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ID PMID Title PublicationDate abstract
32735144 HR-pQCT in vivo imaging of periarticular bone changes in chronic inflammatory diseases: D 2021 Mar Imaging is essential for the assessment of bone and inflammatory joint diseases. There are several imaging techniques available that differ regarding resolution, radiation exposure, time expending, precision, cost, availability or ability to predict disease progression. High-resolution peripheral quantitative computed tomography (HR-pQCT) that was introduced in 2004 allows the in vivo evaluation of peripheral bone microarchitecture and demonstrated high precision in assessing bone changes in inflammatory musculoskeletal diseases. This review summarizes the use of HR-pQCT for the evaluation of the hand skeleton in inflammatory joint diseases. We conducted a review of the literature regarding the protocols that involve hand joints assessment and evaluation of bone changes as erosions and osteophytes in chronic inflammatory diseases. Apart from measuring bone density and structure of the radius and the tibia, HR-pQCT has contributed to assessment of bone erosions and osteophytes, considered the hallmark of diseases as rheumatoid arthritis and psoriatic arthritis, respectively. In this way, there are some conventions recently established by rheumatic study groups that we just summarized here in order to standardize HR-pQCT measurements.
32839939 Rheumatological Manifestations in HIV-Positive Patients: A Single-Center Study. 2020 Oct INTRODUCTION: Rheumatological manifestations (RM) are very common in human immunodeficiency virus (HIV)-infected patients. The aim of this study was to determine the clinical spectrum of musculoskeletal involvement and relationship with the Centers for Disease Control and Prevention (CDC) stage and CD4+ cells and other factors. METHODS: A cross-sectional study was conducted involving 75 patients of over 18 years of either sex with confirmed HIV status attending a tertiary care hospital in north India in one calendar year. Baseline demographic details, relevant history including duration of combination antiretroviral therapy (cART), RM, joints involved, CD4 cell count, and biochemical parameters were evaluated. RESULTS: Of 75 patients, 54 were male and 21 were female (mean age 33.15 ± 5.00 years, range 21-48 years). Most common RM was arthralgia (26.67%), followed by myalgia (18.67%), and arthritis (13.33%). Keratoderma blennorrhagicum (1.33%), tendo-achilles tendinitis (2.67%), and plantar fasciitis (2.67%) were other manifestations. Spondyloarthritis (SpA) was seen in 8% patients (undifferentiated SpA 4%, reactive arthritis 2.67%, psoriatic arthritis 1.67%). HIV-associated arthritis was seen in 2.67% while septic arthritis, rheumatoid arthritis, vasculitis, and diffuse infiltrative lymphocytic syndrome were seen in one patient (1.33%) each. The mean duration of disease in patients with RM was significantly less than patients without RM (p < 0.01). The erythrocyte sedimentation rate in patients with RM was significantly higher than in patients without RM (p < 0.05). Mean CD4 + cells were also significantly lower in patients with RM as compared to patients without RM (p < 0.05). Significantly fewer patients on cART had RM in comparison to patients not on cART (p < 0.001). Of 35 patients with RM,  25 were in CDC stage IV. CONCLUSION: RM are common in HIV-infected patients. HIV arthralgia, myalgia, and undifferentiated SpA are the common manifestations. RM were associated with low CD4 counts. Most of the cases with RM were in CDC stage IV.
