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Scientific Reports Jul 2024This study aims to identify factors influencing the alleviation of knee joint symptoms in patients with rheumatoid arthritis treated with biologic or target synthetic...
This study aims to identify factors influencing the alleviation of knee joint symptoms in patients with rheumatoid arthritis treated with biologic or target synthetic disease-modifying antirheumatic drugs (b/tsDMARDs). Among 2321 patients who started b/tsDMARDs between 2010 and 2023, we focused on 295 patients who had knee swelling or tenderness at the initiation of b/tsDMARDs and continued b/tsDMARDs at least 3 months, with recorded knee symptoms 6 months later. Symptom relief after 6 months was 78.2% for interleukin 6 (IL-6) inhibitors, 68.6% for Janus kinase (JAK) inhibitors, 65.8% for tumor necrosis factor (TNF) inhibitors, and 57.6% for cytotoxic T lymphocyte-associated antigen-4-Ig (CTLA4-Ig). The initial use of b/tsDMARDs and the use of IL-6 inhibitors in comparison to CTLA4-Ig emerged as a significant factor associated with the improvement of knee joint symptoms. Among 141 patients who underwent knee radiography at baseline and two years later, the deterioration in knee joint radiographs was 7.7% for IL-6 inhibitors, 6.3% for JAK inhibitors, 21.9% for TNF inhibitors, and 25.9% for CTLA4-Ig. The use of IL-6 inhibitors was a significant factor associated with the improvement of knee joint symptoms and the inhibition of joint destruction compared to CTLA4-Ig.
Topics: Humans; Arthritis, Rheumatoid; Female; Male; Interleukin-6; Middle Aged; Abatacept; Antirheumatic Agents; Tumor Necrosis Factor Inhibitors; Aged; Knee Joint; Adult; Janus Kinase Inhibitors; Treatment Outcome; Tumor Necrosis Factor-alpha
PubMed: 38956271
DOI: 10.1038/s41598-024-66064-3 -
Nature Structural & Molecular Biology Jul 2024The metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) long noncoding RNA (lncRNA) has key roles in regulating transcription, splicing, tumorigenesis, etc....
The metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) long noncoding RNA (lncRNA) has key roles in regulating transcription, splicing, tumorigenesis, etc. Its maturation and stabilization require precise processing by RNase P, which simultaneously initiates the biogenesis of a 3' cytoplasmic MALAT1-associated small cytoplasmic RNA (mascRNA). mascRNA was proposed to fold into a transfer RNA (tRNA)-like secondary structure but lacks eight conserved linking residues required by the canonical tRNA fold. Here we report crystal structures of human mascRNA before and after processing, which reveal an ultracompact, quasi-tRNA-like structure. Despite lacking all linker residues, mascRNA faithfully recreates the characteristic 'elbow' feature of tRNAs to recruit RNase P and ElaC homolog protein 2 (ELAC2) for processing, which exhibit distinct substrate specificities. Rotation and repositioning of the D-stem and anticodon regions preclude mascRNA from aminoacylation, avoiding interference with translation. Therefore, a class of metazoan lncRNA loci uses a previously unrecognized, unusually streamlined quasi-tRNA architecture to recruit select tRNA-processing enzymes while excluding others to drive bespoke RNA biogenesis, processing and maturation.
PubMed: 38956168
DOI: 10.1038/s41594-024-01340-4 -
Scientific Reports Jul 2024After total knee arthroplasty (TKA), approximately 20% of patients experience persistent postoperative pain (PPP). Although preoperative and postoperative pain intensity...
