Search for: rheumatoid arthritis methotrexate autoimmune disease biomarker gene expression GWAS HLA genes non-HLA genes
| ID | PMID | Title | PublicationDate | abstract |
|---|---|---|---|---|
| 35457564 | Healthcare Professionals' Compliance with the Standard Management Guidelines towards the U | 2022 Apr 13 | Treatment of rheumatoid arthritis (RA) is complicated, with numerous aspects influencing decision-making, including disease severity, comorbidities, and patient preferences. The present study aimed to evaluate healthcare professionals' (HCPs) knowledge of biological disease-modifying anti-rheumatic drugs (bDMARDs) and their compliance with the standard management guidelines for assuring optimal RA therapy. The cross-sectional, survey-based study was performed in various healthcare and academic settings in Karachi, Pakistan to probe HCPs' knowledge of bDMARDs and their compliance with the European League against Rheumatism (EULAR) recommendations for the management of RA patients. Overall, n = 413 questionnaires were included in our study (response rate: 82.6%). The physicians were further well-informed about the indications (n = 276, 91.3%, p = 0.001) and monitoring requirements (n = 258, 85.4%, p = 0.004). The pharmacists were more knowledgeable about the drug targets (n = 96, 86.4%, p = 0.029) and their mechanisms of action (n = 80, 72.0%, p = 0.013). Male respondents as compared with females (41.3% vs. 35.6%, p = 0.04), and physicians as compared with pharmacists (40.7% vs. 37.8%, p = 0.012), were more confident in using bDMARDs than conventional treatment in RA patients. Our findings show that the respondents were familiar with the attributes of bDMARDs and the standard management guidelines for RA care. Our results may be relevant in creating new methods, guidelines, and treatments to enhance RA treatment adherence, satisfaction, and health outcomes. | |
| 34846624 | Use of biologic agents and methotrexate improves renal manifestation and outcome in patien | 2022 Apr | BACKGROUND AND PURPOSE: We examined whether advances in treatment strategies from older disease-modifying antirheumatic drugs (DMARDs) to new biologic agents and methotrexate improved renal complications and outcome in patients with rheumatoid arthritis (RA). METHODS: We reviewed records of 156 patients with RA who underwent kidney biopsy at our institute between January 1990 and December 2019. All patients were assigned to one of three periods: period 1, 1990-1999 (n = 48); period 2, 2000-2009(n = 57); period 3, 2010-2019 (n = 51). RESULTS: Membranous nephropathy, nephrosclerosis, AA-amyloidosis, and IgA nephropathy were the four major renal manifestations of RA. AA-amyloidosis was diagnosed by kidney biopsy in 21 patients: period 1, 7 patients (15%); period 2, 10 patients (18%); and period 3, 4 patients (8%). The 4 patients in period 3 were in the years 2010-2014, and no new case of AA-amyloidosis was recorded from 2015 to 2019. In all 21 of the patients with AA-amyloidosis, neither a biologic agent nor methotrexate was administered. Fifteen of the 21 patients required dialysis, and 13 died in periods 1-3 because of amyloid-related cardiac dysfunction less than 2 years after the initiation of dialysis. Two of them are doing well using biologic agent despite dialysis. The remaining three patients who received a biologic agent or methotrexate does not progress to end-stage renal failure. In addition, the other renal complications showing progression to dialysis also decreased over time. CONCLUSION: Advances in treatment strategies have improved renal outcome and reduced mortality in patients with RA. | |
| 34108129 | Validation of a Spanish version of the Health Assessment Questionnaire-II to assess Mexica | 2022 Apr | OBJECTIVE: To evaluate the validity, reliability, and performance of the Health Assessment Questionnaire-II (HAQ-II) Spanish version questionnaire to measure physical function. METHODS: A cross-sectional study of 496 patients with rheumatoid arthritis (RA), distributed in 2 samples. The construct validity was evaluated employing the confirmatory factor analysis (CFA) and the validity based on the relationship with other variables. Cronbach's alpha (α) and McDonald's omega (ω) coefficient were used to determine reliability. Item performance was analysed by fitting different models of item response theory (IRT). RESULTS: The one-factor model presented a poor fit in the CFA; an exploratory factor analysis (AFE) was carried out, which suggested a 2-factor structure. The