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Objectives: The English version of the Systemic Lupus Erythematosus Quality of Life Questionnaire (SLEQOL) is a validated disease-specific quality of life instrument. The aim of this study was to evaluate the psychometric properties of the Thai version of the SLEQOL (SLEQOL-TH). Methods: Two independent translators translated the SLEQOL into Thai. The back translation of this version was performed by two other independent translators. The final version, SLEQOL-TH, was completed after resolving the discrepancies revealed by the back translation. One hundred and nine patients with SLE were enrolled to test the reliability, construct validity, floor and ceiling effects, and sensitivity to the changes of the SLEQOL-TH at six months. The differential item functioning (DIF) between the Thai and English versions was analyzed using the partial gamma. Results: The internal consistency of the SLEQOL-TH was satisfactory with the overall Cronbach's alpha of 0.86. The test-retest reliability of the SLEQOL-TH was acceptable with the intra-class correlation coefficient of 0.86. Low correlations between the SLEQOL-TH and SLEDAI were observed. The total score of the SLEQOLTH was moderately responsive to changes in quality of life, with a standardized response mean of 0.50. When comparing the SLEQOL-TH from Thai SLE patients with the original SLEQOL version obtained from Singapore SLE patients, 11 out of 40 items showed a moderate to large DIF. Conclusions: The SLEQOL-TH has acceptable psychometric properties and shows construct validity. In comparison with the English version of SLEQOL, there are some items that showed DIF. The applicability of the SLEQOL-TH in real-life clinical practice and clinical trials needs to be determined. [ABSTRACT FROM AUTHOR]

Cyclophosphamide is an important immunosuppressive agent in the treatment of many rheumatic diseases. Urticaria and anaphylaxis to intravenous cyclophosphamide (i.v. CYC) have been reported in patients with haematological and solid organ malignancies. This is the first report in the rheumatology literature of a type I hypersensitivity reaction following monthly i.v. CYC. An 18-year-old girl with systemic lupus erythematosus (SLE) developed generalized urticaria (without concomitant angioedema or anaphylaxis) following i.v. CYC. She had previously developed life-threatening angioedema following a respiratory tract infection. She successfully completed regular pulse i.v. CYC with pre-medication with anti-histamine. In the absence of a severe type I hypersensitivity reaction and other suitable immunosuppressive agents, i.v. CYC may be safely continued with pre-medication and careful monitoring during each infusion. [ABSTRACT FROM AUTHOR]

Antinuclear autoantibodies (ANA) are heterogeneous self-reactive antibodies that target the chromatin network, the speckled, the nucleoli, and other nuclear regions. The immunological aberration for ANA production remains partially understood, but ANA are known to be pathogenic, especially, in systemic lupus erythematosus (SLE). Most SLE patients exhibit a highly polygenic disease involving multiple organs, but in rare complement C1q, C1r, or C1s deficiencies, the disease can become largely monogenic. Increasing evidence point to intrinsic autoimmunogenicity of the nuclei. Necrotic cells release fragmented chromatins as nucleosomes and the alarmin HMGB1 is associated with the nucleosomes to activate TLRs and confer anti-chromatin autoimmunogenecity. In speckled regions, the major ANA targets Sm/RNP and SSA/Ro contain snRNAs that confer autoimmunogenecity to Sm/RNP and SSA/Ro antigens. Recently, three GAR/RGG-containing alarmins have been identified in the nucleolus that helps explain its high autoimmunogenicity. Interestingly, C1q binds to the nucleoli exposed by necrotic cells to cause protease C1r and C1s activation. C1s cleaves HMGB1 to inactive its alarmin activity. C1 proteases also degrade many nucleolar autoantigens including nucleolin, a major GAR/RGG-containing autoantigen and alarmin. It appears that the different nuclear regions are intrinsically autoimmunogenic by containing autoantigens and alarmins. However, the extracellular complement C1 complex function to dampen nuclear autoimmunogenecity by degrading these nuclear proteins., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Wu, Chen, Teo, Wee, Wong, Cui, Chen, Leong and Lu.)

Introduction: Rheumatoid factor (RF) and anti-cyclic citrullinated peptide antibody (ACPA) are used in the diagnosis and prognostication of rheumatoid arthritis (RA). We wanted to determine the specific contributions of RF and ACPA to the biological nature of RA and whether they act synergistically., Methods: We identified 731 patients from our prospective multi-ethnic RA cohort and categorised them into four groups: ACPA-positive, RF-positive, doubly positive and doubly negative. We compared the demographics, Disease Activity Score-28, Health Assessment Questionnaire score, quality of life using Short Form 36 and the use of prednisolone and disease-modifying antirheumatic drugs (DMARDs) of these patient groups., Results: Four hundred and ninety-one patients (67.2%) were ACPA+RF+, 54 (7.4%) were ACPA+RF-, 82 (11.2%) were ACPA-RF+ and 104 (14.2%) were ACPA-RF-. Mean disease duration before the study entry was not different in the four groups. Patients with older age of onset were less likely to be positive for RF and ACPA. Fewer ACPA+RF+ patients were in remission compared to those in the other groups (P < 0.05). Erythrocyte sedimentation rate (ESR) was higher at study entry in the ACPA+RF+ group (40.4 mm/h vs. 30.6-30.9 mm/h, P < 0.05). Prednisolone and number of DMARDs used were higher in the ACPA+RF+ group compared to the doubly negative group. There were no differences in the functional status and quality of life., Conclusions: RA patients who were positive for both ACPA and RF had lower remission rate, higher baseline ESR and required more corticosteroid and DMARD treatment compared to those who were singly positive or doubly negative. Being doubly positive confers a worse outcome to RA patients., Competing Interests: None

