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ID PMID Title PublicationDate abstract
34863654 The role of IL-17 and anti-IL-17 agents in the immunopathogenesis and management of autoim 2022 Jan Interleukin-17 (IL-17) is a proinflammatory cytokine involved in chronic inflammation occurring during the pathogenesis of allergy, malignancy, and autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, and psoriasis. IL-17 is produced by multiple cell types of adaptive and innate immunity, including T helper 17 cells, CD8 + T cells, γδ T cells, natural killer T cells, and innate lymphoid cells. Monoclonal antibodies (mAbs) targeting IL-17 and/or IL-17R would be a potential approach to study this therapeutic tool for these diseases. In the current review, we aimed to highlight the characteristics of IL-17 and its important role in the pathogenesis of related diseases. Critical evaluation of the mAbs targeting IL-17A and IL-17 receptors (e.g., Ixekizumab, Secukinumab, and Brodalumab) in various immune-mediated diseases will be provided, and finally, their clinical efficacy and safety will be reported.
35639246 Physiologically based pharmacokinetic (PBPK) modeling of piroxicam with regard to CYP2C9 g 2022 May 31 Piroxicam is a non-steroidal anti-inflammatory drug used to alleviate symptoms of osteoarthritis and rheumatoid arthritis. CYP2C9 genetic polymorphism significantly influences the pharmacokinetics of piroxicam. The objective of this study was to develop and validate the piroxicam physiologically based pharmacokinetic (PBPK) model related to CYP2C9 genetic polymorphism. PK-Sim(®) version 10.0 was used for the PBPK modeling. The PBPK model was evaluated by predicted and observed plasma concentration-time profiles, fold errors of predicted to observed pharmacokinetic parameters, and a goodness-of-fit plot. The turnover number (k(cat)) of CYP2C9 was adjusted to capture the pharmacokinetics of piroxicam in different CYP2C9 genotypes. The population PBPK model overall accurately described and predicted the plasma concentration-time profiles in different CYP2C9 genotypes. In our simulations, predicted AUC(inf) in CYP2C9*1/*2, CYP2C9*1/*3, and CYP2C9*3/*3 genotypes were 1.83-, 2.07-, and 6.43-fold higher than CYP2C9*1/*1 genotype, respectively. All fold error values for AUC, C(max), and t(1/2) were included in the acceptance criterion with the ranges of 0.57-1.59, 0.63-1.39, and 0.65-1.51, respectively. The range of fold error values for predicted versus observed plasma concentrations was 0.11-3.13. 93.9% of fold error values were within the two-fold range. Average fold error, absolute average fold error, and root mean square error were 0.93, 1.27, and 0.72, respectively. Our model accurately captured the pharmacokinetic alterations of piroxicam according to CYP2C9 genetic polymorphism.
35624835 Auranofin and Pharmacologic Ascorbate as Radiomodulators in the Treatment of Pancreatic Ca 2022 May 14 Pancreatic cancer accounts for nearly one fourth of all new cancers worldwide. Little progress in the development of novel or adjuvant therapies has been made over the past few decades and new approaches to the treatment of pancreatic cancer are desperately needed. Pharmacologic ascorbate (P-AscH(-), high-dose, intravenous vitamin C) is being investigated in clinical trials as an adjunct to standard-of-care chemoradiation treatments. In vitro, P-AscH(-) has been shown to sensitize cancer cells to ionizing radiation in a manner that is dependent on the generation of H(2)O(2) while simultaneously protecting normal tissue from radiation damage. There is renewed interest in Auranofin (Au), an FDA-approved medication utilized in the treatment of rheumatoid arthritis, as an anti-cancer agent. Au inhibits the thioredoxin antioxidant system, thus increasing the overall peroxide burden on cancer cells. In support of current literature demonstrating Au's effectiveness in breast, colon, lung, and ovarian cancer, we offer additional data that demonstrate the effectiveness of Au alone and in combination with P-AscH(-) and ionizing radiation in pancreatic cancer treatment. Combining P-AscH(-) and Au in the treatment of pancreatic cancer may confer multiple mechanisms to increase H(2)O(2)-dependent toxicity amongst cancer cells and provide a promising translatable avenue by which to enhance radiation effectiveness and improve patient outcomes.