CFA in the second sample confirmed that the second-order model had a good fit to the data. The general factor explained more than 70% of the variance. The reliability indices showed adequate internal consistency (α = .92-.95; ω = .88-.93). Ninety-three percent of the contrasting hypotheses about the relationship of the HAQ-II scores with other variables were confirmed, demonstrating their convergent, divergent, and known group validity. The multidimensional graduated response model was the one that best predicted person's interaction with the items. CONCLUSION: The Spanish version of the HAQ-II presents adequate validity and reliability for measuring Mexican patients' physical function with RA. | |
| 34937469 | Clinical utility of therapy selection informed by predicted nonresponse to tumor necrosis | 2022 Jan | BACKGROUND: The molecular signature response classifier (MSRC) is a blood-based precision medicine test that predicts nonresponders to tumor necrosis factor-ɑ inhibitors (TNFi) in rheumatoid arthritis (RA) so that patients with a molecular signature of non-response to TNFi can be directed to a treatment with an alternative mechanism of action. RESEARCH DESIGN AND METHODS: This study evaluated decision choice and treatment outcomes resulting from MSRC-informed treatment selection within a real-world cohort. RESULTS: Therapy selection by providers was informed by MSRC results for 73.5% (277/377) of patients. When MSRC results were not incorporated into decision-making, 62.0% (62/100) of providers reported deviating from test recommendations due to insurance-related restrictions. The 24-week ACR50 responses in patients prescribed a therapy in alignment with MSRC results were 39.6%. Patients with a molecular signature of non-response had significantly improved responses to non-TNFi therapies compared with TNFi therapies (ACR50 34.8% vs 10.3%, p-value = 0.05). This indicates that predicted non-responders to TNFi therapies are not nonresponders to other classes of RA targeted therapy. Significant changes were also observed for CDAI, ACR20, ACR70, and for responses at 12 weeks. CONCLUSIONS: Adoption of the MSRC into patient care could fundamentally shift treatment paradigms in RA, resulting in substantial improvements in real-world treatment outcomes. | |
| 35062319 | New Evidence of Significant Association between EBV Presence and Lymphoproliferative Disor | 2022 Jan 10 | Development of lymphoproliferative disorders (LPDs) is one of the well-known life-threatening complications in rheumatoid arthritis (RA) patients. However, there is a lack of definitive conclusions regarding the role of Epstein-Barr virus (EBV) activity in RA initiation and progression, especially in promoting LPDs. A systematic review and meta-analysis of studies that reported an EBV positive result in RA-LPD patients and controls were conducted. Studies published before 27 July 2021 were identified through PubMed, Web of Science, and SCOPUS. A total of 79 articles were included in the systematic review. The prevalence of EBV positive result among RA-LPD patients was 54% (OR = 1.54, 95% CI = 1.45-1.64). There was a statistically significant association between EBV presence and LPD susceptibility in RA patients in comparison with all controls (OR = 1.88, 95% CI = 1.29-2.73) and in comparison with LPD patients only (OR = 1.92, 95% CI = 1.15-3.19). This association was not shown in comparison with patients with autoimmune diseases other than RA who developed LPD (OR = 0.79, 95% CI = 0.30-2.09). This meta-analysis confirmed a high prevalence of EBV in the RA-LPD population. Furthermore, it provides evidence for the association between EBV presence and LPD susceptibility in RA patients, but not in those with other autoimmune diseases who developed LPD. | |
| 34524270 | Risk Factors Associated with Aggravation of Cervical Spine Lesions in Patients with Rheuma | 2022 Mar 15 | STUDY DESIGN: A retrospective cohort study. OBJECTIVE: To examine factors related to severe aggravation of preexisting cervical lesions in patients with rheumatoid arthritis (RA) under current pharmacologic treatments with biologics. SUMMARY OF BACKGROUND DATA: Advanced RA cervical lesions carry a risk of irreversible damage to the spinal cord; however, risk factors for aggravation are unclear after the use of biologics became more popular. METHODS: Of 166 patients with preexisting cervical lesions at baseline, 87 who had cervical X-ray images taken at baseline and at the final visit (with an interval of more than 