effect of education on self-assessment of joints that included initial brief patient training on tender (TJC) and swollen (SJC) joint counts followed by US feedback every 3 months vs standard care without education. Patient and physician independently performed 28-joint counts at each visit. Outcome variables included the percentage of patients with good agreement with physician-derived swollen joints [prevalence-adjusted bias-adjusted kappa (PABAK) >0.6] as well as agreement in the SJC (Bland and Altman 95% limits of agreement), feasibility/patient satisfaction survey and disease activity at 6 months. RESULTS: Of the 101 randomized patients, 95 were included (51 in the education arm and 44 in the standard care arm). At 6 months there was a significant difference in the proportion of patients with swollen joint PABAK >0.6 in the education arm compared with standard care (98 vs 85%, P = 0.02). Limits of agreement for the SJC difference between physician and patients were reduced only in the education arm. The training method is considered feasible, with 94% of patients reporting it as useful. A trend of higher rates of disease remission (28-joint DAS <2.6) in the education arm vs standard care (47% vs 29%, P = 0.07) was seen. CONCLUSION: A short course of education with US feedback may be helpful in educating patients to assess for clinical synovitis. TRIAL REGISTRATION: Clinical trials.gov, https://clinicaltrials.gov, NCT02351401.

Disabling foot pain and its impact on daily living among people with psoriatic arthritis in Singapore: a cross-sectional observational investigation.

BACKGROUND: Psoriatic Arthritis (PsA)-related foot involvement has been shown to have a profound impact on daily functioning, with most studies having focused on predominantly Caucasian populations. The aim was to describe disabling foot pain (DFP) and its impact on daily living in PsA in Singapore. METHODS: A cross-sectional, retrospective study was conducted using clinical data collected during a single-visit to a rheumatology clinic in Singapore. Records for adults with physician-diagnosed PsA were reviewed for sociodemographic information, disease characteristics, global disease activity and burden. Foot-specific measures included clinical assessment and the Manchester Foot Pain and Disability Index used to define DFP and evaluate between-group differences. RESULTS: Forty-two participants with PsA (83% female, 57% Chinese, 31% Malay, 9.5% Indian, mean (SD) age 54-years (16)) attended the rheumatology clinic over the study-period. The median (IQR) disease duration was 2-years (11) and all were taking current DMARDs. Global disease measures demonstrated mild-to-moderate global disease activity and mild functional impairment, and were significantly higher in those with DFP. Despite 90% reporting to be coping well with their condition, self-care and having emotional support (n = 38), this study sample demonstrated high levels of anxiety/depression (29%), sleep disturbance (34%) and fatigue (24%), and a lack of disease- and drug-specific knowledge (64%). Further management was indicated for medication adherence counselling (48%), occupational therapy (43%), physiotherapy (36%) and podiatry (30%). Nearly half had current foot pain with 40% reporting DFP (n = 17), which caused significantly greater difficulty walking 3 km than those without DFP (p < 0.05). Rearfoot enthesitis (plantar fasciitis, Achilles enthesitis) was the most common cause of DFP (67%) with pain lasting longer than 1-year. 72% were overweight or obese, with a high proportion not engaging in any cardiovascular exercise (70%). Three of 42 participants had previously seen a podiatrist. CONCLUSIONS: People with DFP in PsA experience more severe global disease activity, reduced mobility and higher levels of negative impact on their daily lives in Singapore. In the absence of working in a multidisciplinary-team, there is value in comprehensive assessments that have potential to capture a holistic view of personal impact and improve person-centred care in PsA.

Comparable fitness and transmissibility between oseltamivir-resistant pandemic 2009 and seasonal H1N1 influenza viruses with the H275Y neuraminidase mutation.

