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ID PMID Title PublicationDate abstract
32232558 Role of IRF8 in immune cells functions, protection against infections, and susceptibility 2020 Jun The transcription factor IRF8 (ICSBP) is required for the development and maturation of myeloid cells (dendritic cells, monocytes, macrophages), and for expression of intrinsic anti-microbial function such as antigen capture, processing and presentation to lymphoid cells, and for activation of these cells in response to cytokines and pro-inflammatory stimuli (IFN-γ, IFN-β, LPS). IRF8 deficiency in humans causes a severe primary immunodeficiency presenting as susceptibility to infections, complete or severe depletion of blood dendritic cells (DC) subsets, depletion of CD14(+) and CD16(+) monocytes and reduced numbers and impaired activity of NK cells. In genome-wide association studies (GWAS), sequence variants near IRF8 are significant risk factors for multiple chronic inflammatory diseases in humans including inflammatory bowel disease, lupus, rheumatoid arthritis, multiple sclerosis, and several others. Recent studies have cataloged all the genes bound by and transcriptionally activated by IRF8 in myeloid cells, either alone or in combination with other transcription factors (PU.1, IRF1, STAT1) at steady state and in response to pro-inflammatory stimuli. This IRF1/IRF8 regulome comprises immune pathways such as antigen processing and presentation pathways, expression of costimulatory molecules, cytokines and chemokines, response to stimuli such as cytokine receptors, pathogen-associated molecular pattern receptors, TLRs and nucleotide-binding oligomerization domain-like receptor signaling pathways, and small antiviral GTPases. Members of the IRF8/IRF1 regulome are over-represented amongst genes in which mutations cause primary immunodeficiencies, and are specifically enriched at GWAS loci associated with chronic inflammatory diseases in humans. These recent studies highlight a critical role of IRF8 in the activity of several immune cell types for protection against infections, but also in pathological inflammation associated with common human inflammatory conditions.
32057655 An Embolic Stroke in a Patient With PROC p.Lys193del. 2020 May We report a 58-year-old woman who suddenly developed brain infarction with weakness of the left lower extremity and left perioral dysesthesia during postoperative tamoxifen therapy for breast cancer and prednisolone therapy for rheumatoid arthritis. Diffusion-weighted images detected multiple areas of hyperintensity in the posterior circulation system of the brain. Despite extensive examinations, we could not identify any embolic sources except hypoplasia of the right vertebral artery. We found decreased activity of protein C against its antigen level (activity: 59% versus antigen: 122%) with enhanced activity of coagulation factor VIII (178%) and von Willebrand factor (285%). DNA sequencing identified trinucleotide deletion of the PROC gene leading to 1 amino acid deletion at Lys-193 (p.Lys193del). We speculate that the PROC gene polymorphism may have participated in tamoxifen- and prednisolone- associated hypercoagulable state, leading to development of an embolic stroke in this patient.
31982165 Outcomes of percutaneous coronary intervention (PCI) among patients with connective tissue 2020 Apr 1 BACKGROUND: Inflammation is the hallmark of coronary artery disease (CAD) and CTD. There are reports of increased prevalence of CAD among patients with CTD such as Rheumatoid Arthritis. However, there is a paucity of data regarding the outcomes of PCI among patients with CTD. METHODS: Using the National Inpatient Database, patients that underwent PCI between 2007 and 2015 were identified using ICD-9-CM codes. Propensity match analysis with 1: 3 matching of patients with and without CTD was performed. Outcomes were acute kidney injury (AKI), access site complication (ASC), ventricular fibrillation (VF), cardiogenic shock (CS), Stroke, In-hospital mortality and hospital length of stay (LOS) compared between both groups. RESULT: We identified 17,422 patients with CTD and matched with 52, 266 patients without CTD. Patients were predominantly female (63.1%) and white (77.2%), with a mean age of 63 ± 12.1 years. AKI (8.3% vs. 6.6%, p < 0.001), ASC (3.2% vs. 2.7%, p = 0.01) and hospital stay (4.2 ± 4.8 vs. 3.8 ± 5.2, p < 0.001) were higher among patients with CTD. There was no statistically significant difference in rates of VF, CS, stroke, and In-hospital mortality among the two groups. However, in subgroup analysis, rates of VF were lower among patients with Systemic Lupus Erythematosus (SLE) (1.5% vs. 2.2%, p = 0.006). CONCLUSIONS: Patients with CTD undergoing PCI have a higher rate of AKI, Access site complications, and prolonged hospital stay.
