Relation of Doppler ultrasound synovitis versus clinical synovitis with changes in native complement component levels in rheumatoid arthritis patients treated with biologic disease-modifying anti-rheumatic drugs.

OBJECTIVES: The complement system plays a fundamental role in mediating the activity of rheumatoid arthritis (RA). Biologic therapy can reduce native complement component levels and its activation. We aimed to study the relation of Doppler ultrasound (US) synovitis versus clinical synovitis with changes in native complement component levels in RA patients on biologic therapy. METHODS: This was a cross-sectional study. Ninety-seven consecutive patients with RA on biologic therapy for at least 3 months were recruited. Clinical, laboratory and Doppler US assessments were performed. The Disease Activity Score in 28 joints (DAS28), Simplified Disease Activity Index (SDAI) and a 12-joint US assessment were carried out. Synovitis was semiquantitatively scored in B-mode and power Doppler (PD) mode. RESULTS: A significant decrease in native complement (i.e. C3 and C4) and C-reactive protein (CRP) levels was observed. This was highly significant for C3 decrease (p<0.0005), and C4 decrease (p<0.0005). Synovitis detected by PD US showed significant negative association with C3 change (p<0.008), where patients with higher C3 change were more likely to have PD US inactive status on assessment. CONCLUSIONS: Our results suggested that disease inactive status determined by PD US but not by clinical assessment can be related with decrease in complement in RA patients treated with biologic therapy.

Associated Factors of Tophaceous Gout: A Study Involving 20 Primary Care Clinics in an Urbanized State in Malaysia.

Objectives: Gout is a treatable disease. A complication of untreated or poorly-controlled gout is tophi formation. We conducted this study to investigate the associated factors of tophaceous gout among patients who attended 20 primary care clinics in Selangor, an urbanized state in Malaysia. Methods: We conducted a cross-sectional study from July to October 2019 that included all patients with gout who attended the clinics. Data on clinical demographics and laboratory results were collected. Comparison between tophaceous and non-tophaceous groups was performed using descriptive analysis. Results: A total of 421 patients with gout were involved in this study, 83 (19.7%) patients had visible tophi and were categorized into the tophaceous group, while the other 338 (80.3%) patients were categorized into the non-tophaceous group. The majority of patients were male with a mean age of 57.6±12.8 years. Three factors found to be significantly associated with tophaceous gout were age at symptom onset [tophaceous (45.6±13.3 years) vs. non-tophaceous (49.7±13.9 years), p = 0.026], mean disease duration of gout [tophaceous (105.2±92.6 months) vs. non-tophaceous (77.6±88.6 months), p = 0.013], and baseline serum uric acid level [tophaceous (622.3±129.1 µmol/L) vs. non-tophaceous (582.6±102.3 µmol/L), p = 0.021]. Conclusions: Tophaceous gout is associated with longer disease duration, higher baseline serum uric acid level, and younger age at symptoms onset. Hence, early initiation of urate-lowering therapy with a treat-to-target approach is crucial to prevent tophi formation.

Genetic variations in methotrexate metabolic pathway genes influence methotrexate responses in rheumatoid arthritis patients in Malaysia.

Methotrexate (MTX) is the most widely used disease-modifying anti-rheumatic drug (DMARD) for rheumatoid arthritis (RA). Many studies have attempted to understand the genetic risk factors that affect the therapeutic outcomes in RA patients treated with MTX. Unlike other studies that focus on the populations of Caucasians, Indian and east Asian countries, this study investigated the impacts of six single nucleotide polymorphisms (SNPs) that are hypothesized to affect the outcomes of MTX treatment in Malaysian RA patients. A total of 647 RA patients from three ethnicities (NMalay = 153; NChinese = 326; NIndian = 168) who received MTX monotherapy (minimum 15 mg per week) were sampled from three hospitals in Malaysia. SNPs were genotyped in patients using TaqMan real-time PCR assay. Data obtained were statistically analysed for the association between SNPs and MTX efficacy and toxicity. Analysis of all 647 RA patients indicated that none of the SNPs has influence on either MTX efficacy or MTX toxicity according to the Chi-square test and binary logistic regression. However, stratification by self-identified ancestries revealed that two out of six SNPs, ATIC C347G (rs2372536) (OR 0.5478, 95% CI 0.3396-0.8835, p = 0.01321) and ATIC T675C (rs4673993) (OR 0.5247, 95% CI 0.3248-0.8478, p = 0.008111), were significantly associated with MTX adequate response in RA patients with Malay ancestry (p < 0.05). As for the MTX toxicity, no significant association was identified for any SNPs selected in this study. Taken all together, ATIC C347G and ATIC T675C can be further evaluated on their impact in MTX efficacy using larger ancestry-specific cohort, and also incorporating high-order gene-gene and gene-environment interactions.