Limited antiviral compounds are available for the control of influenza, and the emergence of resistant variants would further narrow the options for defense. The H275Y neuraminidase (NA) mutation, which confers resistance to oseltamivir carboxylate, has been identified among the seasonal H1N1 and 2009 pandemic influenza viruses; however, those H275Y resistant variants demonstrated distinct epidemiological outcomes in humans. Specifically, dominance of the H275Y variant over the oseltamivir-sensitive viruses was only reported for a seasonal H1N1 variant during 2008-2009. Here, we systematically analyze the effect of the H275Y NA mutation on viral fitness and transmissibility of A(H1N1)pdm09 and seasonal H1N1 influenza viruses. The NA genes from A(H1N1)pdm09 A/California/04/09 (CA04), seasonal H1N1 A/New Caledonia/20/1999 (NewCal), and A/Brisbane/59/2007 (Brisbane) were individually introduced into the genetic background of CA04. The H275Y mutation led to reduced NA enzyme activity, an increased K(m) for 3'-sialylactose or 6'-sialylactose, and decreased infectivity in mucin-secreting human airway epithelial cells compared to the oseltamivir-sensitive wild-type counterparts. Attenuated pathogenicity in both RG-CA04(NA-H275Y) and RG-CA04 × Brisbane(NA-H275Y) viruses was observed in ferrets compared to RG-CA04 virus, although the transmissibility was minimally affected. In parallel experiments using recombinant Brisbane viruses differing by hemagglutinin and NA, comparable direct contact and respiratory droplet transmissibilities were observed among RG-NewCal(HA,NA), RG-NewCal(HA,NA-H275Y), RG-Brisbane(HA,NA-H275Y), and RG-NewCal(HA) × Brisbane(NA-H275Y) viruses. Our results demonstrate that, despite the H275Y mutation leading to a minor reduction in viral fitness, the transmission potentials of three different antigenic strains carrying this mutation were comparable in the naïve ferret model.

The relationship of patient-reported joints with active synovitis detected by power Doppler ultrasonography in rheumatoid arthritis.

OBJECTIVES: This paper aims to evaluate the relationship of patient-reported tender and swollen joints with active inflammation as detected by power Doppler (PDUS) and whether this relationship is affected by significant joint damage. METHODS: Fifty rheumatoid arthritis patients self-assessed 28 tender and swollen joints and were followed by PDUS assessment. Relationship of tender and swollen joints with active synovitis (PDUS 'gold standard') was assessed at the joint level by: a) percentage agreement at each PDUS semiquantitative grade (grade 1 to 3), b) positive likelihood ratio (LR) of agreement with PDUS, and c) LR of agreement with PDUS according to radiographic damage (significant erosive disease vs. non-erosive disease). Correlation of tender and swollen joint counts with disease activity markers was analysed by Spearman's. Sensitivity analyses examined the influence of disease activity or global pain on level of agreement at the joint level. RESULTS: Of joints with significant active inflammation (e.g. grade 3 PDUS), patients identified 75% as tender and 63% as swollen. Swollen joints showed strong association at the joint level with active synovitis when there was no significant radiographic damage (LR 2.54, 95%CI 1.93-3.34), but with no significant radiographic damage (LR 1.32, 95%CI 0.75-2.32). Swollen joint counts were statistically correlated with PDUS-DAS28 and CRP, but not PDUS score. Sensitivity analysis showed better agreement of tender and swollen joints with active synovitis when DAS28 was ≤ 3.2 and when patient global pain was <50mm on visual analogue scale. CONCLUSIONS: The relationship between patient-reported joints and active synovitis is stronger in the setting of low disease activity without erosive disease, affected also by degree of reported global pain. Further longitudinal studies of patient-reported joints are needed.

Attitudes and Behaviors of Patients With Rheumatic Diseases During the Early Stages of the COVID-19 Outbreak.

OBJECTIVE: To evaluate attitudes and behaviors of patients with rheumatic diseases during the coronavirus disease 2019 (COVID-19) pandemic. METHODS: An online survey delivered by text message to 4695 patients on follow-up at a tertiary rheumatology center. Latent class analysis was performed on the survey variables. RESULTS: There were 2239 (47.7%) who responded to the survey and 3 clusters were identified. Cluster 3 (C3) was defined by patients who were most worried about COVID-19, more likely to wear face masks, and more likely to alter or stop their medications. Patients in C3 were more likely to be female, Malay, and unemployed. CONCLUSION: We identified 3 clusters with different healthcare beliefs and distinct sociodemographics.

An evaluation of the effectiveness of teaching anatomy to rheumatologists through combined musculoskeletal sonoanatomy and human cadaveric dissection.

