Search for: rheumatoid arthritis methotrexate autoimmune disease biomarker gene expression GWAS HLA genes non-HLA genes
| ID | PMID | Title | PublicationDate | abstract |
|---|---|---|---|---|
| 32461524 | Methotrexate-associated Hodgkin Lymphoma in a Patient with Rheumatoid Arthritis Successful | 2020 Sep 1 | A 53-year-old woman had been diagnosed with rheumatoid arthritis (RA) in X-6. She was started on methotrexate (MTX) in X-1. She developed a cough, and chest computed tomography showed abnormalities. In X, MTX was discontinued, but the cough persisted. A lung biopsy revealed a diagnosis of nodular sclerosis classic Hodgkin lymphoma (CHL-NS). She was considered to have "other iatrogenic immunodeficiency-associated lymphoproliferative disorders" (OIIA-LPD), MTX-associated Hodgkin lymphoma (MTX-HL). She received six courses of brentuximab vedotin (BV) in addition to AVD (BV+AVD). A complete metabolic response was obtained, and the RA went into remission. This is the fourth reported case of BV+AVD for MTX-HL. | |
| 33028675 | Changes in selected haematological parameters associated with JAK1/JAK2 inhibition observe | 2020 Oct | OBJECTIVE: To characterise changes in selected haematological parameters following once-daily oral baricitinib dosing. METHODS: Data were pooled from eight randomised clinical trials (four phase 3, three phase 2, one phase 1b) and one long-term extension. Changes in haematological parameters were evaluated up to 128 weeks (N=2387); overall safety of baricitinib was assessed up to 6 years (N=3492). RESULTS: Mean absolute neutrophil counts decreased (-1.36×10(9)/L) within 1 month, followed by stabilisation within the normal reference range through week 128. The incidence of serious infections was not elevated in patients with neutropenia during the 24-week placebo-controlled period. Mean lymphocyte counts increased (+0.30×10(9)/L) within 1 month, then decreased to baseline (weeks 12-24). Mean platelet counts increased at week 2 (+51×10(9)/L), then decreased towards baseline. Overall, mean haemoglobin concentrations decreased (-0.12 mmol/L), then returned to baseline; however, reduced baseline haemoglobin concentrations observed in the highest baseline high-sensitivity C reactive protein quartile increased over time. Permanent drug discontinuation occurred due to laboratory abnormalities related to neutrophil count in 8 (0.2%), lymphocyte counts in 6 (0.2%), platelet counts in 8 (0.2%), and haemoglobin levels in 16 (0.5%) of all baricitinib-treated patients (N=3492 with 7993 total person-years of exposure). CONCLUSIONS: Moderate decreases in neutrophils were seen during baricitinib treatment; however, serious infection was uncommon in patients with neutropenia. Transient increases were observed in lymphocytes and platelets, which returned to baseline over time. Changes in haemoglobin concentration were generally small. Haematological abnormalities seldom led to drug discontinuation. | |
| 31267801 | Effectiveness, safety, and methotrexate dose-tapering pattern over two years of treatment | 2020 May | Objectives: To investigate the long-term effectiveness, safety, and methotrexate (MTX) dose-tapering patterns in patients with rheumatoid arthritis (RA) receiving adalimumab plus high-dose MTX.Methods: In this prospective, postmarketing study (2012-2017), conducted at 128 sites in Japan, biologic-naïve patients with RA (duration ≤2 years) previously treated with MTX for ≥3 months, initiated treatment with adalimumab and MTX (≥12 mg/week). Effectiveness by Disease Activity Score in 28 joints using C-reactive protein (DAS28-CRP), safety, and MTX dose-tapering were assessed from baseline to 104 weeks.Results: In the effectiveness analysis set (n = 292), DAS28-CRP remission (<2.6) was achieved in 92.3% (n = 120/130) of patients at week 104. The proportions of patients receiving MTX dose <10 mg/week increased to 32.3% (n = 50/155) and ≥12 mg/week reduced to 52.9% (n = 82/155) by week 104. Per univariate regression analysis, MTX dose tapering was associated with longer adalimumab drug survival. Of 70 patients with joint X-rays available, 59 (84.3%) achieved Δ modified total Sharp score ≤1.0 at 104 weeks. In the safety analysis set (n = 300), 143 adverse drug reactions were reported in 92 patients (30.7%, non-serious; 24.7%, serious 8.7%).Conclusion: The long-term effectiveness and safety of adalimumab with high-dose MTX was confirmed in biologic-naïve patients with early RA in a real-world setting in Japan.Clinical Trial Registration: This study is registered at ClinicalTrials.gov (identifier: NCT01736189; retrospectively registered 29 November 2012, due to administrative reasons). | |