33177160 Screening of a Panel of Low Molecular Weight Compounds That Inhibit Synovial Fibroblast In 2020 Dec 15 Increased invasion of synovial fibroblasts and their involvement in cartilage damage are characteristic phenotypes of rheumatoid arthritis (RA). To identify low molecular weight compounds that suppress synovial fibroblast invasion, a panel of inhibitors (n = 330) was initially screened using a real-time cell analysis system for human synovial fibroblasts that were enzymatically isolated from surgical samples of RA patients. To evaluate the effects of the inhibitors identified in the screen, synovial fibroblast migration was measured using a wound-healing assay, and phosphorylation of intracellular signaling molecules was determined by immunoblots. Several candidate inhibitors were identified in the screen, including inhibitors against platelet-derived growth factor receptor (PDGFR), Akt, PI3K, and glycogen kinase synthetase 3 (GSK-3). These inhibitors strongly suppressed synovial fibroblast migration after 72 h and downregulated phosphorylation of Akt (Ser(473)) at 48 h. When the inhibitors were removed from the culture conditions, both migration and phosphorylated Akt (Ser(473)) levels were restored. Furthermore, all the categories of inhibitors except for PDGFR inhibitor IV decreased cell proliferation as well as IL-6 production in synovial fibroblasts. Interestingly, GSK-3 inhibitors increased anti-inflammatory cytokine IL-10 production but suppressed IL-23 production from LPS-primed macrophages obtained from healthy donors. In conclusion, blocking PDGFR, PI3K, or GSK-3 could have therapeutic value as an RA treatment that targets the invasion/migration of synovial fibroblasts.
32696282 Ultrasound assessment of carpal tunnel in rheumatoid arthritis and idiopathic carpal tunne 2021 Mar OBJECTIVES: To comparatively assess the sonographic spectrum of carpal tunnel syndrome (CTS) in patients with rheumatoid arthritis (RA) and in patients with idiopathic CTS. METHODS: Fifty-seven RA patients and 25 idiopathic CTS patients were consecutively enrolled. The diagnosis of CTS in RA patients was made according to clinical history and examination. The following sonographic findings were assessed at carpal tunnel level: median nerve cross-sectional area (CSA) at the carpal tunnel proximal inlet, finger flexor tendons tenosynovitis, radio-carpal synovitis and intraneural power Doppler (PD) signal. RESULTS: CTS was diagnosed in 15/57 RA patients (26.3%). Twenty-three RA wrists with CTS, 84 RA wrists without CTS and 34 idiopathic CTS wrists were evaluated. The average CSA of the median nerve was higher in idiopathic CTS than in RA wrists with CTS (17.7 mm(2) vs 10.6 mm(2), p < 0.01). A higher rate of inflammation of synovial structures (flexor tendons sheath and/or radio-carpal joint) was found in RA wrists with CTS compared with those without CTS (p = 0.04) and idiopathic CTS (p = 0.02). Intraneural PD signal was more common in CTS (in both RA and idiopathic CTS) wrists compared with wrists without CTS (p < 0.01). CONCLUSION: The sonographic spectrum of CTS in RA patients is characterized by an inflammatory pattern, defined by the presence of finger flexor tendons tenosynovitis and/or radio-carpal joint synovitis. Conversely, a marked median nerve swelling is the dominant feature in idiopathic CTS. Intraneural PD signal is a frequent finding in both conditions. Key Points • Carpal tunnel syndrome (CTS) associated with rheumatoid arthritis (RA) and idiopathic CTS have distinct ultrasound patterns. • The most characteristic sonographic features of CTS in RA patients are those indicative of synovial tissue inflammation at carpal tunnel level. Conversely, marked median nerve swelling is the dominant finding in idiopathic CTS. • Intraneural power Doppler signal is a frequent finding in both conditions. • In patients with CTS, differently from electrophysiology, US can provide clues prompting a rheumatology referral in case of prominent inflammatory findings at carpal tunnel level.