1 yr) were evaluated retrospectively. Aggravated instabilities determined at the final visit, were defined as follows: atlantoaxial subluxation (AAS) = atlantodental interval ≧ 10 mm; vertebral subluxation (VS) = a Ranawat value < 10 mm; and subaxial subluxation (SAS) = an anterior vertebral slip ≧ 4 mm or a multilevel slip ≧ 2 mm. Patients were divided into two groups based on the radiographic results: severe aggravation and non-severe aggravation. Explanatory variables were gender, age of RA onset, duration of disease, average observation period, Disease Activity Score 28 based on C-reactive protein (DAS28-CRP) at baseline, drug treatment history, presence of mutilating deformities in the hands, presence of RA-related joint surgery, and the prevalence of each cervical lesion at baseline. RESULTS: The severe group comprised 14 patients (16.1%). There was no significant difference between the two groups with respect to demographic data. Multivariate logistic regression analysis revealed that preexisting SAS lesions (odds ratio: 7.59, 95% confidence interval: 1.16-49.6) and no history of biologic treatment (odds ratio, 0.10; 95% confidence interval, 0.17-0.58) were associated with aggravation. CONCLUSION: Preexisting SAS lesions were associated with aggravation. Meanwhile, biologics may be effective at preventing aggravation.Level of Evidence: 3. | |
| 35303795 | Exosomal microRNA-140-3p from human umbilical cord mesenchymal stem cells attenuates joint | 2022 Mar 18 | OBJECTIVE: Over the years, microRNAs (miRNAs) have been involved in the pathogenesis of rheumatoid arthritis (RA). We aim to investigate the role of human umbilical cord mesenchymal stem cells (HUCMSCs)-derived exosomal miR-140-3p in RA development. METHODS: Exosomes(exo) were isolated from human umbilical cord-derived mesenchymal stem cells (HUCMSCs), and this isolation was followed by the transfer of miR-140-3p. RA rat models were constructed by collagen II adjuvant and respectively treated with HUCMSCs-exo or HUCMSCs-exo carrying miR-140-3p mimic/inhibitor, and expression of miR-140-3p and serum- and glucocorticoid-inducible kinase 1 (SGK1) was assessed. Then, RA score and inflammation scoring, fibrosis degree and apoptosis, serum inflammatory response and oxidative stress in joint tissues were determined. The RA synovial fibroblasts (RASFs) were extracted from rats and identified. Conducted with relative treatment, the migration, proliferation and apoptosis in RASFs were determined. RESULTS: MiR-140-3p was decreased while SGK1 was increased in RA rats. HUCMSCs-exo or upregulated exosomal miR-140-3p improved pathological changes and suppressed inflammation, oxidative stress and fibrosis in RA rats, and also constrained and RASF growth. Overexpression of SGK1 reversed the inhibition of RASF growth caused by overexpression of miR-140-3p. CONCLUSION: Upregulated exosomal miR-140-3p attenuated joint injury of RA rats by silencing SGK1. This research provided further understanding of the role of exosomal miR-140-3p in RA development. | |
| 34811816 | Measurement of synovium and serum dual specificity phosphatase 22 level: Their inter-corre | 2022 Jan | BACKGROUND: Dual specificity phosphatase 22 (DUSP22), also named as Jun N-terminal kinase pathway associated phosphatase recently, is reported to be closely engaged in immune and inflammation regulation. This study aimed to investigate the interaction between synovium DUSP22 and serum DUSP22 levels and to explore their correlation with rheumatoid arthritis (RA) risk, inflammation, and disease activity. METHODS: Synovium and serum samples from 42 RA patients with knee involvement underwent arthroscopy, and 20 knee trauma patients were collected. Besides, serum samples from 40 healthy controls were also obtained. Synovium DUSP22 expression was detected by reverse transcription quantitative polymerase chain reaction, while serum DUSP22 level was detected by enzyme-linked immunosorbent assay. RESULTS: Synovium DUSP22 level was greatly decreased in RA patients compared to trauma controls (p < 0.001), and it was negatively correlated with tender joint count (TJC) (r = -0.318, p = 0.040), C-reactive protein (CRP) (r = -0.330, p = 0.033), and Lysholm score (r = -0.423, p = 0.005) in RA patients. Serum DUSP22 level was lowest in RA patients, followed by trauma controls, then highest in healthy controls (p < 0.001). Serum DUSP22 level was negatively associated with TJC (r = -0.438, p = 0.004), swollen joint count (SJC) (r = -0.372, p = 0.015), CRP (r = -0.391, p = 0.011), and disease activity score in 28 joints (DAS28(ESR) ) score (r = -0.406, p = 0.008), and it increased after treatment (p = 0.001) in RA patients. In addition, serum DUSP22 level positively related to synovium DUSP22 level in RA patients (r = 0.394, p = 0.010). CONCLUSION: Synovium and serum DUSP22 are intercorrelated and insufficiently expressed in RA patients; meanwhile, their deficiency correlates with increased systemic inflammation, disease activity, and joint dysfunction. | |