35255979 Shining the light on clinical application of mesenchymal stem cell therapy in autoimmune d 2022 Mar 7 The autoimmune diseases are associated with the host immune system, chronic inflammation, and immune reaction against self-antigens, which leads to the injury and failure of several tissues. The onset of autoimmune diseases is related to unbalanced immune homeostasis. Mesenchymal stem cells (MSCs) are multipotent cells which have capability to self-renew and differentiate into various cell types that exert a critical role in immunomodulation and regenerative therapy. Under the certain condition in vitro, MSCs are able to differentiate into multiple lineage such as osteoblasts, adipocytes, and neuron-like cells. Consequently, MSCs have a valuable application in cell treatment. Accordingly, in this review we present the last observations of researches on different MSCs and their efficiency and feasibility in the clinical treatment of several autoimmune disorders including rheumatoid arthritis, type 1 diabetes, multiple sclerosis, systemic lupus erythematosus, inflammatory bowel disease, autoimmune liver disease, and Sjogren's syndrome.
32948119 In silico drug discovery of IKK-β inhibitors from 2-amino-3-cyano-4-alkyl-6-(2-hydroxyphe 2022 Feb The Inhibitor of IKK-β (nuclear factor kappa B kinase subunit beta), a specific modulator of NF-κB (nuclear factor-κB), is considered a valid target to discover new active compounds for various cancers and rheumatoid arthritis treatment. In this study a series of thirty 2-amino-3-cyano-4-alkyl-6-(2-hydroxyphenyl) pyridine derivatives was involved for a quantitative structure activity relationship model (QSAR) elaboration which allows the prediction of the pIC50 values of new designed compounds. The model can be used to predict the activity of new compounds within its applicability domain. Then a molecular docking study was carried out to identify the interactions between the compounds and the amino acids of the active site. After that, golden triangle, Veber's rule, and Lipinski's rule properties were calculated to identify the drug-likeness properties of the investigated compounds. Finally, in-silico-toxicity studies were performed to predict the toxicity of the new designed compounds. The analysis of the results of QSAR model and molecular docking succeeded to screen 21 interesting compounds with better inhibitory concentration having a good affinity to IKK-β. All compounds were within the range set by Veber's rule and Lipinski's rule. the analysis of golden triangle showed that the thirty 2-amino-3-cyano-4-alkyl-6-(2-hydroxyphenyl) pyridine derivatives would not have clearance and cell membrane permeability problems except comp6 comp12,comp20, comp21, and comp26.As for the new designed compounds, their properties may have these problems, except two compounds which are: A8m, A8p. The A1m, A1p, A3p and A11m compounds were predicted to be nontoxic. These findings indicate that the novel potent candidate drugs have promising potential to IKK-β enzyme inhibition and should motivate future experimental investigations.Communicated by Ramaswamy H. Sarma.
35587833 Nanotechnology applications in rheumatology. 2022 May 19 Nanomedicine (NM) is the medical use of nanotechnology (NT). NT is the study and control of nanoscale structures (between approximately 1 and 100 nm). Nanomaterials are created by manipulating atoms and molecules at the nanoscale, resulting in novel physical and chemical properties. With its targeted tissue delivery capabilities, NT has enabled molecular modulation of the immune response and underlying inflammatory responses in individuals with rheumatic diseases (RD). NM has enabled targeted drug delivery, reduced adverse effects on non-target organs, raised drug concentration in synovial tissue, and slowed the progression of immune-mediated RD such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Thus, NM has evolved in rheumatology prevention, diagnosis, and therapy. Animal models have proven superior outcomes to conventional techniques of treating specific illnesses. Nanodiamond (ND) immunomodulatory applications have been proposed as an alternative to traditional nanoparticles in the diagnosis and treatment of RA due to their small size and ability to be removed from the body without causing harm to the patient's organs, such as the liver. However, human clinical NM needs more research. We conducted a literature review to assess the present role of NM in clinical rheumatology, describing its current and future applications in the diagnosis and treatment of rheumatic diseases.
