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ID PMID Title PublicationDate abstract
32769933 Primary Sjögren syndrome-associated acute interstitial nephritis and type 3 renal tubular 2020 Aug 7 INTRODUCTION: The kidney is one of the common extraglandular sites involved in primary Sjögren syndrome (pSS), with chronic tubulointerstitial nephritis (TIN) the most common pathology type. Renal involvement in pSS often presents as chronic TIN accompanied by type 1 or 2 renal tubular acidosis (RTA). Description of renal involvement as acute TIN with type III RTA in pSS has been rarely reported. PATIENT CONCERNS: A 37-year-old woman was admitted with complaints of dry mouth, dry eyes, and progressive muscle weakness for 17 months. Two months before admission, the patient had a blood potassium level of 1.7 mmol/L. DIAGNOSIS: Further tests confirmed pSS and type III RTA. Renal biopsy demonstrated acute TIN and thin basement membrane nephropathy (TBMN). INTERVENTIONS: Full-dose corticosteroid (1 mg/kg/day) and cyclophosphamide (100 mg/day) were applied. OUTCOMES: The creatinine levels of the patient decreased 0.28 mg/dL (1.18-0.90 mg/dL) during 3-month follow-up. CONCLUSIONS: We reported a patient with pSS-associated kidney injury, presenting as acute TIN with type 3 RTA and TBMN. This case increases the awareness of a rare manifestation of pSS-associated kidney injury. In pSS-associated acute TIN, cyclophosphamide combined with full-dose corticosteroids may achieve good outcomes.
32259032 The necessity, efficacy and safety of biologics in juvenile idiopathic arthritis. 2020 OBJECTIVE: Juvenile idiopathic arthritis (JIA) is the most common cause of chronic arthritis in children. Biologics have changed the faith of children with rheumatic diseases. The main objective of this study was to demonstrate the rate of usage, efficacy and safety of biologics in JIA subtypes. METHODS: This retrospective observational cohort study was conducted between May 2010 and September 2017. All children with the diagnosis of JIA and children under a biological agent treatment were recorded into the local registry system. Age, gender, JIA subtype, medications used, the clinical status of the patient, tuberculosis screening results, and side effects observed under biologics were retrieved from the registry. RESULTS: There were 405 patients with the diagnosis of JIA in the cohort. Biologics were used in 123 (30.3%) JIA patients. Subtype frequencies of JIA patients were as follows: persistent oligoarticular JIA (33.6%), enthesitis-related arthritis (29.2%), systemic JIA (13%), rheumatoid factor (RF)-negative polyarticular JIA (13%), extended oligoarticular JIA (4.2%), RF-positive polyarticular JIA (3.4%), psoriatic arthritis (1.8%) and unclassified arthritis (1.8%). The rate of biologic use was high in extended oligoarticular JIA (64.7% of the cases), RF-positive polyarticular JIA (57.1%), psoriatic arthritis (57.1%), RF-negative polyarticular JIA (41.5%), and in systemic JIA (39.6%). Enthesitis-related arthritis (27.1%), persistent oligoarticular JIA (17.6%) and unclassified arthritis (16.6%) patients were the cases that needed a biologic agent in the last order. At the last control, 78.9% of the cases were in remission, while 21.1% of them were active despite biologic treatment. Isoniazid prophylaxis was used in 30.8% of the patients. None of the patients developed active tuberculosis infection under prophylaxis. Adverse events were observed in 18.6% of patients under biologics as recurrent uncomplicated upper respiratory tract infections being the most common. CONCLUSION: Biologics are safe and effective treatment options in children with JIA. Most of the JIA patients with polyarticular involvement require biologics earlier in the disease course. The risk of tuberculosis infection seems not to be increased after appropriate screening and prophylaxis.