Genomic researchers increasingly utilize commercial cloud service providers (CSPs) to manage data and analytics needs. CSPs allow researchers to grow Information Technology (IT) infrastructure on demand to overcome bottlenecks when combining large datasets. However, without adequate security controls, the risk of unauthorized access may be higher for data stored on the cloud. Additionally, regulators are mandating data access patterns and specific security protocols for the storage and use of genomic data. While CSP provides tools for security and regulatory compliance, building the necessary controls required for cloud solutions is not trivial. Research Assets Provisioning and Tracking Online Repository (RAPTOR) by the Genome Institute of Singapore is a cloud-native genomics data repository and analytics platform that implements a "five-safes" framework to provide security and governance controls to data contributors and users, leveraging CSP for sharing and analysis of genomic datasets without the risk of security breaches or running afoul of regulations., Competing Interests: The authors declare no competing interests., (© 2023 The Author(s).)

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., (© 2023. The Author(s).)

Precision medicine promises to transform healthcare for groups and individuals through early disease detection, refining diagnoses and tailoring treatments. Analysis of large-scale genomic-phenotypic databases is a critical enabler of precision medicine. Although Asia is home to 60% of the world's population, many Asian ancestries are under-represented in existing databases, leading to missed opportunities for new discoveries, particularly for diseases most relevant for these populations. The Singapore National Precision Medicine initiative is a whole-of-government 10-year initiative aiming to generate precision medicine data of up to one million individuals, integrating genomic, lifestyle, health, social and environmental data. Beyond technologies, routine adoption of precision medicine in clinical practice requires social, ethical, legal and regulatory barriers to be addressed. Identifying driver use cases in which precision medicine results in standardized changes to clinical workflows or improvements in population health, coupled with health economic analysis to demonstrate value-based healthcare, is a vital prerequisite for responsible health system adoption., (© 2023. Springer Nature America, Inc.)

Asian populations are under-represented in human genomics research. Here, we characterize clinically significant genetic variation in 9051 genomes representing East Asian, South Asian, and severely under-represented Austronesian-speaking Southeast Asian ancestries. We observe disparate genetic risk burden attributable to ancestry-specific recurrent variants and identify individuals with variants specific to ancestries discordant to their self-reported ethnicity, mostly due to cryptic admixture. About 27% of severe recessive disorder genes with appreciable carrier frequencies in Asians are missed by carrier screening panels, and we estimate 0.5% Asian couples at-risk of having an affected child. Prevalence of medically-actionable variant carriers is 3.4% and a further 1.6% harbour variants with potential for pathogenic classification upon additional clinical/experimental evidence. We profile 23 pharmacogenes with high-confidence gene-drug associations and find 22.4% of Asians at-risk of Centers for Disease Control and Prevention Tier 1 genetic conditions concurrently harbour pharmacogenetic variants with actionable phenotypes, highlighting the benefits of pre-emptive pharmacogenomics. Our findings illuminate the diversity in genetic disease epidemiology and opportunities for precision medicine for a large, diverse Asian population., (© 2022. The Author(s).)