35585642 Intimate partner violence and women living with episodic disabilities: a scoping review pr 2022 May 18 BACKGROUND: Violence towards women with disabilities is most commonly perpetrated by current or former intimate partners and more than half of disabled women experience intimate partner violence in their lifetime. Disabilities differ by presence, type, and complexity, yet are commonly researched collectively. A more nuanced understanding of the relationship between intimate partner violence and episodic disability is required to better support women living with these concurrent challenges. The objective of this scoping review is to investigate and synthesize the literature reporting on intimate partner violence for women living with an episodic disability to identify key concepts and knowledge gaps on this topic. Ultimately, this review aims to improve health services for this stigmatized group of women with episodic disabilities. METHODS: This scoping review will consider all studies that focus on women (18 years of age or older) who have experienced intimate partner violence and have an episodic disability. Episodic disabilities will include multiple sclerosis, chronic fatigue syndrome, fibromyalgia, lupus, or rheumatoid arthritis. The broad review question is what is known about intimate partner violence within the context of women living with an episodic disability? Databases to be searched include MEDLINE (OVID), CINAHL, Embase, PsychInfo, and Scopus with no limits on language or time frame. Joanna Briggs Institute methodology will guide this scoping review to address the review questions outlined in the protocol. For papers that meet the inclusion criteria, data will be extracted, and findings will be presented in tables and narrative form. A PRISMA table will be included to enhance the transparency of the process. A descriptive qualitative approach to analysis will be conducted following Braun and Clarke's reflexive thematic analysis. The findings of the scoping review will be presented through a thematic narrative. DISCUSSION: Findings from this review will be used to identify important priorities for future research based on knowledge gaps and inform both health care practices and health and social interventions for women living with intimate partner violence and episodic disabilities.
35222432 Cohesin-Mediated Chromatin Interactions and Autoimmunity. 2022 Proper physiological functioning of any cell type requires ordered chromatin organization. In this context, cohesin complex performs important functions preventing premature separation of sister chromatids after DNA replication. In partnership with CCCTC-binding factor, it ensures insulator activity to organize enhancers and promoters within regulatory chromatin. Homozygous mutations and dysfunction of individual cohesin proteins are embryonically lethal in humans and mice, which limits in vivo research work to embryonic stem cells and progenitors. Conditional alleles of cohesin complex proteins have been generated to investigate their functional roles in greater detail at later developmental stages. Thus, genome regulation enabled by action of cohesin proteins is potentially crucial in lineage cell development, including immune homeostasis. In this review, we provide current knowledge on the role of cohesin complex in leukocyte maturation and adaptive immunity. Conditional knockout and shRNA-mediated inhibition of individual cohesin proteins in mice demonstrated their importance in haematopoiesis, adipogenesis and inflammation. Notably, these effects occur rather through changes in transcriptional gene regulation than through expected cell cycle defects. This positions cohesin at the crossroad of immune pathways including NF-kB, IL-6, and IFNγ signaling. Cohesin proteins emerged as vital regulators at early developmental stages of thymocytes and B cells and after antigen challenge. Human genome-wide association studies are remarkably concordant with these findings and present associations between cohesin and rheumatoid arthritis, multiple sclerosis and HLA-B27 related chronic inflammatory conditions. Furthermore, bioinformatic prediction based on protein-protein interactions reveal a tight connection between the cohesin complex and immune relevant processes supporting the notion that cohesin will unearth new clues in regulation of autoimmunity.
35062924 Factors affecting spine-femur discordance in the percentage of young adult mean on dual-en 2022 Jan 21 BACKGROUND: Several retrospective studies have reported spine-femur discordance in bone mineral density (BMD) values. However, the average age of individuals in these studies was the mid-50s, which is younger than the typical age of individuals requiring treatment for primary osteoporosis. Therefore, we aimed to investigate factors associated with discordance in the percentage of young adult mean (YAM) between the lumbar spine and femoral neck in the elderly population. METHODS: We evaluated 4549 dual-energy X-ray absorptiometry (DXA) measurements obtained from 2161 patients (269 men and 1892 women) between January 2014 and December 2017 at our hospital. For individuals with more than one eligible set of measurements, the first record was used. We investigated each patient's age, sex, body mass index, current smoking status, alcohol consumption, use of steroids, presence of diabetes mellitus, and presence of rheumatoid arthritis. RESULTS: The mean age of the patients was 76.4 ± 8.9 years. Older age (p <  0.001), male sex (p <  0.001), and diabetes mellitus (p = 0.007) were significantly associated with spine-femur discordance in the percentage of YAM. CONCLUSION: The frequency and magnitude of spine-femur discordance in the percentage of YAM from DXA scans increased with age. Notably, more than 77.4% of patients in their 90s had spine-femur discordance > 10% of YAM. Furthermore, the frequency of spine-femur discordance was higher in men and in patients with diabetes mellitus, suggesting that the percentage of YAM at the lumbar spine may not be reliable for diagnosis of osteoporosis in patients with these factors.
