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ID PMID Title PublicationDate abstract
32226163 The level of TGF-β in sera of patients with primary Sjögren's syndrome. 2019 OBJECTIVES: Tumor growth factor β (TGF-β) is a pleiotropic cytokine which controls autoimmune reactions, cell proliferation, and the organ accumulation of lymphocytes. This cytokine has a protective and anti-inflammatory effect in autoimmune processes, but also has a pro-fibrinous activity. Therefore, its importance in the development of systemic sclerosis has been proven. The role of TGF-β in Sjögren's syndrome is also a valid direction of research. The aim of the presented study is to evaluate the level of TGF-β in sera of primary Sjögren's syndrome patients and to investigate possible correlations with autoantibodies, cytokines, and cells in biopsy of minor salivary glands active in the pathogenesis of this syndrome. MATERIAL AND METHODS: Thirty-three primary Sjögren's syndrome patients were included. Routine laboratory tests and immunological assessment (ANA, anti SS-A, anti SS-B antibodies, rheumatoid factor), ophthalmological assessment with ocular staining scoring, chest X-ray, and high-resolution computed tomography (if necessary) were performed. Serum concentrations of cytokines such as TGF-β, BAFF, APRIL, FLT-3L, LT-α, IL-21, and TNF-α were evaluated using standard ELISA assays. The histopathological evaluation (focus score) and the determination of CD3+, CD4+, CD19+, CD21+, CD35+ cells was performed. RESULTS: There was no significant correlation between TGF-β and other tested cytokines or autoantibodies, other than TNF-α. A negative correlation (ρ = -0.472) between TGF-β and TNF-α was found. There were no correlations between TGF-β and: results of ocular examinations, elements of histopathological variables, or lungs changes. CONCLUSIONS: The authors state that: 1) the results may indicate that TGF-β influences the serum TNF-α activity in pSS patients, 2) our findings suggest that TGF-β may be the strongest inhibitor of TNF-α among cytokines involved in pSS pathogenesis, and 3) the results may explain the ineffectiveness of anti-TNF drugs in the treatment of pSS.
30216210 Buttress plating for volar Barton fractures in children: Salter-Harris II distal radius fr 2019 Jan We observed an unusual type of volar Barton fracture in the pediatric age and performed open reduction and internal fixation of the fragment, using the buttress plate in consecutive children. We report the radiological and clinical outcomes after follow-up for at least 3 years. From March 2008 to September 2014, nine consecutive children were treated by buttress plating. Their mean age at the time of injury was 13.1 years. All of the fractures were metaphyseal fractures in the coronal plane and typical Salter-Harris II fractures in the sagittal plane. After accurate reduction of the fragment, a cortical screw was inserted in the proximal area until the maximum compressive force against the fragment was obtained. Then, one or two locking screws were added adjacent to the initial cortical screw. No screw was fixed in the distal fragment. All evaluations were done at least 3 years postoperatively with a mean follow-up of 48.8 months. At final follow-up, the radial inclinations, volar tiltings, and ulnar variances were 23.2°±1.78° (98.7% of contralateral side), 9.4°±2.12° (98.4% of contralateral side), and -1.56±0.88 mm (93% of contralateral side), respectively. All radiological parameters of the distal radius were not significantly different from the contralateral values. The flexion-extension arc was 140.56°±5.27°, and the pronation-supination arc was 165.00°±8.29°. The grip strength was 26.67±5.56 kg. All clinical outcomes except the flexion-extension arc were similar to those of the normal side, with statistical significance. A volar Barton type injury can occur in the pediatric age involving the physis, and the buttress plating that is used in adults is also a useful treatment method. However, there is little information on this injury, and it was difficult to compare treatment outcomes with other methods. Because of the rarity of the injury, a larger, multicenter prospective comparative study is required to further explore appropriate treatment options, long-term outcomes, and complications. Level of Evidence: Therapeutic, Level IV.