Objective: To develop a hypothesis-free model that best predicts response to MTX drug in RA patients utilizing biologically meaningful genetic feature selection of potentially functional single nucleotide polymorphisms (pfSNPs) through robust machine learning (ML) feature selection methods., Methods: MTX-treated RA patients with known response were divided in a 4:1 ratio into training and test sets. From the patients' exomes, potential features for classifier prediction were identified from pfSNPs and non-genetic factors through ML using recursive feature elimination with cross-validation incorporating the random forest classifier. Feature selection was repeated on random subsets of the training cohort, and consensus features were assembled into the final feature set. This feature set was evaluated for predictive potential using six ML classifiers, first by cross-validation within the training set, and finally by analysing its performance with the unseen test set., Results: The final feature set contains 56 pfSNPs and five non-genetic factors. The majority of these pfSNPs are located in pathways related to RA pathogenesis or MTX action and are predicted to modulate gene expression. When used for training in six ML classifiers, performance was good in both the training set (area under the curve: 0.855-0.916; sensitivity: 0.715-0.892; and specificity: 0.733-0.862) and the unseen test set (area under the curve: 0.751-0.826; sensitivity: 0.581-0.839; and specificity: 0.641-0.923)., Conclusion: Sensitive and specific predictors of MTX response in RA patients were identified in this study through a novel strategy combining biologically meaningful and machine learning feature selection and training. These predictors may facilitate better treatment decision-making in RA management., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Variants in thiopurine methyltransferase ( TPMT ) and nudix hydrolase 15 ( NUDT15 ) are associated with an accumulation of cytotoxic metabolites leading to increased risk of drug-related toxicity with standard doses of thiopurine drugs. We established TPMT and NUDT15 genetic testing for clinical use and evaluated the utilization, service outcomes and potential value of multi-gene PGx testing for 210 patients that underwent pharmacogenetics (PGx) testing for thiopurine therapy with the aim to optimize service delivery for future prescribing. The test was most commonly ordered for Gastroenterology (40.0%) and Neurology (31.4%), with an average turnaround time of 2 days. Following testing, 24.3% patients were identified as intermediate or poor metabolizers, resulting in 51 recommendations for a drug or dose change in thiopurine therapy, which were implemented in 28 (54.9%) patients. In the remaining patients, 14 were not adjusted and 9 had no data available. Focusing on drug gene interactions available for testing in our laboratory, multi-gene PGx results would present opportunities for treatment optimization for at least 33.8% of these patients who were on 2 or more concurrent medications with actionable PGx guidance. However, the use of PGx panel testing in clinical practice will require the development of guidelines and education as revealed by a survey with the test providers. The evaluation demonstrated successful implementation of single gene PGx testing and this experience guides the transition to a pre-emptive multi-gene testing approach that provides the opportunity to improve clinical care., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Goh, Lim, Leong and Ong.)

Considering the female preponderance of rheumatoid arthritis (RA), and disease onset typically after the reproductive years, pregnancy and childbirth may play a role in the aetiology of the disease. Adverse outcomes of pregnancy have been found to precede the diagnosis of autoimmune diseases, including RA, but the evidence is scant and inconsistent. Therefore, we investigate whether pregnancy loss is associated with the risk of RA in Chinese women. Data from the China Kadoorie Biobank, conducted by the University of Oxford and the Chinese Centre for Disease Control and Prevention, of 299,629 Chinese women who had been pregnant were used. Multivariable logistic regression and stratified analyses were employed to analyse the association between types of pregnancy loss with the risk of RA. Pregnancy loss was significantly associated with increased risk of RA (OR 1.12, 95% CI 1.06-1.18), specifically, spontaneous (OR 1.11, 95% CI 1.03-1.20) and induced abortions (OR 1.11, 95% CI 1.06-1.17). There was no significant association between stillbirth and the risk of RA (OR 1.07, 95% CI 0.97-1.18). The risk of developing RA increases with the number of pregnancy losses: one loss confers an OR of 1.09 (95% CI 1.03-1.16), two an OR of 1.13 (95% CI 1.05-1.20), three or more an OR of 1.19 (95% CI 1.10-1.28) and OR of 1.06 (95% CI 1.03-1.08) for each additional. Spontaneous and induced abortions are associated with an increased risk of RA in Chinese women., (© 2022. The Author(s).)

During the initial rollout of coronavirus disease 2019 (COVID-19) vaccination in Singapore, the Ministry of Health (MOH) issued a recommendation that patients with a history of any previous vaccine allergy be referred to an allergist for further review of their suitability to proceed with mRNA-based COVID-19 vaccines. Patients fulfilling the above criterion were divided into three groups: immediate reaction (Group A), delayed reaction (Group B) and no/irrelevant reaction (Group C). They were subjected to either a skin prick test (SPT) and intradermal test (IDT) with polyethylene glycol (PEG) or polysorbate-containing products; direct injection with the Pfizer BNT162b2 vaccine in the allergy clinic; or injection at community vaccination centres, respectively. Groups A and B were also invited to complete a questionnaire survey on post-vaccination reactions, and blood sampling pre-vaccination and 1 h after the first dose of the BNT162b2 vaccine to measure immunoglobulin (Ig) G, IgM and IgE antibodies to the Pfizer BNT162b2 vaccine via ELISA assays immobilised with the BNT162b2 vaccine, as well as levels of allergic cytokines interleukin (IL)-4 and IL-33, complement C5a and the endothelial activation marker intercellular adhesion molecule-1 (ICAM-1). Groups A and B comprised 62 (20.5%) patients each. In Group A, two subjects (3.2%) with equivocal IDT results tolerated both doses of the BNT162b2 vaccine without major allergic reactions. The remaining 60 (96.8%) in Group A and 62 (100%) in Group B completed both doses of BNT162b2 vaccination without major adverse reactions. Among the 99 who completed the questionnaire survey, 13 (13%) patients reported mild allergic reactions after the first dose of the vaccine. Immunoglobulin (Ig) G and M antibodies, but not IgE antibodies to the Pfizer BNT162b2 vaccine were detected in 67 subjects prior to vaccination. The presence of anti-Pfizer BNT162b2 IgG and IgM prior to vaccination did not result in major allergic reactions nor increases in Th2-related cytokines (IL-4, IL-33), complement activation products (C5a) or endothelial activation (ICAM-1). The majority of those with suspected reactions to non-COVID-19 polysorbate-containing vaccines tolerated the BNT162b2 vaccine. Excipient skin tests for PEG and polysorbate prior to vaccination are unnecessary.