33139687 Strategies for the withdrawal of classic and biological DMARD in clinically inactive patie 2020 Jul OBJECTIVE: To evaluate and describe the strategies of Portuguese rheumatologists and paediatricians, regarding either the maintenance or the withdrawal of classic and biologic disease-modifying anti-rheumatic drugs (cDMARDs and bDMARDs, respectively), when patients with Juvenile Idiopathic Arthritis (JIA) achieved clinical inactive disease (CID). METHODS: We performed a 30-question questionnaire, which was sent to all the 35 clinicians enrolled in the Portuguese group of paediatric rheumatology. RESULTS: Twenty-three complete responses were obtained. The factors with the greatest impact on the decision to withdraw cDMARDs were: the duration of the CID, the therapy-induced toxicity, the presence of erosive disease and joint damage, the subtype of JIA, the time to reach inactive disease and the low adherence to therapy. These factors were classified as "very important" in this decision by more than 50% of the clinicians. The same factors, except for low adherence, had the greatest impact, when considering the withdrawal of bDMARDs. Withdrawal was more likely in patients with persistent oligoarticular JIA and less likely in rheumatoid factor positive polyarticular JIA. Sulfasalazine was more susceptible to be discontinued than methotrexate. Contrariwise, there were no differences concerning bDMARDs. Most participants reported that they started the drug withdrawal only after 12 months of sustained remission, by progressively tapering the dose of the cDMARD and spacing the intake of the bDMARD. Also, they reported that the decision to suspend the DMARD was based on imaging methods, preferably ultrasound, and in patient-reported outcomes. For patients on combination therapy, bDMARDs are reported to be the first to be withdrawn. CONCLUSIONS: Literature is scarce on this matter and there are no well-defined guidelines on how to withdrawal cDMARDs or bDMARDs on JIA. Notwithstanding, most Portuguese physicians were in agreement on the factors that needed to be taken into account with respect to the withdraw decision.
32793902 IFN- γ and TNF- α drive a CXCL10 + CCL2 + macrophage phenotype expanded in severe COVID- 2020 Aug 5 Immunosuppressive and anti-cytokine treatment may have a protective effect for patients with COVID-19. Understanding the immune cell states shared between COVID-19 and other inflammatory diseases with established therapies may help nominate immunomodulatory therapies. Using an integrative strategy, we built a reference by meta-analyzing > 300,000 immune cells from COVID-19 and 5 inflammatory diseases including rheumatoid arthritis (RA), Crohn's disease (CD), ulcerative colitis (UC), lupus, and interstitial lung disease. Our cross-disease analysis revealed that an FCN1 + inflammatory macrophage state is common to COVID-19 bronchoalveolar lavage samples, RA synovium, CD ileum, and UC colon. We also observed that a CXCL10 + CCL2 + inflammatory macrophage state is abundant in severe COVID-19, inflamed CD and RA, and expresses inflammatory genes such as GBP1, STAT1 , and IL1B . We found that the CXCL10 + CCL2 + macrophages are transcriptionally similar to blood-derived macrophages stimulated with TNF- α and IFN- γ ex vivo . Our findings suggest that IFN- γ , alongside TNF- α , might be a key driver of this abundant inflammatory macrophage phenotype in severe COVID-19 and other inflammatory diseases, which may be targeted by existing immunomodulatory therapies.