OBJECTIVE: Our aim was to evaluate the effectiveness of teaching anatomy through combined musculoskeletal sonoanatomy and human cadaveric dissection for rheumatologists practising musculoskeletal US. METHODS: The principal focus was on scanning and then dissecting relevant musculoskeletal structures. Outcomes measured included confidence levels and objective knowledge. A mixed-methods approach of evaluation and descriptive statistical data analysis was performed. RESULTS: The change in confidence ratings by delegates after the teaching event as represented by the mean difference (s.d.) (s.e.m.) for identification of surface anatomy was 1.846 (1.281) (0.355), with Student's paired t = 5.196 and P=0.000223. The mean difference (s.d.) (s.e.m) for performing IA injections was 1.538 (1.266) (0.351), with Student's paired t = 4.382, P=0.001, and for recognizing sonoanatomical structures it was 1.769 (1.235) (0.343), with Student's paired t = 5.165 and P= 0.000235. There was a significant increase in correct identification of anatomical and sonoanatomical knowledge in the pre- and post-course assessments. Rotator cuff interval region improved from 13 to 73%, P = 0.004; knee tendons insertion sites from 47 to 93%, P = 0.016; and muscles not adjacent to joints from 27 to 93%, P = 0.002. CONCLUSION: Dissection of joints enabled a three-dimensional relational mind map of the relevant regions of the human body, producing clarity in understanding regional relational topographic anatomy and sonoanatomy. The combination of US and cadaveric dissection improved learners' satisfaction, confidence and knowledge in areas where soft tissue complaints are common, which is likely to lead to accurate early diagnosis and cost-conscious, better overall care.

Sociodemographic factors as determinants of disease, disability and quality of life trajectories in early rheumatoid arthritis: A multi-ethnic inception cohort study.

OBJECTIVE: This study aims to describe the association between sociodemographic factors and trajectories of disease, disability and health-related quality of life (HRQoL) in early rheumatoid arthritis (ERA). METHODS: Data were collected prospectively over 3 years in the Singapore Early Arthritis Cohort study. Trajectories were modeled using multi-trajectory group-based trajectory modeling (GBTM) and determinants of trajectory membership were identified using multinomial logistic regression. RESULTS: Two hundred and thirteen patients were included: 58.2% Chinese, 16.4% Malay, 21.6% Indian, mean (SD) age 51.3 (12.6) years and symptom duration 21.8 (15.3) weeks. In the multi-trajectory analysis, three groups of disease trajectories and corresponding disability and HRQoL trajectories were identified: group 1 (moderate disease rapid response, 49.9%), group 2 (high disease rapid response, 31.1%) and group 3 (high disease slow response, 19.1%). Malay patients had higher relative risk ratio (RRR) of being in trajectory groups 2 and 3 compared to group 1 (RRR = 2.30, 95% CI 1.05-3.98 and RRR = 4.02, 95% CI 1.45-6.43, respectively) while patients with tertiary education had lower relative risk (RRR = 0.56, 95% CI 0.45-0.89 and RRR = 0.33, (95% CI 0.14-0.83, respectively). In the analysis of individual outcomes, ethnicity, education level and body mass index were determinants of the heterogeneous disease activity trajectories. Gender and education level were determinants of the disability trajectories. Only gender was a determinant of the HRQoL trajectories. Further, 96.2% of the patients were treated with conventional synthetic disease-modifying antirheumatic drugs. CONCLUSION: Disparities in sociodemographic factors should be taken into consideration in formulating treatment strategies in ERA.

Singapore chapter of rheumatologists' updated consensus statement on the eligibility for government subsidization of biologic and targeted therapy for the treatment of psoriatic arthritis.