| 32912264 | The prevalence and impact of comorbidities on patients with axial spondyloarthritis: resul | 2020 Sep 10 | BACKGROUND: In contrast to other chronic rheumatic musculoskeletal diseases such as rheumatoid arthritis, comorbidities in axial spondyloarthritis (axSpA) and their impact on disease outcomes are less well studied. The aim of this study was to investigate the prevalence of comorbidities and their association with disease activity and functional impairment in a large population-based cohort of patients with axSpA. METHODS: A random sample of patients with axSpA, stratified by age and sex, was drawn from health insurance data. Patients in the sample received a survey on demographic, socioeconomic, and disease-related parameters. Comorbidities were defined using the Elixhauser coding algorithms excluding rheumatoid arthritis/collagen vascular diseases and including osteoporosis and fibromyalgia, resulting in a set of 32 comorbidities. The prevalence of comorbidities in the axSpA patients and their pharmacological treatment were examined. Multivariable linear regression models were calculated to determine the association of comorbidities with disease activity and functional status. RESULTS: A total of 1776 axSpA patients were included in the analyses (response, 47%; mean age, 56 years; 46% female). The most prevalent comorbidities were hypertension, depression, and chronic pulmonary disorders. The number of comorbidities was significantly associated with both the BASDAI and BASFI: β (95% CI) = 0.17 (0.09-0.24) and 0.24 (0.15-0.32), respectively. When analysed separately, hypertension, depression, and chronic pulmonary disease were comorbidities with a significant and independent association with BASFI, while for BASDAI, such an association was found for depression and chronic pulmonary disease only. CONCLUSIONS: Comorbidities are common in axSpA patients and are associated with higher disease activity and higher levels of functional impairment. Higher disease activity and higher levels of functional impairment might be indicators of severe disease resulting in the development of comorbidities. | |
| 33268527 | Active conventional treatment and three different biological treatments in early rheumatoi | 2020 Dec 2 | OBJECTIVE: To evaluate and compare benefits and harms of three biological treatments with different modes of action versus active conventional treatment in patients with early rheumatoid arthritis. DESIGN: Investigator initiated, randomised, open label, blinded assessor, multiarm, phase IV study. SETTING: Twenty nine rheumatology departments in Sweden, Denmark, Norway, Finland, the Netherlands, and Iceland between 2012 and 2018. PARTICIPANTS: Patients aged 18 years and older with treatment naive rheumatoid arthritis, symptom duration less than 24 months, moderate to severe disease activity, and rheumatoid factor or anti-citrullinated protein antibody positivity, or increased C reactive protein. INTERVENTIONS: Randomised 1:1:1:1, stratified by country, sex, and anti-citrullinated protein antibody status. All participants started methotrexate combined with (a) active conventional treatment (either prednisolone tapered to 5 mg/day, or sulfasalazine combined with hydroxychloroquine and intra-articular corticosteroids), (b) certolizumab pegol, (c) abatacept, or (d) tocilizumab. MAIN OUTCOME MEASURES: The primary outcome was adjusted clinical disease activity index remission (CDAI≤2.8) at 24 weeks with active conventional treatment as the reference. Key secondary outcomes and analyses included CDAI remission at 12 weeks and over time, other remission criteria, a non-inferiority analysis, and harms. RESULTS: 812 patients underwent randomisation. The mean age was 54.3 years (standard deviation 14.7) and 68.8% were women. Baseline disease activity score of 28 joints was 5.0 (standard deviation 1.1). Adjusted 24 week CDAI remission rates were 42.7% (95% confidence interval 36.1% to 49.3%) for active conventional