30799840 An Immunohistopathologic Study to Profile the Folate Receptor Beta Macrophage and Vascular 2019 Feb 8 Giant cell arteritis (GCA) is a chronic immune-mediated disease of medium-to-large sized arteries that affects older adults. GCA manifests with arthritis and occlusive symptoms of headaches, stroke or vision loss. Macrophages and T-helper lymphocytes infiltrate the vascular wall and produce a pro-inflammatory response that lead to vessel damage and ischemia. To date, there is no GCA biomarker that can monitor disease activity and guide therapeutic response. Folate receptor beta (FRB) is a glycosylphosphatidylinositol protein that is anchored on cell membranes and normally expressed in the myelomonocytic lineage and in the majority of myeloid leukemia cells as well as in tumor and rheumatoid synovial macrophages, where its expression correlates with disease severity. The ability of FRB to bind folate compounds, folic acid-conjugates and antifolate drugs has made it a druggable target in cancer and inflammatory disease research. This report describes the histopathologic and immunohistochemical methods used to assess expression and distribution of FRB in relation to GCAimmunopathology. Formalin-fixed and paraffin-embedded temporal artery biopsies from GCA and normal controls were stained with Hematoxylin and Eosin to review tissue histology and identify pathognomonic features.Immunohistochemistry was used to detect FRB, CD68 and CD3 expression. A microscopic analysis was performed to quantify the number of positively stained cells on 10 selected high-power-field sections and their respective locations in the arterial wall. Lymphohistiocytic (LH) inflammation accompanied by intimal hyperplasia and disrupted elastic lamina was seen in GCA with none found in controls. The LH infiltrate was composed of approximately 60% lymphocytes and 40% macrophages. FRB expression was restricted to macrophages, comprising 31% of the total CD68+ macrophage population and localized to the media and adventitia. No FRB was seen in controls. This protocol demonstrated a distinct numerical and spatial pattern of the FRB macrophage relative to the vascular immune microenvironment in GCA.
31211814 Systems analysis of subjects acutely infected with the Chikungunya virus. 2019 Jun The largest ever recorded epidemic of the Chikungunya virus (CHIKV) broke out in 2004 and affected four continents. Acute symptomatic infections are typically associated with the onset of fever and often debilitating polyarthralgia/polyarthritis. In this study, a systems biology approach was adopted to analyze the blood transcriptomes of adults acutely infected with the CHIKV. Gene signatures that were associated with viral RNA levels and the onset of symptoms were identified. Among these genes, the putative role of the Eukaryotic Initiation Factor (eIF) family genes and apolipoprotein B mRNA editing catalytic polypeptide-like (APOBEC3A) in the CHIKV replication process were displayed. We further compared these signatures with signatures induced by the Dengue virus infection and rheumatoid arthritis. Finally, we demonstrated that the CHIKV in vitro infection of murine bone marrow-derived macrophages induced IL-1 beta production in a mechanism that is significantly dependent on the inflammasome NLRP3 activation. The observations provided valuable insights into virus-host interactions during the acute phase and can be instrumental in the investigation of new and effective therapeutic interventions.
30300223 Cross-sectional Area Just Proximal to the Carpal Tunnel According to the Ulnar Variances: 2019 Jan PURPOSE: We evaluated the relationship between the area around the distal radioulnar joint according to the ulnar variances and the cross-sectional area using magnetic resonance imaging (MRI) scans in this prospective study of patients with carpal tunnel syndrome (CTS). METHODS: From among a total of 243 patients who had been diagnosed with CTS between March 2012 and February 2017 at our hospital, 41 patients with positive ulnar variance were enrolled in group 1. As control groups, 39 healthy volunteers who underwent MRI evaluations were included in group 2 (neutral ulnar variance) and group 3 (negative variance). Basic demographic data, including age, sex, and body mass index, were recorded for all 3 groups. An area encompassing the contents of carpal tunnel (nerves/tendons) was designated as area "A," and the area just beneath the subcutaneous fat was designated as area "B" at the levels of the lunate (L) and pisiform (P) on axial MRI. Ratios of these areas ("A/B at L" and "A/B at P") were evaluated in terms of their correlations with ulnar variance. RESULTS: Mean age, sex, and body mass index were not statistically different among the groups, respectively. Within each group, there was no difference between "A/B at L" and "A/B at P," respectively. When comparing the 3 groups, "A/B at L" and "A/B at P" were all significantly decreased in group 1 than in other groups. Regardless of the group, ulnar length negatively correlated with both "A/B at L" and "A/B at P" ratios. CONCLUSIONS: We found a positive relationship between decreased cross-sectional area around the distal radioulnar joint and positive ulnar variance on radiologic investigation. These findings show the importance of variance in the positive ulna variance to the development of CTS.