31617429 Association of MTHFR and RFC1 gene polymorphisms with methotrexate efficacy and toxicity i 2020 Feb OBJECTIVE: The objective was to explore the association of methylene tetrahydrofolate reductase (MTHFR) C667T and A1298C and reduced folate carrier 1 (RFC-1) A80G single nucleotide polymorphisms (SNP) with rheumatoid arthritis (RA) and efficacy and toxicity of methotrexate (MTX) treatment in Chinese Han patients in Henan, China. METHODS: Two hundred ninety-six patients with RA were enrolled (cases) and 120 healthy individuals served as controls. The genotypes of MTHFR C667T and A1298C SNP and RFC-1 A80G SNP were detected by restriction fragment length polymorphism-PCR and compared between cases and controls. We analyzed correlations of clinical effect, toxicity, and SNPs after 6 months of MTX treatment. RESULTS: We detected no significant differences in MTHFR C677T and A1298C and RFC-1 A80G SNPs between cases and controls. The RFC-1 A80G SNP differed between RA patients with good and poor efficacy after 6 months of MTX, and was an independent factor of MTX efficacy. The MTHFR C677T SNP was differently distributed in the adverse drug reaction (ADR) and non-ADR groups and was an independent factor of MTX toxicity. CONCLUSIONS: In Chinese Han patients with RA, the MTHFR C667T SNP may correlate with MTX toxicity, whereas the RFC-1 A80G SNP may correlate with MTX efficacy rather than toxicity.
33203195 Breast Cancer and Microcalcifications: An Osteoimmunological Disorder? 2020 Nov 15 The presence of microcalcifications in the breast microenvironment, combined with the growing evidences of the possible presence of osteoblast-like or osteoclast-like cells in the breast, suggest the existence of active processes of calcification in the breast tissue during a woman's life. Furthermore, much evidence that osteoimmunological disorders, such as osteoarthritis, rheumatoid arthritis, or periodontitis influence the risk of developing breast cancer in women exists and vice versa. Antiresorptive drugs benefits on breast cancer incidence and progression have been reported in the past decades. More recently, biological agents targeting pro-inflammatory cytokines used against rheumatoid arthritis also demonstrated benefits against breast cancer cell lines proliferation, viability, and migratory abilities, both in vitro and in vivo in xenografted mice. Hence, it is tempting to hypothesize that breast carcinogenesis should be considered as a potential osteoimmunological disorder. In this review, we compare microenvironments and molecular characteristics in the most frequent osteoimmunological disorders with major events occurring in a woman's breast during her lifetime. We also highlight what the use of bone anabolic drugs, antiresorptive, and biological agents targeting pro-inflammatory cytokines against breast cancer can teach us.
31876028 Insights into the study and origin of the citrullinome in rheumatoid arthritis. 2020 Mar The presence of autoantibodies and autoreactive T cells to citrullinated proteins and citrullinating enzymes in patients with rheumatoid arthritis (RA), together with the accumulation of citrullinated proteins in rheumatoid joints, provides substantial evidence that dysregulated citrullination is a hallmark feature of RA. However, understanding mechanisms that dysregulate citrullination in RA has important challenges. Citrullination is a normal process in immune and non-immune cells, which is likely activated by different conditions (eg, inflammation) with no pathogenic consequences. In a complex inflammatory environment such as the RA joint, unique strategies are therefore required to dissect specific mechanisms involved in the abnormal production of citrullinated proteins. Here, we will review current models of citrullination in RA and discuss critical components that, in our view, are relevant to understanding the accumulation of citrullinated proteins in the RA joint, collectively referred to as the RA citrullinome. In particular, we will focus on potential caveats in the study of citrullination in RA and will highlight methods to precisely detect citrullinated proteins in complex biological samples, which is a confirmatory approach to mechanistically link the RA citrullinome with unique pathogenic pathways in RA.
