Genetic, Epigenetic and Pharmacogenetic Aspects of Psoriasis and Psoriatic Arthritis.

There is a strong familial component to psoriatic disease as well as a complex array of genetic, immunologic, and environmental factors. The dominant genetic effect is located on chromosome 6p21.3 within the major histocompatibility complex region, accounting for one-third of genetic contribution.

Genome-wide DNA methylation study of hip and knee cartilage reveals embryonic organ and skeletal system morphogenesis as major pathways involved in osteoarthritis.

Background: Evidence suggests that epigenetics plays a role in osteoarthrits (OA). The aim of the study was to describe the genome wide DNA methylation changes in hip and knee OA and identify novel genes and pathways involved in OA by comparing the DNA methylome of the hip and knee osteoarthritic cartilage tissues with those of OA-free individuals.

Methods: Cartilage samples were collected from hip or knee joint replacement patients either due to primary OA or hip fractures as controls.

Secukinumab Inhibition of Interleukin-17A in Patients with Psoriatic Arthritis.

Background: In a phase 2 study, the inhibition of the interleukin-17A receptor improved signs and symptoms of psoriatic arthritis. We sought to evaluate the efficacy and safety of secukinumab, an anti-interleukin-17A monoclonal antibody, in such patients.

Methods: In this double-blind, phase 3 study, 606 patients with psoriatic arthritis were randomly assigned in a 1:1:1 ratio to receive intravenous secukinumab (at a dose of 10 mg per kilogram) at weeks 0, 2, and 4, followed by subcutaneous secukinumab at a dose of either 150 mg or 75 mg every 4 weeks, or placebo.

Ottawa Panel evidence-based clinical practice guidelines for therapeutic exercise in the management of hip osteoarthritis.

Objectives: The primary objective is to identify effective land-based therapeutic exercise interventions and provide evidence-based recommendations for managing hip osteoarthritis. A secondary objective is to develop an Ottawa Panel evidence-based clinical practice guideline for hip osteoarthritis.

Methods: The search strategy and modified selection criteria from a Cochrane review were used.

Overexpression of MMP13 in human osteoarthritic cartilage is associated with the SMAD-independent TGF-β signalling pathway.

Introduction: In vitro and animal model of osteoarthritis (OA) studies suggest that TGF-β signalling is involved in OA, but human data is limited. We undertook this study to elucidate the role of TGF-β signalling pathway in OA by comparing the expression levels of TGFB1 and BMP2 as ligands, SMAD3 as an intracellular mediator, and MMP13 as a targeted gene between human osteoarthritic and healthy cartilage.

Methods: Human cartilage samples were collected from patients undergoing total hip/knee joint replacement surgery due to primary OA or hip fractures as controls.

A Systematic Critical Appraisal of Clinical Practice Guidelines in Juvenile Idiopathic Arthritis Using the Appraisal of Guidelines for Research and Evaluation II (AGREE II) Instrument.

Objectives: The objectives of this review are to: 1) appraise the methodological quality of clinical practice guidelines (CPGs) in juvenile idiopathic arthritis (JIA) providing pharmacological and/or non-pharmacological intervention recommendations, and 2) summarize the recommendations provided by the included CPGs and compare them where possible.

Methods: A systematic search was performed. Three trained appraisers independently evaluated the methodological quality of the CPGs using a validated and reliable instrument, the Appraisal of Guidelines in Research and Evaluation II.

Widespread non-additive and interaction effects within HLA loci modulate the risk of autoimmune diseases.

Human leukocyte antigen (HLA) genes confer substantial risk for autoimmune diseases on a log-additive scale. Here we speculated that differences in autoantigen-binding repertoires between a heterozygote's two expressed HLA variants might result in additional non-additive risk effects. We tested the non-additive disease contributions of classical HLA alleles in patients and matched controls for five common autoimmune diseases: rheumatoid arthritis (ncases = 5,337), type 1 diabetes (T1D; ncases = 5,567), psoriasis vulgaris (ncases = 3,089), idiopathic achalasia (ncases = 727) and celiac disease (ncases = 11,115).

