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ID PMID Title PublicationDate abstract
32480098 Incident diabetes associated with hydroxychloroquine, methotrexate, biologics and glucocor 2020 Aug OBJECTIVES: To evaluate the impact of disease-modifying antirheumatic drugs on the risk of developing diabetes in rheumatoid arthritis (RA) patients without diabetes. METHODS: Electronic database searches of PubMed, EMBASE and Cochrane Library plus a hand search of conference proceedings were performed from inception to October 2019. The studies assessing the association between diabetes and antirheumatic agents in RA patients in cohort or case-control design were included. Data were pooled using fixed-effects or random-effects meta-analysis according to I(2) and pooled hazard ratios (HRs), and 95% confidence intervals (CIs) were used as summary statistic. RESULTS: A total of 15 studies involving 552,019 patients with RA (11 for hydroxychloroquine, 7 for methotrexate, 6 for tumor necrosis factor inhibitors [TNFi], and 8 for glucocorticoids) were included. In pooled analysis, a reduced risk of diabetes was reported with hydroxychloroquine (meta-HR 0.61, 95% CI 0.56-0.66), methotrexate (meta-HR 0.81, 95% CI 0.75-0.87), TNFi (meta-HR 0.63, 95% CI 0.55-0.71), while glucocorticoids was associated with an increased risk of developing diabetes in a dose-dependent manner (Any dose: meta-HR 1.46, 95% CI 1.39-1.53; <10 mg/day prednisolone or equivalent: meta-HR 1.30, 95% CI 1.13-1.51; ≥10 mg/day prednisolone or equivalent: meta-HR 2.25, 95% CI 1.88-2.70). CONCLUSIONS: Hydroxychloroquine, methotrexate and TNFi were associated with decreased risk of diabetes, and glucocorticoids with increased risk in RA patients. These important findings may aid clinical decision-making in the management of RA. Large, prospective, well-designed studies are needed in the RA patients with high-risk diabetes.
32308655 Phthalate Exposure During the Prenatal and Lactational Period Increases the Susceptibility 2020 The prenatal and early postnatal period is highly sensitive to environmental exposures that may interfere with the developmental programming of the immune system leading to an altered disease risk in later life. To clarify the role of early influences in activation or exacerbation of autoimmune diseases like rheumatoid arthritis (RA) we investigated the effect of maternal exposure during the prenatal and lactational period of DBA/1 mice to the plasticizer benzyl butyl phthalate (BBP) on the development of RA in the offspring. Using a mild collagen-induced arthritis (CIA) model, maternal BBP-exposure increased both the prevalence and the severity of RA in the progeny compared to un-exposed dams. Additionally, maternal BBP exposure led to elevated serum IgG(1) and IgG(2a) level in the offspring and increased the IFN-γ and IL-17 release from collagen-re-stimulated spleen cells. Transcriptome analysis of splenocytes isolated from 3-week-old pups before RA-induction revealed considerable changes in gene expression in the offspring from BBP-exposed dams. Among them were regulator of G-protein signaling 1 (rgs1), interleukin-7 receptor (il-7r) and CXC chemokine 4 (cxcr4), all genes that have previously been described as associated with RA pathology. In summary, our results demonstrate that perinatal exposure to BBP increases the susceptibility of the offspring to RA, probably via a phthalate-induced disturbed regulation of RA-relevant genes or signaling pathways.
