pinecone/core-2020-05-10-deduplication huggingface dataset:
Long intergenic non-coding RNAs mediate the human chondrocyte inflammatory response and are differentially expressed in osteoarthritis cartilage

ABSTRACT Objective: To identify long non-coding RNAs (lncRNAs) including intergenic lncRNAs (lincRNAs), antisense and pseudogenes associated with the inflammatory response in human primary OA chondrocytes and to explore their expression and function in OA. Methods: OA cartilage was obtained from hip and knee OA patients following joint replacement surgery. Non-OA cartilage was obtained from post-mortem donors and neck of femur fracture patients. Primary OA chondrocytes were isolated by collagenase digestion. LncRNA expression analysis was performed by RNA sequencing (RNAseq) and qRT-PCR. Modulation of lncRNA chondrocyte expression was achieved using LNA longRNA GapmeRs (Exiqon). Cytokine production was measured by Luminex. Results: RNAseq identified 983 lncRNAs in primary human hip OA chondrocytes, of which 183 had previously not been identified. Following IL-1β stimulation we identified 125 lincRNAs that were differentially expressed. The lincRNAs PACER, and two novel chondrocyte inflammation-associated lincRNAs (CILinc01 and CILinc02) were differentially expressed in both knee and hip OA cartilage compared to non-OA cartilage. In primary OA chondrocytes, these lincRNAs were rapidly and transiently induced in response to multiple pro-inflammatory cytokines. Knockdown of CILinc01 and CILinc02 expression in human chondrocytes significantly enhanced the IL-1-stimulated secretion of pro-inflammatory cytokines. Conclusion: The inflammatory response in human OA chondrocytes is associated with widespread changes in the profile of lncRNAs including PACER, CILinc01 and CILinc02. Differential expression of CILinc01 and CIinc02 in hip and knee OA cartilage, and their role in modulating cytokine production during the chondrocyte inflammatory response suggest they may play an important role in mediating inflammation driven cartilage degeneration in OA
Group for research and assessment of psoriasis and psoriatic arthritis:treatment recommendations for psoriatic arthritis 2015

OBJECTIVE: Update the 2009 Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) treatment recommendations for the spectrum of manifestations affecting patients with psoriatic arthritis (PsA). METHODS: GRAPPA rheumatologists, dermatologists, and PsA patients drafted overarching principles for the management of PsA patients based on consensus at face-to-face meetings and via online surveys. We published literature reviews regarding treatment for the key domains of PsA (arthritis, spondylitis, enthesitis, dactylitis, skin, and nail disease), and convened a new group to identify pertinent comorbidities and their effect on treatment. Finally, we drafted treatment recommendations for each of the clinical manifestations and assessed the level of agreement for the overarching principles and treatment recommendations among GRAPPA members, with an online questionnaire. RESULTS: Six overarching principles had at least 80% agreement among both health care professionals (HCPs; n=135) and patient research partners (PRPs; n=10). We developed treatment recommendations and a schema incorporating these principles for arthritis, spondylitis, enthesitis, dactylitis, skin, and nail disease, and comorbidities in the setting of PsA, using the GRADE process. Over 80% agreement was reached for approval of the individual recommendations and the overall schema. CONCLUSION: Herein, we present overarching principles and updated treatment recommendations for the key manifestations of PsA, including related comorbidities, based on a literature review and consensus of GRAPPA members (rheumatologists, dermatologists, other HCPs, and PRPs). Further updates are anticipated as the therapeutic landscape in PsA evolves
Histone demethylation and TLR8-dependent crosstalk in monocytes promotes trans-differentiation of fibroblasts in systemic sclerosis via Fra2.