31595721 Biotransformation of cladribine using a stabilized biocatalyst in calcium alginate beads. 2020 Mar Cladribine is a nucleoside analogue widely used in the pharmaceutical industry for the treatment of several neoplasms, including hairy-cell leukemia among others. This compound has also shown efficacy in the treatment of autoimmune diseases such as rheumatoid arthritis and multiple sclerosis. In this work, a green bioprocess for cladribine biosynthesis using immobilized Arthrobacter oxydans was developed. The microorganism was stabilized by entrapment immobilization in the natural matrix alginate. Different reaction parameters were optimized obtaining a biocatalyst able to achieve cladribine bioconversion values close to 85% after 1 hr, the shortest reaction times reported so far. The developed bioprocess was successfully scaled-up reaching a productivity of 138 mg L(-1) hr(-1) . Also, the biocatalyst was stable for 5 months in storage and in 96 hr at operational conditions.
32564047 Chloroquine in controlling biological infections. 2020 Jun 17 From the middle of the 17th century, Cinchona tree's bark, which contains quinine, was used as an anti-malarial agent. It wasn't until the midtwentieth century that chloroquine was synthesized, followed by its further derivatives. Chloroquine inhibits protozoan polymerase activity, leading to an increase in heme, which is toxic to Plasmodium. The sensitivity of the protozoan to chloroquine depends on its ability to accumulate the drug in aquatic vacuolas. The medicine is also directly toxic to protozoa of the genus Entamoeba histolytica. The immunomodulatory properties of chloroquine have led to its use in collagen diseases, rheumatic disease, chronic rheumatoid and ankylosing arthritis and autoimmune skin disease. Chloroquine has recently been shown to be effective in controlling infection caused by the new Corona virus 2019- nCov (SARS-CoV-2). The drug inhibits viral infectivity by increasing endosomal pH in cells and blocking virus-cell interference by glycosylating SARS-CoV-2 cell receptors. Chloroquine has been shown to be able to bind sialic acid and gangliosides effectively by blocking the combination of virus S protein with gangliosides, which prevents the infection from starting. The effectiveness of the drug in the first stage of infection by SARS-CoV-2 was confirmed in clinical observations and the drug was included in the developed therapeutic recommendations.
33581041 Medium term outcomes of the Universal 2 total wrist arthroplasty in patients with degenera 2020 Sep This retrospective study reports medium term outcomes of 14 total wrist arthroplasties in patients with especially, non-rheumatoid, degenerative osteo- arthritis and post-traumatic osteoarthritis with a mean follow up of 5 to 10 years. Information of fourteen patients, 6 men and 8 women with a mean age of 61 years, was collected before and after total wrist arthroplasty (Universal 2 prosthesis, Integra) carried out by a single surgeon. Pre-operative mobility was determined by range of motion and compared to post- operative range of motion. Post-operative function was determined using the DASH (The disabilities of the arm, shoulder and hand) score and the PRWE (patient-rated wrist evaluation and grip strength) score. Grip force between the operated and non- operated hand were compared postoperatively. Three patients experienced complications. Range of motion improved post-operatively, although not significantly, due to an increase in palmar flexion. The mean DASH score was 20% and the mean total PRWE was 54%. This study shows that total wrist arthroplasty, using the Universal 2 wrist prosthesis, gives reasonable results (survival rate 84%) by decreasing pain while preserving range of motion in patients with degenerative osteoarthritis of the wrist after 5 years. However the 10-year survival rate decreases steeply to an unsatisfying 35%.
32572369 Measurement and Interpretation of Handgrip Strength for Research on Sarcopenia and Osteopo 2020 May Handgrip strength (HGS) is associated with several chronic diseases, cognitive decline, length of hospital-stay, and mortality. More importantly, HGS is one of the diagnostic criteria of sarcopenia and gaining attention because of its relevance to bone mineral density (BMD) and osteoporotic fractures. As the measurement of HGS is widely used in clinical practice as well as in research, its accurate measurement and interpretation are becoming more crucial. This review describes how to use different types of dynamometers accurately, the impact of body and arm positions and anthropometric parameters on HGS, the current reference values of HGS for sarcopenia research, and the updates on the relationship between HGS and BMD and osteoporotic fractures.