treatment, 46.5% (39.9% to 53.1%) for certolizumab pegol, 52.0% (45.5% to 58.6%) for abatacept, and 42.1% (35.3% to 48.8%) for tocilizumab. Corresponding absolute differences were 3.9% (95% confidence interval -5.5% to 13.2%) for certolizumab pegol, 9.4% (0.1% to 18.7%) for abatacept, and -0.6% (-10.1% to 8.9%) for tocilizumab. Key secondary outcomes showed no major differences among the four treatments. Differences in CDAI remission rates for active conventional treatment versus certolizumab pegol and tocilizumab, but not abatacept, remained within the prespecified non-inferiority margin of 15% (per protocol population). The total number of serious adverse events was 13 (percentage of patients who experienced at least one event 5.6%) for active conventional treatment, 20 (8.4%) for certolizumab pegol, 10 (4.9%) for abatacept, and 10 (4.9%) for tocilizumab. Eleven patients treated with abatacept stopped treatment early compared with 20-23 patients in the other arms. CONCLUSIONS: All four treatments achieved high remission rates. Higher CDAI remission rate was observed for abatacept versus active conventional treatment, but not for certolizumab pegol or tocilizumab versus active conventional treatment. Other remission rates were similar across treatments. Non-inferiority analysis indicated that active conventional treatment was non-inferior to certolizumab pegol and tocilizumab, but not to abatacept. The results highlight the efficacy and safety of active conventional treatment based on methotrexate combined with corticosteroids, with nominally better results for abatacept, in treatment naive early rheumatoid arthritis. TRIAL REGISTRATION: EudraCT2011-004720-35, NCT01491815. | |
| 32785018 | PPARs and Angiogenesis-Implications in Pathology. | 2020 Aug 10 | Peroxisome proliferator-activated receptors (PPARs) belong to the family of ligand-activated nuclear receptors. The PPAR family consists of three subtypes encoded by three separate genes: PPARα (NR1C1), PPARβ/δ (NR1C2), and PPARγ (NR1C3). PPARs are critical regulators of metabolism and exhibit tissue and cell type-specific expression patterns and functions. Specific PPAR ligands have been proposed as potential therapies for a variety of diseases such as metabolic syndrome, cancer, neurogenerative disorders, diabetes, cardiovascular diseases, endometriosis, and retinopathies. In this review, we focus on the knowledge of PPAR function in angiogenesis, a complex process that plays important roles in numerous pathological conditions for which therapeutic use of PPAR modulation has been suggested. | |
| 32707885 | Benzylideneacetophenone Derivative Alleviates Arthritic Symptoms via Modulation of the MAP | 2020 Jul 22 | The benzylideneacetophenone derivative 3-(4-hydroxy-3-methoxy-phenyl)-1-{3-[1]-phenyl}-propenone (JC3 dimer) was synthesized through the dimerization of JC3. To investigate the inhibitory effects of JC3 dimer, the carrageenan/kaolin (C/K)-induced knee arthritis rat model was used in vivo and rheumatoid arthritis (RA) patient-derived fibroblast-like synoviocytes (FLS) were used in vitro. In the C/K rat model, JC3 dimer was given after arthritis induction for 6 days at the concentrations of 1, 5, or 10 mg/kg/day. Manifestation of arthritis was evaluated using knee thickness, weight distribution ratio (WDR), and squeaking test. The levels of prostaglandin E(2) (PGE(2)), interleukin (IL)-6, and tumor necrosis factor (TNF)-α in the serum of JC3 dimer-treated arthritic rats were also analyzed. Histological examination of the knee joints was also done. For the FLS, the cells were stimulated using IL-1β and concentrations of 1, 5, and 10 μg/mL JC3 dimer were used. The levels of IL-8, IL-6, and PGE(2) were measured in stimulated FLS treated with JC3 dimer. At days 5 to 6 after arthritis induction, JC3 dimer treatment significantly decreased arthritic symptoms and reduced the inflammation in the knee joints in the histology of knee tissues in C/K-arthritic rats. In stimulated FLS, JC3 dimer suppressed the increase of IL-8, IL-6, and PGE(2). These findings suggest that JC3 dimer has suppressive effects on arthritis, and that JC3 dimer can be a potential agent for arthritis therapy. | |