31347413 Predicting lymphoma development in patients with Sjögren's syndrome. 2019 Sep Introduction: The issue of predicting lymphoma in primary Sjögren's syndrome (pSS) starts from its clinical and biologic essence, i.e., an autoimmune exocrinopathy with sicca syndrome, inflammation and lymphoproliferation of MALT (mucosa-associated lymphoid tissue) in exocrine glands. Areas covered: The two major predictors to be firstly focused are persistent salivary gland (SG) swelling and cryoglobulinemic vasculitis with related features as purpura and low C4, or the sole serum cryoglobulinemia repeatedly detected. They are pathogenetically linked and reflect a heavier MALT involvement by histopathology, with the expansion of peculiar rheumatoid factor (RF)-positive clones/idiotypes. Other predictors include lymphadenopathy, splenomegaly, neutropenia, lymphopenia, serum beta2-microglobulin, monoclonal immunoglobulins, light chains, and RF. Composite indexes/scores may also predict lymphoma. Expert opinion: Prediction at baseline needs amelioration, and must be repeated in the follow-up. Careful clinical characterization, with harmonization and stratification of large cohorts, is a relevant preliminary step. Validated and new biomarkers are needed in biologic fluids and tissues. SG echography with automatic scoring could represent a future imaging biomarker, still lacking. Scoring MALT involvement in pSS, as an additional tool to evaluate disease activity and possibly to predict lymphoma, is welcomed. All these efforts are now ongoing within the HarmonicSS project and in other research initiatives in pSS.
30518570 Siglec-1 Macrophages and the Contribution of IFN to the Development of Autoimmune Congenit 2019 Jan 1 Given that diseases associated with anti-SSA/Ro autoantibodies, such as systemic lupus erythematosus and Sjögren syndrome, are linked with an upregulation of IFN and type I IFN-stimulated genes, including sialic acid-binding Ig-like lectin 1 (Siglec-1), a receptor on monocytes/macrophages, recent attention has focused on a potential role for IFN and IFN-stimulated genes in the pathogenesis of congenital heart block (CHB). Accordingly, three approaches were leveraged to address the association of IFN, IFN-stimulated genes, and the phenotype of macrophages in affected fetal cardiac tissue: 1) cultured healthy human macrophages transfected with hY3, an anti-SSA/Ro-associated ssRNA, 2) RNA isolated from freshly sorted human leukocytes/macrophages after Langendorff perfusion of three fetal hearts dying with CHB and three healthy gestational age-matched hearts, and 3) autopsy tissue from three additional human CHB hearts and one healthy heart. TLR ligation of macrophages with hY3 led to the upregulation of a panel of IFN transcripts, including SIGLEC1, a result corroborated using quantitative PCR. Using independent and agnostic bioinformatics approaches, CD45(+)CD11c(+) and CD45(+)CD11c(-) human leukocytes flow sorted from the CHB hearts highly expressed type I IFN response genes inclusive of SIGLEC1. Furthermore, Siglec-1 expression was identified in the septal region of several affected fetal hearts. These data now provide a link between IFN, IFN-stimulated genes, and the inflammatory and possibly fibrosing components of CHB, positioning Siglec-1-positive macrophages as integral to the process.
30304371 The Association of Inflammatory Bowel Diseases with Autoimmune Disorders: A Report from th 2019 Mar 26 BACKGROUND AND AIMS: There are conflicting data on the association between inflammatory bowel diseases [IBD] and autoimmunity disorders. The aim of this study was to explore this association including the effect of medications. METHODS: We utilized health administrative data collected by three of the four health maintenance organizations [HMOs] in Israel, covering 52% of the country's population. We explored the prevalence of the following autoimmune disorders: insulin-dependent diabetes mellitus [IDDM], psoriasis, Sjögren syndrome, coeliac disease, systemic lupus erythematosus [SLE], primary sclerosis cholangitis [PSC] and autoimmune thyroiditis, among all IBD patients vs non-IBD controls. Case ascertainment was determined according to validated computerized algorithms. RESULTS: In total, 12625 IBD patients were compared to 12625 controls. A total of 1395 [11.1%] IBD patients had at least one autoimmune disease compared with 740 [5.9%] of non-IBD controls (odds ratio [OR] = 1.99 [95% confidence interval 1.81-2.19]; p < 0.05); all autoimmune diseases, except for thyroiditis, were more prevalent among IBD patients. Adjusted for confounding variables, anti-tumour necrosis factor [anti-TNF] medications were associated with a higher prevalence of psoriasis (54 [5.7%] in IBD vs 177 [4.1%] in controls; OR = 1.50 [1.07-2.08]; p < 0.05) but lower prevalence of Sjögren (1 [0.1%] vs 39 [0.9%]; OR [95% CI] = 0.13 [0.02-0.94]; p < 0.05) and coeliac disease (11 [1.2%] vs 68 [1.6%]; OR [95% CI] = 0.51 [0.27-0.99]; p < 0.05). Thiopurines and 5-aminosalicylates were not associated with any autoimmune disorder. CONCLUSION: IBD is associated with all autoimmune diseases explored here except for thyroiditis. Anti-TNF users have a higher prevalence of psoriasis, and lower prevalence of Sjögren and coeliac disease.