35625771 De-Escalation of Anti-Tumor Necrosis Factor Alpha Agents and Reduction in Adverse Effects: 2022 Apr 29 BACKGROUND: The long-term use of anti-TNF-α agents can lead to adverse effects, such as infections and immune-mediated cutaneous reactions. Whether de-escalation by dose reduction or interval lengthening reduces these adverse effects is uncertain. This systematic review aims to compare the incidence of infections and skin manifestations after anti-TNF-α dose de-escalation with standard dosing. METHODS: MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials were searched from inception to 14 January 2022. Randomized controlled trials (RCTs) and observational studies comparing anti-TNF-α de-escalation strategies with standard dosing among patients with inflammatory conditions, that report on infections, skin manifestations, or both, were included. The risk of bias was assessed with the revised Cochrane risk-of bias tool (RCTs) or the Newcastle-Ottawa scale (non-RCTs). RESULTS: Fourteen RCTs and six observational studies (or 2706 patients) were included. Eight RCTs had low risk of bias or some concerns. Four non-RCTs were of good methodological quality. The studies described patients with axial spondyloarthritis (8 studies, 780 patients), rheumatoid arthritis (7 studies, 1458 patients), psoriasis (3 studies, 332 patients), or inflammatory bowel disease (2 studies, 136 patients). De-escalation strategies included interval lengthening (12 studies, 1317 patients), dose reduction (6 studies, 1130 patients), or both (2 studies, 259 patients). Overall, the occurrence of infections and skin manifestations did not differ between standard treatment and de-escalation. The disappearance of infections or skin manifestations after de-escalation was only reported in two studies. The majority of studies focused on etanercept and adalimumab. Heterogeneity in reporting of infections and skin manifestations precluded meta-analysis. CONCLUSION: We found that anti-TNF-α de-escalation does not reduce infections or skin reactions. A de-escalation strategy should not be recommended for the sole purpose of reducing drug-related adverse effects. The meticulous documentation of adverse effects is recommended to further address this question. REGISTRATION: PROSPERO CRD42021252977.
35453350 Synergistic Effect of L-Carnosine and Hyaluronic Acid in Their Covalent Conjugates on the 2022 Mar 30 Hyaluronic acid (Hy) is a natural linear polymer that is widely distributed in different organisms, especially in the articular cartilage and the synovial fluid. During tissue injury due to oxidative stress, Hy plays an important protective role. All the beneficial properties of Hy make the polymer attractive for many biomedical uses; however, the low stability and short biological half-life limit Hy application. To overcome these problems, the addition of small antioxidant molecules to Hy solution has been employed to protect the molecular integrity of Hy or delay its degradation. Carnosine (β-alanyl-L-histidine, Car) protects cells from the damage due to the reactive species derived from oxygen (ROS), nitrogen (RNS) or carbonyl groups (RCS). Car inhibits the degradation of hyaluronan induced by free radical processes in vitro but, like Hy, the potential protective action of Car is drastically hampered by the enzymatic hydrolysis in vivo. Recently, we conjugated Hy to Car and the derivatives (HyCar) showed protective effects in experimental models of osteoarthritis and rheumatoid arthritis in vivo. Here we report the antioxidant activity exerted by HyCar against ROS, RNS and RCS. Moreover, we tested if the covalent conjugation between Hy and Car inhibits the enzymatic hydrolysis of the polymer and the dipeptide backbone. We found that the antioxidant properties and the resistance to the enzymatic hydrolysis of Hy and Car are greatly improved by the conjugation.