| 33851898 | Region specificity of rheumatoid foot symptoms associated with ultrasound-detected synovit | 2022 Jan 5 | OBJECTIVES: We aimed to clarify the clinical implication of ultrasound (US)-detected foot joint inflammation in tightly controlled patients with rheumatoid arthritis (RA). METHODS: We evaluated bilateral foot joints (second to fifth metatarsophalangeal joints of forefoot; tarsometatarsal, cuneonavicular and midtarsal joints of midfoot) of 430 RA patients for synovitis using Power Doppler (PD) imaging by US. We made a cross-sectional and a 3-year longitudinal analysis about the associations of US-detected synovitis with clinical, laboratory and radiographic data as well as foot-specific outcomes using a self-administered foot evaluation questionnaire (SAFE-Q). RESULTS: The US-detected foot synovitis was seen in 28% of patients. The US-detected synovitis was closely related to 28 joint-disease activity score (DAS28) more in the forefoot than in the midfoot, while related to joint destruction in both. Multiple regression analyses showed significant associations between midfoot PD positivity and SAFE-Q in the remission group. SAFE-Q was worsened after the 3-year interval, but PD positivity at baseline did not contribute to the changes. On the other hand, destruction of the joints with US-detected synovitis significantly progressed in 3 years than with not. CONCLUSIONS: US-detected synovitis on foot joints were related to systemic inflammation, clinical symptoms, and future joint destruction with region specificity. | |
| 35124619 | Integrating molecular interactions and gene expression to identify biomarkers to predict r | 2022 | BACKGROUND: Targeted therapy using anti-TNF (tumor necrosis factor) is the first option for patients with rheumatoid arthritis (RA). Anti-TNF therapy, however, does not lead to meaningful clinical improvement in many RA patients. To predict which patients will not benefit from anti-TNF therapy, clinical tests should be performed prior to treatment beginning. OBJECTIVE: Although various efforts have been made to identify biomarkers and pathways that may be helpful to predict the response to anti-TNF treatment, gaps remain in clinical use due to the low predictive power of the selected biomarkers. METHODS: In this paper, we used a network-based computational method to identify the select the predictive biomarkers to guide the treatment of RA patients. RESULTS: We select 69 genes from peripheral blood expression data from 46 subjects using a sparse network-based method. The result shows that the selected 69 genes might influence biological processes and molecular functions related to the treatment. CONCLUSIONS: Our approach advances the predictive power of anti-TNF therapy response and provides new genetic markers and pathways that may influence the treatment. | |
| 33337811 | Drug Survival of Biologic Therapy in Elderly Patients With Rheumatoid Arthritis Compared W | 2022 Jan 1 | OBJECTIVE: Although the proportion of elderly patients with rheumatoid arthritis (RA) is increasing, the persistency of biologic therapy in elderly patients requires additional investigation. This study evaluated the drug survival of biologic therapy and associated factors in elderly compared with nonelderly patients. METHODS: This longitudinal observational study included RA patients who were enrolled in the Korean College of Rheumatology Biologics Registry (NCT01965132, started from January 1, 2013) between 2013 and 2015. We compared the retention rate of biologic therapy between elderly (age ≥70 years) and nonelderly (age <70 years) patients, and investigated the causes and predictors of biologic withdrawal in both groups. RESULTS: Of 682 patients, 122 were aged 70 years or older. The retention rate of biologic therapy at 24 months was 57.8% and 46.5% in nonelderly and elderly patients, respectively (p = 0.027). Biologic withdrawal due to adverse events and inefficacy within 24 months was not significantly different between the 2 groups, although