30950876 Histological Evidence of Intrinsic Muscle Degeneration in Compression Ulnar Neuropathy. 2019 May PURPOSE: We investigated the histological characteristics of the tissues in the intrinsic hand muscles of patients with compressive ulnar neuropathy (CUN) to determine how the compromised nerve influences the target muscle. METHODS: In total, 83 patients underwent surgery for CUN in our institution between March 2015 and August 2017. Of these, 45 patients who met our inclusion/exclusion criteria were initially included in this study. Basic demographic data including age, sex, hand dominance, duration of symptoms, bone mineral density, and clinical stage were evaluated. During the ulnar nerve decompression surgery, a biopsy of the ipsilateral adductor pollicis was performed. Using the biopsy samples, we analyzed the tissue composition and degree of degeneration, and investigated the association with demographic factors and clinical status. RESULTS: The ratio of muscle/connective tissue/fat was 62.62 ± 8.27%/23.44 ± 4.10%/14.16 ± 6.68% in the affected muscle. The ratio was different than that of samples taken from control groups. In samples containing muscle fibers, although the total fat content remained low, fat was consistently concentrated at the fascicular borders, between fascicles (perifascicular fat, 62.3 ± 18.2% of fascicles), and within fascicles (intrafascicular fat, 35.6 ± 11.8% of fascicles). The proportion of centrally nucleated muscle fibers was also significantly elevated (5.58 ± 4.25%; P < 0.001) compared with that of both controls (1.09 ± 1.26%) and the clinical threshold for abnormal central nuclei (3%). Preoperative scores assessed using Gabel and Amadio criteria were positively correlated with the muscle composition (r = 0.89, P < 0.001). In addition, the clinical status was negatively correlated with the degree of fat accumulation and the proportion of centrally nucleated muscle fibers (r = -0.94, P < 0.001, r = -0.82, P < 0.001). CONCLUSIONS: We demonstrated that target muscle in CUN underwent degeneration, which was potentially exacerbated by inflammation, and that the degree of degeneration was correlated with the patient's clinical status. Histologically, reversible recovery of the hand muscles may be possible if decompression of the ulnar nerve is performed at earlier stages.
30938759 Data linkages between patient-powered research networks and health plans: a foundation for 2019 Jul 1 OBJECTIVE: Patient-powered research networks (PPRNs) are a valuable source of patient-generated information. Diagnosis code-based algorithms developed by PPRNs can be used to query health plans' claims data to identify patients for research opportunities. Our objective was to implement privacy-preserving record linkage processes between PPRN members' and health plan enrollees' data, compare linked and nonlinked members, and measure disease-specific confirmation rates for specific health conditions. MATERIALS AND METHODS: This descriptive study identified overlapping members from 4 PPRN registries and 14 health plans. Our methods for the anonymous linkage of overlapping members used secure Health Insurance Portability and Accountability Act-compliant, 1-way, cryptographic hash functions. Self-reported diagnoses by PPRN members were compared with claims-based computable phenotypes to calculate confirmation rates across varying durations of health plan coverage. RESULTS: Data for 21 616 PPRN members were hashed. Of these, 4487 (21%) members were linked, regardless of any expected overlap with the health plans. Linked members were more likely to be female and younger than nonlinked members were. Irrespective of duration of enrollment, the confirmation rates for the breast or ovarian cancer, rheumatoid or psoriatic arthritis or psoriasis, multiple sclerosis, or vasculitis PPRNs were 72%, 50%, 75%, and 67%, increasing to 91%, 67%, 93%, and 80%, respectively, for members with ≥5 years of continuous health plan enrollment. CONCLUSIONS: This study demonstrated that PPRN membership and health plan data can be successfully linked using privacy-preserving record linkage methodology, and used to confirm self-reported diagnosis. Identifying and confirming self-reported diagnosis of members can expedite patient selection for research opportunities, shorten study recruitment timelines, and optimize costs.