35265152 Saireito (114) Increases IC50 and Changes T-Cell Phenotype When Used in Combination with P 2022 Prednisolone (PSL), a type of corticosteroid used to treat autoimmune diseases, can increase the risk of infection and osteoporosis. Saireito (114), a Kampo medicine, has an immunosuppressive effect; with its use, the dose of steroids can be reduced. However, its mechanism when used with PSL is still unclear. We used peripheral blood mononuclear cells (PBMCs) from healthy adults to examine the effect of 114 and PSL treatment on PBMC proliferation, T-cell subsets, and cytokine production. PBMCs were cotreated with concanavalin A and 300 μM 114 (either Tsumura & Co. (TJ) or Kracie Holdings (KR)) and 0.0001-1.0 μM PSL for 96 h to create the T-cell mitogen. We then measured the PBMC proliferation; ratio of CD4(+) T cells, CD8(+) T cells, and T-follicular helper (Tfh) cells; and concentration of cytokines (TNF, IFN-γ, IL-6, IL-10, IL-17A, and IL-21). The proliferation of PBMCs was dose dependently suppressed in both the PSL and PSL + 114 groups (p  <  0.05). Combination therapy increased the IC(50) in the PSL group (0.0947 μM) by 2.02 and 1.64-fold in the PSL + TJ114 and PSL + KR114 groups, respectively. Both the PSL + 114 groups had an increased ratio of CD4(+) T cells compared to the PSL group, with no effect on the ratio of CD8(+) T and Tfh cells. Furthermore, the PSL + 114 groups showed increased IL-6 and IL-10 compared to the PSL monotherapy group, although the difference was not significant. There was no significant difference in the TNF, IFN-γ, IL-17A, and IL-21 concentrations between the PSL and PSL + 114 groups. The elevated IC(50) with 114 cotreatment suggests diminished immunosuppressive action. Moreover, increased cytokine production by Th2 with 114 cotreatment suggests a restoration of T-cell balance in Th1-mediated autoimmune diseases. However, increased IL-6 suggests potential exacerbation of IL-6-mediated diseases, such as rheumatoid arthritis. Therefore, it is necessary to monitor these clinical parameters when using 114 in combination with PSL.
35240238 Aconitum carmichaelii Debeaux: A systematic review on traditional use, and the chemical st 2022 Jun 12 ETHNOPHARMACOLOGICAL RELEVANCE: Aconitum carmichaelii, belonging to the Ranunculaceae family, is a widely used traditional herbal plant in Asian countries, especially in China. The lateral ("Fuzi") and mother ("Chuanwu") roots are the two main plant parts used in Traditional Chinese Medicine (TCM), where they are used in the treatment of acute myocardial infarction, heart failure, rheumatoid arthritis, and as analgesics. AIM OF THE STUDY: In order to further guide the research direction and application of A. carmichaelii, this study aims to give a systematic and in-depth overview on the phytochemical and pharmacological studies of non-alkaloid natural products with focus on polysaccharides and phenolic compounds. MATERIALS AND METHODS: A comprehensive search in the literature was conducted based on the databases Google Scholar, SciFinder (American Chemical Society), Springer Link, PubMed Science, Science Direct and China National Knowledge Internet, Wanfang Data, in addition to books, doctoral and master's dissertations, and official website. The main keywords were: "Aconitum carmichaelii", "Aconiti Lateralis Radix Praeparata", "Fuzi", "Chuanwu", "Aconiti Radix", "monkshood" and "Bushi". RESULTS: A. carmichaelii is known for the use of its different root parts, including "Fuzi" and "Chuanwu". Different types of polysaccharides, both neutral and acidic, and 39 phenolic compounds like flavonoids, phenylpropanoids, lignans, neolignans, and benzoic acid derivatives have been isolated and identified from the roots. Pharmacological studies of the isolated polysaccharides have demonstrated various biological effects such as hypoglycemic, hypolipidemic, cardiovascular, immunomodulatory, anti-tumor, and neuropharmacological activities. Studies on pharmacological effects of the phenolic compounds isolated from the roots are however limited. CONCLUSIONS: This review shows that polysaccharides could be one of the active components in the roots of A. carmichaelii, and they are promising for future applications due to their pharmacological properties. In addition, polysaccharides are generally non-toxic, biocompatible, and biodegradable. This review also sheds light on new research directions for A. carmichaelii. A more detailed structural characterization of polysaccharides from different root parts of A. carmichaelii, and their structure-activity relationships are required. Additionally, their pharmacological properties as immunomodulators in the intestinal system should be investigated. Further, more knowledge about the pharmacological effects and molecular mechanisms of the phenolic compounds that have been identified are needed.