| 32963355 | A shedding soluble form of interleukin-17 receptor D exacerbates collagen-induced arthrit | 2021 Aug | Rheumatoid arthritis (RA) is exacerbated by TNF-alpha signaling. However, it remains unclear whether TNF-α-activated TNFR1 and TNFR2 are regulated by extracellular factors. Here, we showed that soluble glycosylated interleukin-17 receptor D (sIL-17RD), which was produced by proteolytic cleavage, enhanced TNF-α-induced RA. We revealed that IL-17RD shedding was induced by the proteolytic enzyme TACE and enhanced by TNF-α expression in macrophages. Intriguingly, sIL-17RD was elevated in the sera of arthritic mice and rats. Recombinant sIL-17RD significantly enhanced the TNF-α-induced proinflammatory response by promoting TNF-α-TNFR-sIL-17RD complex formation and receptor clustering, leading to the accelerated development of collagen-induced arthritis. Our observations revealed that ectodomain shedding of IL-17RD occurred in RA to boost the TNF-α-induced inflammatory response. Targeting sIL-17RD may provide a new strategy for the therapy of RA. | |
| 33145365 | Knockdown of YAP/TAZ Inhibits the Migration and Invasion of Fibroblast Synovial Cells in R | 2020 | The purpose of this study was to investigate the effect of knockdown of the yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) on the migration and invasion of the rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS) and to preliminarily elucidate the mechanisms between YAP/TAZ and autophagy in the migration and invasion of RA-FLS. RA-FLS stable knockdown of YAP or TAZ was successfully established by using lentiviral-mediated gene knockdown techniques. Wound healing assay and Transwell assay were used to evaluate the effect of knockdown of YAP or TAZ on the migration and invasion of RA-FLS. Reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR) and western blotting assays were performed to examine the expression of indicated genes. The results showed that YAP and TAZ were upregulated in RA-FLS, and knockdown of YAP or TAZ inhibited the migration and invasion, reduced the expression of N-cadherin and Vimentin, and increased the accumulation of E-cadherin and β-catenin in RA-FLS. Our results also demonstrated that knockdown of YAP or TAZ promoted autophagy which increased the accumulation of LC3B-II and ULK1 and decreased the amount of SQSTM1/p62 in RA-FLS. Furthermore, our data displayed that inhibition of autophagy either with 3-MA or CQ can partially reverse the decrease of migration and invasion induced by YAP and TAZ knockdown in RA-FLS. Our experiments preliminarily revealed that YAP/TAZ and autophagy play important roles in the migration and invasion of RA-FLS, which might provide novel targets for the treatment of RA. | |
| 33825393 | [Sjögren's Syndrome: Epidemiological, Diagnostic, Therapeutic and Evolutionary Aspects in | 2020 | Sjögren's syndrome (SS) is an autoimmune epithelitis, rarely described in black Africa. We report its epidemiological, diagnostic, therapeutic and evolutionary aspects in a Senegalese hospital environment. A retrospective, crosssectional study was carried out in the rheumatology and internal medicine departments of Aristide-Le-Dantec University Hospital of Dakar, between January 2012 and September 2016, where the observations of SS whose diagnosis, in line with the American-European consensus criteria of 2002, were enrolled. We collected 370 observations of SS, 327 women and 43 men, a sex-ratio of 1:9. These were 251 primitive forms (pSS) and 119 secondary forms (sSS). The hospital prevalence of pSS was 5%. The mean age was 42 ± 15 years and the time taken for diagnosis was 7 years. The familial forms totaled 47 index cases with a relative risk of occurrence of the disease estimated at 6.3% for firstdegree relatives. The juvenile forms totaled 7 cases of pSS. Dry syndrome was constant: oral (87%) and ocular (84%). Extra glandular manifestations were present in 87%. Arthritis was erosive in 75 cases and secondary to Rheumatoid arthritis. Autoantibodies (rheumatoid factors [49/147], anti-CCP [24/79], Sjögren's syndrome autoantigen A [anti- Ro/SSA] 41/140, Sjögren's syndrome autoantigen B [anti-La/SSB] [22/140], anti-nuclear [14/55] and cryoglobulin 1) were objectified. The histology practiced in 253/370 patients was contributory in 229 of them. According to the ESSPRI score (Eular Sjögren's Syndrome Patient Reported Index), 77% of patients had unbearable symptoms. NHP (Nottingham Health Profile) and SF-36 (Short Form [36] Health Survey) confirmed this deterioration in the quality of life. The ESSDAI score (Eular Sjögren Syndrome Disease Activity Index) showed persistent activity of the disease. The evolution was overall favorable. The hospital prevalence of pSS was 5%. It is predominant in women with an average age of 42 years. Glandular and systemic manifestations are frequent. The functional repercussions and the alteration of the quality of life are notable. | |