31624483 Clinical Assessments of Hand Function in First Carpometacarpal Osteoarthritis Do Not Appea 2019 Oct BACKGROUND: Thumb carpometacarpal (first CMC) osteoarthritis (OA), a degenerative process affecting hand use, is typically assessed by clinical examination and radiographs. This assessment determines treatment, but it may not reflect functional limitations. QUESTIONS/PURPOSES: We aimed to explore the relationship between measures of hand function and radiographs in individuals with and without first CMC OA. METHODS: We designed a cross-sectional, observational pilot study, enrolling five patients with first CMC OA (nine thumbs with modified Eaton-Littler grades ranging from 1 to 4, using retrospective radiographic data) and nine healthy controls. They underwent evaluation of hand function using four patient-reported outcome measures (PROMs)-the Patient-Specific Functional Scale (PSFS); the Patient-Rated Wrist/Hand Evaluation (PRWHE); the Disabilities of the Arm, Shoulder, and Hand (DASH); and the Modified Score for the Assessment and Quantification of Chronic Rheumatoid Affections of the Hands (M-SACRAH)-and one performance measure, the Arthritis Hand Function Test (AHFT). Spearman's ρ with 95% subject clustered bootstrapped confidence intervals was calculated to assess for correlations between radiographic findings and measures of hand function. RESULTS: Only the DASH work score showed strong positive correlation with radiographic OA grade, with PSFS, PRWHE, M-SACRAH, and AHFT scores demonstrating low to moderate correlations. Notable differences were found between patients and control subjects in median scores of the DASH, PSFS, PRWHE, and M-SACRAH, as well as in the grip, pinch, and button scores of the AHFT. CONCLUSION: While only the DASH work score strongly correlated with radiographic grade of first CMC OA, several measures detected considerable differences in functional hand use between patients and control subjects. The findings of this pilot study suggest that hand function scores be considered in addition to radiographs when determining severity of first CMC OA. The findings can also inform the design of a larger, powered study.
31301418 (5R)-5-hydroxytriptolide ameliorates liver lipid accumulation by suppressing lipid synthes 2019 Sep 1 AIMS: (5R)-5-hydroxytriptolide (LLDT-8) is a triptolide analog with excellent capability against cancers, cerebral ischemic injury and rheumatoid arthritis. Here, we discovered its hepatoprotective effects in a mouse model of non-alcoholic fatty liver disease (NAFLD) by ameliorating liver lipid accumulation. MAIN METHODS: Male C57BL/6J mice were fed with a high-fat/high-fructose (HFHFr) diet for 29 weeks to induce the pathological phenomena of NAFLD. Then the mice were treated with LLDT-8 (0.5mg/kg and 1mg/kg) or Vehicle for 8 weeks. Finally, the serum biochemical indexes, liver histological features, fatty acids (FAs) profile and related gene expression in liver were detected to investigate the effect of LLDT-8 on lipid accumulation and its possible mechanism. KEY FINDINGS: LLDT-8 treatment significantly inhibited hepatic injury featured by the decrease of serum alanine aminotransferase (ALT) and aspartate transaminase (AST), the lessening of hepatic ballooning and macrovesicular steatosis. Moreover, LLDT-8 could downregulate the expression of stearoyl-CoA desaturase 1 (SCD1), which further led to the lower ratios of C16:1/C16:0 and C18:1/C18:0 and thus inhibited lipid synthesis. LLDT-8 treatment also could upregulate liver peroxisome proliferator-activated receptor α (PPARα), carnitine palmitoyltransferase 1a (Cpt1a), peroxisomal acyl-CoA oxidase 1 (Acox1), long-chain acyl-CoA dehydrogenase (Acadl) and medium-chain acyl-CoA dehydrogenase (Acadm) expression levels involved in fatty acids oxidation (FAO) and markedly promoted lipolysis. SIGNIFICANCE: Our results provide a novel application of LLDT-8 in improving NAFLD.
31129432 Therapeutic effects of artesunate on lupus-prone MRL/lpr mice are dependent on T follicula 2019 Sep BACKGROUND: Anti-malarial drug artesunate (ART), a semi-synthetic derivative of artemisnin, has immunosuppressive effects on several autoimmune diseases, including Systemic lupus erythematosus (SLE), Rheumatoid arthritis (RA), and Colitis. However, molecular mechanisms of ART, especially on follicular helper T cells (Tfh), central players in SLE pathology, are far from clear. PURPOSE: The object for this work is to investigate the therapeutic effect of ART on lupus-prone MRL/lpr mice and its regulatory function on Tfh cells. STUDY DESIGN AND METHODS: MRL/lpr mice were used to explore therapeutic effects of ART on lupus-prone MRL/lpr mice and its regulatory functions on Tfh cells. Then, experiments of renal function were accomplished using the biochemical kits. Effects of ART on histopathology of kidneys, inflammatory factors and autoantibodies were examined using H&E staining, ELISA and real-time PCR. Flow cytometry and western blot analysis were used to examine effects of ART on Tfh differentiation and Jak2-Stat3 signaling pathway. RESULTS: Upon oral administration, ART significantly prolonged the survival of MRL/lpr mice, ameliorated the lupus nephritis symptoms, decreased the levels of anti-dsDNA antibodies deposited in the kidney, and the levels of pathogenic cytokines (IL-6, IFN-γ and IL-21). After ART treatment, T-cell compartment in the spleen of MRL/lpr mice was restored in terms of reduction in the number of Tfh cells and in the maintenance of the ratio of Tfr to follicular regulatory T cells (Tfh). In addition, ART has significantly inhibited the phosphorylation levels of Jak2 and Stat3 in the MRL/lpr mice. CONCLUSION: ART showed therapeutic effects on lupus-prone MRL/lpr mice by inhibiting the differentiation of Tfh cells as well as altering the activation status of Jak2-Stat3 signaling cascade.