adverse events were more common in elderly patients (20.6% vs 12.8%, p = 0.360). Drug withdrawal due to patient refusal was more common in elderly patients (9.8% vs 1.8%, p < 0.001). In elderly patients, biologic withdrawal was associated with current smoking and older age at disease onset, whereas the use of tumor necrosis factor inhibitors, nonuse of methotrexate, and combination of corticosteroid were important in nonelderly patients. CONCLUSIONS: Elderly RA patients are more likely to discontinue biologic agents within 24 months. To increase the retention rate of biologic therapy, rheumatologists should consider patient characteristics before and during biologic therapy. | |
| 35192592 | Can Intra-articular Injection of Glucocorticoids Be an Alternative Intervention to Achieve | 2022 Mar 1 | BACKGROUND/OBJECTIVE: This study aimed at investigating whether a single intra-articular (IA) injection of triamcinolone acetonide (TA) could facilitate to achieve clinical remission in patients with rheumatoid arthritis (RA) exhibiting low disease activity (LDA). METHODS: This longitudinal study included 22 patients with RA exhibiting LDA involving wrist arthritis at our institution between April 2016 and March 2019. A single IA injection of 20 mg TA was administered into the symptomatic wrist joint. Efficacy was assessed by the primary end point of proportion of patients reaching clinical remission. Secondary end points included Clinical Disease Activity Index (CDAI), Simplified Disease Activity Index (SDAI), Health Assessment Questionnaire Disability Index, adverse events, and ultrasonographic assessment of the injected wrist joints. RESULTS: Remission rates were 40% and 50% at weeks 4 and 12, respectively, and were maintained at approximately 50% until week 24. The secondary outcomes of CDAI, SDAI, and Health Assessment Questionnaire Disability Index were improved significantly at week 4, and the improvements in CDAI and SDAI continued up to week 24. Ultrasonography showed that synovial hypertrophy, power Doppler signals, and the combined score were significantly reduced at weeks 4, 12, and 24 compared with the baseline. No patient developed severe, irreversible adverse events. CONCLUSIONS: Approximately half of the patients with RA exhibiting LDA who received a single IA injection of TA into the wrist joints achieved clinical remission without serious adverse events in the midterm period, suggesting that IA injection of TA might be considered as an alternative intervention to achieve remission in patients with RA exhibiting LDA. | |
| 35285200 | [Mechanism of Tibetan medicine Pterocephalus hookeri extract in treatment of rheumatoid ar | 2022 Feb | Ultra-high performance liquid chromatography-quadrupole time-of-flight tandem mass spectrometry(UPLC-Q-TOF/MS) was used to investigate the effect of Pterocephalus hookeri on serum metabolism of adjuvant arthritis(AA) model rats induced by complete Freund's adjuvant. After the AA model was properly induced, the serum of rats was collected 30 days after treatment. UPLC-Q-TOF-MS chromatograms were collected and analyzed by principal component analysis(PCA) and orthogonal partial least squares discriminant analysis(OPLS-DA). The results revealed that compared with the control group, the model group showed increased content of 12 biomarkers in the serum(P<0.05) and reduced content of the other nine biomarkers(P<0.05). P. hookeri extract could recover the above-mentioned 19 biomarkers to a certain range. Pathway enrichment showed that these markers mainly involved eight metabolic pathways, including valine, leucine, and isoleucine degradation, arachidonic acid metabolism, arginine and proline metabolism, glycerol phospholipid metabolism, primary bile acid biosynthesis, bile acid biosynthesis, tryptophan metabolism, and unsaturated fatty acid biosynthesis. The findings of this study demonstrate that P. hookeri extract can regulate metabolic disorders and promote the regression of metabolic phenotype to the normal level to exert the therapeutic effect on AA rats. This study is expected to provide a certain scientific basis for the biological research on the treatment of rheumatoid arthritis by P. hookeri. | |