| 30902523 | Berberine and musculoskeletal disorders: The therapeutic potential and underlying molecula | 2020 Jul 15 | BACKGROUND: Musculoskeletal disorders are a group of disorders that affect the joints, bones, and muscles, causing long-term disability. Berberine, an isoquinoline alkaloid, has been previously established to exhibit beneficial properties in preventing various diseases, including musculoskeletal disorders. PURPOSE: This review article aims to recapitulate the therapeutic potential of berberine and its mechanism of action in treating musculoskeletal disorders. METHODS: A wide range of literature illustrating the effects of berberine in ameliorating musculoskeletal disorders was retrieved from online electronic databases (PubMed and Medline) and reviewed. RESULTS: Berberine may potentially retard the progression of osteoporosis, osteoarthritis and rheumatoid arthritis. Limited studies reported the effects of berberine in suppressing the proliferation of osteosarcoma cells. These beneficial properties of berberine are mediated in part through its ability to target multiple signaling pathways, including PKA, p38 MAPK, Wnt/β-catenin, AMPK, RANK/RANKL/OPG, PI3K/Akt, NFAT, NF-κB, Hedgehog, and oxidative stress signaling. In addition, berberine exhibited anti-apoptotic, anti-inflammatory, and immunosuppressive properties. CONCLUSION: The current evidence indicates that berberine may be effective in preventing musculoskeletal disorders. However, findings from in vitro and in vivo investigations await further validation from human clinical trial. | |
| 32163016 | PADI4 (rs2240340), PDCD1 (rs10204525), and CTLA4 (231775) gene polymorphisms and polyartic | 2020 Jul | BACKGROUND: Certain single nucleotide polymorphisms (SNPs) in genes such as PADI4 (coding for peptidyl arginine deiminase 4), PDCD1 (coding for programmed cell death 1), and CTLA4 (coding for cytotoxic T-lymphocyte-associated protein 4) are linked to rheumatoid arthritis (RA). However, links between SNPs rs2240340, rs10204525 and rs231775 in PADI4, PDCD1 and CTLA4 respectively, and juvenile idiopathic arthritis (JIA), the commonest type of childhood arthritis, are unclear. We aimed to determine whether any of these SNPs are associated with JIA, and to clinical indices disease activity score (JADAS 71) and functional disability score (CHAQ). METHODS: We genotyped the three SNPs in 150 children with polyarticular JIA and 160 healthy children, recording standard health questionnaires, clinical features and laboratory markers. RESULTS: The TT genotype of PADI4 rs2240340 (aOR/95%CI 2.64: 1.31-5.30, P =Â 0.006) and CT genotype of PDCD1 rs10204525 (aOR/95%CI 4.99: 2.98-8.36, P <Â 0.0001) were associated with JIA. The AG+GG genotype of CTLA4 rs231175 was modestly linked to disease activity (aOR/95%CI 2.44 (1.19-5.04), p =Â 0.015). PADI4 rs2240340 was linked to CHAQ score (genotypes p =Â 0.013, alleles p =Â 0.006), whilst PDCD1 rs10204525 was linked to anti-CCP antibodies (genotypes p =Â 0.004), RF (genotypes p =Â 0.01), and the CHAQ score (genotypes p =Â 0.005, alleles p =Â 0.013). CONCLUSIONS: There are various roles for these SNPs in PADI4, CTLA4 and PDCD1 in the diagnosis and, potentially, in the management of JIA. | |
| 32401414 | S1P facilitates IL-1β production in osteoblasts via the JAK and STAT3 signaling pathways. | 2020 Sep | Rheumatoid arthritis (RA) is a systemic autoimmune inflammatory disease, in which the immune system attacks synovial joint tissues. Interleukin (IL)-1β is a critical proinflammatory cytokine in RA progression. Sphingosine-1-phosphate (S1P), a platelet-derived lysophospholipid mediator, reportedly regulates osteoimmunology. Here, we investigated how S1P mediates IL-1β expression in osteoblasts. Our analysis of records from the Gene Expression Omnibus (GEO) database demonstrate higher levels of IL-1β in patients with RA compared with those with osteoarthritis. Stimulation of osteoblasts with S1P concentration dependently increased mRNA and protein expression of IL-1β. Elevations in IL-1β mRNA expression induced by S1P were reduced by the small interfering RNA (siRNA) against the S1P(1) receptor. S1P also augmented JAK and STAT3 molecular cascades. We also found that JAK and STAT3 inhibitors and their siRNAs antagonized S1P-promoted IL-1β expression. Our results indicate that S1P promotes the expression of IL-1β in osteoblasts via the S1P(1) receptor and the JAK and STAT3 signaling pathways. | |