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., (© 2021. International League of Associations for Rheumatology (ILAR).)

Background: Major challenges in large scale genetic association studies include not only the identification of causative single nucleotide polymorphisms (SNPs), but also accounting for SNP-SNP interactions. This study thus proposes a novel feature engineering approach integrating potentially functional coding haplotypes (pfcHap) with machine-learning (ML) feature selection to identify biologically meaningful, possibly causative genetic factors, that take into consideration potential SNP-SNP interactions within the pfcHap, to best predict for methotrexate (MTX) response in rheumatoid arthritis (RA) patients., Methods: Exome sequencing from 349 RA patients were analysed, of which they were split into training and unseen test set. Inferred pfcHaps were combined with 30 non-genetic features to undergo ML recursive feature elimination with cross-validation using the training set. Predictive capacity and robustness of the selected features were assessed using six popular machine learning models through a train set cross-validation and evaluated in an unseen test set., Findings: Significantly, 100 features (95 pfcHaps, 5 non-genetic factors) were identified to have good predictive performance (AUC: 0.776-0.828; Sensitivity: 0.656-0.813; Specificity: 0.684-0.868) across all six ML models in an unseen test dataset for the prediction of MTX response in RA patients., Interpretation: Majority of the predictive pfcHap SNPs were predicted to be potentially functional and some of the genes in which the pfcHap resides in were identified to be associated with previously reported MTX/RA pathways., Funding: Singapore Ministry of Health's National Medical Research Council (NMRC) [NMRC/CBRG/0095/2015; CG12Aug17; CGAug16M012; NMRC/CG/017/2013]; National Cancer Center Research Fund and block funding Duke-NUS Medical School.; Singapore Ministry of Education Academic Research Fund Tier 2 grant MOE2019-T2-1-138., Competing Interests: Declaration of Competing Interest CGL, KPL, CCK, SSC, AJWL, and LJL declare that they have a pending Coversheet IP application., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Objectives: We evaluated the impact of type 2 diabetes mellitus (T2DM) on RA treatment and outcomes in a longitudinal RA cohort., Methods: We analysed data collected in the period 2001-2013 involving 583 RA patients, including demographics, diabetes diagnosis, clinical features, treatment, ACR functional class, HAQ, and quality-of-life measurement using the Short-Form 36., Results: Seventy-seven (13.2%) of the RA patients had T2DM. DAS28 was not different in patients with T2DM at 5 years post-RA diagnosis. Fewer T2DM patients received MTX than those without T2DM (51% vs 80%, P < 0.001). Using univariate analysis, T2DM patients were more likely to experience poorer outcomes in terms of ACR functional status ( P = 0.009), joint surgery ( P = 0.007), knee arthroplasty ( P < 0.001) and hospital admissions ( P = 0.006). Multivariate regression analyses showed more knee arthroplasty ( P = 0.047) in patients with T2DM., Conclusion: Fewer patients with T2DM received MTX compared with those without T2DM. Patients with RA and T2DM were at higher risk of knee arthroplasty than RA patients without T2DM., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Feature selection (marker gene selection) is widely believed to improve clustering accuracy, and is thus a key component of single cell clustering pipelines. Existing feature selection methods perform inconsistently across datasets, occasionally even resulting in poorer clustering accuracy than without feature selection. Moreover, existing methods ignore information contained in gene-gene correlations. Here, we introduce DUBStepR (Determining the Underlying Basis using Stepwise Regression), a feature selection algorithm that leverages gene-gene correlations with a novel measure of inhomogeneity in feature space, termed the Density Index (DI). Despite selecting a relatively small number of genes, DUBStepR substantially outperformed existing single-cell feature selection methods across diverse clustering benchmarks. Additionally, DUBStepR was the only method to robustly deconvolve T and NK heterogeneity by identifying disease-associated common and rare cell types and subtypes in PBMCs from rheumatoid arthritis patients. DUBStepR is scalable to over a million cells, and can be straightforwardly applied to other data types such as single-cell ATAC-seq. We propose DUBStepR as a general-purpose feature selection solution for accurately clustering single-cell data., (© 2021. The Author(s).)