33124557 Systematic analysis of the molecular mechanisms of methotrexate therapy for rheumatoid art 2021 Jul OBJECTIVES: The purpose of this study was to determine the expression of related genes in patients with rheumatoid arthritis (RA) treated with methotrexate (MTX), to identify hub genes, and to systematically analyse the functions, pathways, and networks of these genes. METHODS: The PubMed identifiers (PMIDs) of relevant publications were obtained from the PubMed database, and gene data were extracted from these documents using the text mining software PubTator. The Database for Annotation, Visualization and Integrated Discovery (DAVID) was used to obtain enriched Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway information. In addition, the STRING database was used to construct a protein-protein interaction (PPI) network. Genes with which at least 10 other genes interacted were identified as hub genes. RESULTS: A total of 216 genes were identified as being associated with treatment efficacy for MTX, of which 14 pathways exhibited significant correlation (p<0.05, FDR<0.05). In addition, the constructed MTX treatment-related network consisted of 267 interactions. Fourteen genes were found to interact with at least 10 other genes (p<0.05, FDR<0.05) and identified as hub genes in the PPI network. These genes were JAK1, MAPK1, JUN, AKT1, MAPK14, MAPK8, FGB, FN1, ALB, B2M, IL2RB, GGH, IL2RA, and TP53. CONCLUSIONS: This study will assist in elucidating the molecular mechanisms associated with the treatment efficacy of MTX for RA and provide a scientific rationale for guiding patient medication. However, the relationship between particular genes and the efficacy of MTX treatment for RA patients requires additional investigation.
32909047 Cross-diagnostic scale-banking using rasch analysis: Developing a common reference metric 2020 Oct 1 OBJECTIVES: To develop a common reference metric of functioning, incorporating generic and health condition-specific disability instruments, and to test whether this reference metric is invariant across 2 health conditions. DESIGN: Psychometric study using secondary data analysis. Firstly, the International Classification of Functioning, Disability and Health (ICF) Linking Rules were used to examine the concept equivalence between the World Health Organization Disability Assessment Schedule (WHODAS 2.0), Health Assessment Questionnaire (HAQ) and Functional Independence Measure (FIMTM). Secondly, a scale-bank was developed using a reference metric approach to test-equating, based on the Rasch measurement model. PARTICIPANTS: Secondary analysis was performed on data from 487 people; 61.4% with rheumatoid arthritis and 38.6% with stroke. RESULTS: Three sub-domains of the WHODAS 2.0 and all items of the HAQ and FIMTM motor mapped on to the ICF chapters d4 Mobility, d5 Self-care and d6 Domestic life. Test-equating of these scales resulted in good model fit, indicating that a scale bank and associated reference metric across these 3 instruments could be created. CONCLUSION: This study provides a transformation table to enable direct comparisons among instruments measuring physical functioning commonly used in rheumatoid arthritis (HAQ) and stroke (FIMTM motor scale), as well as in people with disability in general (WHODAS 2.0).
32909867 Associations of genetic polymorphisms within MALAT1, UCA1, FAM211A-AS1 and AC000111.6 with 2020 Nov Recently, several long non-coding RNAs (lncRNAs) including MALAT1, UCA1, ENST00000483588, and ENST00000456270 have been implicated in the pathogenesis of rheumatoid arthritis (RA), and we hypothesized that polymorphisms within these lncRNA genes might be genetic modifiers for the development of RA. A total of 10 potentially functional single-nucleotide polymorphisms (SNPs) were selected and genotyped in 1198 participants, including 594 RA patients and 604 healthy controls. Significant associations of FAM211A-AS1 rs2882581 (G vs. A, OR = 1.31, 95%CI 1.07-1.62, p = .01; G/G + A/G vs. A/A, OR = 1.40, 95%CI 1.08-1.83, p = .01), rs3744281 (T vs. A, OR = 1.25, 95%CI 1.02-1.54, p = .03; T/T vs. A/T + A/A, OR = 1.69, 95%CI 1.01-2.82, p = 4.59 × 10(-2)), and rs3760235 (A vs. G, OR = 1.32, 95%CI 1.04-1.68, p = .02; A/A vs. A/G + G/G, OR = 1.32, 95%CI 1.00-1.74, p = 4.89 × 10(-2)) with RF-positive RA were found. Functional annotation results indicated that these identified polymorphisms might regulate the expression of FAM211A-AS1 and nearby genes via impacting on transcription factor binding. Taken together, our results indicated that FAM211A-AS1 rs2882581, rs3744281, and rs3760235 were involved in the genetic background of RF-positive RA.