Objectives: To investigate whether epigenetic changes can modulate monocytes to produce tissue-inhibitor of metalloproteinase-1 (TIMP-1) via Fra2 (AP-1 family member), a novel downstream mediator promoting fibrogenesis.\ud
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Methods: AP-1 transcription factors and TIMP-1 expression was measured in monocytes from systemic sclerosis (SSc) patients and healthy controls (HC). Involvement of Fra2 in the regulation of TIMP-1 following TLR8 agonist treatment was investigated using luciferase activity assay and ChIP analysis. Expression of TIMP-1 and Fra2 was determined in response to TLR8 treatment and different histone modifications including 3'deazaneplanocin (DZNep) and apicidin. HC fibroblasts were co-cultured with DZNep plus TLR8-treated HC monocytes.\ud
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Results: Upregulation of Fra2 was detected in bleomycin-challenged mice and SSc skin biopsies. Enhanced expression of Fra2 and TIMP-1 was correlated in SSc monocytes (p=0.021). The expression of Fra1 was significantly (p=0.037) reduced in SSc monocytes. Inhibiting AP-1 activity reduced TIMP-1 production in TLR8 stimulated HC and SSc monocytes. ChIP experiments revealed binding of Fra-2 to the TIMP-1 promoter. Combination of DZNep plus TLR8 enhanced Fra2 and TIMP-1 expression in HC monocytes, whereas TLR8 plus apicidin repressed Fra2 and TIMP-1 expression. Finally, DZNep plus TLR8-treated HC monocytes induced strong production of α-SMA in dermal fibroblasts, which was inhibited by TIMP-1 blocking antibody.\ud
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Conclusions: These data demonstrate a novel role of histone demethylation induced by DZNep on Fra2-mediated TIMP-1 production by monocytes in the presence of TLR8 agonist. This consequently orchestrates fibroblasts' trans-differentiation, a key event in the pathogenesis of SSc
Interleukin-9 Overexpression and Th9 Polarization Characterize the Inflamed Gut, the Synovial Tissue, and the Peripheral Blood of Patients With Psoriatic Arthritis

Objective. To investigate the expression and tis- sue distribution of Th9-related cytokines in patients with psoriatic arthritis (PsA).\ud
Methods. Quantitative gene expression analysis of Th1, Th17, and Th9 cytokines was performed in intestinal biopsy samples obtained from patients with PsA, HLA2B272positive patients with ankylosing spondylitis (AS), patients with Crohn’s disease (CD), and healthy controls. Expression and tissue distribu- tion of interleukin-23 (IL-23), IL-17, IL-22, IL-9, and IL-9 receptor (IL-9R) were evaluated by immunohisto- chemistry and confocal microscopy. Flow cytometry was used to study the frequency of Th9 cells among periph- eral blood, lamina propria, and synovial fluid mononuclear cells. The functional relevance of IL-9R expression on epithelial cells was assessed in functional in vitro studies. Th9 cells in synovial tissue from patients with PsA were also studied.\ud
Results. Subclinical gut inflammation in PsA patients was characterized by a clear Th17 and Th22, but not Th1, polarized immune response. Unlike AS and CD, a strong and significant up-regulation of IL-9 was observed in PsA gut, especially among infiltrating mononuclear cells, high endothelial venules, and Pan- eth cells. IL-92positive mononuclear cells were demon- strated to be in large part Th9 cells. IL-9 overexpression was accompanied by significant Paneth cell hyperplasia. Paneth cells strongly overexpressed IL-9R, and stimula- tion of epithelial cells, isolated from PsA patients, with IL-9 resulted in overexpression of a-defensin 5 and IL-23p19. Peripheral and synovial expansion of a4b71 Th9 cells was also observed in patients with PsA. Increased expression of IL-9 and IL-9R was also found in synovial tissue.\ud
Conclusion. Strong IL-9/Th9 polarization seems to be the predominant immunologic signature in patients in PsA
The effect of comedication with a csDMARD on drug retention and clinical effectiveness of anti-TNF therapy in patients with axial spondyloarthritis