32817143 First-in-Humans Study of (68)Ga-DOTA-Siglec-9, a PET Ligand Targeting Vascular Adhesion Pr 2021 Apr Sialic acid-binding immunoglubulinlike lectin 9 (Siglec-9) is a ligand of vascular adhesion protein 1. A (68)Ga-labeled peptide of Siglec-9, (68)Ga-DOTA-Siglec-9, holds promise as a novel PET tracer for imaging of inflammation. This first-in-humans study investigated the safety, tolerability, biodistribution, and radiation dosimetry of this radiopharmaceutical. Methods: Six healthy men underwent dynamic whole-body PET/CT. Serial venous blood samples were drawn from 1 to 240 min after intravenous injection of 162 ± 4 MBq of (68)Ga-DOTA-Siglec-9. In addition to γ-counting, the plasma samples were analyzed by high-performance liquid chromatography to detect intact tracer and radioactive metabolites. Radiation doses were calculated using the OLINDA/EXM software, version 2.2. In addition, a patient with early rheumatoid arthritis was studied with both (68)Ga-DOTA-Siglec-9 and (18)F-FDG PET/CT to determine the ability of the new tracer to detect arthritis. Results: (68)Ga-DOTA-Siglec-9 was well tolerated by all subjects. (68)Ga-DOTA-Siglec-9 was rapidly cleared from the blood circulation, and several radioactive metabolites were detected. The organs with the highest absorbed doses were the urinary bladder wall (0.38 mSv/MBq) and kidneys (0.054 mSv/MBq). The mean effective dose was 0.022 mSv/MBq (range, 0.020-0.024 mSv/MBq). Most importantly, however, (68)Ga-DOTA-Siglec-9 was comparable to (18)F-FDG in detecting arthritis. Conclusion: Intravenous injection of (68)Ga-DOTA-Siglec-9 was safe and biodistribution was favorable for testing of the tracer in larger group of patients with rheumatoid arthritis, as is planned for the next phase of clinical trials. The effective radiation dose of (68)Ga-DOTA-Siglec-9 was within the same range as the effective radiation doses of other (68)Ga-labeled tracers. Injection of 150 MBq of (68)Ga-DOTA-Siglec-9 would expose a subject to 3.3 mSv. These findings support the possible repeated clinical use of (68)Ga-DOTA-Siglec-9, such as in trials to elucidate the treatment efficacy of novel drug candidates.
33037004 Mechanisms of progressive fibrosis in connective tissue disease (CTD)-associated interstit 2021 Feb Interstitial lung diseases (ILDs), which can arise from a broad spectrum of distinct aetiologies, can manifest as a pulmonary complication of an underlying autoimmune and connective tissue disease (CTD-ILD), such as rheumatoid arthritis-ILD and systemic sclerosis (SSc-ILD). Patients with clinically distinct ILDs, whether CTD-related or not, can exhibit a pattern of common clinical disease behaviour (declining lung function, worsening respiratory symptoms and higher mortality), attributable to progressive fibrosis in the lungs. In recent years, the tyrosine kinase inhibitor nintedanib has demonstrated efficacy and safety in idiopathic pulmonary fibrosis (IPF), SSc-ILD and a broad range of other fibrosing ILDs with a progressive phenotype, including those associated with CTDs. Data from phase II studies also suggest that pirfenidone, which has a different-yet largely unknown-mechanism of action, may also have activity in other fibrosing ILDs with a progressive phenotype, in addition to its known efficacy in IPF. Collectively, these studies add weight to the hypothesis that, irrespective of the original clinical diagnosis of ILD, a progressive fibrosing phenotype may arise from common, underlying pathophysiological mechanisms of fibrosis involving pathways associated with the targets of nintedanib and, potentially, pirfenidone. However, despite the early proof of concept provided by these clinical studies, very little is known about the mechanistic commonalities and differences between ILDs with a progressive phenotype. In this review, we explore the biological and genetic mechanisms that drive fibrosis, and identify the missing evidence needed to provide the rationale for further studies that use the progressive phenotype as a target population.