31820195 Influence of treatments on cell adhesion molecules in patients with systemic lupus erythem 2020 Apr BACKGROUND: Systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) are autoimmune diseases characterized by changes in cell adhesion molecules (CAMs). OBJECTIVE: To review the influence of the main drugs used in the treatment of SLE and RA on CAM levels. METHODS: A bibliographic search was performed using electronic databases. The research included human studies, in vivo or in vitro, with an experimental or observational design, and with no limit of publication date or number of subjects. Animal studies and non-standard treatments were not considered. RESULTS: We included 21 studies, 3 on SLE and 18 on RA with monotherapy or combined trials. The most used drugs were cyclophosphamide (CY, in 2 studies) and methylprednisolone pulse (pMP, n = 2) in SLE; and methotrexate (MTX, n = 9) and infliximab (IFX, n = 4) in RA. In addition, the most frequently examined CAMs to predict response to treatment were vascular cell adhesion molecule-1 (VCAM-1, n = 2) in SLE, and intercellular adhesion molecule-1 (ICAM-1, n = 12), VCAM-1 (n = 12), and E-selectin (n = 14) in RA. After treatment, CAM levels were decreased in SLE and RA patients with active disease. CONCLUSIONS: It is concluded that the CAM biomarkers may reflect disease activity and the response to treatment in SLE and RA patients.
31884392 Untargeted metabolomics reveals novel serum biomarker of renal damage in rheumatoid arthri 2020 Feb 20 Rheumatoid arthritis (RA) is a chronic progressive disease, it often involves kidney, lung, heart, and other systems.Renal damage is quite common in RA. Exploring of biomarkers of renal damage in the course of RA progression is of significant importance for disease diagnosis and treatment. We use type II Collagen-Induced Arthritis(CIA) Model. Serums were collected at the 4th, 6th, 8th, and 10th week after the first immunization. An untargeted metabonomic strategy based on UPLC-Q/TOF/MS with support vector machine(SVM) was developed to discover the biomarkers in the rats' serum samples between the RA stage(4-6 weeks in RA model, at which time the kidneys are not affected) and renal damage in RA stage(8-10 weeks in RA model, and the kidneys are affected). Principal component analysis (PCA) and orthogonal partial least squares-discriminant analysis (OPLS-DA) were used to analyze the metabolic profiles of rat serum. The support vector machine (SVM) method was used to screen the specific markers of renal damage in RA. Following multivariate statistical and integration analysis, 5 specific markers of renal damage in RA were screened and found. After the analysis of these metabolites, pentose and glucuronate interconversions are closely related to the pathogenesis of RA renal damage. The present study first use untargeted dmetabonomics combined with the pathological features in the different phases of CIA model rats. This will provide a basis for the choice of treatment drugs for patients with RA who may be complicated by renal damage.