Objective To explore the effect of comedication with conventional synthetic disease modifying antirheumatic drugs (csDMARDs) on drug retention and clinical effectiveness of tumour necrosis factor inhibitors (TNFi) in patients with axial spondyloarthritis (axSpA). Methods Inclusion of all patients starting treatment with a TNFi in a large prospective axSpA cohort (SCQM-axSpA). Crude drug retention was analyzed using the Kaplan Meier method and in adjusted analyses we used Cox proportional hazard regression to model TNFi discontinuation. We evaluated multiple disease activity measures and validated clinical response criteria over time. Results A total of 2765 TNFi treatment courses were included from 1914 axSpA patients, with 20.4% in combination with a csDMARD. In unadjusted analyses, the monotherapy group had significantly shorter median TNFi retention time (32.7 months), compared to the co-therapy group (39.1 months) (p= 0.04). In multivariate adjusted analyses, the monotherapy group had significantly lower TNFi retention, with a hazard ratio (HR) of 1.17 (95%CI: 1.01;1.35). This effect was even larger when considering only Infliximab treated patients, with a HR for monotherapy of 1.36 (95%CI: 1.06;1.74). Clinical response rates were almost identical at 1 year with a change in the Bath Ankylosing Spondylitis Disease Activity Index of -2.02 and -2.00 (p=0.83) and a change in the Ankylosing Spondylitis Disease Activity Score using CRP of -1.14 and -1.12 (p=0.45) in the monotherapy and co-therapy groups respectively. Conclusion We demonstrate an association between the combination of a TNFi with csDMARDs and improved drug retention in axSpA patients, particularly in the subgroup of patients with Infliximab. This article is protected by copyright. All rights reserved
Nailfold videocapillaroscopic and other clinical risk factors for digital ulcers in systemic sclerosis: a multicenter, prospective cohort study

OBJECTIVE: To identify nailfold videocapillaroscopic and other clinical risk factors for new digital ulcers (DUs) in a 6-month period in patients with systemic sclerosis (SSc), the videoCAPillaroscopy (CAP) study.\ud
METHODS: Overall 623 patients with SSc from 59 centers (14 countries) were stratified into two groups: "DU History" and "No-DU History". At enrollment, patients underwent detailed nailfold videocapillaroscopic evaluation and an assessment of demographics, DU status, and clinical and SSc characteristics. Risk factors for developing new DUs were assessed using univariable and multivariable logistic regression analyses.\ud
RESULTS: Of the "DU History" group (n = 468), 79.5% were female, the mean age was 54.0 ± 13.7 years, 59.8% had limited cutaneous SSc, and 22% developed a new DU during follow-up. The strongest risk factors for new DUs identified by multivariable logistic regression (MLR) in the "DU History" group included: mean number of capillaries/mm in the middle finger of the dominant hand, number of DUs (0, 1, 2, ≥3), and presence of critical digital ischemia. The receiver operating characteristic area under the curve (ROC-AUC) (95% confidence interval [CI]) of the final MLR model was 0.738 (0.681-0.795). Internal validation through bootstrap generated a ROC-AUC (95% CI) of 0.633 (0.510-0.756).\ud
CONCLUSION: This international, prospective study including detailed nailfold videocapillaroscopic evaluation and extensive clinical characterization of patients with SSc identified the mean number of capillaries/mm in the middle finger of the dominant hand, number of DUs and presence of critical digital ischemia at enrollment as risk factors for the development of new DUs. This article is protected by copyright. All rights reserved
anti-eukaryotic initiation factor 2B autoantibodies are associated with interstitial lung disease in patients with systemic sclerosis

Objective Anti-nuclear autoantibodies are known to occur in 85-99% of Systemic Sclerosis (SSc) patients, with each SSc autoantibody correlating with a distinct clinical subset of patients. The objective of this study was to investigate novel SSc autoantibodies in the remaining autoantibody negative patients and establish clinical associations. Methods Serum samples and clinical data were collected from 548 SSc patients. Sera were tested for known SSc autoantibodies by routine serological techniques, with negative samples being further investigated by radiolabelled protein immunoprecipitation (IPP). Sera that immunoprecipitated a novel 30 kDa band were analysed by indirect immunofluorescence and IPP using depleted cell extracts to establish a common reactivity. Mass spectrometry (MS) was used to identify the novel autoantigen and findings were confirmed using commercial antibodies. Sera from 426 patients with other forms of connective tissue disease, 103 patients with rheumatoid arthritis, 114 patients with idiopathic ILD and 150 healthy controls were serotyped as controls. Results A novel autoantigen with a molecular weight of ∼30 kDa was recognised by seven sera with SSc, six of whom had interstitial lung disease (ILD) and by no controls. Six of the patients had diffuse cutaneous involvement and four had overlap features with other autoimmune diseases. Immunodepletion experiments indicated that all samples targeted the same autoantigen and MS identified the novel autoantigen as eIF2B (Eukaryotic Initiation Factor 2B). Conclusion We report a novel autoantibody (anti-eIF2B) in a small number of patients with SSc (approximately 1%) that is closely associated with diffuse cutaneous manifestations and the presence of ILD
The Phenotype and Genotype of Mevalonate Kinase Deficiency: A Series of 114 Cases From the Eurofever Registry