30422384 Propeptide glycosylation and galectin-3 binding decrease proteolytic activation of human p 2019 Mar Matrix metalloproteinases (MMPs) are secreted as proenzymes, containing propeptides that interact with the catalytic zinc, thereby controlling MMP activation. The MMP-9 propeptide is unique in the MMP family because of its post-translational modification with an N-linked oligosaccharide. ProMMP-9 activation by MMP-3 occurs stepwise by cleavage of the propeptide in an aminoterminal (pro-AT) and carboxyterminal (pro-CT) peptide. We chemically synthesized aglycosyl pro-AT and pro-CT and purified recombinant glycosylated pro-AT(S) (f-9) . First, we report new cleavage sites in the MMP-9 propeptide by MMP-3 and neutrophil elastase. Additionally, we demonstrated with the use of western blot analysis a higher resistance of glycosylated versus aglycosyl pro-AT against proteolysis by MMP-3, MMP-9, meprin α, neutrophil elastase and by protease-rich synovial fluids from rheumatoid arthritis patients. Moreover, we investigated the effect of glycosylation on proteolytic activation of human proMMP-9 with the use of zymography and dye-quenched gelatin cleavage analysis. Compared to recombinant Sf-9 proMMP-9 glycoforms, larger oligosaccharides of human neutrophil proMMP-9 increased resistance against proteolytic activation. Additionally, proMMP-9 from Congenital Disorder of Glycosylation patients, compared to healthy controls, showed a higher activation rate by MMP-3. Finally, we demonstrated that glycan-galectin-3 interactions reduced proMMP-9 activation. In conclusion, modification of MMP-9 propeptide glycosylation is a fine-tuning mechanism and co-determines the specific activity of MMP-9 in physiology and pathology. ENZYMES: MMP-9 EC 3.4.24.35, MMP-3 EC 3.4.24.17, meprin α EC 3.4.24.18, neutrophil elastase EC 3.4.21.37, trypsin EC 3.4.21.4 and PNGase F EC 3.5.1.52.
29959099 Risk factors for newly developed osteoporotic vertebral compression fractures following tr 2019 Feb BACKGROUND CONTEXT: It has been reported that newly developed osteoporotic vertebral compression fractures (OVCFs) occur at a relatively high frequency after treatment. While there are many reports on possible risk factors, these have not yet been clearly established. PURPOSE: The purpose of this study was to investigate the risk factors for newly developed OVCFs after treatment by vertebroplasty (VP), kyphoplasty (KP), or conservative treatment. STUDY DESIGN/SETTING: A retrospective comparative study. PATIENT SAMPLE: One hundred thirty-two patients who had radiographic follow-up data for one year or longer among 356 patients who were diagnosed with OVCF and underwent VP, KP or conservative treatment between March 2007 and February 2016. OUTCOME MEASURES: All records were examined for age, sex, body mass index (BMI), rheumatoid arthritis and other medical comorbidities, osteoporosis medication, bone mineral density (BMD), history of vertebral and nonvertebral fractures, treatment methods used, level of fractures, and presence of multiple fracture sites. METHODS: Patients were divided into those who manifested new OVCF (Group A) and those who did not (Group B). For the risk factor analysis, student's t-tests and chi-square tests were used in univariate analysis. Multivariate logistic regression analysis was carried out on variables with a p<.1 in the univariate analysis. RESULTS: Newly developed OVCFs occurred in 46 of the 132 patients (34.8%). Newly developed OVCF increased significantly with factors such as average age (p=.047), low BMD T-score of the lumbar spine (p=.04) and of the femoral neck (p=.046), advanced age (>70 years) (p=.011), treatment by cement augmentation (p=.047) and low compliance with osteoporosis medication (p=.029). In multivariate regression analysis, BMD T-score of the lumbar spine (p=.009) and treatment by cement augmentation (p=.044) showed significant correlations with the occurrence of new OVCFs with a predictability of 71.4%. CONCLUSION: Osteoporotic vertebral compression fracture patients with low BMD T-score of the lumbar spine and those who have been treated by cement augmentation have an increased risk of new OVCFs after treatment and, therefore, require especially careful observation and attention.
