2019 revised algorithm for the management of knee osteoarthritis: the Southeast Asian viewpoint

Background: Since 2014, the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO) algorithm for the management of knee osteoarthritis (OA) is available worldwide. Aim: Based on this document, a Southeast Asia Working Group (SEAWG) wished to see how the new ESCEO algorithm developed in 2019 was perceived by Southeast Asian experts and how it was integrated into their clinical practice. Methods: A SEAWG was set up between members of the international ESCEO task force and a group of Southeast Asian experts. Results: Non-pharmacological management should always be combined with pharmacological management. In step 1, symptomatic slow-acting drugs for osteoarthritis are the main background therapy, for which high-quality evidence is available only for the formulations of patented crystalline glucosamine sulfate and chondroitin sulfate. In step 2, oral NSAIDs are a useful option, considering the cardiovascular/renal/gastrointestinal profiles of the individual patient. Intra-articular hyaluronic acid and corticosteroids are a possible alternative to oral NSAIDs, but limited evidence is available. If steps 1 and 2 do not give adequate relief of symptoms, tramadol can be used, but its safety is debated. In general, the indications of the ESCEO algorithm are important in Southeast Asian countries, but the reimbursement criteria of local health systems are an important aspect for adherence to the ESCEO algorithm. Conclusion This guidance provides evidence-based and easy-to-follow advice on how to establish a treatment algorithm in knee OA, for practical implementation in clinical practice in Southeast Asian countries

Identification of a Sjögren's syndrome susceptibility locus at OAS1 that influences isoform switching, protein expression, and responsiveness to type I interferons

Sjögren’s syndrome (SS) is a common, autoimmune exocrinopathy distinguished by keratoconjunctivitis sicca and xerostomia. Patients frequently develop serious complications including lymphoma, pulmonary dysfunction, neuropathy, vasculitis, and debilitating fatigue. Dysregulation of type I interferon (IFN) pathway is a prominent feature of SS and is correlated with increased autoantibody titers and disease severity. To identify genetic determinants of IFN pathway dysregulation in SS, we performed cis-expression quantitative trait locus (eQTL) analyses focusing on differentially expressed type I IFN-inducible transcripts identified through a transcriptome profiling study. Multiple cis-eQTLs were associated with transcript levels of 2'-5'-oligoadenylate synthetase 1 (OAS1) peaking at rs10774671 (PeQTL= 6.05 × 10−14). Association of rs10774671 with SS susceptibility was identified and confirmed through meta-analysis of two independent cohorts (Pmeta= 2.59 × 10−9; odds ratio = 0.75; 95% confidence interval = 0.66–0.86). The risk allele of rs10774671 shifts splicing of OAS1 from production of the p46 isoform to multiple alternative transcripts, including p42, p48, and p44. We found that the isoforms were differentially expressed within each genotype in controls and patients with and without autoantibodies. Furthermore, our results showed that the three alternatively spliced isoforms lacked translational response to type I IFN stimulation. The p48 and p44 isoforms also had impaired protein expression governed by the 3' end of the transcripts. The SS risk allele of rs10774671 has been shown by others to be associated with reduced OAS1 enzymatic activity and ability to clear viral infections, as well as reduced responsiveness to IFN treatment. Our results establish OAS1 as a risk locus for SS and support a potential role for defective viral clearance due to altered IFN response as a genetic pathophysiological basis of this complex autoimmune disease. © 2017 Public Library of Science. All Rights Reserved

Identification of a Sjögren's syndrome susceptibility locus at OAS1 that influences isoform switching, protein expression, and responsiveness to type I interferons