Aim: To compare the risk of death, the prevalence of comorbid chronic physical illness and mortality among an Asian population of patients with mental disorders., Methods: This was a retrospective data analysing of medical records of patients with schizophrenia, depression, anxiety, bipolar disorder, alcohol use disorder (AUD) or substance use disorder and the comorbid chronic physical illnesses. The hazard risk of death was calculated with Cox regression and compared between patients with and without comorbid chronic physical illness(es). Odds ratios of specific comorbid chronic physical illness were calculated with logistic regression and mean crude death rate was calculated for patients with different mental disorders., Results: A total of 56,447 patients with mental disorders were included in the analysis. Compared to patients without comorbid physical illness, patients with mental-physical comorbidity were associated with a higher risk of death [2.36 (2.22-2.52); hazard ratio (95% CI)] and less estimated survival days [2157 (2142-2172) vs 2508 (2504-2513)]. Compared to other mental disorders, those with AUD had the highest prevalence of two or more comorbid chronic physical illnesses and associated with the highest odds of comorbid hypertension, diabetes mellitus, stroke, nephritis, chronic kidney disease, and cancer. The highest one-year crude death rate was similarly observed in patients with AUD., Conclusions: Mental-physical comorbidity was associated with a higher risk of death compared to patients with mental disorders only. The highest prevalence of mental-physical comorbidity and mortality were observed in patients with AUD. More attention and resources may be needed to tackle the burden of AUD., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Objective: Disease activity indices for rheumatoid arthritis (RA) are important in clinical practice and research. Although they are closely correlated, they are not in good agreement. We derived formulae to convert values from one of the four 28-joint count indices (disease activity score using erythrocyte sedimentation rate [DAS28-ESR], disease activity score using C-reactive protein [DAS28-CRP], clinical disease activity index [CDAI], and simple disease activity index [SDAI]) to any of the others., Methods: We obtained data from 175 patients from our RA registry with concurrent CRP and ESR and established the nature of relationships between the indices using these data. Subsequently, we developed empiric conversion formulae. Furthermore, we developed new cutoff values for classifying disease activity to minimize the disparity among indices, using an iterative method., Results: The relationships between DAS28-ESR and DAS28-CRP and between SDAI and CDAI were approximately linear; the others were quadratic. Quadratic equations approximated the relationship between DAS, SDAI, and CDAI, whereas natural logarithms function approximated the relationship between DAS28-ESR and DAS28-CRP. Patients are frequently categorized into inconsistent disease activity states with any two indices, with the disparity ranging from 9.7% to 40.6%. The new cutoff values were developed to minimize the discrepant activity state categorization, reducing the disparity range to 6.3%-32.6%., Conclusion: We derived empiric formulae that connect DAS28-ESR, DAS28-CRP, SDAI, and CDAI. Moreover, we developed new cutoff values to minimize the discrepant activity state categorization with different indices.

Underrepresentation of Asian genomes has hindered population and medical genetics research on Asians, leading to population disparities in precision medicine. By whole-genome sequencing of 4,810 Singapore Chinese, Malays, and Indians, we found 98.3 million SNPs and small insertions or deletions, over half of which are novel. Population structure analysis demonstrated great representation of Asian genetic diversity by three ethnicities in Singapore and revealed a Malay-related novel ancestry component. Furthermore, demographic inference suggested that Malays split from Chinese ∼24,800 years ago and experienced significant admixture with East Asians ∼1,700 years ago, coinciding with the Austronesian expansion. Additionally, we identified 20 candidate loci for natural selection, 14 of which harbored robust associations with complex traits and diseases. Finally, we show that our data can substantially improve genotype imputation in diverse Asian and Oceanian populations. These results highlight the value of our data as a resource to empower human genetics discovery across broad geographic regions., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Aim: This study was undertaken to determine the incidence and patterns of malignancies in rheumatoid arthritis (RA) patients in our cohort., Methods: Between 2001 and 2013, we analyzed 1117 patients in the prospective Tan Tock Seng Hospital (TTSH) RA Registry. Patients who developed malignancies after the onset of RA were identified from this registry. Age- and sex-adjusted standardized incidence ratios (SIRs) were calculated to compare observed to expected numbers of malignancies based on data from the Singapore Cancer Registry., Results: Out of 19 839 person-years of follow-up, 132 incident malignancies were diagnosed during the observation period. There were 114 (86.4%) solid-organ tumors and 18 (13.6%) hematological malignancies. The SIR (95% confidence interval) for all malignancies combined was 1.28 (0.88-1.87) for males and 1.21 (1.00-1.46) for females. Compared to the general population, we found a 4- to 5-fold increase in lymphoma among our RA patients compared to the general population (SIR 5.05 [1.90-13.46] for males and 3.75 [1.95-7.20] for females). The SIR of lung malignancy in male RA patients is 2.36 (1.23-4.53) and SIR of cervical malignancy in female RA patients is 3.72 (2.20-6.23)., Conclusion: There is a trend toward an overall increased malignancy risk in our RA patients compared to the general population. Specifically, there is an increased risk of lymphomas in all RA patients, lung malignancy in male patients, and cervical malignancy in female patients, compared to the general population., (© 2019 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

The human microbiota provides tonic signals that calibrate the host immune response 1,2 , but their identity is unknown. Bacterial peptidoglycan (PGN) subunits are likely candidates since they are well-known immunity-enhancing adjuvants, released by most bacteria during growth, and have been found in the blood of healthy people 3-7 . We developed a monoclonal antibody (mAb), 2E7, that targets muramyl-L-alanyl-D-isoglutamine (MDP), a conserved and minimal immunostimulatory structure of PGN. Using 2E7-based assays, we detected PGN ubiquitously in human blood at a broad range of concentrations that is relatively stable in each individual. We also detected PGN in the serum of several warm-blooded animals. However, PGN is barely detectable in the serum of germ-free mice, indicating that its origin is the host microbiota. Neutralization of circulating PGN via intraperitoneal administration of 2E7 suppressed the development of autoimmune arthritis and experimental autoimmune encephalomyelitis in mice. Arthritic NOD2 -/- mice lacking the MDP sensor did not respond to 2E7, indicating that 2E7 dampens inflammation by blocking nucleotide-binding oligomerization domain-containing protein 2 (NOD2)-mediated pathways. We propose that circulating PGN acts as a natural immune potentiator that tunes the host immune response; altering its level is a promising therapeutic strategy for immune-mediated diseases.