31498072 Variation in the synovial fluid metabolome according to disease activity of rheumatoid art 2020 May OBJECTIVES: Because genetic and environmental factors both contribute to rheumatoid arthritis (RA), metabolomics could be a very useful tool to elucidate the pathophysiology of RA, and to predict response to treatment. This study was carried out to investigate synovial fluid (SF) metabolic perturbation in RA patients according to the degree of disease activity using gas chromatography/time-of-flight mass spectrometry (GC/TOF MS). METHODS: SF samples were obtained from 48 RA patients. Disease activity was assessed using DAS28-ESR(3). SF metabolomics profiling was performed using GC/TOF-MS, in conjunction with multivariate statistical analyses and pathway analyses. RESULTS: Significant discrimination of metabolite profiles between moderate and high disease activity groups was shown by PLS-DA, which provided evidence that SF metabolic profiles predicted disease activity. We found the significant correlation between DAS28-ESR(3) value and the intensities of 12 metabolites. The intensities of glycocyamine and indol-3-lactate positively correlated with DAS28-ESR(3) value. On the other hand, β-alanine, asparagine, citrate, cyano-L-alanine, leucine, nicotinamide, citrulline, methionine, oxoproline, and salicylaldehyde negatively correlated with DAS28-ESR(3) value. We found fifteen pathways that were significantly associated with disease activity in RA and that the higher the disease activity, the more amino acid metabolic processes were affected. CONCLUSIONS: We found the SF metabolic alterations in RA patients according to disease activity by using GC/TOF MS and identified 12 candidate metabolic biomarkers that may well reflect the disease activity of RA. SF metabolomic approaches based on GC/TOF MS might provide additional information relating to monitoring disease activity in RA.
33227945 Identification and Validation of Carbonic Anhydrase II as the First Target of the Anti-Inf 2020 Nov 19 Background and purpose: Identifying the macromolecular targets of drug molecules is a fundamental aspect of drug discovery and pharmacology. Several drugs remain without known targets (orphan) despite large-scale in silico and in vitro target prediction efforts. Ligand-centric chemical-similarity-based methods for in silico target prediction have been found to be particularly powerful, but the question remains of whether they are able to discover targets for target-orphan drugs. Experimental Approach: We used one of these in silico methods to carry out a target prediction analysis for two orphan drugs: actarit and malotilate. The top target predicted for each drug was carbonic anhydrase II (CAII). Each drug was therefore quantitatively evaluated for CAII inhibition to validate these two prospective predictions. Key Results: Actarit showed in vitro concentration-dependent inhibition of CAII activity with submicromolar potency (IC(50) = 422 nM) whilst no consistent inhibition was observed for malotilate. Among the other 25 targets predicted for actarit, RORγ (RAR-related orphan receptor-gamma) is promising in that it is strongly related to actarit's indication, rheumatoid arthritis (RA). Conclusion and Implications: This study is a proof-of-concept of the utility of MolTarPred for the fast and cost-effective identification of targets of orphan drugs. Furthermore, the mechanism of action of actarit as an anti-RA agent can now be re-examined from a CAII-inhibitor perspective, given existing relationships between this target and RA. Moreover, the confirmed CAII-actarit association supports investigating the repositioning of actarit on other CAII-linked indications (e.g., hypertension, epilepsy, migraine, anemia and bone, eye and cardiac disorders).
32871476 Total glucosides of paeony for the treatment of rheumatoid arthritis: A methodological and 2020 Nov OBJECTIVE: To assess the methodological, reporting and evidence quality of systematic reviews and meta-analyses of total glucosides of paeony (TGP) for rheumatoid arthritis (RA). METHODS: We comprehensively searched the literature in numerous databases from inception to July 29th, 2020. Two appraisers collected data and assessed the methodological and reporting quality of the included reviews by revised A MeaSurement Tool to Assess systematic Reviews (AMSTAR-2) tool and the Preferred Reporting Items for Systematic reviews and Meta-analyses (PRISMA), respectively. The level of evidence quality was evaluated by employing the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) scale. RESULTS: Eleven relevant articles were collected. The results from AMSTAR-2 showed that the methodological quality of all included reviews was critically low; no authors met the standard of those critical domains (0%), particularly in item 2, item 4 and item 7. The PRISMA scores ranged from 16.5 to 25, and one meta-analysis almost conformed to the PRISMA structure. According to GRADE, the 11 studies included 59 outcomes: 27 had very low quality, 22 had low quality, 10 had moderate quality, and none had high quality evidence. The most prominent downgrading factors were risk of bias, followed by publication bias, inconsistency, imprecision, and indirectness. CONCLUSIONS: Although included studies summarized that TGP was effective and safe in the treatment of RA, the methodological and reporting quality and the quality of evidence was poor overall; decision-makers should be prudent when using TGP in treating RA patients. High-quality and multicenter studies investigating TGP for RA are urgently needed.