TGFB1 Functional Gene Polymorphisms (C-509T and T869C) in the Maternal Susceptibility to Pre-eclampsia in South Indian Women.

Pre-eclampsia (PE), a pregnancy-specific vascular disorder characterized by hypertension and proteinuria, is hypothesized to be the result of inadequate placental angiogenesis with attendant systemic inflammation. The pleiotropic cytokine, Transforming Growth Factor-β1 (TGF-β1), is considered to be a key candidate gene in the molecular pathogenesis of PE by virtue of its ability to not only regulate angiogenesis and apoptosis of target cells, but also by acting as a master controller of Th1/Th2 cytokine balance and production of the anti-inflammatory peripheral regulatory T cells (FOXP3+ Tregs). Based on this presumption, we screened a total of 469 pregnant women from South India that include 239 patients with PE and 230 healthy controls for the two functional polymorphisms of TGFB1 gene (C-509T and T869C).

Secukinumab, a human anti-interleukin-17A monoclonal antibody, in patients with psoriatic arthritis (FUTURE 2): a randomised, double-blind, placebo-controlled, phase 3 trial.

Background: Interleukin 17A is a proinflammatory cytokine that is implicated in the pathogenesis of psoriatic arthritis. We assessed the efficacy and safety of subcutaneous secukinumab, a human anti-interleukin-17A monoclonal antibody, in patients with psoriatic arthritis.

Methods: In this phase 3, double-blind, placebo-controlled study undertaken at 76 centres in Asia, Australia, Canada, Europe, and the USA, adults (aged ≥18 years old) with active psoriatic arthritis were randomly allocated in a 1:1:1:1 ratio with computer-generated blocks to receive subcutaneous placebo or secukinumab 300 mg, 150 mg, or 75 mg once a week from baseline and then every 4 weeks from week 4.

Maintenance of Clinical Efficacy and Radiographic Benefit Through Two Years of Ustekinumab Therapy in Patients With Active Psoriatic Arthritis: Results From a Randomized, Placebo-Controlled Phase III Trial.

Objective: To evaluate the efficacy and safety of ustekinumab through 2 years in adult patients with active psoriatic arthritis (PsA).

Methods: A total of 615 adult patients with active PsA were randomized to placebo, ustekinumab 45 mg, or ustekinumab 90 mg, at weeks 0, 4, and every 12 weeks through week 88 (last dose). At week 16, patients with <5% improvement in both tender and swollen joint counts entered blinded early escape (placebo to 45 mg, 45 mg to 90 mg, and 90 mg to 90 mg).

Differential Analysis of the Secretome of WRL68 Cells Infected with the Chikungunya Virus.

The Chikungunya virus (CHIKV) is an arthropod borne virus. In the last 50 years, it has been the cause of numerous outbreaks in tropical and temperate regions, worldwide. There is limited understanding regarding the underlying molecular mechanisms involved in CHIKV replication and how the virus interacts with its host.

Incorporating the Last Four Digits of Social Security Numbers Substantially Improves Linking Patient Data from De-identified Hospital Claims Databases.

Objective: Assess algorithms for linking patients across de-identified databases without compromising confidentiality.

Data Sources/study Setting: Hospital discharges from 11 Mayo Clinic hospitals during January 2008-September 2012 (assessment and validation data). Minnesota death certificates and hospital discharges from 2009 to 2012 for entire state (application data).

Further Evidence Supporting a Parent-of-Origin Effect in Psoriatic Disease.

Objective: To further explore the "parent-of-origin" effect in a large cohort of well-phenotyped patients with cutaneous psoriasis without arthritis (PsC) and psoriatic arthritis (PsA).