32541026 Macrophage metabolic reprogramming presents a therapeutic target in lupus nephritis. 2020 Jun 30 IgG antibodies cause inflammation and organ damage in autoimmune diseases such as systemic lupus erythematosus (SLE). We investigated the metabolic profile of macrophages isolated from inflamed tissues in immune complex (IC)-associated diseases, including SLE and rheumatoid arthritis, and following IgG Fcγ receptor cross-linking. We found that human and mouse macrophages undergo a switch to glycolysis in response to IgG IC stimulation, mirroring macrophage metabolic changes in inflamed tissue in vivo. This metabolic reprogramming was required to generate a number of proinflammatory mediators, including IL-1β, and was dependent on mTOR and hypoxia-inducible factor (HIF)1α. Inhibition of glycolysis, or genetic depletion of HIF1α, attenuated IgG IC-induced activation of macrophages in vitro, including primary human kidney macrophages. In vivo, glycolysis inhibition led to a reduction in kidney macrophage IL-1β and reduced neutrophil recruitment in a murine model of antibody-mediated nephritis. Together, our data reveal the molecular mechanisms underpinning FcγR-mediated metabolic reprogramming in macrophages and suggest a therapeutic strategy for autoantibody-induced inflammation, including lupus nephritis.
32189044 [Frequencies of musculoskeletal symptoms and disorders in the population-based German Nati 2020 Apr BACKGROUND: Musculoskeletal diseases and symptoms are very common in the general population. They lead to high healthcare costs and pose a significant burden to the national economy. OBJECTIVES: Based on data from the population-based German National Cohort (GNC), frequencies of musculoskeletal symptoms and diseases are reported, including back pain, osteoporosis, osteoarthritis, and arthritis. MATERIALS AND METHODS: Data were collected from March 2014 to March 2017 in adults aged 20-75 years during the first half of the baseline survey of the GNC. The sample comprised 101,779 interviewed subjects, including 9370 subjects who underwent clinical musculoskeletal examinations. The interview included questions about specific musculoskeletal disorders. A clinical examination of the hand provided information about palpable swollen joints and pressure-sensitive joints. Resting pain of the knees and hips was also assessed by a clinical examination. Frequencies were standardized to the German standard population of the year 2011. RESULTS: Having ever been diagnosed with recurrent back pain (22.5%) or osteoarthritis (20.6%) were the most common complaints reported in the interview; osteoporosis (2.9%) and rheumatoid arthritis (1.9%) were stated more seldom. According to the hand examination, 6.0% of all participants experienced pain in at least one finger joint. Resting pain was present in at least one knee among 8.2% and in at least one hip among 5.1% of the participants as assessed during the clinical examination. Women were more likely to report musculoskeletal disorders and symptoms than men. The proportion of adults affected by musculoskeletal diseases increased strongly with age. CONCLUSION: Musculoskeletal disorders and symptoms occur frequently. The burden of complaints and diagnoses is comparable to previous population-based surveys.