Sjogren's syndrome (SS) is a common, autoimmune exocrinopathy distinguished by keratoconjunctivitis sicca and xerostomia. Patients frequently develop serious complications including lymphoma, pulmonary dysfunction, neuropathy, vasculitis, and debilitating fatigue. Dysregulation of type I interferon (IFN) pathway is a prominent feature of SS and is correlated with increased autoantibody titers and disease severity. To identify genetic determinants of IFN pathway dysregulation in SS, we performed cis-expression quantitative trait locus (eQTL) analyses focusing on differentially expressed type I IFN-inducible transcripts identified through a transcriptome profiling study. Multiple cis-eQTLs were associated with transcript levels of 2'-5'-oligoadenylate synthetase 1 (OAS1) peaking at rs10774671 (PeQTL = 6.05 x 10(-14)). Association of rs10774671 with SS susceptibility was identified and confirmed through meta-analysis of two independent cohorts (P-meta = 2.59 x 10(-9); odds ratio = 0.75; 95% confidence interval = 0.66-0.86). The risk allele of rs10774671 shifts splicing of OAS1 from production of the p46 isoform to multiple alternative transcripts, including p42, p48, and p44. We found that the isoforms were differentially expressed within each genotype in controls and patients with and without autoantibodies. Furthermore, our results showed that the three alternatively spliced isoforms lacked translational response to type I IFN stimulation. The p48 and p44 isoforms also had impaired protein expression governed by the 3' end of the transcripts. The SS risk allele of rs10774671 has been shown by others to be associated with reduced OAS1 enzymatic activity and ability to clear viral infections, as well as reduced responsiveness to IFN treatment. Our results establish OAS1 as a risk locus for SS and support a potential role for defective viral clearance due to altered IFN response as a genetic pathophysiological basis of this complex autoimmune disease

Composition of independent cohorts used in the genetic association analyses.

<p>Composition of independent cohorts used in the genetic association analyses.</p

Differentially expressed transcripts between 115 anti-Ro/SSA positive SS cases and 56 controls identified through transcriptome profiling.

<p>(A) We identified 73 genes (represented by 83 probes on the heatmap) differentially expressed between anti-Ro/SSA positive SS cases and healthy controls (absolute FC >2 and <i>q</i><0.05). Among the differentially expressed genes, 57 were type I IFN-regulated genes (black bar on right) and formed an IFN signature where most genes were overexpressed in SS patients (yellow indicates overexpressed genes compared to controls). (B) The 57 differentially expressed type I IFN-regulated genes were re-clustered in anti-Ro/SSA positive SS cases using <i>k</i>-means (<i>k</i> = 3) algorithm and heterogeneity of the IFN signature levels in anti-Ro/SSA positive SS cases was observed.</p

Functional characterizations of <i>OAS1</i> isoforms.

<p>(A) Protein expression of OAS1 isoforms was evaluated in EBV-transformed B cells from SS patients (four independent samples from each genotype group) using anti-OAS1 antibody targeting the shared epitope of all the isoforms. The stimulated cells were treated with universal type I IFN (1500U/ml) for 24hrs. The p44 isoform was not detectable using western-blot due to its low expression. The right panel shows quantified band intensity normalized to the GAPDH in each sample. (B) The transcript levels of each <i>OAS1</i> isoform from the same sets of cells described above were determined using real-time PCR. Consistent with the RNA-seq results, the SS-associated risk allele A of rs10774671 was correlated with decreased levels of p46 and increased expression of the p42, p48, and p44 isoforms (significance levels are shown at the bottom). The transcript levels of all the isoforms significantly increased after IFN stimulation (two-tailed <i>t</i> test); however, only p46 had increased protein production after IFN stimulation. (Significance level: ** <i>P</i><0.01; *** <i>P</i><0.001) (C) Individual isoforms of <i>OAS1</i> tagged with Xpress epitope were cloned and transfected into HEK 293T cells for 48hrs. The p48 and p44 isoforms had impaired protein expression compared to p46 and p42, although their transcript levels were equivalent as determined by real-time PCR (n = 4; normalized to <i>HMBS</i>). (D) The full-length and truncated <i>OAS1</i> p48 and p44 isoforms were cloned into HEK 293T cells. Western-blot indicated the lack of expression of the full-length p48 and p44 isoforms, whereas the truncation of both isoform transcripts (T2 and T4) was able to restore protein expression. (E) The 3' alternatively spliced terminus of different <i>OAS1</i> isoforms were linked to the 3'-end of GFP to observe their influence on GFP protein expression in HEK 293T cells. The 3'-terminus from the p48 and p44 isoforms resulted in decreased expression of GFP.</p

Results of <i>cis</i>-eQTL analysis in <i>OAS1</i> region.