After total knee arthroplasty (TKA), approximately 20% of patients experience persistent postoperative pain (PPP). Although preoperative and postoperative pain intensity is a relevant factor, more detailed description of pain is needed to determine specific intervention strategies for clinical conditions. This study aimed to clarify the associations between preoperative and postoperative descriptions of pain and PPP. Fifty-two TKA patients were evaluated for pain intensity and description of pain preoperatively and 2 weeks postoperatively, and the intensities were compared. In addition, the relationship between pain intensity and PPP at 3 and 6 months after surgery was analyzed using a Bayesian approach. Descriptions of arthritis ("Throbbing" and "aching") improved from preoperative to 2 weeks postoperative. Several preoperative ("Shooting", "Aching", "Caused by touch", "Numbness") and postoperative ("Cramping pain") descriptors were associated with pain intensity at 3 months postoperatively, but only "cramping pain" at 2 weeks postoperatively was associated with the presence of PPP at 3 and 6 months postoperatively. In conclusion, it is important to carefully listen to the patient's complaints and determine the appropriate intervention strategy for the clinical condition during perioperative pain management.
Topics: Humans; Arthroplasty, Replacement, Knee; Pain, Postoperative; Female; Male; Aged; Middle Aged; Pain Measurement; Bayes Theorem; Pain Management; Aged, 80 and over
PubMed: 38956120
DOI: 10.1038/s41598-024-66122-w -
Scientific Reports Jul 2024Analyze the relationship between genetic variations in the MTHFR gene at SNPs (rs1801131 and rs1801133) and the therapy outcomes for Iraqi patients with rheumatoid...
Analyze the relationship between genetic variations in the MTHFR gene at SNPs (rs1801131 and rs1801133) and the therapy outcomes for Iraqi patients with rheumatoid arthritis (RA). The study was conducted on a cohort of 95 RA Iraqi patients. Based on their treatment response, the cohort was divided into two groups: the responder (47 patients) and the nonresponder (48 patients), identified after at least three months of methotrexate (MTX) treatment. A polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique was employed to analyze the MTHFR variations, specifically at rs1801133 and rs1801131. Overall, rs1801131 followed both codominant and dominate models, in which in the codominant model, GG [OR (95% CI) 0.11 (0.022-0.553)] and TG [OR (95% CI) 0.106 (0.021-0.528)] predict responders compared to the TT genotype; meanwhile, for the dominate model, the presence of both GG and TG genotypes [OR (95% CI) 0.108 (0.023-0.507)] together predict responders compared to the TT genotype. The AG haplotype was significantly associated with responders [OR (95% CI): 0.388 (0.208-0.723)], while the GT haplotype was associated marginally with nonresponders [OR (95% CI) 1.980 (0.965-4.064)]. In the final multivariate analysis, GG/TG genotypes were independently related to responders after adjustment for patients, disease, and treatment characteristics, while TT genotypes were associated with nonresponders. The Iraqi RA patients showed genetic polymorphism in MTHFR gene rs1801131 with T carrier allele associated with nonresponders to MTX therapy. The rs1801131 followed both codominant and dominant models. The G-carried allele for rs1801131 showed an independent association with responder to MTX therapy after adjustment for patients, disease, and treatment characteristics.
Topics: Humans; Methylenetetrahydrofolate Reductase (NADPH2); Arthritis, Rheumatoid; Methotrexate; Male; Female; Polymorphism, Single Nucleotide; Iraq; Middle Aged; Adult; Treatment Outcome; Antirheumatic Agents; Genotype
PubMed: 38956106
DOI: 10.1038/s41598-024-65199-7 -
Nature Communications Jul 2024Statin drugs lower blood cholesterol levels for cardiovascular disease prevention. Women are more likely than men to experience adverse statin effects, particularly...
