21 research outputs found

    Serum microRNA screening and functional studies reveal miR-483-5p as a potential driver of fibrosis in systemic sclerosis

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    Abstract Objective MicroRNAs (miRNAs) are regulatory molecules, which have been addressed as potential biomarkers and therapeutic targets in rheumatic diseases. Here, we investigated the miRNA signature in the serum of systemic sclerosis (SSc) patients and we further assessed their expression in early stages of the disease. Methods The levels of 758 miRNAs were evaluated in the serum of 26 SSc patients as compared to 9 healthy controls by using an Openarray platform. Three miRNAs were examined in an additional cohort of 107 SSc patients and 24 healthy donors by single qPCR. MiR-483-5p expression was further analysed in the serum of patients with localized scleroderma (LoS) (n = 22), systemic lupus erythematosus (SLE) (n = 33) and primary Sjogren's syndrome (pSS) (n = 23). The function of miR-483-5p was examined by transfecting miR-483-5p into primary human dermal fibroblasts and pulmonary endothelial cells. Results 30 miRNAs were significantly increased in patients with SSc. Of these, miR-483-5p showed reproducibly higher levels in an independent SSc cohort and was also elevated in patients with preclinical-SSc symptoms (early SSc). Notably, miR-483-5p was not differentially expressed in patients with SLE or pSS, whereas it was up-regulated in LoS, indicating that this miRNA could be involved in the development of skin fibrosis. Consistently, miR-483-5p overexpression in fibroblasts and endothelial cells modulated the expression of fibrosis-related genes. Conclusions Our findings showed that miR-483-5p is up-regulated in the serum of SSc patients, from the early stages of the disease onwards, and indicated its potential function as a fine regulator of fibrosis in SSc

    Galectin-9 is an easy to measure biomarker for the interferon signature in systemic lupus erythematosus and antiphospholipid syndrome

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    The interferon (IFN) signature is related to disease activity and vascular disease in systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS) and represents a promising therapeutic target. Quantification of the IFN signature is currently performed by gene expression analysis, limiting its current applicability in clinical practice. Therefore, the objective of this study was to establish an easy to measure biomarker for the IFN signature

    Beliefs About Medicines in Patients with Psoriasis Treated with Methotrexate or Biologics: A Cross-sectional Survey Study

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    Methotrexate (MTX) and biologics are frequently used treatments for psoriasis. Exploring patients’ beliefs about their treatment may help to elucidate patients’ attitudes towards these therapies. A cross-sectional survey was conducted using the Beliefs about Medicines Questionnaire-Specific (BMQ-Specific) in patients treated with methotrexate or biologics. BMQ-Specific scores (Necessity and Concerns scales) were calculated and patients were classified as “accepting”, “indifferent”, “ambivalent” or “sceptical” towards their treat­ment. Biologics users scored higher on the Necessity scale than did methotrexate users. Both groups had lower Concerns scores than Necessity scores. A high Necessity scale was associated with a low Psoriasis Area and Severity Index score in both groups and long treatment duration in the methotrexate group. Although this study cannot make a direct comparison, it was observed that most patients on biologics could be classified as “accepting” (59%), and most patients on MTX could be classified as “indifferent” (47%). In conclusion, the BMQ-Specific is useful to identify patients with a sceptical, ambivalent or indifferent profile. These profiles may negatively influence patient’s attitude towards their medication

    Drug Survival and Predictors of Drug Survival for Methotrexate Treatment in a Retrospective Cohort of Adult Patients with Localized Scleroderma

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    Data regarding the efficacy and safety of methotrexate (MTX) in adults with localized scleroderma (LoS) is scarce. This study gathered data from a retrospective cohort of adult patients with LoS (n?=?107), treated with MTX (1993-2015). MTX drug survival and predictors thereof were analysed. After 1 and 2 years, 26% and 63% of patients stopped MTX due to disease remission, respectively. Patients with younger age at MTX initiation (hazard ratio (HR) 1.159 (95% confidence interval (CI) 1.052-1.277)) and those with no other autoimmune diseases (HR 3.268 (95% CI 1.334-8.009)) more often stopped MTX due to disease remission. In addition, 24% of patients stopped MTX due to treatment failure within one year. Patients with circumscribed superficial LoS (HR 0.221 (95% CI 0.081-0.601)) experienced treatment failure less often than those with other LoS subtypes. Finally, adding folic acid (HR 0.184 (95% CI 0.079-0.425)) and reducing treatment delay (HR 1.056 (95% CI 1.004-1.112)) could be the most important factors in minimizing MTX treatment failure in LoS in clinical practice

    Use of mycophenolate mofetil in patients with severe localized scleroderma resistant or intolerant to methotrexate

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    To assess the efficacy and safety of mycophenolate mofetil (MMF) in patients with localized scleroderma (LoS) resistant or intolerant to previous treatment with methotrexate (MTX). A case series of patients with LoS treated with MMF. Outcome was assessed through clinical examination. Adverse events were documented. Seven patients with LoS were treated with MMF. Median age at MMF initiation was 15 years (range 7–74 years). Three patients received MMF due to MTX ineffectiveness and 4 due to MTX intolerance. Disease remission was achieved in 4 patients and maintained in one patient. One patient showed a favourable response, but had to discontinue treatment due to elevated liver enzymes. The remaining patient experienced disease progression. MMF was shown to improve the clinical condition of patients with refractory LoS and may be a relatively safe alternative in patients who are intolerant to MTX