| 31624844 | Phosphorylation-related SNPs influence lipid levels and rheumatoid arthritis risk by alter | 2020 Apr 1 | OBJECTIVES: Phosphorylation-related single-nucleotide polymorphisms (phosSNPs) are missense SNPs that may influence protein phosphorylation. The aim of this study was to evaluate the effect of phosSNPs on lipid levels and RA. METHODS: We examined the association of phosSNPs with lipid levels and RA in large-scale genome-wide association studies (GWAS) and performed random sampling and fgwas analyses to determine whether the phosSNPs associated with lipid levels and RA were significantly enriched. Furthermore, we performed QTL analysis and Mendelian randomization analysis to obtain additional evidence to be associated with the identified phosSNPs and genes. RESULTS: We found 483 phosSNPs for lipid levels and 243 phosSNPs for RA in the GWAS loci (P < 1.0 × 10-5). SNPs associated with high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, Total cholesterol (TC) and RA were significantly enriched with phosSNPs. Almost all of the identified phosSNPs showed expression quantitative trait loci (eQTL) effects. A total of 48 protein QTLs and 9 metabolite QTLs were found. The phosSNP rs3184504 (p.Trp262Arg) at SH2B3 was significantly associated with RA, SH2B3 expression level, and plasma levels of high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, TC, hypoxanthine and 80 proteins, including beta-2-microglobulin. SH2B3 was differentially expressed between RA cases and controls in peripheral blood mononuclear cells and synovial tissues. Mendelian randomization analysis showed that SH2B3 expression level was significantly associated with TC level and RA. Plasma beta-2-microglobulin level was causally associated with high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, TC levels and RA. CONCLUSION: The findings suggested that phosSNPs may play important roles in lipid metabolism and the pathological mechanisms of RA. PhosSNPs may influence lipid levels and RA risk by altering gene expression and plasma protein levels. | |
| 31990337 | Percutaneous coronary intervention outcomes in patients with rheumatoid arthritis, systemi | 2020 Sep 1 | OBJECTIVE: Patients with autoimmune rheumatic disease (AIRD) are at an increased risk of coronary artery disease. The present study sought to examine the prevalence and outcomes of AIRD patients undergoing percutaneous coronary intervention (PCI) from a national perspective. METHODS: All PCI-related hospitalizations recorded in the US National Inpatient Sample (2004-2014) were included, stratified into four groups: no AIRD, RA, SLE and SSc. We examined the prevalence of AIRD subtypes and assessed their association with in-hospital adverse events using multivariable logistic regression [odds ratios (OR) (95% CI)]. RESULTS: Patients with AIRD represented 1.4% (n = 90 469) of PCI hospitalizations. The prevalence of RA increased from 0.8% in 2004 to 1.4% in 2014, but other AIRD subtypes remained stable. In multivariable analysis, the adjusted odds ratio (aOR) of in-hospital complications [aOR any complication 1.13 (95% CI 1.01, 1.26), all-cause mortality 1.32 (1.03, 1.71), bleeding 1.50 (1.30, 1.74), stroke 1.36 (1.14, 1.62)] were significantly higher in patients with SSc compared with those without AIRD. There was no difference in complications between the SLE and RA groups and those without AIRD, except higher odds of bleeding in SLE patients [aOR 1.19 (95% CI 1.09, 1.29)] and reduced odds of all-cause mortality in RA patients [aOR 0.79 (95% CI 0.70, 0.88)]. CONCLUSION: In a nationwide cohort of US hospitalizations, we demonstrate increased rates of all adverse clinical outcomes following PCI in people with SSc and increased bleeding in SLE. Management of such patients should involve a multiteam approach with rheumatologists. | |