31350812 Sepiapterin Reductase Inhibition Leading to Selective Reduction of Inflammatory Joint Pain 2020 Jan OBJECTIVE: To evaluate the antiinflammatory and analgesic effects of sepiapterin reductase (SPR) inhibition in a mouse model of inflammatory joint disease, and to determine whether urinary sepiapterin levels, as measured in mice and healthy human volunteers, could be useful as a noninvasive, translational biomarker of SPR inhibition/target engagement. METHODS: The collagen antibody-induced arthritis (CAIA) model was used to induce joint inflammation in mice. The effects of pharmacologic inhibition of SPR on thresholds of heat-, cold-, and mechanical-evoked pain sensitivity and on signs of inflammation were tested in mice with CAIA. In addition, mice and healthy human volunteers were treated with SPR inhibitors, and changes in urinary sepiapterin levels were analyzed by high-performance liquid chromatography. RESULTS: CAIA in mice was characterized by 2 phases: in the acute inflammation (early) phase, joint inflammation and heat-, mechanical-, and cold-induced pain hypersensitivity were present, while in the postinflammation (late) phase, no joint inflammation was observed but heat- and mechanical-induced hypersensitivity, but not cold hypersensitivity, were present. Inhibition of SPR in mice with CAIA significantly attenuated the heat-induced hyperalgesia in both phases, and the mechanical allodynia in the late phase. Signs of inflammation were unaffected by SPR inhibition. Urinary tetrahydrobiopterin levels, as a marker of inflammatory pain, were increased during inflammation in mice with CAIA (2-fold increase over controls; P < 0.05) and significantly reduced by SPR inhibition (P < 0.05 versus vehicle-treated mice). Increased urinary sepiapterin levels in the presence of SPR inhibition in both mice and healthy human volunteers were associated with high sensitivity (70-85%) and high specificity (82-88%) for the prediction of SPR inhibition/target engagement. CONCLUSION: SPR inhibition reduces the pain associated with joint inflammation, thus showing its potential utility as an analgesic strategy for inflammatory joint pain. In addition, SPR inhibition increases urinary sepiapterin levels, indicating the potential of this measurement as a noninvasive biomarker of target engagement of SPR inhibitors, such as sulfasalazine, a disease-modifying antirheumatic drug that is currently used as a first-line treatment for rheumatoid arthritis.
33718577 New or vanishing frontiers: LACC1-associated juvenile arthritis. 2021 Mar BACKGROUND: The classification and pathogenic basis of juvenile idiopathic arthritis (JIA) are a subject of some controversy. Essentially, JIA is an exclusion diagnosis that represents a phenotypically heterogeneous group of arthritis of unknown origin. Familial aggregation of JIA supports the concept of genetic influence in the pathogenesis of JIA. OBJECTIVE: To present the spectrum of laccase domain-containing 1 (LACC1)-associated juvenile arthritis with clinical, biochemical, and molecular genetic data of a cohort of 43 patients, including 11 previously unpublished cases. METHODS: We studied 11 patients with different categories of juvenile idiopathic arthritis from 5 consanguineous families, all from Saudi Arabia, except 2 patients who were of Jordanian ethnicity. Whole-exome sequencing was used to identify the disease-causing variant of LACC1. We also reviewed the clinical spectrum and molecular genetic data of previously published cases of LACC1-associated juvenile arthritis. RESULTS: This study describes 43 (29 females, 14 males) patients from consanguineous multiplex families. Most of the included patients were of Arab origin with 86% having early onset disease. The most frequent categories were systemic (19 patients) and rheumatoid factor-negative polyarticular (19 patients). Thirty-seven (86%) had progressive erosive arthritis and 10 (23.3%) had persistent limb lymphedema. None of the patients had features of macrophage activation syndrome. Genetic analysis confirmed LACC1 variant in all patients; 22 patients had common founder mutation (LACC1: c.850T > C,p.C284R), while the others showed different LACC1 variants. All patients were treated aggressively with methotrexate and sequential biologic agents. Most of them showed a poor response to treatment. CONCLUSION: This report expands the pathogenic variants of LACC1 and the clinical spectrum associated with this genetic subset of juvenile arthritis. The predominance of autosomal-recessive inheritance and strong genetic evidence allowed us to propose LACC1-associated juvenile arthritis as a distinct disorder.