32226525 PET Imaging of Liposomal Glucocorticoids using (89)Zr-oxine: Theranostic Applications in I 2020 The encapsulation of Glucocorticoids (GCs) into long-circulating liposomes (LCLs) is a proven strategy to reduce the side effects of glucocorticoids and improve the treatment of inflammatory diseases, such as rheumatoid arthritis (RA). With the aim of supporting the development of GC-loaded LCLs, and potentially predict patient response to therapy clinically, we evaluated a direct PET imaging radiolabelling approach for preformed GC-LCLs in an animal model of human inflammatory arthritis. Methods: A preformed PEGylated liposomal methylprednisolone hemisuccinate (NSSL-MPS) nanomedicine was radiolabelled using [(89)Zr]Zr(oxinate)(4) ((89)Zr-oxine), characterised and tracked in vivo using PET imaging in a K/BxN serum-transfer arthritis (STA) mouse model of inflammatory arthritis and non-inflamed controls. Histology and joint size measurements were used to confirm inflammation. The biodistribution of (89)Zr-NSSL-MPS was compared to that of free (89)Zr in the same model. A therapeutic study using NSSL-MPS using the same time points as the PET/CT imaging was carried out. Results: The radiolabelling efficiency of NSSL-MPS with [(89)Zr]Zr(oxinate)(4) was 69 ± 8 %. PET/CT imaging of (89)Zr-NSSL-MPS showed high uptake (3.6 ± 1.5 % ID; 17.4 ± 9.3 % ID/mL) at inflamed joints, with low activity present in non-inflamed joints (0.5 ± 0.1 % ID; 2.7 ± 1.1 % ID/mL). Importantly, a clear correlation between joint swelling and high (89)Zr-NSSL-MPS uptake was observed, which was not observed with free (89)Zr. STA mice receiving a therapeutic dose of NSSL-MPS showed a reduction in inflammation at the time points used for the PET/CT imaging compared with the control group. Conclusions: PET imaging was used for the first time to track a liposomal glucocorticoid, showing high uptake at visible and occult inflamed sites and a good correlation with the degree of inflammation. A subsequent therapeutic response matching imaging time points in the same model demonstrated the potential of this radiolabeling method as a theranostic tool for the prediction of therapeutic response - with NSSL-MPS and similar nanomedicines - in the treatment of inflammatory diseases.
31953914 TL1A/TNFR2-mediated mitochondrial dysfunction of fibroblast-like synoviocytes increases in 2020 Jul Rheumatoid arthritis (RA) is the major autoimmune destructive disease of joints with a complicated pathogenesis. The contribution of tumor necrosis factor-like ligand 1A (TL1A) in RA pathogenesis, especially on fibroblast-like synoviocytes (FLS), has been suggested clinically. The present study investigated the role of TL1A in mitochondrial dysfunction, induced oxidative stress in mitochondria, apoptosis resistance and the inflammatory response in FLS obtained from RA patients (RA-FLS). RA-FLS were incubated with TL1A and tumor necrosis factor receptor 2 (TNFR2) antagonist. Respiratory function, mitochondrial membrane potential and respiration associated genes of mitochondria were measured in both TL1A stimulated and non-stimulated RA-FLS. Additionally, the effects of TL1A on reactive oxygen species (ROS) production in mitochondria, apoptosis and the inflammatory response in RA-FLS were also assessed. The role of TL1A in association between ROS generation, especially mitochondrial type and the inflammatory response, was evaluated by measuring inflammation-related cytokines and signaling pathways using ROS inhibitors, diphenyleneiodonium chloride and Mito-TEMPO (Sigma-Aldrich, Miamisburg, OH, USA). We found that TL1A induced mitochondrial dysfunction by weakening mitochondrial respiration and membrane potential, which was blocked by a TNFR2 antagonist. Increased ROS synthesis in impaired mitochondria was observed with MitoSOX (Invitrogen, CA, USA) immunofluorescence staining in TL1A-stimulated RA-FLS but inhibited by a TNFR2 antagonist. TL1A influenced apoptosis resistance and inflammatory mediators via TNFR2. Inhibition of mitochondria-derived ROS compromised the production of inflammatory factors in TL1A-stimulated RA-FLS, suggesting that mitochondrial dysfunction mediated by the TL1A/TNFR2 axis might amplify the inflammatory response via regulation of mitochondria-derived ROS generation. Collectively, our results reveal that TL1A might be involved in making FLS more aggressive in RA pathogenesis via cell respiration interruption.