32937019 Quality of Care for Patients With Systemic Lupus Erythematosus: Data From the American Col 2022 Feb OBJECTIVE: Although multiple national quality measures focus on the management and safety of rheumatoid arthritis, few measures address the care of patients with systemic lupus erythematosus (SLE). Our objective was to apply a group of quality measures relevant to the care of patients with SLE, and we used the American College of Rheumatology's Rheumatology Informatics System for Effectiveness (RISE) registry to assess nationwide variations in care. METHODS: The data derived from RISE and included patients who had ≥2 visits with SLE codes ≥30 days apart in 2017-2018. We calculated performance on 5 quality measures: renal disease screening, blood pressure assessment and management, hydroxychloroquine (HCQ) prescribing, safe dosing for HCQ, and prolonged glucocorticoid use at doses of >7.5 mg/day. We reported performance on these measures at the practice level. We used logistic regression to assess independent predictors of performance after adjusting for sociodemographic and utilization factors. RESULTS: We included 27,567 unique patients from 186 practices; 91.7% were female and 48% White, with a mean age of 53.5 ± 15.2 years. Few patients had adequate screening for the development of renal manifestations (39.5%). Although blood pressure assessment was common (94.4%), a meaningful fraction of patients had untreated hypertension (17.7%). Many received HCQ (71.5%), but only 62% at doses of ≤5.0 mg/kg/day. Some received at least moderate-dose steroids for ≥90 days (18.5%). We observed significant practice variation on every measure. CONCLUSION: We found potential gaps in care for patients with SLE across the US. Although some performance variation may be explained by differences in disease severity, dramatic differences suggest that developing quality measures to address important health care processes in SLE may improve care.
35635731 Machine learning identifies a common signature for anti-SSA/Ro60 antibody expression acros 2022 May 30 OBJECTIVES: Anti-Ro autoantibodies are among the most frequently detected extractable nuclear antigen autoantibodies, mainly associated with primary Sjögren's syndrome (pSS), systemic lupus erythematosus (SLE) and undifferentiated connective tissue disease (UCTD). Is there a common signature to all patients expressing anti-Ro60 autoantibodies regardless of their disease phenotype? METHODS: Using high-throughput multi-omics data collected within the cross-sectional cohort from the PRECISESADS IMI project (genetic, epigenomic, transcriptomic, combined with flow cytometric data, multiplexed cytokines, classical serology and clinical data), we assessed by machine learning the integrated molecular profiling of 520 anti-Ro60-positive (anti-Ro60(+) ) compared to 511 anti-Ro60-negative (anti-Ro60(-) ) patients with pSS, SLE and UCTD, and 279 healthy controls (HCs). RESULTS: The selected features for RNA-Seq, DNA methylation and GWAS data allowed a clear separation between anti-Ro60(+) and anti-Ro60(-) patients. The different features selected by machine learning from the anti-Ro60(+) patients constitute specific signatures when compared to anti-Ro60(-) patients and HCs. Remarkably, the transcript z-score of three genes (ATP10A, MX1 and PARP14), presenting an overexpression associated with a hypomethylation and genetic variation, and independently identified by the Boruta algorithm, was clearly higher in anti-Ro60(+) patients compared to anti-Ro60(-) patients in all the diseases. We demonstrate that these signatures, enriched in interferon stimulated genes, were also found in anti-Ro60(+) patients with rheumatoid arthritis and systemic sclerosis and remained stable over time and not influenced by treatment. CONCLUSION: Anti-Ro60(+) patients present a specific inflammatory signature regardless of their disease suggesting that a dual therapeutic approach targeting both Ro-associated RNAs and anti-Ro60 autoantibodies should be considered.