| 35209942 | The effect of probiotic cheese consumption on inflammatory and anti-inflammatory markers, | 2022 Feb 24 | BACKGROUND: In recent decades, several studies have shown changes in the intestinal microflora among patients with rheumatoid arthritis (RA). Therapeutic measures using probiotics have shown favorable effects on the recovery of these patients. However, most studies have used probiotic supplements. In this study, we aimed to investigate the effect of probiotic cheese consumption on inflammatory and anti-inflammatory factors, disease severity, and symptoms in these patients. METHODS: This study is a randomized, double-blind clinical trial, in which forty patients with mild to moderate severity of RA will be randomly allocated to receive either 30 g/day probiotic cheese (n = 20) or only low-salt and low-fat cheese without any added probiotic (n = 20) for 12 weeks. Assessment of anthropometric measures and biochemical indicators, including serum concentrations of high-sensitivity C-reactive protein (hs-CRP), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-10 (IL-10), will be done at the study baseline and end of the trial. In addition, disease severity and disability will be assessed by DAS-28 and the HAQ-DI questionnaire, respectively. DISCUSSION: Diet is the leading environmental factor affecting the gut microbiota. A prebiotic-rich diet and probiotics might be beneficial in this regard. To the best of our knowledge, the effect of probiotic supplements on inflammation in these patients has widely been assessed; however, there is only one study that examined the effect of probiotic-containing food in these patients. Further studies are needed to investigate the effect of probiotic-containing foods on inflammatory markers and symptoms in patients with RA. TRIAL REGISTRATION: Iranian Registry of Clinical Trials IRCT20201120049449N1 . Registered on 14 February 2021. | |
| 35426800 | [Triptolide inhibits inflammatory response and migration of fibroblast like synovial cells | 2022 Mar 20 | OBJECTIVE: To investigate the effect of triptolide (TPL) on inflammatory response and migration of fibroblast like synovial cells (FLS) in rheumatoid arthritis (RA-FLS) and the mechanism of circular noncoding RNA (circRNA) 0003353 for mediating this effect. METHODS: We collected peripheral blood mononuclear cells (PBMCs) and serum samples from 50 hospitalized RA patients and 30 healthy individuals for detecting the expression of circRNA 0003353, immune and inflammatory indexes (ESR, CRP, RF, anti-CCP, IgA, IgG, IgM, C3, and C4) and DAS28 score. Cultured RA-FLS was treated with 10 ng/mL TPL and transfected with a circRNA 0003353 overexpression plasmid, and cell counting kit-8 (CCK-8) assay and Transwell assay were used to detect the changes in the viability and migration of the cells. Enzyme-linked immunosorbent assay (ELISA) was used to examine the cytokines IL-4, IL-6, and IL-17, and real-time fluorescence quantitative PCR (RT-qPCR) was performed to detect the expression of circRNA 003353; Western blotting was used to detect the expressions of p-JAK2, pSTAT3, JAK2 and STAT3 proteins in the treated cells. RESULTS: The expression of circRNA 0003353 was significantly increased in PBMCs from RA patients and showed a good performance in assisting the diagnosis of RA (AUC=90.5%, P < 0.001, 95% CI: 0.83-0.98). CircRNA 0003353 expression was positively correlated with ESR, RF and DAS28 (P < 0.05). Treatment with TPL significantly decreased the expression of circRNA 0003353, suppressed the viability and migration ability, decreased the expressions of IL-6 and IL-17, and increased the expression IL-4 in cultured RA-FLS in a time-dependent manner (P < 0.01). TNF-α stimulation of RA-FLS significantly increased the ratios of p-JAK2/JAK2 and p-STAT3/STAT3, which were obviously lowered by TPL treatment (P < 0.01). TPL-treated RA-FLS overexpressing circRNA 0003353 showed significantly increased cell viability and migration ability with decreased IL-4 expression and increased IL-6 and IL-17 expressions and ratios of p-JAK2/ JAK2 and p-STAT3/STAT3 (P < 0.01). CONCLUSION: The expression of circRNA 0003353 is increased in PBMCs in RA patients and in RA-FLS. TPL treatment can regulate JAK2/STAT3 signal pathway and inhibit the inflammatory response and migration of RA-FLS through circRNA 0003353. | |