Aim: To update recommendations based on current best evidence concerning the treatment of rheumatoid arthritis (RA), focusing particularly on the role of targeted therapies, to inform clinicians on new developments that will impact their current practice., Materials and Methods: A search of relevant literature from 2014 to 2016 concerning targeted therapies in RA was conducted. The RA Update Working Group evaluated the evidence and proposed updated recommendations using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach, to describe the quality of evidence and strength of recommendations. Recommendations were finalized through consensus using the Delphi technique., Results: This update provides 16 RA treatment recommendations based on current best evidence and expert clinical opinion. Recommendations 1-3 deal with the use of conventional synthetic disease-modifying antirheumatic drugs. The next three recommendations (4-6) cover the need for screening and management of infections and comorbid conditions prior to starting targeted therapy, while the following seven recommendations focus on use of these agents. We address choice of targeted therapy, switch, tapering and discontinuation. The last three recommendations elaborate on targeted therapy for RA in special situations such as pregnancy, cancer, and major surgery., Conclusion: Rheumatoid arthritis remains a significant health problem in the Asia-Pacific region. Patients with RA can benefit from the availability of effective targeted therapies, and these updated recommendations provide clinicians with guidance on their use., (© 2019 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

Background: All Singaporean males undergo medical screening prior to compulsory military service. A history of possible food allergy may require referral to a specialist Allergy clinic to ensure that special dietary needs can be taken into account during field training and deployment., Objective: To study the pattern of food allergy among pre-enlistees who were referred to a specialist allergy clinic to work up suspected food allergy., Methods: Retrospective study of all pre-enlistees registered in the Clinical Immunology/Allergy New Case Registry referred to the Allergy Clinic from 1 August 2015 to 31 May 2016 for suspected food allergy., Results: One hundred twenty pre-enlistees reporting food allergy symptoms other than rash alone were referred to the Allergy Clinic during the study period. Of these, 77 (64.2%) had food allergy. Among those with food allergy, mean age was 19.1 ± 1.5 years. They comprised predominantly Chinese (66.2%) and Malays (20.8%). The most commonly reported foods were shellfish/crustaceans (78%), peanut (15.6%), and egg (6.5%). Self-limiting oral allergy syndrome, OAS (itchy lips and throat with/without lip angioedema) was the most common manifestation (n = 33, 42.9%) followed by anaphylaxis (n = 23, 29.9%). Majority of OAS was from shellfish/crustacean (90.6%); of which shrimp (30.3%), crab (15.2%), and lobster (3.0%) were the most common. Mild childhood asthma (69.7%), allergic rhinitis (6.3%), and eczema (6.1%) were the most common atopic conditions among individuals with shellfish/crustacean OAS. This pattern was similar for shellfish/crustacean anaphylaxis. Skin prick tests were most commonly positive for shrimp (OAS 87.1% vs. anaphylaxis 100%), crab (OAS 95.8% vs. 90.9%), and lobster (OAS 91.7% vs. 63.6%)., Conclusion: OAS to shellfish/crustaceans was more common than anaphylaxis among this study population of young males referred for food allergy symptoms other than rash alone.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease which affects all aspects of quality of life (QoL) of the patients. Comprehensive patient assessment should include QoL measures in addition to the objective clinical measures of the disease. There is no specific Arabic instrument for assessment of QoL of SLE patients. The objective of this study was to translate and cross culturally adapt the SLEQOL questionnaire into Arabic and test its reliability and validity. The SLEQOL questionnaire was translated into Arabic based on the Guidelines for Translation and Cross-cultural Adaptation into other languages. Reliability was assessed by interviewing patients three times: two interviews on the same day by different interviewers and the third interview 14 days later by one of the first interviewers. Validity was assessed by correlating SLEQOL scores of 91 patients with 36-item Short Form Health Survey (SF-36) scores and clinical parameters of the patients. We found that the Arabic version of SLEQOL has a Cronbach's alpha of 0.936, interobserver and intraobserver correlation coefficients of 0.809 and 0.886 respectively. Strong correlations were also found between SLEQOL scores and SF-36 Physical and Mental Component summaries. In conclusion, the Arabic version of SLEQOL is a reliable and valid instrument for measuring QoL of Egyptian SLE patients.