OBJECTIVE:Mevalonate kinase deficiency (MKD) is a rare metabolic disease characterized by recurrent inflammatory episodes. This study was undertaken to describe the genotype, phenotype, and response to treatment in an international cohort of MKD patients.\ud
METHODS:All MKD cases were extracted from the Eurofever registry (Executive Agency for Health and Consumers project no. 2007332), an international, multicenter registry that retrospectively collects data on children and adults with autoinflammatory diseases.\ud
RESULTS:The study included 114 MKD patients. The median age at onset was 0.5 years. Patients had on average 12 episodes per year. Most patients had gastrointestinal symptoms (n = 112), mucocutaneous involvement (n = 99), lymphadenopathy (n = 102), or musculoskeletal symptoms (n = 89). Neurologic symptoms included headache (n = 43), cerebellar syndrome (n = 2), and mental retardation (n = 4). AA amyloidosis was noted in 5 patients, almost twice as many as expected from findings in previous cohorts. Macrophage activation syndrome occurred in 1 patient. Patients were generally well between attacks, but 10-20% of the patients had constitutional symptoms, such as fatigue, between fever episodes. Patients with p.V377I/p.I268T compound heterozygosity had AA amyloidosis significantly more often. Patients without a p.V377I mutation more often had severe musculoskeletal involvement. Treatment with nonsteroidal antiinflammatory drugs relieved symptoms. Steroids given during attacks, anakinra, and etanercept appeared to improve symptoms and could induce complete remission in patients with MKD.\ud
CONCLUSION:We describe the clinical and genetic characteristics of 114 MKD patients, which is the largest cohort studied so far. The clinical manifestations confirm earlier reports. However, the prevalence of AA amyloidosis is far higher than expected
Frontiers of antifibrotic therapy in systemic sclerosis

Although fibrosis is becoming increasingly recognized as a major cause of morbidity and mortality in modern societies, targeted anti-fibrotic therapies are still not approved for most fibrotic disorders. However, intense research over the last decade has improved our understanding of the underlying pathogenesis of fibrotic diseases. We now appreciate fibrosis as the consequence of a persistent tissue repair responses, which, in contrast to normal wound healing, fails to be effectively terminated. Profibrotic mediators released from infiltrating leukocytes, activated endothelial cells and degranulated platelets may predominantly drive fibroblast activation and collagen release in early stages, whereas endogenous activation of fibroblasts due epigenetic modifications and biomechanical or physical factors such as stiffening of the extracellular matrix and hypoxia may play pivotal role for disease progression in later stages. In the present review, we discuss novel insights into the pathogenesis of fibrotic diseases using systemic sclerosis (SSc) as example for an idiopathic, multisystem disorder. We set a strong translational focus and predominantly discuss approaches with very high potential for rapid transfer from bench-to-bedside. We highlight the molecular basis for ongoing clinical trials in SSc and also provide an outlook on upcoming trials
Cam Deformity and Acetabular Dysplasia as Risk Factors for Hip Osteoarthritis

Objective: Cam deformity and acetabular dysplasia have been recognized as relevant risk factors for hip osteoarthritis (OA) in a few prospective studies with limited sample sizes. To date, however, no evidence is available from prospective studies regarding whether the magnitude of these associations differs according to sex, body mass index (BMI), and age. Methods: Participants in the Rotterdam Study cohort including men and women ages 55 years or older without OA at baseline (n=4,438) and a mean follow-up of 9.2 years were included in the study. Incident radiographic OA was defined as a Kellgren/Lawrence grade of ≥2 or a total hip replacement at follow-up. Alpha and center-edge angles were measured to determine the presence of cam deformity and acetabular dysplasia/pincer deformity, respectively. Odds ratios (ORs) were calculated to assess the associations between both deformities and the development of OA. Results: Subjects with cam deformity (OR 2.11, 95% confidence interval [95% CI] 1.55-2.87) and those with acetabular dysplasia (OR 2.19, 95% CI 1.50-3.21) had a 2-fold increased risk of developing OA compared with subjects without deformity, while pincer deformity did not increase the risk of OA. Stratification analyses showed that the associations of cam deformity and acetabular dysplasia with OA were driven by younger individuals, whereas BMI did not influence the associations. Female sex appears to modify the risk of hip OA related to acetabular dysplasia. Conclusion: Individuals with cam deformity and those with acetabular dysplasia are predisposed to OA; these associations were independent of other well-known risk factors. Interestingly, both deformities predisposed to OA only in relatively young individuals. Therefore, early identification of these conditions is important
Polymorphisms in the F pocket of HLA-B27 subtypes strongly affect assembly, chaperone interactions and heavy-chain misfolding