32550295 Points to consider in cardiovascular disease risk management among patients with rheumatoi 2020 BACKGROUND: It is plausible that optimal cardiovascular disease (CVD) risk management differs in patients with rheumatoid arthritis (RA) from low or middle income compared to high income populations. This study aimed at producing evidence-based points to consider for CVD prevention in South African RA patients. METHODS: Five rheumatologists, one cardiologist and one epidemiologist with experience in CVD risk management in RA patients, as well as two patient representatives, two health professionals and one radiologist, one rheumatology fellow and 11 rheumatologists that treat RA patients regularly contributed. Systematic literature searches were performed and the level of evidence was determined according to standard guidelines. RESULTS: Eighteen points to consider were formulated. These were grouped into 6 categories that comprised overall CVD risk assessment and management (n = 4), and specific interventions aimed at reducing CVD risk including RA control with disease modifying anti-rheumatic drugs, glucocorticoids and non-steroidal anti-inflammatory drugs (n = 3), lipid lowering agents (n = 8), antihypertensive drugs (n = 1), low dose aspirin (n = 1) and lifestyle modification (n = 1). Each point to consider differs partially or completely from recommendations previously reported for CVD risk management in RA patients from high income populations. Currently recommended CVD risk calculators do not reliably identify South African black RA patients with very high-risk atherosclerosis as represented by carotid artery plaque presence on ultrasound. CONCLUSIONS: Our findings indicate that optimal cardiovascular risk management likely differs substantially in RA patients from low or middle income compared to high income populations. There is an urgent need for future multicentre longitudinal studies on CVD risk in black African patients with RA.
32987162 A systematic review finds Core Outcome Set uptake varies widely across different areas of 2021 Jan OBJECTIVE: The aim of our review was to bring together studies that had assessed the uptake of core outcome sets (COS) to explore the level of uptake across different COS and areas of health. STUDY DESIGN AND SETTING: We examined the citations of 337 COS reports to identify studies that had assessed the uptake of a particular COS in randomized controlled trials (RCTs) or systematic reviews (SRs). RESULTS: We identified 24 studies that had assessed uptake in RCTs and two studies that had assessed uptake in SRs. The studies covered a total of 17/337 (5%) COS. Uptake rates reported for RCTs varied from 0% of RCTs (gout) to 82% RCTs (rheumatoid arthritis) measuring the full COS. Studies that assessed uptake of individual core outcomes showed a wide variation in uptake between the outcomes. Suggested barriers to uptake included lack of validated measures, lack of patient and other key stakeholder involvement in COS development, and lack of awareness of the COS. CONCLUSIONS: Few studies have been undertaken to assess the uptake of COS in RCTs and SRs. Further studies are needed to assess whether COS have been implemented across a wider range of disease categories and to explore the barriers and facilitators to COS uptake.
32738973 Potent, non-covalent reversible BTK inhibitors with 8-amino-imidazo[1,5-a]pyrazine core fe 2020 Sep 1 Bruton's tyrosine kinase (BTK) is a Tec family kinase with a well-defined role in the B cell receptor (BCR) pathway. It has become an attractive kinase target for selective B cell inhibition, and for the treatment of B cell related diseases. Many BTK inhibitors have been discovered for the treatment of cancer and rheumatoid arthritis, including a series of BTK inhibitors based on 8-amino-imidazo[1,5-a]pyrazine we recently reported. The X-ray crystal structures of BTK with inhibitors were also published, which provided great help for the SAR design. Here we report our SAR work introducing ring constraints for the 3-position piperidine amides on the BTK inhibitors based on 8-amino-imidazo[1,5-a]pyrazine. This modification improved the potency in BTK inhibitions, as well as the PK profile and the off-target selectivity. The dose-dependent efficacy of two BTK inhibitors was observed in the rat collagen induced arthritis (CIA) model.