35211119 Chloroquine Suppresses Effector B-Cell Functions and Has Differential Impact on Regulatory 2022 OBJECTIVES: Chloroquine (CQ) is approved for treatment of B-cell mediated diseases such as rheumatoid arthritis and systemic lupus erythematosus. However, the exact mode of action in these diseases has not been studied and it remains unclear which effect CQ has on B-cells. Thus, it was the aim of this study to investigate to which extent CQ affects functionality of effector and regulatory B-cell. METHODS: For this purpose, B-cells were isolated from peripheral blood of healthy controls and renal transplant patients. B-cells were stimulated in presence or absence of CQ and Interleukin-10 (IL-10) and Granzyme B (GrB) secretion were assessed. In addition, effector functions such as plasma cell formation, and Immunoglobulin G (IgG) secretion were studied. RESULTS: CQ suppressed Toll-Like-Receptor (TLR)-9 induced B-cell proliferation in a dose-dependent manner. IL-10(pos) regulatory B-cells were suppressed by CQ already at low concentrations whereas anti-IgG/IgM-induced GrB secreting regulatory B-cells were less susceptible. Plasma blast formation and IgG secretion was potently suppressed by CQ. Moreover, purified B-cells from renal transplant patients were also susceptible to CQ-induced suppression of effector B-cell functions as observed by diminished IgG secretion. CONCLUSION: In conclusion, CQ had a suppressive effect on IL-10 regulatory B-cells whereas GrB secreting regulatory B-cells were less affected. Effector functions of B-cells such as plasma blast formation and IgG secretion were also inhibited by CQ. Effector B-cells derived from renal transplant patients already under immunosuppression could be suppressed by CQ. These findings may partly explain the clinical efficacy of CQ in B-cell mediated autoimmune diseases. The application of CQ in other disease contexts where suppression of effector B-cells could offer a benefit, such as renal transplantation, may hypothetically be advantageous.
35032694 Elevated Basal Serum Tryptase: Disease Distribution and Variability in a Regional Health S 2022 Jan 12 BACKGROUND: Hereditary-alpha tryptasemia (HαT) is the most common etiology for elevated basal serum tryptase (BST). However, the utility of tryptase genotyping of individuals with elevated BST in general clinical practice remains undefined. Moreover, studies showing associations between elevated BST and chronic kidney disease (CKD), myelodysplastic syndrome (MDS), rheumatoid arthritis, or eosinophilic esophagitis did not include tryptase genotyping. OBJECTIVE: To determine the utility of tryptase genotyping among individuals with moderate elevations in BST at a regional health system. METHODS: Clinical and laboratory data from 109 subjects with basal tryptase values of 7.5 ng/mL or greater who were tested for HαT or had a disorder previously linked to elevated BST were collected retrospectively by chart review. RESULTS: Fifty-eight subjects had elevated BST defined as 11.5 ng/mL or greater. HαT was found in 63.8% (n = 37), 12.1% (n = 7) had CKD, and 20.7% (n = 12) had clonal myeloid disorders. A total of 6.9% (n = 4) with elevated BST had negative testing for HαT, CKD, and myeloid neoplasms. Two subjects with CKD, 1 subject with MDS, and 1 with myeloid hypereosinophilic syndrome had negative testing for HαT. Among subjects with elevated BST and more than 1 tryptase measurement, 41.5% (n = 22) had BST variability that exceeded the 20% plus 2 formula. Increased BST variability was found in subjects with HαT, all forms of mastocytosis, CKD, MDS, and those with no associated diagnosis. CONCLUSIONS: HαT, CKD, and clonal myeloid disorders or a combination of the 3 constitute approximately 90% of individuals with elevated BST in clinical practice. Myeloid neoplasms were over-represented in this cohort relative to population prevalence data suggesting tryptase measurement selection bias by clinicians or higher prevalence. Elevated BST is associated with increased tryptase variability, regardless of etiology.
34100976 Pulsed electromagnetic field (PEMF) as an adjunct therapy for pain management in interstit 2022 Mar INTRODUCTION AND HYPOTHESIS: Patients with interstitial cystitis/bladder pain syndrome (IC/BPS) often experience chronic pelvic and even systemic pain that can be difficult to clinically manage. Pulsed electromagnetic field (PEMF) therapy, a non-invasive strategy that has shown significant efficacy for pain reduction in other chronic pain conditions, may provide benefit for pain management in patients with IC/BPS. METHODS: PEMF delivery to patients occurs via a bio-electromagnetic-energy device which consists of a flexible mat (180 × 50 cm) that the patient lies on for systemic, full-body delivery and/or a flexible pad (50 × 15 cm) for targeted delivery to a specific body region (e.g., pelvic area). The duration of individual sessions, number of sessions per day, total number of sessions, and follow-up observation period vary between previously published studies. Positive outcomes are typically reported as a significant reduction in visual analog scale (VAS) pain score and functional improvement assessed using validated questionnaires specific to the condition under study. RESULTS AND CONCLUSIONS: The use of PEMF has been evaluated as a therapeutic strategy for pain management in several clinical scenarios. Randomized, double-blinded, placebo-controlled trials have reported positive efficacy and safety profiles when PEMF was used to treat non-specific low back pain, patellofemoral pain syndrome, chronic post-operative pain, osteoarthritis-related pain, rheumatoid arthritis-related pain, and fibromyalgia-related pain. Based on these positive outcomes in a variety of pain conditions, clinical trials to evaluate whether PEMF can provide a safe, non-invasive therapeutic approach to improve symptoms of chronic pain and fatigue in patients with IC/BPS are warranted.