32326657 A Multivalent ICAM-1 Binding Nanoparticle which Inhibits ICAM-1 and LFA-1 Interaction Repr 2020 Apr 15 The autoimmune disorder, Sjögren's syndrome (SS), is characterized by lymphocytic infiltration and loss of function of exocrine glands such as the lacrimal gland (LG) and salivary gland. SS-associated changes in the LG are associated with the development of autoimmune-mediated dry eye disease. We have previously reported the accumulation of intercellular adhesion molecule 1 (ICAM-1) in the LG of Non-Obese Diabetic (NOD) mice, a murine model of autoimmune-mediated dry eye in SS, in both LG acinar cells and infiltrating lymphocytes. ICAM-1 initiates T-cell activation and can trigger T-cell migration through binding to lymphocyte function-associated 1 antigen (LFA). To modulate this interaction, this study introduces a new tool, a multivalent biopolymeric nanoparticle assembled from a diblock elastin-like polypeptide (ELP) using the S48I48 (SI) ELP scaffold fused with a mouse ICAM-1 targeting peptide to form IBP-SI. IBP-SI forms a multivalent, monodisperse nanoparticle with a radius of 21.9 nm. Unlike the parent SI, IBP-SI binds mouse ICAM-1 and is internalized by endocytosis into transfected HeLa cells before it accumulates in lysosomes. In vitro assays measuring lymphocyte adhesion to Tumor Necrosis Factor TNF-α-treated bEnd.3 cells, which express high levels of ICAM-1, show that adhesion is inhibited by IBP-SI but not by SI, with IC(50) values of 62.7 μM and 81.2 μM, respectively, in two different assay formats. IBP-SI, but not SI, also blocked T-cell proliferation in a mixed lymphocyte reaction by 74% relative to proliferation in an untreated mixed cell reaction. These data suggest that a biopolymeric nanoparticle with affinity for ICAM-1 can disrupt ICAM-1 and LFA interactions in vitro and may have further utility as an in vivo tool or potential therapeutic.
32171889 Complex syndromes of chronic pain, fatigue and cognitive impairment linked to autoimmune d 2020 May Chronic fatigue syndrome, postural orthostatic tachycardia syndrome, complex regional pain syndrome and silicone implant incompatibility syndrome are a subject of debate among clinicians and researchers. Both the pathogenesis and treatment of these disorders require further study. In this paper we summarize the evidence regarding the role of autoimmunity in these four syndromes with respect to immunogenetics, autoimmune co-morbidities, alteration in immune cell subsets, production of autoantibodies and presentation in animal models. These syndromes could be incorporated in a new concept of autoimmune neurosensory dysautonomia with the common denominators of autoantibodies against G-protein coupled receptors and small fiber neuropathy. Sjogren's syndrome, which is a classical autoimmune disease, could serve as a disease model, illustrating the concept. Development of this concept aims to identify an apparently autoimmune subgroup of the disputable disorders, addressed in the review, which may most benefit from the immunotherapy.
31773391 Enthesitis and its relationship with disease activity, functional status, and quality of l 2020 Feb Psoriatic arthritis (PsA) is an inflammatory arthritis with distinct phenotypic subtypes. Enthesitis is assigned as a hallmark of the disease, given its significant relations to disease activity and quality of life. Our objective is to evaluate the prevalence of enthesitis and its association with some clinical parameters, particularly quality of life, using data from a national registry. Patients with PsA meeting ClASsification criteria for Psoriatic Arthritis (CASPAR) were enrolled by means of a multi-centre Turkish League Against Rheumatism (TLAR) Network Project. The following information was recorded in web-based case report forms: demographic, clinical and radiographic data; physical examination findings, including tender and swollen joint counts (TJC and SJC); nail and skin involvement; Disease Activity Score-28 for Rheumatoid Arthritis with Erythrocyte Sedimentation Rate (DAS 28-ESR); Bath Ankylosing Spondylitis Disease Activity Index (BASDAI); Maastricht Ankylosing Spondylitis Enthesitis Score (MASES); Psoriasis Area Severity Index (PASI); Bath Ankylosing Spondylitis Radiology Index for the spine (BASRI-s); Health Assessment Questionnaire (HAQ); Bath Ankylosing Spondylitis Functional Index (BASFI); Health Assessment Questionnaire for the spondyloarthropathies (HAQ-s); Psoriatic arthritis quality of Life scale (PsAQoL); Short Form 36 (SF-36); Hospital Anxiety Depression Scale (HADS); Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F); and Fibromyalgia Rapid Screening Tool (FiRST) scores. The patients were divided into two groups, namely with and without enthesitis, based on the triple Likert-type physician-reported statement of 'active enthesitis', 'history of enthesitis' or 'none' in the case report forms. Patients with active enthesitis were compared to others in terms of these clinical parameters. A total of 1130 patients were enrolled in this observational study. Of these patients, 251 (22.2%) had active enthesitis according to the clinical assessment. TJC, HAQ-s, BASDAI, FiRST and PsAQoL were significantly higher whereas the SF-36 scores were lower in patients with enthesitis (p < 0.05). Chronic back pain, dactylitis, and tenosynovitis were more frequent in the enthesopathy group (59.4%/39%, 13.1%/6.5% and 24.7%/3.4%, respectively). Significant positive correlations between the MASES score and the TJC, HAQ, DAS 28-ESR, BASDAI, FiRST and PsAQoL scores, and a negative correlation with the SF-36 score were found. When linear regression analysis was performed, the SF-36 MCS and PCS scores decreased by - 9.740 and - 11.795 units, and the FiRST scores increased by 1.223 units in patients with enthesitis. Enthesitis is an important involvement of PsA with significant relations to quality of life determined with PsAQoL and SF-36 scores. Our study found higher frequency of dactylitis and chronic back pain, and worse quality of life determined with SF-36 and PsAQoL scores in patients with enthesitis.