Statin drugs lower blood cholesterol levels for cardiovascular disease prevention. Women are more likely than men to experience adverse statin effects, particularly new-onset diabetes (NOD) and muscle weakness. Here we find that impaired glucose homeostasis and muscle weakness in statin-treated female mice are associated with reduced levels of the omega-3 fatty acid, docosahexaenoic acid (DHA), impaired redox tone, and reduced mitochondrial respiration. Statin adverse effects are prevented in females by administering fish oil as a source of DHA, by reducing dosage of the X chromosome or the Kdm5c gene, which escapes X chromosome inactivation and is normally expressed at higher levels in females than males. As seen in female mice, we find that women experience more severe reductions than men in DHA levels after statin administration, and that DHA levels are inversely correlated with glucose levels. Furthermore, induced pluripotent stem cells from women who developed NOD exhibit impaired mitochondrial function when treated with statin, whereas cells from men do not. These studies identify X chromosome dosage as a genetic risk factor for statin adverse effects and suggest DHA supplementation as a preventive co-therapy.
Topics: Animals; Female; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Mice; Mitochondria; Humans; X Chromosome; Docosahexaenoic Acids; Induced Pluripotent Stem Cells; Gene Dosage; Mice, Inbred C57BL; Blood Glucose; Glucose; Diabetes Mellitus
PubMed: 38956041
DOI: 10.1038/s41467-024-49764-2 -
Rheumatology and Therapy Jul 2024Some retrospective data sources, such as electronic health records in the USA, report composite outcome measures not fully validated in psoriatic arthritis (PsA)....
INTRODUCTION
Some retrospective data sources, such as electronic health records in the USA, report composite outcome measures not fully validated in psoriatic arthritis (PsA). However, they often contain global assessments, such as a Physician Global Assessment (PhGA) and Patient Global Assessment (PatGA), along with patient-reported pain scores, which individually are considered validated in PsA. This research described the performance characteristics of a 3-item global assessment and pain (GAP) composite endpoint using data from the ixekizumab phase 3 PsA clinical trial program.
METHODS
Discrimination of GAP was assessed by comparing placebo to active treatment arms. The magnitude of treatment effect and responsiveness were compared to Disease Activity Index for PsA (DAPSA), clinical DAPSA, DAPSA28, and Psoriatic Arthritis Disease Activity Score (PASDAS) using effect size (ES) and standardized response mean (SRM), respectively. Construct validity was evaluated through correlation among the composite endpoints, and with other physician- and patient-reported outcomes. Change in GAP was compared in patients who reached low disease activity (LDA) levels based on DAPSA, cDAPSA, and PASDAS vs those who did not.
RESULTS
GAP discriminated between active treatment and placebo with statistically significant separation as early as week 1. The largest ES/SRM was seen with GAP (2.29/1.74) and PASDAS (2.47/1.68). GAP had the strongest correlation with PASDAS (0.81-0.92) and showed moderate correlations with patient-assessed physical function, low correlations with physician-assessed skin and nail psoriasis, and low to moderate correlation with physician-assessed enthesitis. A significantly greater improvement in GAP was seen in the groups achieving LDA states compared to those not (p < 0.001).
CONCLUSION
The GAP composite, an abbreviated endpoint comprising measures common in electronic health records, has promising performance characteristics and could be used to address important clinical questions regarding outcomes and impact of PsA in existing datasets. CLINTRIALS.
GOV IDENTIFIER
NCT01695239; NCT02349295.
PubMed: 38955921
DOI: 10.1007/s40744-024-00690-1 -
Doklady. Biochemistry and Biophysics Jul 2024ABSTTACT: -The COVID-19 pandemic has significantly changed the understanding of the safety profile of therapies for immunoinflammatory rheumatic diseases (IRDs). This is...
Results of a 12-Week Open-Label, Non-Interventional Study of the Efficacy and Safety of Olokizumab Therapy in Patients with Rheumatoid Arthritis after Switching from Anti-B-Cell Therapy during the SARS-CoV-2 Pandemic.
