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Annals of the rheumatic diseases [journal]
- Development of patient-centred standards of care for osteoarthritis in Europe: the eumusc.net-project. [JOURNAL ARTICLE]
- Ann Rheum Dis 2014 Nov 21.
The eumusc.net project is an initiative founded by the European Community and the European League Against Rheumatism. One aim of the project was to facilitate equal standards for musculoskeletal health across Europe. The aim of this work-package was to develop patient-centred and consensus based standards of care (SOC) for osteoarthritis (OA), which should be available in a professional and a patient version.A systematic review concerning guidelines dealing with OA was conducted. Furthermore, experts in musculoskeletal diseases were contacted to ensure that 'grey' literature was not excluded. Documents that fulfilled predefined inclusion/exclusion criteria were included and all interventions for OA were extracted and categorised. Based on this list of interventions, a three round Delphi exercise with an international and multidisciplinary expert panel, including patient research partners, was performed to achieve expert consensus.Six documents were included and used for further analysis. Out of them, 46 interventions have been extracted and 10 consensus based SOC were formulated. In addition, a patient version, written in a lay-understandable wording and in the format of checklist questions was developed. An example is SOC 5: "People with OA should achieve optimal pain control using pharmacological and non-pharmacological means." The matching patient-centred checklist question reads: "Do I know how to control pain associated with OA?"The SOC for OA will be available in the 23 languages of the European Union to enhance unified information to patients and professionals and to further harmonise the treatment/care of OA within Europe.
- Rsk2 controls synovial fibroblast hyperplasia and the course of arthritis. [JOURNAL ARTICLE]
- Ann Rheum Dis 2014 Nov 20.
Arthritis is a chronic inflammatory disease characterised by immune cell infiltration and mesenchymal cell expansion in the joints. Although the role of immune cells in arthritis is well characterised, the development of mesenchymal cell hyperplasia needs to be better defined. Here, we analysed the role of the ribosomal S6 kinase Rsk2, which we found to be highly activated in joints of patients with arthritis, in the development of mesenchymal cell hyperplasia.We genetically inactivated Rsk2 in the tumour necrosis factor (TNF)-α transgenic (TNFtg) mice, an animal model for human inflammatory arthritis. Clinical and histological signs of arthritis as well as molecular markers of inflammation and joint destruction were quantified. Fibroblast-like synoviocytes (FLS) were characterised in vitro and the effect of Rsk2 deletion on the pattern of gene expression was determined.Rsk2 deficiency in TNFtg mice results in earlier and exacerbated inflammation as well as increased bone and cartilage destruction. The production of inflammatory cytokines, matrix metalloproteinases and osteoclastogenic molecules was significantly increased in vivo upon Rsk2 inactivation. Bone marrow deficient in Rsk2 could not transfer this phenotype, indicating that Rsk2 expression in mesenchymal cells controls the course of arthritis. Indeed, Rsk2 deficiency was associated with a more activated phenotype and higher proliferative capacity of FLS, thereby increasing cytokines and production of matrix proteinases.Rsk2 emerges as a key regulator of mesenchymal cell numbers in the joint and thereby could be targeted to control the inflammatory and tissue-destructive feature of joints in arthritis.
- Comorbidities in patients with gout prior to and following diagnosis: case-control study. [JOURNAL ARTICLE]
- Ann Rheum Dis 2014 Nov 14.
To determine the burden of comorbidities in patients with gout at diagnosis and the risk of developing new comorbidities post diagnosis.There were 39 111 patients with incident gout and 39 111 matched controls identified from the UK Clinical Practice Research Data-link. The risk of comorbidity before (ORs) and after the diagnosis of gout (HRs) were estimated, adjusted for age, sex, diagnosis year, body mass index, smoking and alcohol consumption.Gout was associated with adjusted ORs (95% CIs) of 1.39 (1.34 to 1.45), 1.89 (1.76 to 2.03) and 2.51 (2.19 to 2.86) for the Charlson index of 1-2, 3-4 and ≥5, respectively. Cardiovascular and genitourinary diseases, in addition to hyperlipidaemia, hypothyroidism, anaemia, psoriasis, chronic pulmonary diseases, osteoarthritis and depression, were associated with a higher risk for gout. Gout was also associated with an adjusted HR (95% CI) of 1.41 (1.34 to 1.48) for having a Charlson index ≥1. Median time to first comorbidity was 43 months in cases and 111 months in controls. Risks for incident comorbidity were higher in cardiovascular, genitourinary, metabolic/endocrine and musculoskeletal diseases, in addition to liver diseases, hemiplegia, depression, anaemia and psoriasis in patients with gout. After additionally adjusting for all comorbidities at diagnosis, gout was associated with a HR (95% CI) for all-cause mortality of 1.13 (1.08 to 1.18; p<0.001).The majority of patients with gout have worse pre-existing health status at diagnosis and the risk of incident comorbidity continues to rise following diagnosis. The range of associated comorbidities is broader than previously recognised and merits further evaluation.
- The JAK inhibitor tofacitinib suppresses synovial JAK1-STAT signalling in rheumatoid arthritis. [JOURNAL ARTICLE]
- Ann Rheum Dis 2014 Nov 14.