32620868 CP-25 alleviates antigen-induced experimental Sjögren's syndrome in mice by inhibiting JA 2021 Aug The etiology of primary Sjögren's syndrome (pSS) remains unknown, and there is no complete curative drug. In this study, we treated a mouse model of the submandibular gland (SG) protein-immunized experimental Sjögren's syndrome (ESS) with paeoniflorin-6'-O-benzene sulfonate (termed CP-25) to evaluate the potential therapeutic effects of CP-25. Through in vivo experiments, we found that CP-25 increased saliva flow, alleviated the salivary gland indexes, and improved tissue integrity in the ESS model. The viability of splenocytes and B-lymphocyte migration from spleen were reduced in ESS mice. Furthermore, CP-25 decreased the expression of IgG antibodies, anti-SSA and anti-SSB antibodies and modulated the levels of cytokines in the serum of SS mice. The numbers of total B lymphocytes, plasma cells (PCs), and memory B cells diminished in the salivary gland. Increased expression of the JAK1-STAT1-CXCL13 axis and IFNα was found in human tissue isolated from pSS patients. In vitro, after stimulation with IFNα, the levels of CXCL13 mRNA and CXCL13 in human salivary gland epithelial cells (HSGEC) increased, while CP-25 counteracted the secretion of CXCL13 and downregulated the expression of CXCL13. IFN-α activated the JAK1-STAT1/2-CXCL13 signaling pathway in HSGEC, which was negatively regulated by additional CP-25. As a consequence, B-cell migration was downregulated in coculture with IFN-α-stimulated HSGEC. Taken together, this study demonstrated that the therapeutic effects of CP-25 were associated with the inhibition of the JAK1-STAT1/2-CXCL13 signaling pathway in HSGEC, which impedes the migration of B cells into the salivary gland. We identified the underlying mechanisms of the therapeutic effect of CP-25 and provided an experimental foundation for CP-25 as a potential drug in the treatment of the human autoimmune disorder pSS.
32521323 Cryoglobulinemia after the era of chronic hepatitis C infection. 2020 Aug OBJECTIVES: Historically chronic hepatitis C virus (HCV) infection accounted for the majority of mixed cryoglobulinemia (MC). The advent of direct-acting antivirals (DAA) against HCV has dramatically changed the management and the prevalence of chronic HCV infection. We aimed to describe the spectrum of MC in the era of DAA agents. METHODS: We performed a longitudinal cohort study between 2011 and 2018 from a single-center French university hospital's database of 15 970 patients screened for MC. Epidemiological, clinical and immunological data of MC were recorded. We evaluated the incidence and evolution of MC before and after the era of DAA agents and compared HCV and non-HCV related MC. RESULTS: Among 742 patients who tested positive for cryoglobulin, 679 [mean age 55.5 years, 54.5% female and 381 (56.1%) with chronic HCV infection] patients with persistent MC were included in the study. 373 (54.9%) had type II and 306 (45.1%) type III cryoglobulin, and 139 (21.5%) had cryoglobulinemia vasculitis (CryoVas). The incidence of MC decreased steadily with 395 and 284 incident cases during 2011-2014 and 2015-2018, respectively. In 2011, the leading cause was chronic HCV infection (62.5% of all MC). Currently, autoimmune diseases [systemic lupus erythematosus (28.9%) and Sjögren's syndrome (10.7%)] are the main cause of MC. The incidence of CryoVas was similar between HCV-and non HCV-related MC. CONCLUSION: Direct-acting antivirals have dramatically changed the landscape and the incidence of MC.