AIM: There have been major advances in biologic treatment options for psoriatic arthritis (PsA) since the publication of the 2015 consensus recommendations by the Chapter of Rheumatologists, College of Physicians, Academy of Medicine, Singapore, for government-assisted funding, thus warranting a revision of this guideline. METHODS: Recent trials and nine published guidelines on the use of biologic therapy for PsA were reviewed. Based on the synthesized evidence, a task force panel (TFP), consisting of 10 practicing rheumatologists in Singapore, rated the statements pertaining to the use of biologic therapy, using a modified Delphi approach. Consensus was obtained if >70% agreed on a statement. RESULTS: The TFP agreed on 10 recommendations pertaining to the initiation, choice and continuation of biologic therapy. A biologic is indicated in patients with PsA: (a) with at least three swollen and tender joints, digits or entheses; and (b) who have failed at least two conventional synthetic disease-modifying anti-rheumatic drug (csDMARD) strategies for a minimum of 3 months each. Any approved drug class including tumor necrosis factor inhibitors, interleukin-17 inhibitors (IL-17i), IL-12/23i or targeted synthetic DMARDs may be considered as first-line treatment, and continued only if a response is achieved by 6 months. CONCLUSION: These recommendations developed through a formal consensus method may be useful to guide funding considerations for appropriate and equitable use of biologic therapy for eligible patients with PsA.

Update on recommendations for eligibility of government subsidization of biologic disease-modifying antirheumatic drugs for the treatment of axial spondyloarthritis in Singapore.

AIMS: The field of axial spondyloarthritis (axSpA) has undergone significant changes recently in particular with disease classification, assessment of disease activity and increased treatment options for biologics. In order to reflect these developments, we aimed to update the local consensus recommendations for subsidization of biologics. METHODS: A modified Delphi approach was used. Six published guidelines from major rheumatology societies and healthcare authorities on axSpA were reviewed. Findings were synthesized and used in formulating updated recommendation statements. Recommendations were rated by 10 practicing rheumatologists in Singapore. Consensus was reached if there was more than 70% agreement or disagreement. RESULTS: Ten statements achieved consensus. Patients may be considered for subsidization of biologic therapy if they fulfill the Assessment of Spondyloarthritis International Society or modified New York criteria, with persistently active disease (defined either by Ankylosing Spondylitis Disease Activity Score ≥ 2.1 or Bath Spondylitis Disease Activity Index ≥ 4), despite 4 weeks of full-dose non-steroidal anti-inflammatory drugs and regular exercise. Either tumor necrosis factor inhibitors or interleukin 17 inhibitors may be used as first-line therapy, and should be continued if adequate response is achieved at 6 months. CONCLUSION: Recommendation statements were formulated through a formal consensus process by local experts with a view to assist relevant authorities in funding considerations and for use in clinical practice.

Singapore Chapter of Rheumatologists updated consensus statement on the eligibility for government subsidization of biologic and targeted-synthetic therapy for the treatment of rheumatoid arthritis.

INTRODUCTION: Approximately 30% of patients with rheumatoid arthritis (RA) respond inadequately to conventional-synthetic disease-modifying anti-rheumatic drugs (csDMARDs). However, widespread use of biologic DMARDs (bDMARDs) and targeted-synthetic (tsDMARDs) is limited by cost. We formulated updated recommendations for eligibility criteria for government-assisted funding of bDMARDs/tsDMARDs for RA patients in Singapore. MATERIALS AND METHODS: Published guidelines regarding use of bDMARD and tsDMARDs were reviewed. We excluded those without a systematic literature review, formal consensus process or evidence grading. Separately, unpublished national reimbursement guidelines were included. RESULTS: Eleven recommendations regarding choice of disease activity measure, initiation, order of selection and continuation of bDMARD/tsDMARDs were formulated. A bDMARD/tsDMARD is indicated if a patient has: (a) at least moderately active RA with a Disease Activity Score in 28 joints/erythrocyte sedimentation rate (DAS28-ESR) score of ≥3.2; (b) failed ≥2 csDMARD strategies, 1 of which must be a combination; (c) received an adequate dose regimen of ≥3 months for each strategy. For the first-line bDMARD/tsDMARD, either tumor necrosis factor inhibitors (TNFi), non-TNFi (abatacept, tocilizumab, rituximab), or tsDMARDs, may be considered. If a first-line TNFi fails, options include another TNFi, non-TNFi biologic or tsDMARDs. If a first-line non-TNFi biologic or tsDMARD fails, options include TNFi or another non-TNF biologic or tsDMARD. For continued bDMARD/tsDMARD subsidization, a patient must have a documented DAS28-ESR every 3 months and at least a moderate European League Against Rheumatism response by 6 months. CONCLUSION: These recommendations are useful for guiding funding decisions, making bDMARD/tsDMARDs usage accessible and equitable in RA patients who fail csDMARDs.