31521702 Mechanism of Caulophyllum robustum Maxim against rheumatoid arthritis using LncRNA-mRNA ch 2020 Jan 5 BACKGROUND: Caulophyllum robustum Maxim (CRM) is a medicinal compound of the Northeast and is commonly used in China for the treatment of rheumatic pain and rheumatoid arthritis (RA). A preliminary study found that CRM has good anti-inflammatory, analgesic and immunosuppressive effects. However, the specific links and targets for its function remain unclear. Our study aimed to provide a mechanism for the action of Caulophyllum robustum Maxim extraction (CRME) against RA and to establish a method for studying disease treatment using Chinese medicine. METHODS: The 3-(4, 5-dimethyl-2-thiazolyl)-2, 5-diphenyl-2-H-tetrazolium bromide (MTT) method was used to detect the toxicity of CRME in L929 cells, and the concentration ranges of the blank, model, and CRME drug groups were determined. Differentially expressed long non-coding RNAs (lncRNAs) and messenger RNAs (mRNAs) were identified between the three groups. Gene Ontology (GO) and pathway enrichment analyses were performed to analyze the biological functions and pathways of the differentially expressed genes. Expression of Hist1h2bj, Hist1h2ba, Zfp36, Ccl3, Cxcl2 and Egr1 in the blank, model and drug groups was detected by quantitative real-time PCR (qRT-PCR), and the role of CRME on the above factors was determined to ensure consistency with the chip data. RESULTS: A total of 329 significantly upregulated genes and 141 downregulated genes were identified between the blank and model groups. A total of 218 significantly upregulated genes and 191 downregulated genes were identified between the CRME drug group and model group. CRME has a significant role in multiple pathways involved in the occurrence and development of RA. Additionally, Hist1h2bj, Hist1h2ba, Zfp36, Ccl3, Cxcl2, and Egr1 were observed in modules of the lncRNA-mRNA weighted co-expression network, consistent with the chip data. CONCLUSIONS: CRME has regulatory effects on inflammatory factors, the histone family, chemokines and their ligands that are related to RA-related cytokines, the RA pathway, the TNF signaling pathway, the Toll receptor-like signaling pathway, the chemokine signaling pathways and other pathways are related to the course of RA.
33113770 Modeling Rheumatoid Arthritis In Vitro: From Experimental Feasibility to Physiological Pro 2020 Oct 25 Rheumatoid arthritis (RA) is a chronic, inflammatory, and systemic autoimmune disease that affects the connective tissue and primarily the joints. If not treated, RA ultimately leads to progressive cartilage and bone degeneration. The etiology of the pathogenesis of RA is unknown, demonstrating heterogeneity in its clinical presentation, and is associated with autoantibodies directed against modified self-epitopes. Although many models already exist for RA for preclinical research, many current model systems of arthritis have limited predictive value because they are either based on animals of phylogenetically distant origin or suffer from overly simplified in vitro culture conditions. These limitations pose considerable challenges for preclinical research and therefore clinical translation. Thus, a sophisticated experimental human-based in vitro approach mimicking RA is essential to (i) investigate key mechanisms in the pathogenesis of human RA, (ii) identify targets for new therapeutic approaches, (iii) test these approaches, (iv) facilitate the clinical transferability of results, and (v) reduce the use of laboratory animals. Here, we summarize the most commonly used in vitro models of RA and discuss their experimental feasibility and physiological proximity to the pathophysiology of human RA to highlight new human-based avenues in RA research to increase our knowledge on human pathophysiology and develop effective targeted therapies.
31865506 Evaluating the role of serum sclerostin as an indicator of activity and damage in Egyptian 2020 Apr OBJECTIVE: Sclerostin is an osteocyte-derived glycoprotein which inhibits the canonical Wnt pathway essential for osteoblastic activity decreasing bone formation. Its potential role in rheumatoid arthritis (RA) pathogenesis was highlighted by experimental studies. Here we measured the serum sclerostin in RA patients and evaluated its relationship with disease activity and damage. METHODS: One hundred RA patients and 80 age and sex-matched healthy controls were enrolled in the study. Bone biomarkers were evaluated for all participants including total calcium, phosphorus, alkaline phosphatase, 25-hydroxy vitamin D, and intact parathyroid hormone, in addition to fibroblast growth factor-23 (FGF23) and serum sclerostin. For RA patients, carotid intima-media thickness, brachial artery flow dilatation, and musculoskeletal ultrasonography using ultrasonography-7 joint score were done, and DAS28-ESR was calculated. RESULTS: Median serum sclerostin in our patients was 186.5 ± 22.7 pg/ml which was significantly higher than in controls 60.6 ± 7.1 pg/ml (p < 0.002). Serum sclerostin showed no correlation with disease activity, bone erosions, carotid intima-media thickness, brachial flow dilatation, and the examined bone biomarkers. However, it had a strong correlation with FGF23 (r coefficient 0.988, p < 0.000). CONCLUSION: Although serum sclerostin was elevated in RA patients, it could not be used as a prognostic marker for disease activity, bone erosions or atherosclerosis.Key Points• Serum sclerostin may not reflect changes in the joint microenvironment being not correlated with ultrasonography-detected synovitis or erosions.• Serum sclerostin was elevated in RA patients irrespective to their age or gender.• The positive correlation with FGF23 may provide evidence for sclerostin contribution in bone demineralization in RA patients.