32760405 Repertoire Analysis of B-Cells Located in Striated Ducts of Salivary Glands of Patients Wi 2020 A major complication of primary Sjögren's syndrome (pSS) is development of mucosa associated lymphoid tissue (MALT) B-cell lymphoma, particularly in salivary glands. These lymphomas express FcRL4 and are characteristically associated with lymphoepithelial lesions. Neoplastic B-cells may be derived from non-neoplastic glandular intraductal B-cells, also virtually all expressing FcRL4. A characteristic feature of MALT lymphomas is the production of rheumatoid factors (RFs), which are largely encoded by stereotypic immunoglobulin variable heavy chain (IGHV) sequences. The aim of this study was to examine whether there is a relationship between the intraductal and periductal B-cells and whether the intraductal B-cells are selected for RF. RNA was extracted from laser-microdissected infiltrated ductal areas and periductal infiltrates from frozen parotid gland tissue sections of 5 pSS patients. PCR amplified IGHV transcripts were cloned into pCR™4-TOPO vector and subsequently sequenced. Microdissected ducts yielded 96 unique IGHV sequences derived from intraductal B-cells, while 119 unique IGHV sequences were obtained from periductal infiltrates. No major difference in VH-gene usage was observed between intraductal and periductal B-cells. Nearly all (>90%) IGHV sequences derived from both intraductal and periductal B-cells were mutated. Clonal expansions as defined by shared VDJ rearrangements were also present among both intraductal and periductal B-cells: in total 32 clones were found, from which 12 were located within ducts, 15 in periductal areas, and five clones shared members in both areas. We observed 12 IGHV rearrangements encoding for RF sequences from which two were derived from intraductal B-cells and 10 from periductal B-cells. Nine RF sequences were part of a clone. Together these findings indicate that intraductal and periductal B-cells are closely related to each other. Intraductal B-cells are most likely derived from periductal B-cells. We did not obtain evidence that RF-specific B-cells are enriched within the striated ducts. We speculate that in principle any activated B-cell can enter the striated ducts from the periductal infiltrate, irrespective of its antigenic specificity. Within the ducts, these B-cells may receive additional activation and proliferation signals, to further expand at these sites and by acquisition of driver-mutations develop toward lymphoma.
31913524 Prediction of outcome in fetal autoimmune complete heart block. 2020 Apr Assessing cardiac function and risk stratification in a fetal anti-Sjögren syndrome type A (SSA) or anti-Sjögren syndrome type B (SSB) complete atrioventricular block (CAVB) is challenging. We aimed to evaluate the cardiovascular profile score (CVP) and its components in surveillance of fetuses with autoimmune CAVB. METHODS: Retrospective cohort review of CAVB pregnancies, excluding fetuses with significant cardiac anomalies. RESULTS: CAVBs are in 17 fetuses, diagnosed at mean gestational age of 23 ± 5 weeks. Overall mortality is 18%: 1 termination, 1 fetal demise (intrauterine fetal demise [IUFD]), and 1 postnatal death. Both mortalities had intrauterine growth restriction; IUFD had placental infarction. Presenting CVP 8.7 ± 1. No fetus had CVP <7; the score correlated with increased risk of perinatal death. The 2 mortalities had initial CVP scores of 8 and 9; both increased to 10 on subsequent exams. 30% of fetuses had low middle cerebral artery pulsatility (MCA-PI) on the last study. All had high umbilical artery pulsatility (UA-PI) throughout gestation. The 2 deaths had the lowest MCA-PI. CONCLUSION: Despite low heart rates, high CVP scores in our cohort remained high and were not predictive of mortality. Abnormalities in MCA flow reflects fetal cerebral vasodilation that may indicate altered hemodynamics and be predictive of outcomes, but data is limited. Abnormal umbilical artery (UA) flow suggests that perinatal mortality may also be related to placental disease.