30189769 Pregnancy outcomes in women with rheumatoid arthritis: a retrospective population-based co 2020 Feb Purpose: To assess if pregnancies in women with rheumatoid arthritis (RA) are at a higher risk for adverse maternal and neonatal outcomes.Materials and methods: A retrospective cohort study was carried out using the Healthcare Cost and Utilization Project - National Inpatient Sample (HCUP-NIS) from the USA. All births that took place from 2004 to 2013 were identified and women were classified as having RA or not on the basis of ICD-9 coding. Unconditional logistic regression was used to evaluate the adjusted effect of RA on maternal and neonatal outcomes.Results: Of the total 8,417,607 births in our cohort, 6068 were among women with RA for an overall prevalence of 72 per 100,000 births. There was a steady increase in reported RA in pregnancy from 47 to 100 per 100,000 over the 10-year study period. Compared with women without RA, women with RA were more likely to develop pre-eclampsia/eclampsia, gestational diabetes, to present with preterm premature rupture of membranes(PPROM), to experience placental abruption and placenta previa, and to deliver by caesarean section. Postpartum, RA-complicated pregnancies were associated with wound complications and thromboembolisms. Congenital anomalies, small for gestational age and preterm birth were more common in neonates of women with RA.Conclusion: RA in pregnancy is associated with a greater likelihood of adverse maternal and neonatal outcomes. Women with RA should be made aware of these risks and be followed as a high risk pregnancy.
32941246 The NADase enzyme CD38: an emerging pharmacological target for systemic sclerosis, systemi 2020 Nov PURPOSE OF REVIEW: Here we review recent literature on the emerging role of nicotinamide adenine dinucleotide (NAD) metabolism and its dysfunction via the enzyme CD38 in the pathogenesis of rheumatologic diseases. We evaluate the potential of targeting CD38 to ameliorate NAD-related metabolic imbalance and tissue dysfunction in the treatment of systemic sclerosis (SSc), systemic lupus erythematous (SLE), and rheumatoid arthritis (RA). RECENT FINDINGS: In this review, we will discuss emerging basic, preclinical, and human data that point to the novel role of CD38 in dysregulated NAD-homeostasis in SSc, SLE, and RA. In particular, recent studies implicate increased activity of CD38, one of the main enzymes in NAD catabolism, in the pathogenesis of persistent systemic fibrosis in SSc, and increased susceptibility of SLE patients to infections. We will also discuss recent studies that demonstrate that a cytotoxic CD38 antibody can promote clearance of plasma cells involved in the generation of RA antibodies. SUMMARY: Recent studies identify potential therapeutic approaches for boosting NAD to treat rheumatologic diseases including SSc, RA, and SLE, with particular attention to inhibition of CD38 enzymatic activity as a target. Key future directions in the field include the determination of the cell-type specificity and role of CD38 enzymatic activity versus CD38 structural roles in human diseases, as well as the indicators and potential side effects of CD38-targeted treatments.