32973793 Blood Lymphocyte Subsets for Early Identification of Non-Remission to TNF Inhibitors in Rh 2020 Background: TNF inhibitors (TNFis) are widely used for the treatment of rheumatoid arthritis (RA), although the response rates to this therapy in patients with RA remains heterogeneous and < 50% achieve remission (REM). Objective: To analyze baseline peripheral blood leukocytes profiles in order to search for biomarkers identifying patients who will most likely not achieve REM under TNFi treatment. Methods: A prospective bi-center pilot study including 98 RA patients treated with TNFis and followed-up during 6 months. Patients were classified according to DAS28 as follows: those who achieved REM (DAS28 ≤ 2.6) and those who did not (DAS28 > 2.6) at 6 months after starting TNFis. These rates were also assessed by simplified disease activity index (SDAI ≤ 3.3 and SDAI > 3.3, respectively). Peripheral blood immune cells were studied by flow cytometry before treatment initiation. Results: At 6 months, 61 or 80% of patients did not achieve REM by DAS28 or SDAI, respectively. Basal leukocyte profiles differed between REM vs. non-REM patients. Non-REM patients showed lower percentages of total and naïve B cells at baseline than REM subjects. A B lymphocyte/CD4+ lymphocyte ratio (BL/CD4 ratio) <0.2 clearly associated with a higher probability of non-REM status based on DAS28 at 6 months (OR = 9.2, p = 0.006). These data were confirmed when patient response was evaluated by SDAI index. Conclusion: Our results strongly suggest that BL/CD4 ratio could be considered as a useful biomarker for the early identification of non-remitters to TNFi in clinical practice.
32112341 A case of esophageal cancer complicated with methotrexate-related lymphoproliferative diso 2020 Aug A 69-year-old woman had been undergoing treatment with methotrexate for rheumatoid arthritis for 9 years. Because fever and right hypochondriac pain continued, she visited the nearby hospital. The enlargement of intraabdominal multiple lymph nodes was detected through abdominal computed tomography. Esophagogastroduodenoscopy showed a depressed lesion in the lower intrathoracic esophagus, and squamous cell carcinoma was diagnosed by a biopsy. Positron emission tomography-computed tomography showed a highly abnormal accumulation of lymph nodes, mainly in the upper abdomen, and some lymph nodes around the aorta. Suspecting methotrexate-lymphoproliferative disorder, we discontinued the oral administration of methotrexate. Multiple lymphadenopathy reduced by the withdrawal of the oral administration of methotrexate. We operated for esophageal cancer, and she was discharged on the 17th postoperative day. The postoperative pathological result showed moderately differentiated squamous cell carcinoma. Metastasis to the lymph nodes around the esophagus was observed, and the patient was diagnosed with T1b (SM3), N2 M0, Stage II cancer. Immunostaining showed enlarged lymph nodes composed of CD20-positive cells and with cells positive for EBV-encoded small RNA in situ hybridization. This case shows that patients with rheumatoid arthritis who are being administered methotrexate may have enlarged lymph nodes due to methotrexate-lymphoproliferative disorder.