Tofacitinib is an oral Janus kinase (JAK) inhibitor for the treatment of rheumatoid arthritis (RA). The pathways affected by tofacitinib and the effects on gene expression in situ are unknown. Therefore, tofacitinib effects on synovial pathobiology were investigated.A randomised, double-blind, phase II serial synovial biopsy study (A3921073; NCT00976599) in patients with RA with an inadequate methotrexate response. Patients on background methotrexate received tofacitinib 10 mg twice daily or placebo for 28 days. Synovial biopsies were performed on Days -7 and 28 and analysed by immunoassay or quantitative PCR. Clinical response was determined by disease activity score and European League Against Rheumatism (EULAR) response on Day 28 in A3921073, and at Month 3 in a long-term extension study (A3921024; NCT00413699).Tofacitinib exposure led to EULAR moderate to good responses (11/14 patients), while placebo was ineffective (1/14 patients) on Day 28. Tofacitinib treatment significantly reduced synovial mRNA expression of matrix metalloproteinase (MMP)-1 and MMP-3 (p<0.05) and chemokines CCL2, CXCL10 and CXCL13 (p<0.05). No overall changes were observed in synovial inflammation score or the presence of T cells, B cells or macrophages. Changes in synovial phosphorylation of signal transducer and activator of transcription 1 (STAT1) and STAT3 strongly correlated with 4-month clinical responses (p<0.002). Tofacitinib significantly decreased plasma CXCL10 (p<0.005) at Day 28 compared with placebo.Tofacitinib reduces metalloproteinase and interferon-regulated gene expression in rheumatoid synovium, and clinical improvement correlates with reductions in STAT1 and STAT3 phosphorylation. JAK1-mediated interferon and interleukin-6 signalling likely play a key role in the synovial response.NCT00976599.
- Golimumab administered subcutaneously every 4 weeks in ankylosing spondylitis: 5-year results of the GO-RAISE study. [JOURNAL ARTICLE]
- Ann Rheum Dis 2014 Nov 11.
Assess golimumab efficacy/safety through 5 years in patients with active ankylosing spondylitis (AS).356 patients with AS were randomly assigned to placebo, golimumab 50 mg or 100 mg every 4 weeks. At week 16, patients with inadequate response early escaped with blinded dose adjustments (placebo to 50 mg, 50 mg to 100 mg). At week 24, all patients receiving placebo crossed over to 50 mg. Blinded active therapy continued through week 104; from week 104 to week 252, the golimumab dose could be adjusted. Intent-to-treat and observed efficacy data were assessed by randomised treatment groups.At week 256, and with >4.5 years of golimumab, overall intent-to-treat Assessment in SpondyloArthritis international Society criteria for 20% improvement (ASAS20) and ASAS40 response rates were 66.0% (235/356) and 57.0% (203/356), respectively; Bath AS Disease Activity Index 50% improvement response was 55.9% (199/356). Observed response rates among the 255 (72%) patients who continued golimumab through week 252 were consistent, albeit somewhat higher. Among patients who increased golimumab from 50 to 100 mg, 60.6% (20/33) and 44.7% (17/38) achieved ASAS20/ASAS40 responses, respectively, following ≥2 consecutive doses of golimumab 100 mg. Golimumab safety through week 268 was similar to that through week 24 regardless of dose.Clinical improvements observed in patients treated with golimumab through week 24 were sustained through week 256 (5 years). Long-term golimumab safety is consistent with that of other established tumour-necrosis-factor-antagonists.ClinicalTrials.gov: NCT00265083.
- Downregulation of miR-193b in systemic sclerosis regulates the proliferative vasculopathy by urokinase-type plasminogen activator expression. [JOURNAL ARTICLE]
- Ann Rheum Dis 2014 Nov 10.
To investigate the role of microRNA-193b-3p (miR-193b) in the vascular pathophysiology of systemic sclerosis (SSc).Expression of miR-193b in skin biopsies and fibroblasts from patients with SSc and normal healthy (NH) controls were determined by real-time PCR. Transfection with miR-193b precursor and inhibitor were used to confirm targets of miR-193b. Proliferative effects of urokinase-type plasminogen activator (uPA) were determined by water-soluble tetrazolium salt-1 assay and by analysis of proliferating cell nuclear antigen expression. Fluorescence activated cell sorting analysis was performed to investigate the effect of uPA on apoptosis. For inhibition of the uPA-cellular receptor for uPA (uPAR) pathway, uPAR neutralising antibodies and low molecular weight uPA were used.We found that miR-193b was downregulated in SSc fibroblasts and skin sections as compared with NH controls. The expression of miR-193b was not affected by major profibrotic cytokines and hypoxia. Induction of miR-193b in SSc fibroblasts suppressed, and accordingly, knockdown of miR-193b increased the levels of messenger RNA and protein for uPA. uPA was found to be upregulated in SSc as compared with NH controls in a transforming growth factor-β dependent manner, and uPA was strongly expressed in vascular smooth muscle cells in SSc skin section. Interestingly, uPA induced cell proliferation and inhibited apoptosis of human pulmonary artery smooth muscle cells, and these effects were independent of uPAR signalling.In SSc, the downregulation of miR-193b induces the expression of uPA, which increases the number of vascular smooth muscle cells in an uPAR-independent manner and thereby contributes to the proliferative vasculopathy with intimal hyperplasia characteristic for SSc.