| 35522243 | Canonical and noncanonical regulatory roles for JAK2 in the pathogenesis of rheumatoid art | 2022 Jun | Idiopathic pulmonary fibrosis (IPF) and rheumatoid arthritis-associated interstitial lung disease (RA-ILD) are two fibrotic interstitial lung diseases that share the usual interstitial pneumonia (UIP) injury pattern. Here, we report that RNA sequencing of lung biopsies from patients with RA-ILD and IPF revealed shared and distinct disease-causing pathways. Analysis of transcriptomic data identified a JAK2 related JAK/STAT signaling pathway gene signature that distinguishes RA-UIP from idiopathic UIP. This was further confirmed by immunohistostaining, which identified JAK2 phosphorylation with two distinct forms of activation: a cytoplasmic form of JAK2 activation in most IPF cases (13/20) and a nuclear form of p-JAK2 in RA-UIP (5/5) and a minority of IPF (6/20) cases. Further immunohistostaining identified STAT5A&B as the downstream transcriptional activator for JAK2-mediated canonical signal transduction and phosphorylation of Tyr41 on histone H3 (H3Y41ph) as the downstream epigenetic regulation site for JAK2-mediated noncanonical signal transduction. Gene Set Enrichment Analysis (GSEA) of the RNA-Seq data further supported this shared pathogenic mechanism for the two diseases with the enrichment of STAT5A&B target gene sets as well as the JAK2 regulated H3Y41ph target gene set. This regulatory role of JAK2 in the pathogenesis of pulmonary fibrosis was further demonstrated by the attenuation of bleomycin-induced murine pulmonary fibrosis using a JAK2-selective pharmacological inhibitor CEP33779. In vitro studies with normal and IPF derived lung fibroblasts revealed a central role for JAK2 as an essential intermediary molecule in TGF-β-mediated myofibroblast trans-differentiation, proliferation, and extracellular matrix protein production. These observations support a crucial role for JAK2 as an intermediary molecule in fibrotic lung disease development. | |
| 35266068 | Repurposing monoamine oxidase inhibitors (MAOI) for the treatment of rheumatoid arthritis | 2022 Apr | Monoamine oxidase inhibitors (MAOI) are presently used to treat depression, parkinsonian, and other psychiatric disorders. The present study was aimed to repurpose the use of MOAI in Rheumatoid Arthritis (RA). The animal model of RA was developed using collagen type II (CII) in Freund's complete adjuvant (FCA) followed by lipopolysaccharide (LPS) and a booster dose of CII in FCA. The effect of MAOI, Selegiline was evaluated whereas the indicators like paw thickness, arthritic score, and the splenic index were measured and compared with the standard drug Methotrexate. Further to explore the molecular mechanism, the expression of serum inflammatory cytokines (IL-6 and TNF-α), radiographical and histopathological study of hind paw were also checked and analyzed. Treatment with MAOI, Selegiline not only reduced the paw thickness, arthritic score, and the splenic index, but also greatly improved the inflammatory biochemical and hematologic parameters and improved the arthritis score. The serum level of IL-6 and TNF-α are considerably decreased dose dependently, however, the notable significant effect (**p < 0.01) observed at concentration of 30 mg/kg b.w. when the RA animals treated by Selegiline. Collectively, Selegiline improved the progression of RA possibly via decreased catecholamine breakdown at synovial fluid resulting decrease hydrogen peroxide (H(2)O(2)) generation and inhibition of pro-inflammatory cytokines in situ. Thus, the finding support and indicate the repurposing of MAOI for the treatment of RA meriting further studies on synovial monoamine oxidase as a new therapeutic target to design a new drug for RA. | |
| 35030369 | Identification of common susceptibility genes and drug target genes in multiple sclerosis, | 2022 Feb | BACKGROUND: Multiple sclerosis (MS) is an autoimmune-mediated demyelinating disease of the white matter in the central nervous system (CNS). In clinical practice, it was found that MS is associated with a variety of autoimmune diseases, such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA). The aim of this study was to identify common susceptibility genes and drug target genes in MS, SLE, and RA and to provide new insights into treatment. METHODS: The common susceptibility genes of MS, SLE, and RA were obtained by searching the GWAS database and using microarray data to validate. The Genome Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed, and the common KEGG pathways were selected. All the genes enriched in the common pathways were obtained and intersected with the susceptibility genes of MS, SLE, and RA to obtain the pathway genes of them respectively, and found the common pathogenesis-related genes of the three diseases. By reviewing the literature and the DrugBank database, the drugs and drug target genes that have been approved for the treatment of the three diseases were obtained. Finally, the DGIdb database