Anti-nuclear autoantibodies, which frequently target the nucleoli, are pathogenic hallmarks of systemic lupus erythematosus (SLE). Although the causes of these Abs remain broad and ill-defined, a genetic deficiency in C1 complex (C1qC1r 2 C1s 2 ) or C4 is able to induce these Abs. Considering a recent finding that, in dead cells, nucleoli were targeted by C1q and two nucleolar autoantigens were degraded by C1r/C1s proteases, we considered that C1 could help protect against antinuclear autoimmunity by broadly degrading nucleolar proteins or autoantigens. Nucleoli were isolated to homogeneity and structurally defined. After C1 treatment, cleaved nucleolar proteins were identified by proteomic two-dimensional fluorescence difference gel electrophoresis and mass spectrometry, and further verified by Western blotting using specific Abs. The extent of nucleolar autoantigen degradation upon C1 treatment was estimated using SLE patient autoantibodies. The isolated nucleoli were broadly reactive with SLE patient autoantibodies. These nucleoli lacked significant autoproteolysis, but many nucleolar proteins and autoantigens were degraded by C1 proteases; >20 nucleolar proteins were identified as C1 cleavable. These were further validated by Western blotting using specific Abs. The broad autoantigenicity of the nucleoli may attribute to their poor autoproteolysis, causing autologous immune stimulation upon necrotic exposure. However, C1q targets at these nucleoli to cause C1 protease activation and the cleavage of many nucleolar proteins or autoantigens. This may represent one important surveillance mechanism against antinuclear autoimmunity because C1 genetic deficiency causes anti-nuclear autoantibodies and SLE disease., (Copyright © 2017 by The American Association of Immunologists, Inc.)

Aim: In Singapore, patients with psoriatic arthritis (PsA) constitute a significant disease burden. There is good evidence for the efficacy of anti-tumor necrosis factor (anti-TNF) in PsA; however cost remains a limiting factor. Non-biologic disease modifying anti-rheumatic drugs (nbDMARDs) hence remain the first-line treatment option in PsA in spite of limited evidence. The Singapore Chapter of Rheumatologists aims to develop national guidelines for clinical eligibility for government-assisted funding of biologic disease modifying anti- rheumatic drugs (bDMARDs) for PsA patients in Singapore., Methods: Evidence synthesis was performed by reviewing seven published guidelines on use of biologics for PsA. Using the modified Research and Development/University of California at Los Angeles Appropriateness Method (RAM), rheumatologists rated indications for therapies for different clinical scenarios. Points reflecting the output from the formal group consensus were used to formulate the practice recommendations., Results: Ten recommendations were formulated relating to initiation, continuation and options of bDMARD therapy. The panellists agreed that a bDMARD is indicated if a patient has active PsA with at least five swollen and tender joints, digits or entheses and has failed two nbDMARD strategies at optimal doses for at least 3 months each. Any anti-TNF may be used and therapy may be continued if an adequate PsARC response is achieved by 3 months after commencement., Conclusion: The recommendations developed by a formal group consensus method may be useful for clinical practice and guiding funding decisions by relevant authorities in making bDMARD usage accessible and equitable to eligible patients in Singapore., (© 2015 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd.)

Introduction: The beneficial effects of biologic disease-modifying anti-rheumatic drugs (bDMARDs), such as tumour necrosis factor inhibitors (anti-TNF) in active ankylosing spondylitis (AS) are well established. The significant costs on patients in the absence of financial subsidization can limit their use. The objective was to describe a consensus development process on recommendations for government-assisted funding of biologic therapy for AS patients in Singapore., Methods: Evidence synthesis followed by a modified RAND/UCLA Appropriateness Method (RAM) was used. Eleven rheumatologists rated indications for therapies for different proposed clinical scenarios. Points reflecting the output from the formal group consensus were used to formulate 10 practice recommendations., Results: It was agreed that a bDMARD (anti-TNF) is indicated if a patient has active AS with a Bath Ankylosing Spondylitis Activity Index (BASDAI) ≥ 4 and spinal pain of ≥ 4 cm on visual analogue scale (VAS) on two occasions at least 12 weeks apart, despite being on a minimum of two sequential non-steroidal anti-inflammatory drugs at maximal tolerated dose for at least 4 weeks, in addition to adherence to an appropriate physiotherapy program for at least 3 months. To qualify for continued biologic therapy, a patient must have documentation of response every 3 months and at least 50% improvement in BASDAI and reduction of spinal pain VAS ≥ 2 cm., Conclusion: A validated and feasible consensus process can enable pragmatic standardized recommendations to be developed for bDMARD subsidization for AS patients in a local Asian context., (© 2015 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd.)

Studies have shown that the genetic risk factors for rheumatoid arthritis (RA) differ substantially between Asian and Caucasian populations. Even among Asian populations, the genetic contributions of NLRP1, PTPN22 and PADI4 have been controversial. Consequently, we sought to address these separate findings and determine whether any of these proposed risk variants are associated with RA susceptibility, onset, DAS activity and erosion in a Singaporean Chinese cohort. We genotyped five SNPs within NLRP1 (rs878329 and rs6502867), PTPN22 (rs2488457 and rs6665194), and PADI4 (rs2240340) in 500 anti-cyclic citrullinated peptide antibody-positive (ACPA) patients with RA and 500 healthy controls using TaqMan assays. The CC genotype of NLRP1 rs878329 and TT genotype of PADI4 rs2240340 were associated with RA susceptibility. The risk association of the T allele of PADI4 rs2240340 with RA was confirmed through a meta-analysis based on previous reports in Asian populations. The GG genotype of PTPN22 rs6665194 (-3508A>G) was associated with significantly reduced risk of RA. No significant association was found for NLRP1 rs6502867 T/C and PTPN22 rs2488457 G/C polymorphisms. None of the five SNPs was associated with RA's clinical features. This work supports the association of the T allele of PADI4 rs2240340 with RA in Asians. The roles of NLRP1 rs878329 G/C and PTPN22 rs6665194 A/G polymorphisms were demonstrated for the first time. We also propose rs6665194 to be a promising candidate for RA risk evaluation between ethnicities.