33057973 Untying the correlation between apolipoproteins and rheumatoid arthritis. 2021 Jan AIM AND OBJECTIVE: The concentration of lipoproteins and apolipoprotein are extremely low in the synovial fluid of any healthy person as compared to the concentrations in plasma. However, in the synovial fluid of any diseased patient the amount of cholesterol and lipids is sharply increased. The current review defines the role of various apolipoproteins and lipoproteins and their constituent subfractions in the synovial fluid embarking its principal role in rheumatoid arthritis. It also explains the need to define synovial fluid lipids, lipoprotein particle subfractions and their constituent apolipoproteins in synovial fluid. MATERIALS AND METHODS: Various research and review articles highlighting the role of apolipoproteins and lipoproteins were procured from medical websites mainly Pubmed, Medline, Science Direct, etc., and studied for the writing of the review paper. CONCLUSION: Mainly apolipoproteins A-1, B and E are prominently increased in chronic inflammatory joint disorders. Several theories have been proposed to understand the source of increase of lipids and apolipoproteins in synovial fluid of the diseased patients compared to healthy individuals, yet the precise mechanism is still not lucid. Lipoproteins are believed to play both functional role and pathological role in the synovial fluid. The activated T-lymphocytes in patients of RA lead to activation of inflammatory cytokines such as tumor necrosis factor and interleukins which embark to be the principal mechanism for induction of the disease. It can be thus concluded that the apolipoproteins prevent the activation of monocytes by blocking their contact of activation and thus play critical role in management of RA by inhibiting the production of proinflammatory cytokines.
31532072 Comparative Profiling of Serum Protein Biomarkers in Rheumatoid Arthritis-Associated Inter 2020 Mar OBJECTIVE: Interstitial lung disease (ILD) is a frequent complication of rheumatoid arthritis (RA), occurring in up to 40% of patients during the course of their disease. Early diagnosis is critical, particularly given the shared clinicoepidemiologic features between advanced rheumatoid arthritis-associated ILD (RA-ILD) and idiopathic pulmonary fibrosis (IPF). This study was undertaken to define the molecular basis of this overlap through comparative profiling of serum proteins in RA-ILD and IPF. METHODS: Multiplex enzyme-linked immunosorbent assays (ELISAs) were used to profile 45 protein biomarkers encompassing cytokines/chemokines, growth factors, and matrix metalloproteinases (MMPs) in sera obtained from RA patients with ILD and those without, individuals with IPF, and healthy controls. Levels of selected serum proteins were compared between patient subgroups using adjusted linear regression, principal component analysis (PCA), and least absolute shrinkage and selection operator (LASSO) modeling. RESULTS: Multiplex ELISA-based assessment of sera from 2 independent cohorts (Veterans Affairs [VA] and Non-VA) revealed a number of non-overlapping biomarkers distinguishing RA-ILD from RA without ILD (RA-no ILD) in adjusted regression models. Parallel analysis of sera from IPF patients also yielded a discriminatory panel of protein markers in models adjusted for age/sex/smoking, which showed differential overlap with profiles linked to RA-ILD in the VA cohort versus the Non-VA cohort. PCA revealed several distinct functional groups of RA-ILD-associated markers that, in the VA cohort, encompassed proinflammatory cytokines/chemokines as well as 2 different subsets of MMPs. Finally, LASSO regression modeling in the Non-VA and VA cohorts revealed distinct biomarker combinations capable of discriminating RA-ILD from RA-no ILD. CONCLUSION: Comparative serum protein biomarker profiling represents a viable method for distinguishing RA-ILD from RA-no ILD and identifying population-specific mediators shared with IPF.
32154754 Higher body mass index is associated with lower foot health in patients with rheumatoid ar 2020 May Objective: Obesity is highly prevalent in patients with rheumatoid arthritis (RA), with likely impact on weight-bearing foot joints. We explored the associations between body mass index (BMI) and measures of foot health in patients with RA and foot complaints.Method: We examined patients with RA presenting for their first custom-made therapeutic footwear or foot orthoses. Domains of foot health comprised: foot pain, foot-related activity limitations, forefoot plantar pressure, foot synovitis, and foot deformity. In regression analyses, BMI was the independent variable and foot health domains were the dependent variables.Results: The cohort at baseline comprised 230 patients [mean ± sd age 58 ± 13 years, 80% female, mean ± sd disease duration 10 ± 9 years, and median (interquartile range) BMI 26.7 (23.5-30.1) kg/m(2)]. Small to modest statistically significant associations were found in the majority of the measures studied between a higher BMI and more foot pain, more foot-related activity limitations, higher in-shoe measured forefoot plantar pressure, and the presence of foot synovitis. No relationships were found between BMI and barefoot measured forefoot plantar pressure or foot deformity.Conclusion: BMI is negatively associated with foot health in patients with RA. Although the clinical relevance of our findings for an individual patient is not immediately obvious, future research should consider BMI as a potential therapeutic target to improve foot health.