    High-dose intravenous pulse methotrexate in patients with eosinophilic fasciitis

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    IMPORTANCE Eosinophilic fasciitis (EF) is a connective tissue disorder in which conventional treatment leads to disappointing results in a proportion of patients. Therefore, we investigated high-dose intravenous (IV) pulse methotrexate (MTX) as a treatment for EF. OBJECTIVE To examine safety and effects of monthly high-dose IV pulse MTX in EF. DESIGN, SETTING, AND PARTICIPANTS For this prospective single-Arm study,we recruited 12 patients diagnosed with biopsy specimen-proven EF between 2006 and 2009 from the Department of Dermatology and Rheumatology at the Radboud University Medical Centre. INTERVENTIONS Intravenous MTX (4mg/kg) monthly for 5 months with folinic acid rescue 24 hours after MTX administration. MAIN OUTCOMES AND MEASURES The primary outcomewas improvement of the modified skin score at month 5 vs baseline. Secondary outcomes were durometry, range of motion, visual analog scale scores for disease activity, and 36-Item Short Form Survey health questionnaires. RESULTS Overall, 12 patients (11 women between 37-69 years old) received a median (range) monthly dose of 288 (230-336)mg MTX. Median (range) modified skin score improved from 17.5 (8.0-24.0) at baseline to 8.5 (1.0-20.0) at month 5 (P = .001). Secondary outcome measures improved significantly, except for durometer scores and range of motion of the elbows. Adverse events included gastrointestinal symptoms (n = 9), mild stomatitis (n = 5), and alopecia (n = 4). CONCLUSIONS AND RELEVANCE High-dose IV pulse MTX is a safe and effective treatment option in EF

    High-dose intravenous pulse methotrexate in patients with eosinophilic fasciitis

    No full text
    IMPORTANCE Eosinophilic fasciitis (EF) is a connective tissue disorder in which conventional treatment leads to disappointing results in a proportion of patients. Therefore, we investigated high-dose intravenous (IV) pulse methotrexate (MTX) as a treatment for EF. OBJECTIVE To examine safety and effects of monthly high-dose IV pulse MTX in EF. DESIGN, SETTING, AND PARTICIPANTS For this prospective single-Arm study,we recruited 12 patients diagnosed with biopsy specimen-proven EF between 2006 and 2009 from the Department of Dermatology and Rheumatology at the Radboud University Medical Centre. INTERVENTIONS Intravenous MTX (4mg/kg) monthly for 5 months with folinic acid rescue 24 hours after MTX administration. MAIN OUTCOMES AND MEASURES The primary outcomewas improvement of the modified skin score at month 5 vs baseline. Secondary outcomes were durometry, range of motion, visual analog scale scores for disease activity, and 36-Item Short Form Survey health questionnaires. RESULTS Overall, 12 patients (11 women between 37-69 years old) received a median (range) monthly dose of 288 (230-336)mg MTX. Median (range) modified skin score improved from 17.5 (8.0-24.0) at baseline to 8.5 (1.0-20.0) at month 5 (P = .001). Secondary outcome measures improved significantly, except for durometer scores and range of motion of the elbows. Adverse events included gastrointestinal symptoms (n = 9), mild stomatitis (n = 5), and alopecia (n = 4). CONCLUSIONS AND RELEVANCE High-dose IV pulse MTX is a safe and effective treatment option in EF

    Induction of Inflammation and Fibrosis by Semaphorin 4A in Systemic Sclerosis

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    OBJECTIVE: To analyze the potential role of semaphorin 4A (Sema4A) in inflammatory and fibrotic processes involved in the pathology of systemic sclerosis (SSc). METHODS: Sema4A levels in the plasma of healthy controls (n = 11) and SSc patients (n = 20) were determined by enzyme-linked immunosorbent assay (ELISA). The expression of Sema4A and its receptors in monocytes and CD4+ T cells from healthy controls and SSc patients (n = 6-7 per group) was determined by ELISA and flow cytometry. Th17 cytokine production by CD4+ T cells (n = 5-7) was analyzed by ELISA and flow cytometry. The production of inflammatory mediators and extracellular matrix (ECM) components by dermal fibroblast cells (n = 6) was analyzed by quantitative polymerase chain reaction, ELISA, Western blotting, confocal microscopy, and ECM deposition assay. RESULTS: Plasma levels of Sema4A, and Sema4A expression by circulating monocytes and CD4+ T cells, were significantly higher in SSc patients than in healthy controls (P < 0.05). Inflammatory mediators significantly up-regulated the secretion of Sema4A by monocytes and CD4+ T cells from SSc patients (P < 0.05 versus unstimulated SSc cells). Functional assays showed that Sema4A significantly enhanced the expression of Th17 cytokines induced by CD3/CD28 in total CD4+ T cells as well in different CD4+ T cell subsets (P < 0.05 versus unstimulated SSc cells). Finally, Sema4A induced a profibrotic phenotype in dermal fibroblasts from both healthy controls and SSc patients, which was abrogated by blocking or silencing the expression of Sema4A receptors. CONCLUSION: Our findings indicate that Sema4A plays direct and dual roles in promoting inflammation and fibrosis, 2 main features of SSc, suggesting that Sema4A might be a novel therapeutic target in SSc
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