Algorithm for the referral of patients with inflammatory back pain from primary care in Malaysia.

Chronic low back pain, defined as back pain lasting for more than three months, can be divided into mechanical or inflammatory back pain (IBP). IBP typically starts in patients below the age of 40, is improved with activity and worsens with rest. IBP is strongly associated with axial spondyloarthritis. Early recognition of IBP among primary care physicians is essential for timely diagnosis and intervention to ensure the best outcomes for patients with axial spondyloarthritis. This paper describes the Malaysian Society of Rheumatology's recently developed Inflammatory Back Pain Referral Algorithm for primary care physicians, which aims to facilitate the early identification and referral of IBP patients to rheumatologists.

The spectrum of association in HLA region with rheumatoid arthritis in a diverse Asian population: evidence from the MyEIRA case-control study.

BACKGROUND: Fine-mapping of human leukocyte antigen (HLA) region for rheumatoid arthritis (RA) risk factors has identified several HLA alleles and its corresponding amino acid residues as independent signals (i.e., HLA-A, HLA-B, HLA-DPB1, and HLA-DQA1 genes), in addition to the well-established genetic factor in HLA-DRB1 gene. However, this was mainly performed in the Caucasian and East Asian populations, and data from different Asian regions is less represented. We aimed to evaluate whether there are independent RA risk variants in both anti-citrullinated protein antibody (ACPA)-positive and ACPA-negative RA patients from the multi-ethnic Malaysian population, using the fine-mapping of HLA region strategy. METHODS: We imputed the classical HLA alleles, amino acids, and haplotypes using the Immunochip genotyping data of 1260 RA cases (i.e., 530 Malays, 259 Chinese, 412 Indians, and 59 mixed ethnicities) and 1571 controls (i.e., 981 Malays, 205 Chinese, 297 Indians, and 87 mixed ethnicities) from the Malaysian Epidemiological Investigation of Rheumatoid Arthritis (MyEIRA) population-based case-control study. Stepwise logistic regression was performed to identify the independent genetic risk factors for RA within the HLA region. RESULTS: We confirmed that the HLA-DRB1 amino acid at position 11 with valine residue conferred the strongest risk effect for ACPA-positive RA (OR = 4.26, 95% CI = 3.30-5.49, PGWAS = 7.22 × 10-29) in the Malays. Our study also revealed that HLA-DRB1 amino acid at position 96 with histidine residue was negatively associated with the risk of developing ACPA-positive RA in the Indians (OR = 0.48, 95% CI = 0.37-0.62, PGWAS = 2.58 × 10-08). Interestingly, we observed that HLA-DQB1*03:02 allele was inversely related to the risk of developing ACPA-positive RA in the Malays (OR = 0.17, 95% CI = 0.09-0.30, PGWAS = 1.60 × 10-09). No association was observed between the HLA variants and risk of developing ACPA-negative RA in any of the three major ethnic groups in Malaysia. CONCLUSIONS: Our results demonstrate that the RA-associated genetic factors in the multi-ethnic Malaysian population are similar to those in the Caucasian population, despite significant differences in the genetic architecture of HLA region across populations. A novel and distinct independent association between the HLA-DQB1*03:02 allele and ACPA-positive RA was observed in the Malays. In common with the Caucasian population, there is little risk from HLA region for ACPA-negative RA.

HLA-A, -B, -C, -DRB1 and -DQB1 alleles and haplotypes in 271 Southeast Asia Indians from Peninsular Malaysia.