31268371 Rare Protein-Altering Telomere-related Gene Variants in Patients with Chronic Hypersensiti 2019 Nov 1 Rationale: Rare genetic variants in telomere-related genes have been identified in familial, idiopathic, and rheumatoid arthritis-associated pulmonary fibrosis. Short peripheral blood leukocyte (PBL) telomere length predicts poor outcomes in chronic hypersensitivity pneumonitis (CHP).Objectives: Determine the prevalence and clinical relevance of rare protein-altering variants in telomere-related genes in patients with CHP.Methods: Next-generation sequences from two CHP cohorts were analyzed to identify variants in TERT (telomerase reverse transcriptase), TERC (telomerase RNA component), DKC1 (dyskerin pseudouridine synthase 1), RTEL1 (regulator of telomere elongation helicase 1), PARN (poly[A]-specific RNase), and TINF2 (TERF1-interacting nuclear factor 2). To qualify, variants were required to have a minor allele frequency less than 0.005 and be predicted to be damaging to protein function. Variant status (binary variable) was used in statistical association tests, including Cox proportional hazard models for transplant-free survival. PBL telomere length was measured using quantitative PCR.Measurements and Main Results: Qualifying variants were identified in 16 of 144 patients (11.1%; 95% confidence interval [CI], 6.5-17.4) in the discovery cohort and 17 of 209 patients (8.1%; 95% CI, 4.8-12.7) in the replication cohort. Age- and ancestry-adjusted PBL telomere length was significantly shorter in the presence of a variant in both cohorts (discovery: -561 bp; 95% CI, -933 to -190; P = 0.003; replication: -612 bp; 95% CI, -870 to -354; P = 5.30 × 10(-6)). Variant status was significantly associated with transplant-free survival in both cohorts (discovery: age-, sex-, and ancestry-adjusted hazard ratio, 3.73; 95% CI, 1.92-7.28; P = 0.0001; replication: hazard ratio, 2.72; 95% CI, 1.26-5.88; P = 0.011).Conclusions: A substantial proportion of patients diagnosed with CHP have rare, protein-altering variants in telomere-related genes, which are associated with short peripheral blood telomere length and significantly reduced transplant-free survival.
31837981 Infertility in women with systemic autoimmune diseases. 2019 Dec Infertility consists by definition in" failure to achieve a clinical pregnancy after 12 months or more of regular unprotected intercourse" while the term subfertility means a delay to achieve pregnancy. Several factors can contribute to infertility or subfertility in patients with systemic autoimmune diseases. The association of systemic autoimmune conditions with endometriosis, celiac disease and thyroid autoimmunity that are well known causes of infertility and/or subfertility need to be taken in consideration when difficulties in the onset of pregnancy is reported. The majority of the used antirheumatic drugs do not interfere with fertility. However, the use of cyclophosphamide, limited to severe disease, can provoke premature ovarian failure; to preserve fertility a preventive treatment is available. Nonsteroidal anti-inflammatory drugs can cause temporary infertility and corticosteroids are associated to a prolonged time to pregnancy in some rheumatic diseases. Data on the association of antiphospholipid antibodies (aPL) with infertility are still debated but in general an increased rate of aPL is described patients undergoing medically assisted reproductive techniques. In systemic lupus erythematosus aPL and other autoantibodies (i.e. anti-oocytes) can contribute to the infertility of some patients. Subfertility, rather than infertility, is observed in patients with rheumatoid arthritis; the particular physical conditions of these women can also account for this. Physicians should not forget the patients' age, that is mandatory in order to preserve their chance to have children.
31561750 Baricitinib reverses HIV-associated neurocognitive disorders in a SCID mouse model and res 2019 Sep 27 BACKGROUND: Since HIV-associated neurocognitive disorders (HANDs) occur in up to half of HIV-positive individuals, even with combined antiretroviral therapy (cART), adjunctive therapies are needed. Chronic CNS inflammation contributes to HAND and HIV encephalitis (HIVE). Baricitinib is a JAK 1/2 inhibitor approved in the USA, EU, and Japan for rheumatoid arthritis, demonstrating potent inhibition of IL-6, D-dimer, CRP, TNF-α, IFN-α/β, and other pro-inflammatory cytokines. METHODS: Our modified murine HAND model was used to evaluate the ability of baricitinib to cross the blood-brain barrier (BBB) and modulate monocyte/macrophage-driven HAND. Severity of HAND was measured by assessing cognitive performance of low- and high-dose baricitinib treated versus untreated HAND mice. The severity of brain neuroinflammation was evaluated in these mouse groups after flow cytometric analyses. We also assessed the ability of baricitinib to block events in myeloid and lymphoid cells in vitro that may undergird the persistence of HIV in the central nervous system (CNS) in primary human macrophages (Mϕ) and lymphocytes including HIV replication, HIV-induced activation, reservoir expansion, and reservoir maintenance. RESULTS: In vivo, both doses of 10 and 50 mg/kg qd baricitinib crossed the BBB and reversed behavioral abnormalities conferred by HIV infection. Moreover, baricitinib significantly reduced HIV-induced neuroinflammation marked by glial activation: activated microglia (MHCII(+)/CD45(+)) and astrogliosis (GFAP). Baricitinib also significantly reduced the percentage of p24+ human macrophages in mouse brains (p < 0.05 versus HAND mice; t test). In vitro, baricitinib significantly reduced markers of persistence, reservoir size, and reseeding in Mϕ. CONCLUSION: These results show that blocking the JAK/STAT pathway reverses cognitive deficits and curtails inflammatory markers in HAND in mice. Our group recently reported safety and tolerability of ruxolitinib in HIV-infected individuals (Marconi et al., Safety, tolerability and immunologic activity of ruxolitinib added to suppressive ART, 2019), underscoring potential safety and utility of JAK inhibitors for additional human trials. The data reported herein coupled with our recent human trial with JAK inhibitors provide compelling preclinical data and impetus for considering a trial of baricitinib in HAND individuals treated with cART to reverse cognitive deficits and key events driving viral persistence.