A cross-sectional study on factors associated with poor work outcomes in patients with axial spondyloarthritis in Singapore.

AIM: Axial spondyloarthritis (axSpA) affects patients in the prime of their economic productivity. We aim to identify factors associated with poor work productivity in patients with axSpA in Singapore. METHODS: A cross-sectional study was performed in two tertiary centers in Singapore. Consecutive adult patients ≥21 years fulfilling Assessment in Spondyloarthritis International Society (ASAS) 2009 criteria for axSpA were recruited. Data on social demographics, clinical, treatment modalities and patient-reported outcome measures (PROMs) were collected. Work productivity was assessed by the Work Productivity and Activity Impairment scale (WPAI:SpA). Factors associated with presenteeism, absenteeism, work productivity loss and activity impairment were evaluated. RESULTS: A total of 156 patients with axSpA were included: 72.4% employed, 80.1% male, 86.5% Chinese, median (Q1:Q3) age and duration of illness 36.7 (28.7:47.9) years, and 6.3 (1.6:12.2) years respectively. The mean (SD) activity impairment was 28.2% (24.3%). Among employed patients, mean (SD) absenteeism, presenteeism and work productivity loss was 4.5% (13.7%), 24.9% (19.9%) and 27.6% (23.2%), respectively. In multivariable analysis, absenteeism was associated with disease duration (P = .02) and EuroQol-5D (EQ-5D) (P = .04). Presenteeism was associated with Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) ≥4 (P = .04), Bath Ankylosing Spondylitis Functional Index (BASFI) (P < .01) and EQ-5D (P = .02). Work productivity loss was associated with BASFI (P = .02) and EQ-5D (P < .01). Activity impairment was associated with age (P = .04), BASDAI ≥ 4 (P < .01), BASFI (P < .01), EQ-5D (P < .01). CONCLUSION: Active disease, reduced physical function and poorer quality of life are associated with reduced work productivity in patients with axSpA in Singapore. Addressing these factors can potentially improve work productivity in patients with axSpA.

Predicting flares in patients with stable systemic lupus erythematosus.

OBJECTIVES: Data on flares in Asian patients with systemic lupus erythematosus (SLE) are scarce. Here, we aim to identify the baseline predictors of flares in a cohort of Southeast Asian patients with SLE. METHODS: Consecutive adult patients with prevalent SLE according to the 1997 ACR or 2012 SLICC criteria were enrolled and followed three-monthly. Clinical and laboratory data were collected at every visit using a standardised protocol. Flares were defined using the SELENA-SLEDAI Flare Index (SFI). Baseline predictors of flare in patients with stable disease (SLE Disease Activity Index-2K (SLEDAI-2K) of ≤ 4) were determined using Cox proportional hazards. RESULTS: Of the 210 patients recruited, 148 (70.5%) were Chinese. The median (IQR) SLEDAI-2K at entry was 2 (0-4) and the median (IQR) disease duration was 10 (4.4-16.4) years. At baseline, 152 (72.4%) patients had stable disease. After a median (IQR) follow-up of 31.5 (24.1-36.3) months, 109 (51.9%) flared. Stable patients who flared tended to be in the lowest tertile of age (HR 3.08, 95% CI 1.72-5.48, p < 0.01), had thrombocytopenia (HR 5.01, 95% CI 1.32-18.99, p = 0.02), hypocomplementemia (HR 3.35, 95% CI 1.54-7.30, p < 0.01) and had the highest baseline prednisolone doses (HR 2.39, 95% CI 1.28-4.46, p = 0.01). Conversely, patients in the lowest tertile of disease duration tended not to flare (HR 0.41, 95% CI 0.21-0.80, p = 0.01). CONCLUSION: Flares are common in Asian SLE patients with initial stable disease. Close monitoring is needed for patients who are younger, with longer disease duration, thrombocytopenia, hypocomplementemia, or who required a higher baseline prednisolone dose.