35628290 Oxy210, a Semi-Synthetic Oxysterol, Exerts Anti-Inflammatory Effects in Macrophages via In 2022 May 13 Inflammatory responses by the innate and adaptive immune systems protect against infections and are essential to health and survival. Many diseases including atherosclerosis, osteoarthritis, rheumatoid arthritis, psoriasis, and obesity involve persistent chronic inflammation. Currently available anti-inflammatory agents, including non-steroidal anti-inflammatory drugs, steroids, and biologics, are often unsafe for chronic use due to adverse effects. The development of effective non-toxic anti-inflammatory agents for chronic use remains an important research arena. We previously reported that oral administration of Oxy210, a semi-synthetic oxysterol, ameliorates non-alcoholic steatohepatitis (NASH) induced by a high-fat diet in APOE*3-Leiden.CETP humanized mouse model of NASH and inhibits expression of hepatic and circulating levels of inflammatory cytokines. Here, we show that Oxy210 also inhibits diet-induced white adipose tissue inflammation in APOE*3-Leiden.CETP mice, evidenced by the inhibition of adipose tissue expression of IL-6, MCP-1, and CD68 macrophage marker. Oxy210 and related analogs exhibit anti-inflammatory effects in macrophages treated with lipopolysaccharide in vitro, mediated through inhibition of toll-like receptor 4 (TLR4), TLR2, and AP-1 signaling, independent of cyclooxygenase enzymes or steroid receptors. The anti-inflammatory effects of Oxy210 are correlated with the inhibition of macrophage polarization. We propose that Oxy210 and its structural analogs may be attractive candidates for future therapeutic development for targeting inflammatory diseases.
35097147 Risk Factors for Loss of Active Shoulder Range of Motion in Massive Rotator Cuff Tears. 2022 Jan BACKGROUND: Patients with massive rotator cuff tears often exhibit loss of active range of shoulder motion, which can interfere with activities of daily living. The risk factors for loss of motion remain largely unknown. PURPOSE: To clarify the predictive factors that affect the range of motion in chronic massive rotator cuff tears using multivariate analyses. STUDY DESIGN: Case-control study; Level of evidence, 3. METHODS: The authors retrospectively reviewed 204 consecutive patients who were evaluated at their institution with chronic massive rotator cuff tears. In this study, the dependent variable was determined to be active anterior elevation limited to ≤90° or external rotation (ER) with the arm at the side limited to ≤0°. Explanatory variables included age; sex; affected side; duration of symptoms; smoking history; existence of diabetes, hypertension, or rheumatoid arthritis; involved tendons; presence of a 3-tendon tear; rupture of the long head of biceps tendon; superior migration of the humeral head; and cuff tear arthropathy. Baseline variables that were observed to be significant in the univariate analyses were included in multivariate models, which used logistic regression to identify independent predictors of loss of motion. RESULTS: Overall, 73 patients (35.8%) exhibited limited anterior elevation, and 27 (13.2%) exhibited limited ER. Multivariate analyses showed that inferior subscapularis tear (odds ratio [OR], 14.66; 95% CI, 2.95-72.93; P = .001), smoking (OR, 4.13; 95% CI, 1.94-8.79; P < .001), superior migration of humeral head (OR, 3.92; 95% CI, 1.80-8.53; P = .001), and 3-tendon tear (OR, 3.29; 95% CI, 1.32-8.20; P = .011) were significantly associated with the loss of anterior elevation. Teres minor tear (OR, 73.37; 95% CI, 9.54-564.28; P < .001) and superior migration of the humeral head (OR, 3.55; 95% CI, 1.04-12.19; P = .044) were significantly associated with loss of ER. CONCLUSION: In the current study, a history of smoking, type of torn tendons, and superior migration of the humeral head were associated with loss of active shoulder motion. In particular, the status of inferior subscapularis or teres minor contributed to the onset of pseudoparalysis in massive rotator cuff tears.