A total of 271 Southeast Asia Indians from Peninsular Malaysia were genotyped for HLA-A, -B, -C, -DRB1, and -DQB1 loci using polymerase chain reaction sequence-specific oligonucleotide probe hybridization methods. In this report, HLA-B and HLA-DQB1 was in Hardy-Weinberg proportions (HWEP) (p > 0.05). We observed significant deviation from the HWEP for HLA-A (p < 0.05), HLA-C (p < 0.01) and HLA-DRB1 (p < 0.01) loci. This genotype data is available in Allele Frequencies Network Database (AFND) Dos Santos et al. (2016).

HLA-A, -B, -C, -DRB1 and -DQB1 alleles and haplotypes in 194 Southeast Asia Chinese from Peninsular Malaysia.

A total of 194 Southeast Asia Chinese from Peninsular Malaysia were genotyped for HLA-A, -B, -C -DRB1, and -DQB1 loci using polymerase chain reaction sequence-specific oligonucleotide probe hybridization methods. In this report, the HLA-B, HLA-DRB1 and HLA-DQB1 were in Hardy-Weinberg proportions (HWEP) (p > 0.05). We observed significant deviation from HWEP in HLA-A (p < 0.05) and HLA-C (p < 0.01) loci. This genotype data was available in Allele Frequencies Network Database (AFND) Dos Santos et al. (2016).

Clinical and economic implications of upper gastrointestinal adverse events in Asian rheumatological patients on long-term non-steroidal anti-inflammatory drugs.

AIM: To determine the incidence and direct costs of NSAID-induced upper GI adverse events in Malaysian rheumatology patients. METHODS: A retrospective, multi-centre, cohort study of rheumatology patients on long-term NSAIDs was conducted. Clinical data of patients treated between 2010 and 2013 were collected for a 24-month follow-up period. The costs of managing upper GI adverse events were based on patient level resource use data. RESULTS: Six hundred and thirty-four patients met the inclusion criteria: mean age 53.4 years, 89.9% female, diagnosis of rheumatoid arthritis (RA; 59.3%), osteoarthritis (OA; 10.3%) and both RA and OA (30.3%). Three hundred and seventy-one (58.5%) patients were prescribed non-selective NSAIDs and 263 (41.5%) had cyclo-oxygenase-2 inhibitors. Eighty-four upper GI adverse events occurred, translating into a risk of 13.2% and an incidence rate of 66.2 per 1000 person-years. GI adverse events comprised: dyspepsia n = 78 (12.3%), peptic ulcer disease (PUD) n = 5 (0.79%) and upper GI bleeding (UGIB) n = 1 (0.16%). The total direct healthcare cost of managing adverse events was Malaysian Ringgit (MR) 37 352 (US dollars [USD] 11 419) with a mean cost of MR 446.81 ± 534.56 (USD 136.60 ± 163.42) per patient, consisting mainly of GI pharmacotherapy (33.8%), oesophagoduodenoscopies (23.1%) and outpatient clinic visits (18.2%). Mean cost per patient by GI events were: dyspepsia, MR 408.98 ± 513.29 (USD125.03 ± 156.92); PUD, MR 805.93 ± 578.80 (USD 246.39 ± 176.95); UGIB, MR 1601.94 (USD 489.74, n = 1). CONCLUSION: The economic burden of GI adverse events due to long-term NSAIDs use in Malaysian patients with chronic rheumatic diseases is modest.

HLA-A, -B, -C, -DRB1 and -DQB1 alleles and haplotypes in 951 Southeast Asia Malays from Peninsular Malaysia.

A total of 951 Southeast Asia Malays from Peninsular Malaysia were genotyped for HLA-A, -B, -C -DRB1, and -DQB1 loci using polymerase chain reaction sequence-specific oligonucleotide probe hybridization methods. In this report, there were significant deviation from Hardy-Weinberg proportions for the HLA-A (p<0.0001), -B (p<0.0001), -DRB1 (p<0.0001) and -DQB1 (p<0.01) loci. Minor deviations from HWEP were detected for HLA-C (p=0.01). This genotype data was available in Allele Frequencies Network Database (AFND) Gonzalez-Galarza et al. (2015).