This work was in part funded by awards to Dr Antoniou (Arthritis Research UK Fellowship 15293) and Dr Powis (Scottish Government Chief Scientist Office ETM/56).Objective - HLA-B27 is associated with the inflammatory spondyloarthropathies (SpAs). Of significance, subtypes HLA-B*27:06 and HLA-B*27:09 are not associated with the SpAs. These subtypes primarily differ from the HLA-B*27:05 disease associated allele at residues 114 and 116 of the heavy chain, part of the F pocket of the antigen-binding groove. Dimerisation of HLA-B27 during assembly has been implicated in disease onset. This study investigated the factors influencing differences in dimerisation between disease associated and non-associated HLA-B27 alleles. Methods – HLA-B*27:05 and mutants resembling the HLA-B*27:06 and 09 subtypes were expressed in the rat C58 T cell line, the human CEM T cell line and its calnexin deficient variant CEM.NKR. Immunoprecipitation, pulse chase, flow cytometry and immunoblotting were performed to study the assembly kinetics, heavy chain dimerisation and chaperone associations. Results - By expressing HLA-B*27:05, 06-like and 09 alleles on a restrictive rat TAP peptide transporter background, we demonstrate that a tyrosine expressed at p116 or together with an aspartic acid residue at p114 inhibited HLA-B27 dimerisation and increased the assembly rate. F pocket residues alter the associations with chaperones of the early MHC class I folding pathway. Calnexin was demonstrated to participate in endoplasmic reticulum (ER) stress mediated degradation of dimers, whereas the oxidoreductase ERp57 does not appear to influence dimerization. Conclusion - Residues within the F pocket of the peptide-binding groove differing between disease-associated and non-disease-associated HLA-B27 subtypes can influence the assembly process and heavy chain dimerisation, events which have been linked to the initiation of disease pathogenesis.PostprintPeer reviewe
Twenty-year outcome and association between early treatment and mortality and disability in an inception cohort of patients with rheumatoid arthritis: Results from the Norfolk Arthritis Register

Objective – To describe the outcome of patients with rheumatoid arthritis (RA) over 20 years from symptom onset; to assess the association between early treatment (DMARDs/steroids) and mortality and disability over follow-up. Methods – Patients from the Norfolk Arthritis Register recruited from 1990-94 who met the 2010 ACR/EULAR RA criteria at baseline were included in this analysis. Demographic/clinical variables were collected at baseline and years 1-3, 5, 7, 10, 15 and 20. Disease activity (swollen/tender joint counts (SJC/TJC)), disability (HAQ) and mortality over 20 years are described. Association between treatment group (early treatment (ET) = treatment ≤6 months after symptom onset; late treatment (LT) = treatment >6 months; never treatment (NT) = no treatment) and mortality and disability were assessed using weighted pooled logistic regression and weighted multilevel mixed-effects linear regression respectively. Inverse weights were used to account for indication/censoring confounding. Results – This study included 602 patients with RA (median (IQR) age = 56 (44, 68) years; 65.9% women). Median disease activity was low over follow-up (SJC 1-3, TJC 3-6). Median HAQ rose after year 1 but remained at low/moderate levels (median 1.25 after year 10). There was reduced mortality risk in the ET and LT compared to NT group. ET group had comparable HAQ to NT group over follow-up (β 0.03, 95% CI -0.06, 0.12); LT group had increased disability (LT vs NT β 0.10, 95% CI 0.02, 0.17). Conclusion – This study indicates the importance of early treatment regarding long-term outcomes of patients with RA. This article is protected by copyright. All rights reserved