31958278 Pathogenesis of ischaemic and non-ischaemic heart diseases in rheumatoid arthritis. 2020 Jan Rheumatoid arthritis (RA) is characterised by a chronic inflammatory condition of the joints, but the comorbidities of RA predominantly contribute to the reduced lifespan associated with this disease. Clinical data indicate that cardiovascular disease is the major comorbidity associated with mortality in RA. In this review, we aimed to describe the pathogenesis of heart failure in RA. First, we emphasised the fundamental differences between ischaemic and non-ischaemic heart diseases and referred to their relevance in excessive cardiovascular-dependent mortality in RA. Second, we highlighted aspects of asymptomatic changes in cardiac tissue and in coronary blood vessels that are commonly found in patients with diagnosed RA. Third, we focused on high-grade systemic inflammation as a key trigger of ischaemic and non-ischaemic heart diseases in RA, and described the implication of conventional and biologic antirheumatic medications on the development and progression of heart disease. In particular, we discussed the roles of tumour necrosis factor-alpha (TNF-α) and anti-TNF-α therapies on the development and progression of ischaemic and non-ischaemic heart diseases in RA.
32829446 Data Mining Study on Prescription Patterns of Different Dosage Forms of Chinese Herbal Med 2022 Mar OBJECTIVE: To explore the prescription patterns of different dosage forms of Chinese herbal medicines (CHMs) for the treatment of rheumatoid arthritis (RA) and their effects on immune-inflammatory indices. METHODS: Clinical data were collected from patients with RA in 4 hospitals (3 Class A comprehensive hospitals and 1 Class B comprehensive hospital) in Anhui Province, China, from August 2012 to June 2018 via the electronic medical record gathering system. Following extraction of prescription information, each prescribed herb was quantified and standardized according to the knowledge base to establish a database of RA treatment formulae. The medical records were divided into the granules group and decoction pieces group. Core herbs and their combination patterns were obtained from the two groups of cases using Liquorice software. Changes in immune-inflammatory and hepatic and renal function indices were compared between the two groups using SPSS 23.0 software. The Aprior module of SPSS Clementine 11.1 software was applied to analyse the correlation between CHMs and improvement in indices. Finally, the ORACLE 10 g tool was used to evaluate the random walk model of the immune-inflammatory indices between the two groups. RESULTS: (1) We retrospectively analysed 35,898 prescriptions for 6,829 patients with RA who received CHM treatment. There were 3,816 patients in the granules group and 3,013 in the decoction pieces group. (2) The core herbs were Pi (Spleen)-strengthening and dampness-resolving drugs, blood-activating and stasis-resolving drugs, wind/dampness-dispelling drugs and heat-clearing and detoxifying drugs. (3) Both dosage forms could improve immune-inflammatory indices in RA patients, with similar efficacy and no influence on hepatic or renal function. (4) Herba Siegesbeckiae and Oldenlandia had a stronger association with immune-inflammatory indices in the two groups. (5) The immune-inflammatory indices showed obvious improvement after treatment with granules and decoction pieces of CHMs, and there were long range correlations between the comprehensive evaluation indices and interventions. CONCLUSIONS: The principal CHM treatment methods for RA in four hospitals in Anhui Province are strengthening Pi and resolving dampness, activating blood and resolving stasis, dispelling wind/dampness and clearing heat. Granules and decoction pieces of CHMs have similar efficacy in improving immune-inflammatory indices in RA patients and could be used as treatment options for RA.