| 32591978 | Investigation of Potential Drug-Drug Interactions between Peficitinib (ASP015K) and Methot | 2020 Sep | BACKGROUND: Methotrexate is frequently used to treat rheumatoid arthritis. Peficitinib (ASP015K; Smyraf(®)), an oral Janus kinase inhibitor indicated for the treatment of rheumatoid arthritis, may be coadministered with methotrexate. OBJECTIVE: The objective of this study was to investigate potential drug-drug interactions of peficitinib with methotrexate and the short-term safety of coadministration. PATIENTS AND METHODS: This phase I, open-label, single-sequence study included patients with rheumatoid arthritis taking a stable dose of methotrexate. Patients received their prescribed methotrexate dose (Day 1) and then peficitinib (100 mg) twice daily from Day 3 until the morning of Day 9; a second methotrexate dose was coadministered with peficitinib on Day 8. Serial blood samples were collected for methotrexate concentration after dosing on Days 1 (methotrexate alone) and 8 (methotrexate plus peficitinib) and for peficitinib concentration after dosing on Days 7 (peficitinib alone) and 8 (methotrexate plus peficitinib). Pre-dose concentrations of peficitinib were measured (Days 3-8). RESULTS: Peficitinib concentrations reached steady state on Day 5. Administration of peficitinib did not result in changes to methotrexate area under the concentration-time curve from time zero to infinity or maximum observed concentration following a methotrexate dose (15-25 mg), and there was no significant effect of methotrexate (15-25 mg) on peficitinib area under the concentration-time curve within a 12-hour dosing interval. There were no new tolerability or safety signals after coadministration of peficitinib and methotrexate. One patient experienced two serious adverse events and withdrew from the study without receiving peficitinib. CONCLUSIONS: Pharmacokinetic results showed no significant interactions between peficitinib and methotrexate. CLINICALTRIALS. GOV IDENTIFIER: NCT01754805. | |
| 30676812 | Efficacy of iguratimod vs. salazosulfapyridine as the first-line csDMARD for rheumatoid ar | 2020 Mar | Objectives: We retrospectively evaluated the retention rate and clinical responses following treatment for rheumatoid arthritis (RA) with iguratimod (IGU) vs. salazosulfapyridine (SASP) as the first-line conventional synthetic disease-modifying antirheumatic drug (csDMARD).Methods: We analyzed 197 RA patients who were treated with IGU or SASP as the initial treatment in the 3-year study period. The retention rate, clinical response, the dosage and percent user of prednisolone (PSL), and safety profiles were evaluated.Results: At month 36, the retention rates of the IGU and SASP groups were 52.4 vs. 32.1%. The rate of responders (good or moderate response) at month 36 was 85.8 vs. 65.2% in the IGU and SASP groups, respectively. At month 36 for the IGU and SASP groups, the percentages of PSL users were 16.7 vs. 46.7%, and the PSL dosage was 0.3 mg/d vs. 2.0 mg/d, respectively. The cumulative rates of any adverse event (AE) at month 36 were 19.8 vs. 29.2% in the IGU and SASP groups, respectively.Conclusion: IGU is a useful first-line csDMARD treatment for RA patients, showing a high retention rate and good efficacy without an increased risk of serious AEs, including serious infections. Our findings also indicate a PSL dose-sparing effect of IGU treatment. | |
| 32062074 | c-Jun NH2-terminal kinase (JNK)/stress-activated protein kinase-associated protein 1 is a | 2020 Apr | Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease. However, the pathogenesis of RA is not fully understood. Here, we reported that c-Jun NH2-terminal kinase (JNK)/stress-activated protein kinase-associated protein 1 (JSAP1, also known as JNK-interacting protein 3 (JIP3)) was significantly important for collagen-induced arthritis (CIA) in mice. Mice with JIP3 knockout (JIP3(-/-)) showed a significant decrease in arthritis index and swollen joint count in CIA mice. The histopathology of spleen and joint was markedly alleviated by JIP3 deficiency in CIA mice. Excessive macrophage activation in CIA mice was also inhibited by JIP3 deletion. CIA-induced RANKL/RANK/OPG system mRNA