32217287 Pulmonary nodular and cystic light chain deposition disease: A retrospective review of 10 2020 Apr INTRODUCTION: Light chain deposition disease (LCDD) rarely involves the lungs. We report clinical and radiologic findings of pulmonary LCDD. METHODS: We retrospectively identified patients with biopsy-proven pulmonary LCDD seen at Mayo Clinic (Rochester, Minnesota) from January 1997 through December 2018. Demographic, clinical, and imaging features were analyzed. RESULTS: We identified 10 patients with pulmonary LCDD (median age at diagnosis, 55 years; range, 39-77 years). Eight patients were women and 7 were never-smokers. Dyspnea (n = 3) and chest pain (n = 3) were the most common respiratory symptoms. Associated conditions included Sjögren syndrome (n = 6), sarcoidosis (n = 1), and limited scleroderma (n = 1). Eight patients had mucosa-associated lymphoid tissue (MALT) lymphoma. Among the 9 patients with chest computed tomography (CT) images, 8 (89%) had cysts. Cysts were predominantly distributed in the lower lung and were round or oval. All patients had multiple cysts (5 patients had 1-5 cysts, 3 had >20 cysts). The median diameter of the largest cyst was 18 mm (range, 5-68 mm). All 9 patients had solid nodules (3 had >10 nodules). Five patients had subsolid nodules. The median diameter of the largest solid nodules was 13 mm (range, 6-26 mm). Positron emission tomography-CT images were available for 8 patients. The median maximum standardized uptake value of the most avid pulmonary nodule was 2.2 (range, 1.9-6.0). Two patients died during a median follow-up of 2.3 years (range, 0.5-9.9 years). CONCLUSIONS: Pulmonary LCDD is characterized by cysts and nodules. The disease is associated with MALT lymphoma, especially in the setting of Sjögren syndrome.
33062721 B7-H4 Inhibits the Development of Primary Sjögren's Syndrome by Regulating Treg Different 2020 BACKGROUND: This study is aimed at exploring the role of B7-H4 in the pathogenesis of primary Sjögren's syndrome (pSS) in NOD/Ltj mouse. METHODS: B7-H4 expression in salivary glands was examined by IHC, and lymphocyte infiltration was showed by H&E. Next, anti-B7-H4 mAb or immunoglobulin isotype was injected into NOD/Ltj mice. Cytokine levels were measured by quantitative RT-PCR, and immunoglobulins were measured by ELISA. T cell subsets were analyzed by flow cytometry. Last, we treated NOD/Ltj mice with B7-H4Ig and control Ig. CD4+Foxp3+ T cells were assessed by immunohistochemistry. Two-tailed Student's t-tests were used to detect the statistical difference in various measures between the two groups. RESULTS: B7-H4 expression was remarkably reduced in salivary glands of NOD/Ltj mice at 15 weeks compared with the NOD/Ltj mice at 8 weeks. Anti-B7-H4 mAb treatment increased lymphocyte infiltration in salivary glands. Inflammatory cytokines including IL-12, IL-18, IL-1α, TNF-α, IFN-α, and BAFF were upregulated markedly in anti-B7-H4 mAb-treated mice compared to IgG isotype-treated mice. Flow cytometry analysis showed that anti-B7-H4 mAb-treated mice had lower levels of CD4+Foxp3+/CD4+ T cells in spleen. Moreover, Foxp3 mRNA levels of salivary glands were diminished in anti-B7-H4 mAb-treated mice. Flow cytometry analysis showed that anti-B7-H4 mAb inhibited CD4+Foxp3+/CD4+ T cell production, while B7-H4Ig would promote naïve CD4+ T into Treg differentiation. Administration with B7-H4Ig displayed significantly decreased lymphocyte infiltration in salivary glands and low levels of total IgM and IgG in serum. Analysis of inflammatory cytokines in salivary glands after B7-H4Ig treatment revealed that the mRNA levels of IL-12, IL-6, IL-18, IL-1α, TNF-α, and IFN-α were significantly downregulated in B7-H4Ig-treated mice compared to control Ig treatment. B7-H4Ig-treated mice had significantly higher levels of CD4+Foxp3+/CD4+ T cells in spleen. IHC in salivary gland revealed that CD4+Foxp3+ T cells of B7-H4Ig treatment mouse were more than control Ig treatment. CONCLUSIONS: Our findings implicate that B7-H4 has a protective role for salivary gland epithelial cells (SGECs) and therapeutic potential in the treatment of pSS.