32565819 Oral Complementary Medicine Use among People with Inflammatory Arthritis: An Australian Rh 2020 OBJECTIVES: To describe oral complementary medicine (CM) use in people with inflammatory arthritis, associations with use, and changes in use over time. METHODS: Demographic, clinical, and patient-reported outcome data from 5,630 participants with rheumatoid arthritis (RA), ankylosing spondylitis (AS), psoriatic arthritis (PsA), and juvenile idiopathic arthritis (JIA) were extracted from the Australian Rheumatology Association Database (ARAD), a national observational database. CM use at entry into ARAD was ascertained for participants recruited between 2002 and 2018. CM was categorised according to the NIH/Cochrane schema (fatty acids, herbs, or supplements). Logistic regression was used to assess associations between demographic characteristics and CM use. Change in CM use between 2006 and 2016 was investigated using a nonparametric test for trend of rate by year. RESULTS: 2,156 (38.3%) ARAD participants were taking CM at enrolment (RA: 1,502/3,960 (37.9%), AS: 281/736 (38.2%), PsA: 334/749 (44.6%), and JIA: 39/185 (21.1%)). CM use was more prevalent in women (OR 1.3; 95% CI: 1.13-1.50), those with tertiary education (OR 1.32; 95% CI: 1.13-1.55), private health insurance (OR 1.26; (95% CI: 1.10-1.44), drinking alcohol sometimes (OR 1.22; 95% CI: 1.05-1.43), poorer function (HAQ) (OR 1.13; 95% CI: 1.02-1.24), use of NSAID (OR 1.32; 95% CI 1.17-1.50), weak (OR 1.21; 95% CI 1.05-1.41) but not strong opioids, and less prevalent in current smokers (OR 0.76; 95%: CI 0.63-0.91). CM use was not associated with pain, disease activity, or quality of life. The most common CMs were fish oils (N = 1,489 users) followed by glucosamine (N = 605). Both declined in use over time between 2006 and 2016 (27.5% to 21.4%, trend p = 0.85 and 15.5% to 6.4%, trend p < 0.01), respectively. CONCLUSION: Oral CM use is common among Australians with inflammatory arthritis. Its use is greater among women and those with tertiary education. Fish oil and glucosamine, the most common CMs, both declined in use over time.
32763956 Reactive arthritis after COVID-19 infection. 2020 Aug Reactive arthritis (ReA) is typically preceded by sexually transmitted disease or gastrointestinal infection. An association has also been reported with bacterial and viral respiratory infections. Herein, we report the first case of ReA after the he severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. This male patient is in his 50s who was admitted with COVID-19 pneumonia. On the second day of admission, SARS-CoV-2 PCR was positive from nasopharyngeal swab specimen. Despite starting standard dose of favipiravir, his respiratory condition deteriorated during hospitalisation. On the fourth hospital day, he developed acute respiratory distress syndrome and was intubated. On day 11, he was successfully extubated, subsequently completing a 14-day course of favipiravir. On day 21, 1 day after starting physical therapy, he developed acute bilateral arthritis in his ankles, with mild enthesitis in his right Achilles tendon, without rash, conjunctivitis, or preceding diarrhoea or urethritis. Arthrocentesis of his left ankle revealed mild inflammatory fluid without monosodium urate or calcium pyrophosphate crystals. Culture of synovial fluid was negative. Plain X-rays of his ankles and feet showed no erosive changes or enthesophytes. Tests for syphilis, HIV, anti-streptolysin O (ASO), Mycoplasma, Chlamydia pneumoniae, antinuclear antibody, rheumatoid factor, anticyclic citrullinated peptide antibody and Human Leukocyte Antigen-B27 (HLA-B27) were negative. Gonococcal and Chlamydia trachomatis urine PCR were also negative. He was diagnosed with ReA. Nonsteroidal Anti-Inflammatory Drug (NSAID)s and intra-articular corticosteroid injection resulted in moderate improvement.
32099965 The effect of glucocorticoid therapy on mortality in patients with rheumatoid arthritis an 2020 BACKGROUND: Patients with rheumatoid arthritis (RA) have increased cardiovascular (CV) and mortality risk. Patients with RA are also frequently prescribed glucocorticoids (GCs) which have been associated with increased risk of mortality. In addition, for patients who have concomitant diabetes mellitus (DM), GCs are known to worsen glycaemic control and hence may further increase CV and mortality risk. This study aimed to understand the relationship between GCs, DM and mortality in patients with RA. METHODS: This was a retrospective cohort study of patients with incident RA identified from UK primary care electronic medical records. Patients with linkage to Office for National Statistics (ONS) for mortality data (N = 9085) were included. DM was identified through Read codes, prescriptions and blood tests, and GC use was identified through prescriptions. Mortality rate ratios (RR) and rate differences (RD) were calculated across the different exposure groups. Cox proportional hazards regression models were used to estimate interaction on the multiplicative and additive scales. RESULTS: In those without DM GC use had a 4.4-fold increased all-cause mortality RR (95% confidence interval (CI): 3.83 to 5.14) compared to non-use, whilst those with DM had a lower RR for GC use (3.02 (95% CI: 2.34, 3.90)). However, those with DM had a higher RD associated with GC use because of their higher baseline risk. In those with DM, GC use was associated with an additional 46.7 deaths/1000 person-years (pyrs) (95% CI: 34.1 to 59.3) compared to non-use, while in those without DM GC use was associated with an additional 36.2 deaths/1000 pyrs (95% CI: 31.6 to 40.8). A similar pattern was seen for CV mortality. The adjusted Cox proportional hazards model showed no evidence of multiplicative interaction, but additive interaction indicated a non-significant increased risk. For CV mortality there was no interaction on either scale. CONCLUSIONS: GC use was associated with higher mortality rates in people with comorbid DM compared to people without DM, despite apparently reassuring similar relative risks. Clinicians need to be aware of the higher baseline risk in patients with DM, and consider this when prescribing GCs in patients with RA and comorbid DM.