expression was blocked in JIP3-knockout mice. In addition, CIA-triggered cytokine secretion and TLRs/NF-κB activation was inactivated by JIP3-deficiency. In line with the inhibition of inflammation by JIP3-knockout, it also significantly suppressed JNK pathway activation induced by CIA, as evidenced by the down-regulation of p-JNK, p-c-Jun, AFT-2 and Elk-1 in joints. In vitro, RANKL-exposed RAW264.7 cells showed a significant reduction of osteoclast formation using TRAP staining. Moreover, JIP3 inhibition reduced the RANKL-caused expression of osteoclastic genes and inflammatory regulators, as well as activation of TLRs/NF-κB and JNK signaling pathways. Importantly, we found that promoting JNK activity could abrogate JIP3 knockdown-suppressed osteoclastic genes expression, inflammatory response and NF-κB activation. These findings suggested that JIP3 could significantly impede osteoclast formation and function by regulating JNK activation, illustrating a novel therapeutic strategy for managing arthritis and preventing bone destruction. | |
| 32079226 | Role of Signal Transduction Pathways and Transcription Factors in Cartilage and Joint Dise | 2020 Feb 17 | : Osteoarthritis and rheumatoid arthritis are common cartilage and joint diseases that globally affect more than 200 million and 20 million people, respectively. Several transcription factors have been implicated in the onset and progression of osteoarthritis, including Runx2, C/EBPβ, HIF2α, Sox4, and Sox11. Interleukin-1 β (IL-1β) leads to osteoarthritis through NF-ĸB, IκBζ, and the Zn(2+)-ZIP8-MTF1 axis. IL-1, IL-6, and tumor necrosis factor α (TNFα) play a major pathological role in rheumatoid arthritis through NF-ĸB and JAK/STAT pathways. Indeed, inhibitory reagents for IL-1, IL-6, and TNFα provide clinical benefits for rheumatoid arthritis patients. Several growth factors, such as bone morphogenetic protein (BMP), fibroblast growth factor (FGF), parathyroid hormone-related protein (PTHrP), and Indian hedgehog, play roles in regulating chondrocyte proliferation and differentiation. Disruption and excess of these signaling pathways cause genetic disorders in cartilage and skeletal tissues. Fibrodysplasia ossificans progressive, an autosomal genetic disorder characterized by ectopic ossification, is induced by mutant ACVR1. Mechanistic target of rapamycin kinase (mTOR) inhibitors can prevent ectopic ossification induced by ACVR1 mutations. C-type natriuretic peptide is currently the most promising therapy for achondroplasia and related autosomal genetic diseases that manifest severe dwarfism. In these ways, investigation of cartilage and chondrocyte diseases at molecular and cellular levels has enlightened the development of effective therapies. Thus, identification of signaling pathways and transcription factors implicated in these diseases is important. | |
| 31106666 | Predictive value of serum amyloid a levels for requirement of concomitant methotrexate in | 2020 May | Objectives: To identify predictive factors for remission by tocilizumab monotherapy in rheumatoid arthritis (RA) patients.Methods: This is a post hoc analysis of the SURPRISE study, a 2-year randomized, controlled study comparing the efficacy of tocilizumab with (ADD-ON) and without methotrexate (SWITCH). The primary endpoint was DAS28-ESR remission (<2.6) at week 24. The change in modified total Sharp score from baseline to week 52 (ΔmTSS/year) was also assessed as an endpoint. The effect of clinical parameters at baseline on remission was estimated by logistic regression analysis.Results: In SWITCH (n = 96), CRP, SAA, RF, and DAS28 at baseline showed predictive value for DAS28 remission in unadjusted analysis. Adjusted analysis confirmed SAA and DAS28 as predictive factors, with SAA having the highest value (ROC-AUC = 0.731). Furthermore, structural remission (ΔmTSS/year ≤ 0.5) rate was significantly higher in patients with SAA of < 50.0 μg/mL than other patients. In contrast, in ADD-ON (n = 98), only DAS28 showed predictive value for DAS28 remission. In patients with SAA < 50.0 μg/mL, both DAS28 remission and structural remission rate were comparable between SWITCH and ADD-ON.Conclusion: RA patients with low SAA levels at baseline may benefit similarly from tocilizumab with and without methotrexate.Trial registration number: NCT01120366. |