32825443 Learning from Monocyte-Macrophage Fusion and Multinucleation: Potential Therapeutic Target 2020 Aug 20 Excessive bone resorption by osteoclasts (OCs) covers an essential role in developing bone diseases, such as osteoporosis (OP) and rheumatoid arthritis (RA). Monocytes or macrophages fusion and multinucleation (M-FM) are key processes for generating multinucleated mature cells with essential roles in bone remodelling. Depending on the phenotypic heterogeneity of monocyte/macrophage precursors and the extracellular milieu, two distinct morphological and functional cell types can arise mature OCs and giant cells (GCs). Despite their biological relevance in several physiological and pathological responses, many gaps exist in our understanding of their formation and role in bone, including the molecular determinants of cell fusion and multinucleation. Here, we outline fusogenic molecules during M-FM involved in OCs and GCs formation in healthy conditions and during OP and RA. Moreover, we discuss the impact of the inflammatory milieu on modulating macrophages phenotype and their differentiation towards mature cells. Methodological approach envisaged searches on Scopus, Web of Science Core Collection, and EMBASE databases to select relevant studies on M-FM, osteoclastogenesis, inflammation, OP, and RA. This review intends to give a state-of-the-art description of mechanisms beyond osteoclastogenesis and M-FM, with a focus on OP and RA, and to highlight potential biological therapeutic targets to prevent extreme bone loss.
32212867 A modeling framework for the economic evaluation of baricitinib in moderate-to-severe rheu 2020 Apr Objectives: The approval in more than 50 countries of baricitinib, an oral Janus Kinase inhibitor for the treatment of Rheumatoid Arthritis (RA), warrants a framework for corresponding economic evaluations. To develop a comprehensive economic model assessing the cost-effectiveness of baricitinib for the treatment of moderately-to-severely active RA patients in comparison to other relevant treatments, considering the natural history of the disease, real world treatment patterns, and clinical evidence from the baricitinib trials.Methods: A systematic literature review of previously developed models in RA was conducted to inform the model structure, key modeling assumptions and data inputs. Consultations with rheumatologists were undertaken to validate the modeling approach and underlying assumptions.Results: A discrete event simulation model was developed to international best practices with flexibility to assess the cost-effectiveness of baricitinib over a lifetime in a variety of markets. The model incorporates treatment sequencing to adequately reflect treatment pathways in clinical practice. Outcomes assessed include cost and quality-adjusted life years, allowing for a full incremental analysis of cost-effectiveness of competing treatments and treatment sequences.Conclusion: The economic model developed provides a robust framework for future analyses assessing the cost-effectiveness of baricitinib for the treatment of RA in specific country settings.
31791581 Theacrine alleviates chronic inflammation by enhancing TGF-β-mediated shifts via TGF-β/S 2020 Feb 12 Rheumatoid arthritis is a chronic and systemic autoimmune disease, which affects approximately 1% of the adult population worldwide. The present study investigated the therapeutic effect of theacrine (TC) on arthritis and its mechanisms in Freund's incomplete adjuvant (FIA)-induced SD rats. Rats were randomly divided into 5 groups: i) healthy control; ii) model; iii) positive control with methotrexate (MTX); iv) treatment with 12.5 mg/kg TC; and v) treatment with 25.0 mg/kg TC. The apparent scores, including changes in body weights, degree of paw swelling and arthritis indicators, were analyzed to evaluate the anti-chronic inflammatory effect of TC. The levels of interleukin (IL)-6 and transforming growth factor-β (TGF-β) in serum were measured by enzyme-linked immunosorbent assay. The protein and RNA expression levels of the critical factors in rats were measured to elucidate the mechanisms responsible for chronic inflammation and to verify molecular indexes of chronic inflammatory conditions. TC notably suppressed the severity of FIA-induced rat by attenuating the apparent scores, animal weight and inflammatory indexes in the 25 mg/kg TC group compared with the FIA rat model. Furthermore, TC significantly decreased the levels of IL-6 and increased the levels of TGF-β. Histopathological examinations indicated that TC rescued the synovial hyperplasia and inflammatory cell infiltration in joint tissues. In addition, TC enhanced TGF-β-mediated shifts in inflammatory marker expression in joint tissue. Overall, the present study demonstrated that TC exerted a superior anti-arthritic effect via the suppression of IL-6 and the activation of TGF-β by the TGF-β/SMAD pathway.