32524889 Changes in hand grip strength and body weight after a dynamic exercise program and Mediter 2022 Apr BACKGROUND: In patients with rheumatoid arthritis (RA) exercise improves muscle strength and decreases fat mass, whereas the consumption of a Mediterranean diet (MD) also has been associated with higher grip strength. Therefore, it is important to explore the combined effects of these interventions on hand grip strength and weight in RA. OBJECTIVE: To determine the combined effect of an MD and a dynamic exercise program (DEP) on hand grip strength in women with RA. METHOD: In a randomized clinical trial, 106 women with RA were included and assigned to the DEP-MD, DEP and MD groups. Weight, body circumferences, Disease Activity Score-28, Health Assessment Questionnaire Disability Index [HAQ-DI], and hand grip strength were measured at baseline and 24 weeks after the interventions. RESULTS: After 24 weeks, hand grip strength showed a significant increase in the DEP group (median 2 kg) compared with DEP-MD (median 0.5 kg) and MD (median -0.5 kg) groups (p = 0.03). In the MD group weight and waist circumference showed a significant decrease (-2.2 kg and -4.3 cm) compared with DEP-MD (0.85 kg and 1.9 cm) and DEP (0.35 kg and 0.5 cm) groups (p < 0.01). Finally, a significant decrease was observed in the HAQ-DI after treatment in the DEP-MD group of -0.5 and the DEP group of -0.25 compared with the MD group with no change (p = 0.03). CONCLUSION: In women with RA, in addition to pharmacological treatment, DEP increases hand grip strength and an MD decreases weight and waist circumferences, while the combination of DEP and MD improves disability.
33115361 Nontraumatic Perforation of the Metacarpal by the Stem of a Flexible Silicone Implant in a 2020 Dec A 49-year-old woman with rheumatoid arthritis who underwent replacement arthroplasty of second to fifth left metacarpophalangeal joints with silastic implant seven years ago presented with a complaint of mild pain and discomfort on the replaced joint of index finger. Ulnar deviation had relapsed, with severe swan neck deformities. Computed tomography examination demonstrated that the tip of the stem of the silicon implant penetrated the second metacarpal. We confirmed that finding surgically, and we performed a revision surgery successfully with autogenous bone grafting from distal radius. As the patient had undergone finger joint replacement surgery with silastic implant, nontraumatic perforation of the bone cortex by the implant could happen in a long-term process. On long-term follow up of silastic arthroplasty of finger joint, the possibility of nontraumatic perforation of the finger bone by the prosthesis should be considered, especially in the coexistence of severe finger deformities such as swan neck deformity.
32434436 Oral microbiome-systemic link studies: perspectives on current limitations and future arti 2020 May In the past decade, there has been a tremendous increase in studies on the link between oral microbiome and systemic diseases. However, variations in study design and confounding variables across studies often lead to inconsistent observations. In this narrative review, we have discussed the potential influence of study design and confounding variables on the current sequencing-based oral microbiome-systemic disease link studies. The current limitations of oral microbiome-systemic link studies on type 2 diabetes mellitus, rheumatoid arthritis, pregnancy, atherosclerosis, and pancreatic cancer are discussed in this review, followed by our perspective on how artificial intelligence (AI), particularly machine learning and deep learning approaches, can be employed for predicting systemic disease and host metadata from the oral microbiome. The application of AI for predicting systemic disease as well as host metadata requires the establishment of a global database repository with microbiome sequences and annotated host metadata. However, this task requires collective efforts from researchers working in the field of oral microbiome to establish more comprehensive datasets with appropriate host metadata. Development of AI-based models by incorporating consistent host metadata will allow prediction of systemic diseases with higher accuracies, bringing considerable clinical benefits.