32547316 S1P promotes IL-6 expression in osteoblasts through the PI3K, MEK/ERK and NF-κB signaling 2020 Rheumatoid arthritis (RA) is a systemic autoimmune inflammatory disease, in which the immune system attacks joint tissue. Interleukin (IL)-6 is a key proinflammatory cytokine in RA progression. Sphingosine-1-phosphate (S1P), a platelet-derived lysophospholipid mediator, reportedly regulates osteoimmunology. Here, we examined the effects of S1P on IL-6 expression in osteoblasts. Our results and records from the Gene Expression Omnibus (GEO) database demonstrate higher levels of IL-6 in patients with RA compared with those with osteoarthritis. Stimulation of osteoblasts with S1P increased mRNA and protein expression of IL-6. PI3K, MEK, ERK and NF-κB inhibitors and their small interfering RNAs (siRNAs) reduced S1P-promoted IL-6 expression. S1P also facilitated PI3K, MEK/ERK and NF-κB signaling cascades. Our results indicate that S1P promotes the expression of IL-6 in osteoblasts via the PI3K, MEK/ERK and NF-κB signaling pathways.
33290261 Integrated proteome and phosphoproteome analyses of peripheral blood mononuclear cells in 2020 Dec 3 Primary Sjögren syndrome (pSS) is a common autoimmune disease. Here, we performed the first proteome and phosphoproteome analyses of peripheral blood mononuclear cells in pSS patients to obtain a comprehensive profile and identify the potential crucial proteins and pathways for the screening and evaluation of pSS patients. Peripheral blood mononuclear cells from 8 pSS-confirmed patients (American-European Consensus Group Criteria, 2002) and 10 normal controls were selected. Label-free quantitative proteomics was utilized to obtain quantitative information. In total, 787 proteins were identified as differentially expressed proteins, and 175 phosphosites on 123 proteins were identified as differentially phosphorylated proteins. We performed functional enrichment analyses with these proteins and phosphoproteins based on public database. Furthermore, protein-protein interaction network analyses were performed by using multiple algorithms. Using module and hub protein analyses, we identified 16 modules for the proteins, 2 clusters for the phosphoproteins and selected the top 10 hub proteins. Finally, we identified 22 motifs using motif analysis of the phosphosites and found 17 newly identified motifs, while 6 motifs were experimentally verified for known protein kinases. The findings distinguished pSS patients from normal controls at the peripheral blood mononuclear cells level and revealed potential candidates for use in pSS diagnosis.
32892887 A 77-Year-Old Woman With Sjogren Syndrome Experiencing Progressive Dyspnea on Exertion and 2020 Sep A 77-year-old woman was referred to our interstitial lung disease unit. She presented with a history of progressive dyspnea on exertion and nonproductive, persistent cough over the previous year. She was diagnosed with Sjogren syndrome two years ago by a rheumatologist. In the context of Sjogren syndrome, she reported chronic xerostomia and xerophthalmia for the last 5 years. Her history was also notable for the presence of arterial hypertension and hypothyroidism. She denied the presence of shortness of breath, chest pain, arthralgia, muscle weakness, weight loss, night sweats, and fatigue. She reported exposure to house mold. There was no family history of respiratory diseases. The patient never smoked and denied alcohol consumption, illicit drug use, or any occupational exposures.