Objective: To describe the demographic characteristics, clinical features, functional status and quality of life of elderly-onset (EORA) and young-onset (YORA) rheumatoid arthritis (RA) patients in an Asian cohort., Methods: We studied all RA patients in our prospective disease registry, utilizing baseline data. EORA was defined as disease onset at 60 years or older. We collected data from January 2001 to December 2012., Results: There were 1206 patients in our cohort, of which 178 (14.8%) had EORA, with a mean age of onset of 66.7 ± 5.6 years. There were more males in the EORA than YORA group (23.0% vs. 14.7%, P = 0.005). EORA patients were diagnosed sooner after symptom onset and had a higher number of comorbidities (median 2 [inter-quartile range 1-3] vs. 1 (0-2), P < 0.001). They were less likely to be rheumatoid factor positive, had higher erythrocyte sedimentation rate values and lower hemoglobin concentrations. There was no significant difference in joint counts, Disease Activity Score of 28 joints activity score and prevalence of radiographic erosions. Though EORA patients had worse Health Assessment Questionnaire scores and poorer functional status than YORA ones, they had lower pain scores and higher scores in the general health and mental component summary of the Short Form-36. EORA patients received significantly lower numbers of disease-modifying anti-rheumatic drugs., Conclusions: EORA and YORA patients had different demographic characteristics. Although they had similar disease activities, EORA patients received less intensive treatment. EORA patients had a higher number of RA-related co-morbidities and poorer physical functioning but they coped better emotionally and mentally., (© 2016 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

Background: Genetic determinants of drug response remain stable throughout life and offer great promise to patient-tailored drug therapy. The adoption of pharmacogenetic (PGx) testing in patient care requires accurate, cost effective and rapid genotyping with clear guidance on the use of the results. Hence, we evaluated a 32 SNPs panel for implementing PGx testing in clinical laboratories., Methods: We designed a 32-SNP panel for PGx testing in clinical laboratories. The variants were selected using the clinical annotations of the Pharmacogenomics Knowledgebase (PharmGKB) and include polymorphisms of CYP2C9, CYP2C19, CYP2D6, CYP3A5 and VKORC1 genes. The CYP2D6 gene allele quantification was determined simultaneously with TaqMan copy number assays targeting intron 2 and exon 9 regions. The genotyping results showed high call rate accuracy according to concordance with genotypes identified by independent analyses on Sequenome massarray and droplet digital PCR. Furthermore, 506 genomic samples across three major ethnic groups of Singapore (Malay, Indian and Chinese) were analysed on our workflow., Results: We found that 98% of our study subjects carry one or more CPIC actionable variants. The major alleles detected include CYP2C9*3, CYP2C19*2, CYP2D6*10, CYP2D6*36, CYP2D6*41, CYP3A5*3 and VKORC1*2. These translate into a high percentage of intermediate (IM) and poor metabolizer (PM) phenotypes for these genes in our population., Conclusion: Genotyping may be useful to identify patients who are prone to drug toxicity with standard doses of drug therapy in our population. The simplicity and robustness of this PGx panel is highly suitable for use in a clinical laboratory., Competing Interests: The authors have declared that no competing interests exist.

Aims: Rheumatoid arthritis is a chronic inflammatory condition that affects approximately 1% of the world's population. There are a wide number of guidelines and recommendations available to support the treatment of rheumatoid arthritis; however, the evidence used for these guidelines is predominantly based on studies in Caucasian subjects and may not be relevant for rheumatoid arthritis patients in the Asia-Pacific region. Therefore, the Asia Pacific League of Associations for Rheumatology established a Steering Committee in 2013 to address this issue., Materials and Methods: The AGREE II instrument and the ADAPTE Collaboration framework were applied to systematically identify, appraise, synthesize, and adapt international rheumatoid arthritis guidelines for use in the Asia-Pacific region., Results: Forty rheumatoid arthritis treatment recommendations, based on evidence and expert opinion, were drafted and are presented in this report., Conclusion: The Asia Pacific of Associations for Rheumatology rheumatoid arthritis treatment recommendations are intended to serve as a reference for best practice management of rheumatoid arthritis in Asia-Pacific, focusing on local issues to ensure the delivery of basic care for these patients, and to improve their outcomes. In addition, the document will serve as a reference for national rheumatology associations in Asia-Pacific for developing guidelines in their respective countries., (© 2015 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd.)