<p>(A) After imputation, 453 variants near <i>OAS1</i> were tested for association with <i>OAS1</i> transcript expression using linear regression. The association of each variant with the transcript level of <i>OAS1</i> (represented by 3 probes on the microarray; see B) are plotted based on the most significant -log₁₀(<i>P</i>_<i>eQTL</i>) values. We identified <i>cis</i>-eQTLs within and near <i>OAS1</i>, with the top association at rs10774671 (<i>P</i>_<i>eQTL</i> = 6.05×10⁻¹⁴). The variant rs10774671 was also the most significant genotyped SS-associated SNP in the genetic association analysis (<i>P</i>_<i>assoc</i> = 8.47×10⁻⁵; The top imputed SS-associated variant rs4767023 is also marked on the plot). The <i>r</i>² coded by colors indicating LD with rs10774671 are given in the figure. Variants above the dashed line were associated with <i>OAS1</i> transcript expression with <i>q</i><0.01. No eQTL was observed for <i>OAS2</i> or <i>OAS3</i>. (B) The genomic structures of the isoforms of <i>OAS1</i> (p46: NM_016816; p42: NM_002534; p48: NM_001032409; and p44, as described previously and identified in our RNA-seq analysis) are shown. The location of rs10774671 and the splicing consensus sequence AG in p46, p48, and p44 are indicated. One probe on the microarray specifically detects the p42 isoform (Probe 3). (C) The <i>cis</i>-eQTL analysis was performed through integration of the microarray expression data of <i>OAS1</i> with the genotype data of rs10774671. The SS-associated risk allele A of rs10774671 was associated with higher expression level of the p42 isoform as determined by Probe 3. The A allele was associated with lower expression of total <i>OAS1</i> as measured by Probe 1 and Probe 2. The <i>cis</i>-eQTL analysis results were determined using both a linear model and ANOVA. The mean value and the standard error of the mean (Mean±SEM) in each group are plotted in red.</p

Results of genetic association analyses in <i>OAS1</i> region.

<p>(A) Genetic association analyses were performed using Dataset 1 (765 SS cases and 3,825 controls). The most significant association before and after imputation was at rs10774671 (<i>P</i>_<i>assoc</i> = 8.47×10⁻⁵) and rs4767023 (<i>P</i>_<i>assoc</i> = 3.82×10⁻⁵), respectively. (B) The LD structure of the <i>OAS1</i> region indicated by <i>r</i>² and D' for SS-associated variants with <i>P</i>_<i>assoc</i><1×10⁻⁴ are shown. All these variants, including the top SS-associated genotyped SNP rs10774671, were in strong LD (<i>r</i>²>0.9). (C, D) In order to determine independency of the association signals observed in the <i>OAS1</i> region, we performed logistic regression analyses adjusting for the top SS-associated variants in the <i>OAS1</i> region. Adjusting for any variant with <i>P</i>_<i>assoc</i><1×10⁻⁴ could account for all other associations in the extended <i>OAS1</i> region (200kb). Examples shown here are conditional analyses adjusting for rs4767023 and rs10774671, respectively. The associations of each variant with SS were plotted based on -log₁₀(<i>P</i>_<i>assoc</i>) values. The <i>r</i>² coded by colors indicating LD with the top SS-associated genotyped SNP rs10774671 are given in the figures.</p