was searched to predict potential drugs or molecular compounds that interact with susceptibility genes common to MS, SLE, and RA. RESULTS: In MS, SLE, and RA, there were 46 common susceptibility genes, of which 23 were significantly differentially expressed in the microarray expression profile. Then, 2117 genes were obtained in the 42 common pathways, among which 17 pathogenesis-related genes were common in MS, SLE, and RA. The Drugbank database was used to obtain 29 drug target genes for MS, 43 drug target genes for RA, and 20 drug target genes for SLE. DHODH is a common drug target gene for MS, SLE, and RA, and its corresponding drugs are Leflunomide and Teriflunomide. A total of 13 genes and 366 potential drugs or molecular compounds were predicted to have interaction relationships after searching the DGIdb database. CONCLUSION: The common susceptibility genes and drug target genes among MS, SLE, and RA provide a theoretical basis for the co-morbidity phenomenon of the three diseases in clinical practice and may guide the clinical treatment. | |
| 33843780 | Epidemiology and Outcomes of Alcohol Use Hospitalizations in People With Gout, Rheumatoid | 2022 Mar 1 | OBJECTIVE: To examine the incidence, time trends, and outcomes of alcohol use disorder (AUD) hospitalizations in people with gout, rheumatoid arthritis (RA), fibromyalgia, osteoarthritis, or low back pain (LBP). METHODS: We used the US National Inpatient Sample data from 1998 to 2016. We examined the rates of AUD hospitalizations in musculoskeletal diseases (MSDs), based on the presence of diagnostic codes for AUD in the primary and MSDs in a secondary position. Multivariable-adjusted (age, sex, race, and income) health care utilization and in-hospital mortality were compared by the presence/absence of MSDs, using linear or logistic regression. RESULTS: Alcohol use disorder hospitalizations increased over the 19-year study period from 1998 to 2014 to 3-fold higher in gout, osteoarthritis, or LBP; 3.5-fold in RA; and 4.5-fold in fibromyalgia. Compared with AUD hospitalizations in people without each respective MSD, adjusted total hospital charges were $3913 higher in people with gout and $1368 to $1614 lower for osteoarthritis, fibromyalgia, or LBP over the study period (all significant) and not significantly different for RA. The adjusted odds of hospital stay of more than 3 days were significantly higher for all 5 MSDs, with odds ratio ranging 1.10 for LBP to 1.34 for gout. The adjusted odds of in-hospital mortality were significantly lower for all 5 MSDs, with odds ratio ranging from 0.21 for fibromyalgia to 0.50 for gout. CONCLUSIONS: In a national US study, the rate of AUD hospitalizations increased in all 5 MSDs. Providers and patients with MSDs should be counseled regarding the risk and impact of alcohol use. Interventions to reduce AUD hospitalization-associated health care burden in MSD are needed. | |
| 33666161 | Interferon regulatory factor 5 gene variants rs2004640 and rs4728142 are associated with c | 2022 Jan | OBJECTIVES: Rheumatoid arthritis (RA) is associated with cardiovascular (CV) morbidity and mortality. Interferon regulatory factor 5 (IRF5) gene polymorphisms rs2004640 and rs4728142 have been associated with autoimmune diseases, but also with atherosclerosis. Differences in IRF5 gene expression can lead to the production of different interferons and might play a role in the atherogenic process in RA. METHODS: We investigated the effects of IRF5 gene variants rs2004640 and rs4728142 on clinical parameters related to atherosclerosis, such as cIMT (in subgroup n=101), and new CV events (in whole cohort n=353). RESULTS: For rs2004640, cIMT values at baseline were highest within the group of patients carrying the GG-genotype, followed by GT- and TT- genotypes, which was statistically significant. Over time patients with the TT-genotype had the highest increase in cIMT. For rs4728142 cIMT values were also the highest for patients with the GG-genotype at baseline, but the difference between the groups was not statistically significant. Over time the highest increase in cIMT was in the patients with the AA-genotype. Both rs2004640 and rs4728142 were not associated with new CV events during follow-up. CONCLUSIONS: IRF5 alleles are associated with changes in cIMT, but not with new CV events in RA. Although these findings implicate a role of the IRF5 transcription pathway in atherosclerosis, IRF5 single nucleotide polymorphisms do not appear to increase the risk of future CV events. |