32332189 Case series of three adult patients with exceptional clinical presentations of haemophagoc 2020 Apr Macrophage activation syndrome (MAS) is a secondary form of haemophagocytic lymphohistiocytosis (HLH). MAS-HLH is an underrecognised and life-threatening condition associated with a heterogeneous group of diseases including connective tissue disease and inflammatory disorders. Here, we report three cases of adult patients with MAS-HLH triggered by different entities, including systemic lupus erythematosus, Griscelli syndrome type 2, and Adult onset Still's disease.
32212831 Functional connectivity and microstructural changes of the brain in primary Sjögren syndr 2020 Dec BACKGROUND: Fatigue and depression are among the most common manifestations of primary Sjögren syndrome (pSS), but information is lacking on the relationship with brain function and microstructural changes. PURPOSE: To investigate microstructural changes and brain connectivity in pSS, and to evaluate their relationship with fatigue and depression. MATERIAL AND METHODS: The study included 29 patients with pSS (mean age 61.2 ± 12.1 years; disease duration 10.5 ± 5.9 years) and 28 controls (mean age 58.4 ± 9.2 years). All the patients completed the Beck's depression and Fatigue Assessment Scale questionnaires. The imaging protocol consisted of: (i) standard magnetic resonance imaging (MRI) pulse sequences (FLAIR, 3D T1W); (ii) a diffusion tensor imaging pulse sequence; and (iii) a resting state functional MRI pulse sequence. Resting state brain networks and maps of diffusion metrics were calculated and compared between patients and controls. RESULTS: Compared with the controls, the patients with pSS and depression showed increased axial, radial, and mean diffusivity and decreased fractional anisotropy; those without depression showed decreased axial diffusivity in major white matter tracts (superior longitudinal fasciculus, inferior longitudinal fasciculus, corticospinal tract, anterior thalamic radiation, inferior fronto-occipital fasciculus, cingulum, uncinate fasciculus, and forceps minor-major). Decreased brain activation in the sensorimotor network was observed in the patients with pSS compared with the controls. No correlation was found between fatigue and structural or functional changes of the brain. CONCLUSION: pSS is associated with functional connectivity abnormalities of the somatosensory cortex and microstructural abnormalities in major white matter tracts, which are more pronounced in depression.
32939030 LAMP3 induces apoptosis and autoantigen release in Sjögren's syndrome patients. 2020 Sep 16 Primary Sjögren's syndrome (pSS) is a complex autoimmune disease characterized by dysfunction of secretory epithelia with only palliative therapy. Patients present with a constellation of symptoms, and the diversity of symptomatic presentation has made it difficult to understand the underlying disease mechanisms. In this study, aggregation of unbiased transcriptome profiling data sets of minor salivary gland biopsies from controls and Sjögren's syndrome patients identified increased expression of lysosome-associated membrane protein 3 (LAMP3/CD208/DC-LAMP) in a subset of Sjögren's syndrome cases. Stratification of patients based on their clinical characteristics suggested an association between increased LAMP3 expression and the presence of serum autoantibodies including anti-Ro/SSA, anti-La/SSB, anti-nuclear antibodies. In vitro studies demonstrated that LAMP3 expression induces epithelial cell dysfunction leading to apoptosis. Interestingly, LAMP3 expression resulted in the accumulation and release of intracellular TRIM21 (one component of SSA), La (SSB), and α-fodrin protein, common autoantigens in Sjögren's syndrome, via extracellular vesicles in an apoptosis-independent mechanism. This study defines a clear role for LAMP3 in the initiation of apoptosis and an independent pathway for the extracellular release of known autoantigens leading to the formation of autoantibodies associated with this disease.ClinicalTrials.gov Identifier: NCT00001196, NCT00001390, NCT02327884.