UNLABELLED
ABSTTACT: -The COVID-19 pandemic has significantly changed the understanding of the safety profile of therapies for immunoinflammatory rheumatic diseases (IRDs). This is primarily due to the negative impact of a number of basic disease-modifying antirheumatic drugs (DMARDs) and genetically engineered biological drugs (biological DMARDs, or biologics) on the course and outcomes of a new coronavirus infection. A number of studies have shown that anti-B-cell therapy (rituximab) gave a statistically significant increase in the risk of severe COVID-19 and an increase in mortality. At the same time, the analysis of real clinical practice data dictated the need to establish a number of restrictions on the use of certain classes of biologics and to search for alternative therapy programs to maintain control over disease activity.
PURPOSE OF THE STUDY
The purpose of the study was to evaluate the efficacy and safety of the drug Artlegia® (olokizumab), solution for subcutaneous injection, 160 mg/ml-0.4 ml, manufactured by R-Pharm JSC, Russia) for the treatment of patients with rheumatoid arthritis in real clinical practice after switching with rituximab during the COVID-19 pandemic.
MATERIALS AND METHODS
The study included 14 patients with a confirmed diagnosis of rheumatoid arthritis (RA), who were previously on rituximab therapy at a dose of 1000-500 mg twice with an interval of 2 weeks, who received at least one course of therapy with this drug. As RA worsened, patients were switched to olokizumab against the background of standard DMARDs. On weeks 0, 4, 8, and 12 after the switch, the severity of pain was assessed on the VAS scale, the number of tender and swollen joints (TJC28 and SJC28), the level of acute-phase inflammation markers, the DAS28 (disease activity score), ESR, CRP, CDAI (clinical activity index), and the functional state index HAQ (Health Assessment Questionnaire) were determined, as well as the safety profile of therapy was assessed.
RESULTS
Data analysis was performed using median values (Me) were used for data analysis. A significant decrease in TJC28 was detected after 8 and 12 weeks of treatment with olokizumab (Artlegia®) (Me baseline = 10, Me 8 weeks = 4, Me 12 weeks = 4, p < 0.05) and a decrease in TSC28 was detected after 4, 8, and 12 weeks of treatment (Me baseline = 9, Me 4 weeks = 3.5, Me 8 weeks = 2.5, Me 12 weeks = 2.0, p < 0.05). Laboratory markers of inflammation showed a decrease in CRP and ESR levels after 4 weeks of treatment (CRP: Me4 weeks = 21, Me4 weeks = 1, p < 0.05, ESR: Mesno = 31, Me4 weeks = 7, p < 0.05). Positive dynamics persisted on 8 and 12 weeks (CRP: Me 8 weeks = 1, Me 12 weeks = 0; ESR: Me 8 weeks = 4, Me 12 weeks = 5). The level of CRP by week 4 became within the normal range, regardless of the initial values. All activity indices improved from week 4 in each evaluation period compared to baseline: DAS28-ESR: Me baseline = 5.52, Me 4 weeks = 3.59, Me 8 weeks = 3.33, Me 12 weeks = 3.22, p < 0.05; DAS28CRP: Me baseline = 5.39, Me 4 weeks = 3.71, Me 8 weeks = 3.35, Me 12 weeks = 3.45, p < 0.05; CDAI: Me baseline = 28.5, Me 4 weeks = 18.0, Me 8 weeks = 16.5, Me 12 weeks = 16.0, p < 0.05. All patients showed a reduction in pain (VAS scale) by week 8. The functional status of patients, according to the HAQ index, showed a significant decrease only by week 12 of the study: Me baseline = 1.62, Me 12 weeks = 1.31, p < 0.05.
CONCLUSIONS
The study found that switching from rituximab to olokizumab was effective and safe during the COVID-19 pandemic.
PubMed: 38955912
DOI: 10.1134/S1607672924701060 -
Archiv Der Pharmazie Jul 2024Necroptosis is a form of regulated necrotic cell death and has been confirmed to play pivotal roles in the pathogenesis of multiple autoimmune diseases such as...