32677423 MicroRNA-495 attenuates proliferation and inflammatory response in rheumatoid arthritis fi 2020 May Fibroblast-like synoviocytes (FLSs) exert a critical effect in the occurrence and progress of rheumatoid arthritis (RA). MicroRNA-495 (miR-495) can regulate many growth behaviors in various cell types. Nevertheless, the role of miR-495 is still unclear in RA-FLS. We aimed to explore the role and molecular mechanism of miR-495 in RA. The FLSs and synovial tissue from normal and RA cases were used in the study. RT-PCR analysis was used to examine the expression of miR-495. Western blot assay was conducted to determine the levels of matrix metalloproteinase-9 (MMP-9), matrix metalloproteinase-2 (MMP-2) and β-catenin. Cell counting kit-8 (CCK-8) assays were performed to determine the proliferation of RA-FLS in different treatment groups. The results showed that miR-495 is down-regulated in both RA-synovial tissue and RA-FLSs. Overexpression of miR-495 could inhibit RA-FLS proliferation and inflammatory factors of interleukin (IL)-6, IL-11 and tumor necrosis factor alpha (TNF-α), and decrease the protein expression of MMP-9 and MMP-2. In addition, miR-495 could negatively regulate the expression of β-catenin in RA-FLSs. We also confirmed that the inhibitory role of miR-495 in RA-FLS is through the regulation of β-catenin expression. Taken together, miR-495 is downregulated in RA-FLS and RA synovial tissue, and miR-495 inhibits proliferation and inflammatory response in RA-FLS, partially via regulating β-catenin expression. The miR-495/β-catenin pathway may serve as a new therapeutic target for RA.
33080875 Anti-Inflammatory Properties of Injectable Betamethasone-Loaded Tyramine-Modified Gellan G 2020 Oct 17 Rheumatoid arthritis is a rheumatic disease for which a healing treatment does not presently exist. Silk fibroin has been extensively studied for use in drug delivery systems due to its uniqueness, versatility and strong clinical track record in medicine. However, in general, natural polymeric materials are not mechanically stable enough, and have high rates of biodegradation. Thus, synthetic materials such as gellan gum can be used to produce composite structures with biological signals to promote tissue-specific interactions while providing the desired mechanical properties. In this work, we aimed to produce hydrogels of tyramine-modified gellan gum with silk fibroin (Ty-GG/SF) via horseradish peroxidase (HRP), with encapsulated betamethasone, to improve the biocompatibility and mechanical properties, and further increase therapeutic efficacy to treat rheumatoid arthritis (RA). The Ty-GG/SF hydrogels presented a β-sheet secondary structure, with gelation time around 2-5 min, good resistance to enzymatic degradation, a suitable injectability profile, viscoelastic capacity with a significant solid component and a betamethasone-controlled release profile over time. In vitro studies showed that Ty-GG/SF hydrogels did not produce a deleterious effect on cellular metabolic activity, morphology or proliferation. Furthermore, Ty-GG/SF hydrogels with encapsulated betamethasone revealed greater therapeutic efficacy than the drug applied alone. Therefore, this strategy can provide an improvement in therapeutic efficacy when compared to the traditional use of drugs for the treatment of rheumatoid arthritis.
33103383 Biofunctionalized Liposomes to Monitor Rheumatoid Arthritis Regression Stimulated by Inter 2021 Jan Even after the revolution of rheumatoid arthritis (RA) treatment with biologic agents, this debilitating disease remains a major clinical problem. The outstanding outcomes of the systemic administration of antibodies (Abs) are narrowed by the risk of serious side effects and limited efficacy due to their short half-life. Interleukin-23 (IL-23) is a crucial pro-inflammatory cytokine involved in inflammation that potently enhances the generation of T-helper type-17 (Th17) cells. Hence, in this work, anti-IL-23 Abs are immobilized at the surface of liposomes to increase their therapeutic efficacy, being gold nanoparticles (AuNPs) incorporated to allow monitoring the biodistribution of the liposomes after systemic administration as well as due to their anti-inflammatory and antioxidant effects. A stable monodispersed liposomes' suspension with around 130 nm is produced and efficiently biofunctionalized with anti-IL-23 Abs. IL-23 capture and neutralization capacity are confirmed using activated macrophages. Biological assays demonstrate their hemocompatibility and cytocompatibility with human articular chondrocytes, macrophages, and endothelial cells. Moreover, the neutralization of IL-23 by the biofunctionalized liposomes efficiently decreases the production of IL-17A by peripheral blood mononuclear cells of healthy donors and RA patients who are activated to Th17 differentiation. Therefore, the developed formulation may be a promising strategy to treat RA.