31378969 Effects of Upadacitinib Coadministration on the Pharmacokinetics of Sensitive Cytochrome P 2020 Jan The aim of this study was to characterize the effects of upadacitinib, a Janus kinase 1 inhibitor, on in vivo activity of different cytochrome P450 (CYP) enzymes using a cocktail approach. Healthy subjects (n = 20) received single oral doses of the modified Cooperstown 5+1 cocktail drugs (midazolam [CYP3A], caffeine [CYP1A2], warfarin + vitamin K [CYP2C9], omeprazole [CYP2C19], and dextromethorphan [CYP2D6]) without upadacitinib and on day 11 (midazolam) or 12 (all other probes) of a 15-day regimen of upadacitinib 30 mg once daily (extended-release formulation). Serial blood samples and 12-hour urine samples were collected for assays of the probe substrates and select metabolites. The ratio (90%CI) of area under the plasma concentration-time curve from time 0 to infinity (AUC(inf) ) central values when the cocktail drugs were administered with upadacitinib relative to when administered alone were 0.74 (0.68-0.80) for midazolam, 1.22 (1.15-1.29) for caffeine, 1.11 (1.07-1.15) for S-warfarin, 1.07 (0.95-1.22) for dextromethorphan, and 0.82 (0.72-0.94) for omeprazole. The ratio (90%CI) was 1.09 (1.00-1.19) for 5-hydroxy-omeprazole to omeprazole AUC(inf) ratio and 1.17 (0.97-1.41) for dextromethorphan to dextrorphan 12-hour molar urinary ratio. Upadacitinib 30 mg once daily (a dose that is twice the optimal dose in rheumatoid arthritis based on phase 3 results) has a limited effect on CYP3A activity (26% decrease in exposure of midazolam, a sensitive CYP3A substrate) and no relevant effects on CYP1A2, CYP2C9, CYP2C19, or CYP2D6 activity in vivo. No clinically relevant changes in plasma exposures are expected for drugs that are substrates for the evaluated CYP enzymes when coadministered with upadacitinib.
31059841 Polyphenols in the treatment of autoimmune diseases. 2019 Jul In addition to protecting body from infections and diseases, the immune system produces auto-antibodies that can cause complex autoimmune disorders, such as Type I diabetes, primary biliary cirrhosis, rheumatoid arthritis, and multiple sclerosis, to name a few. In such cases, the immune system fails to recognize between foreign agents and its own body cells. Different factors, such as genetic factors (CD25, STAT4), epigenetic factors (DNA methylation, histone modifications) and environmental factors (xenobiotics, drugs, hormones) trigger autoimmunity. Glucocorticoids, non-steroidal anti-inflammatory drugs (NSAIDs), immunosuppressive and biological agents are currently used to manage autoimmune diseases of different origins. However, complete cure remains elusive. Many dietary and natural products including polyphenols have been widely studied as possible alternative treatment strategies for the management of autoimmune disorders. Polyphenols possess a wide-range of pharmacological and therapeutic properties, including antioxidant and anti-inflammatory activities. As immunomodulatory agents, polyphenols are emerging pharmaceutical tools for management of various autoimmune disorders including vitiligo, ulcerative colitis and multiple sclerosis (MS). Polyphenols activate intracellular pathways such as arachidonic acid dependent pathway, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathway, mitogen-activated protein kinases (MAPKs) pathway, phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) signaling pathway and epigenetic modulation, which regulate the host's immune response. This timely review discusses putative points of action of polyphenols in autoimmune diseases, characterizing their efficacy and safety as therapeutic agents in managing autoimmune disorders.