Necroptosis is a form of regulated necrotic cell death and has been confirmed to play pivotal roles in the pathogenesis of multiple autoimmune diseases such as rheumatoid arthritis (RA) and psoriasis. The development of necroptosis inhibitors may offer a promising therapeutic strategy for the treatment of these autoimmune diseases. Herein, starting from the in-house hit compound 1, we systematically performed structural optimization to discover potent necroptosis inhibitors with good pharmacokinetic profiles. The resulting compound 33 was a potent necroptosis inhibitor for both human I2.1 cells (IC < 0.2 nM) and murine Hepa1-6 cells (IC < 5 nM). Further target identification revealed that compound 33 was an inhibitor of receptor interacting protein kinase 1 (RIPK1) with favorable selectivity. In addition, compound 33 also exhibited favorable pharmacokinetic profiles (T = 1.32 h, AUC = 1157 ng·h/mL) in Sprague-Dawley rats. Molecular docking and molecular dynamics simulations confirmed that compound 33 could bind to RIPK1 with high affinity. In silico ADMET analysis demonstrated that compound 33 possesses good drug-likeness profiles. Collectively, compound 33 is a promising candidate for antinecroptotic drug discovery.
PubMed: 38955770
DOI: 10.1002/ardp.202400302 -
Best Practice & Research. Clinical... Jul 2024In the past four decades, a plethora of genetic association studies have been carried out in cohorts of patients with rheumatoid arthritis. These studies have... (Review)
Review
In the past four decades, a plethora of genetic association studies have been carried out in cohorts of patients with rheumatoid arthritis. These studies have highlighted key aspects of disease pathogenesis and suggested causal mechanisms. In this review, we discuss major advances in our understanding of the genetic architecture of rheumatoid arthritis susceptibility, severity and treatment response and explain how genetics supports current models of disease pathogenesis and outcome. We outline future research directions, like Mendelian randomisation, and present a number of potential avenues for clinical translation, including risk and outcome prediction, patient stratification into treatment response groups and pharmacological applications.
PubMed: 38955657
DOI: 10.1016/j.berh.2024.101968 -
Neurospine Jun 2024This study aimed to compare and analyze differences in clinical and magnetic resonance imaging (MRI) findings between tuberculous spondylodiscitis (TbS) and pyogenic...
OBJECTIVE
This study aimed to compare and analyze differences in clinical and magnetic resonance imaging (MRI) findings between tuberculous spondylodiscitis (TbS) and pyogenic spondylodiscitis (PyS), and to develop and validate a simplified multiparameter MRIbased scoring system for differentiating TbS from PyS.
METHODS
We compared predisposing factors in 190 patients: 123 with TbS and 67 with PyS, confirmed by laboratory tests, culture, or pathology. Data encompassing patient demographics, clinical characteristics, laboratory results, and MRI findings were collected between 2015 and 2020. Data were analyzed using logistic regression methods, and selected coefficients were transformed into an MRI-based scoring system. Internal validation was performed using bootstrapping method.
RESULTS
Univariate analysis revealed that the significant risk factors associated with TbS included thoracic lesions, vertebral destruction > 50%, intraosseous abscess, thin-walled abscess, well-defined paravertebral abscess, subligamentous spreading, and epidural abscess. Multivariate analysis revealed that only thoracic lesions, absence of epidural phlegmon, subligamentous spreading, intraosseous abscesses, well-defined paravertebral abscesses, epidural abscesses, and absence of facet joint arthritis were independent predictive factors for TbS (all p < 0.05). These potential predictors were used to derive an MRI scoring system. Total scores ≥ 14/29 points significantly predicted the probability of TbS, with a sensitivity of 97.58%, specificity of 92.54%, and an area under the curve of 0.96 (95% confidence interval, 125.40-3,257.95).
CONCLUSION
This simplified MRI-based scoring system for differentiating TbS from PyS helps guide appropriate treatment when the causative organism is not identified.
PubMed: 38955538
DOI: 10.14245/ns.2448120.060