Methods: Self-reported family history was obtained from PsA patients from Toronto and Newfoundland satisfying the Classification of Psoriatic Arthritis criteria, and PsC patients from Toronto, who were examined by a rheumatologist to exclude PsA. Proportions of probands with paternally and maternally transmitted psoriatic disease were compared by McNemar's and chi-square tests.

Major histocompatibility complex associations of ankylosing spondylitis are complex and involve further epistasis with ERAP1.

Ankylosing spondylitis (AS) is a common, highly heritable, inflammatory arthritis for which HLA-B*27 is the major genetic risk factor, although its role in the aetiology of AS remains elusive. To better understand the genetic basis of the MHC susceptibility loci, we genotyped 7,264 MHC SNPs in 22,647 AS cases and controls of European descent. We impute SNPs, classical HLA alleles and amino-acid residues within HLA proteins, and tested these for association to AS status.

Integrated genomics identifies convergence of ankylosing spondylitis with global immune mediated disease pathways.

Ankylosing spondylitis(AS), a highly heritable complex inflammatory arthritis. Although, a handful of non-HLA risk loci have been identified, capturing the unexplained genetic contribution to AS pathogenesis remains a challenge attributed to additive, pleiotropic and epistatic-interactions at the molecular level. Here, we developed multiple integrated genomic approaches to quantify molecular convergence of non-HLA loci with global immune mediated diseases.

Private rare deletions in SEC16A and MAMDC4 may represent novel pathogenic variants in familial axial spondyloarthritis.

Objective: Axial spondyloarthritis (AxSpA) represents a group of inflammatory axial diseases that share common clinical and histopathological manifestations. Ankylosing spondylitis (AS) is the best characterised subset of AxSpA, and its genetic basis has been extensively investigated. Given that genome-wide association studies account for only 25% of AS heritability, the objective of this study was to discover rare, highly penetrant genetic variants in AxSpA pathogenesis using a well-characterised, multigenerational family.

Enhanced meta-analysis and replication studies identify five new psoriasis susceptibility loci.

Psoriasis is a chronic autoimmune disease with complex genetic architecture. Previous genome-wide association studies (GWAS) and a recent meta-analysis using Immunochip data have uncovered 36 susceptibility loci. Here, we extend our previous meta-analysis of European ancestry by refined genotype calling and imputation and by the addition of 5,033 cases and 5,707 controls.

Dengue serotype surveillance among patients admitted for dengue in two major hospitals in Selangor, Malaysia, 2010-2011.

Dengue serotype surveillance is important as any changes in serotype distribution may result in an outbreak or increase in severe dengue cases. This study aimed to determine circulating dengue serotypes in two hospitals in Selangor. Serum samples were collected from patients admitted for dengue at these two major public hospitals i.

TGF-β signal transduction pathways and osteoarthritis.

Osteoarthritis (OA) is the most common form of arthritis, resulting in substantial disability and economic burden worldwide. While its exact pathogenesis remains elusive, both in vitro and human population-based studies have merged to support the hypothesis that TGF-β/BMP-mediated signalling pathways play a role in the development of OA. Unraveling the TGF-β/BMP-mediated mechanism(s) in OA has great potential in identifying novel targets and developing new drugs for OA treatment.

Relationship between blood plasma and synovial fluid metabolite concentrations in patients with osteoarthritis.

Objective: To investigate the relationship between plasma and synovial fluid (SF) metabolite concentrations in patients with osteoarthritis (OA).

Methods: Blood plasma and SF samples were collected from patients with primary knee OA undergoing total knee arthroplasty. Metabolic profiling was performed by electrospray ionization tandem mass spectrometry using the AbsoluteIDQ kit.

Clinical genetic research 2: Genetic epidemiology of complex phenotypes.

Genetic factors play a substantive role in the susceptibility to common diseases. Due to recent and rapid advancements in characterization of genetic variants and large-scale genotyping platforms, multiple genes and genetic variants have now been identified for common, complex diseases. The most efficient method for gene identification at present appears to be large-scale association-based studies, which integrate genetic and epidemiological principles.