33403021 Shared development of targeted therapies among autoimmune and inflammatory diseases: a sys 2020 BACKGROUND: Pathogenic inflammatory pathways are largely shared between different autoimmune and inflammatory diseases (AIDs). This offers the potential to develop a given targeted therapy in several AIDs. METHODS: We analyzed two clinical trials registries (ClinicalTrials.gov and EU Clinical Trials Register) to identify the targeted therapies whose development is shared between at least two of the most common AIDs [rheumatoid arthritis (RA), spondyloarthritis (SpA), cutaneous psoriasis (cPso), inflammatory bowel diseases (IBD), systemic lupus erythematosus (SLE), primary Sjögren's syndrome (pSS), systemic sclerosis (SSc), idiopathic inflammatory myopathies (IIM), giant cell arteritis (GCA), and multiple sclerosis (MS)] using an in-depth repurposing analysis. RESULTS: We identified 142 shared targeted therapies. The four diseases in which shared targeted therapies were the most numerous were RA (n = 92), cPso (n = 67), IBD (n = 58), and SLE (n = 56). The two clusters of diseases between which the overlap of targeted therapies was the most important were RA and SLE as well as RA, SpA, cPso, and IBD. The targeted therapies which were shared by five diseases or more were abatacept, ustekinumab, rituximab, anakinra, etanercept, infliximab, secukinumab, tofacitinib, alemtuzumab, tocilizumab, adalimumab, apremilast, baricitinib, belimumab, brodalumab, filgotinib, and upadacitinib. The most frequently targeted molecules and pathways were (by descending frequency): JAK-STAT pathways, Th17 axis, TNF-α, IL-6, costimulation molecules, BAFF, CD20, BTK, chemokines and integrins, IL-1, and type I interferon. CONCLUSION: Many targeted therapies are developed in several AIDs, reflecting the overlap of pathogenic pathways and potential of drug repurposing. This suggests that a revision of the current, clinically based classification of AIDs towards a more mechanistic-based taxonomy might be relevant.
33240517 Prevalence, Length of Stay, and Hospitalization of Acute Kidney Injury in Patients With an 2020 BACKGROUND: Literature on the outcome of acute kidney injury (AKI) in Sjogren's syndrome (SJS) is quite scanty. Acute kidney injury has emerged as a significant cause of morbidity and mortality in patients with autoimmune diseases such as systemic lupus erythematosus. OBJECTIVE: To examine the outcome of AKI with and without SJS. To achieve this, we examined the prevalence, mortality, outcomes, length of stay (LOS), and hospital charges in patients with AKI with SJS compared with patients without SJS from a National Inpatient Sample (NIS) database in the period 2010 to 2013. DESIGN: A retrospective cohort study using NIS. SETTING: United States. SAMPLE: Cohort of 97 055 weighted patient discharges with AKI from the NIS. MEASUREMENTS: Not applicable. METHODS: Data were retrieved from the NIS for adult patients admitted with a principal diagnosis of AKI between 2010 and 2013, using the respective International Classification of Diseases, Ninth Revision (ICD-9) codes. The study population divided into 2 groups, with and without Sjogren's disease. Multivariate and linear regression analysis conducted to adjust for covariates. We omitted patients with systemic sclerosis and rheumatoid arthritis from the analysis to avoid any discrepancy as they were not meant to be a primary outcome in our study. RESULTS: The study population represented 97 055 weighted patient discharges with AKI. Analysis revealed AKI patients with Sjogren's compared with patients without Sjogren's had statistically significant lower hyperkalemia rates (adjusted odds ratio: 0.65, confidence interval: 0.46-0.92; P = .017. There was no statistically significant difference in mortality, LOS, hospital charges, and other outcomes. LIMITATIONS: Study is not up to date as data are from ICD-9 which are testing data from 2010 to 2013, and data were obtained through SJS codes, which have their limitations. Also, limitations included lack of data on metabolic acidosis, hypokalemia, and not including all causes of AKI. CONCLUSIONS: At present, our study is unique as it has examined prevalence, mortality, and outcomes of Sjogren's in patients with AKI. Patients with Sjogren's had significantly lower hyperkalemia during the hospitalization. Further research is needed to identify the underlying protective mechanisms associated with Sjogren's that resulted in lower hyperkalemia. TRIAL REGISTRATION: Not applicable.