Browse

Search for: rheumatoid arthritis    methotrexate    autoimmune disease    biomarker    gene expression    GWAS    HLA genes    non-HLA genes   

ID PMID Title PublicationDate abstract
30746589 Production of functional recombinant cyclic citrullinated peptide monoclonal antibody in t 2019 Apr Cyclic citrullinated peptide (CCP) antibody has been shown recently to be a promising marker for early detection and diagnosis of rheumatoid arthritis (RA). In order to exploit newly developed therapies for RA, early intervention is crucial in preventing irreversible joint damage. Here, we describe use of a plant expression system to produce a CCP antibody that could be used in the early diagnosis of RA. Heavy and light chain gene sequences of a CCP monoclonal antibody (CCP mAb) were cloned from the hybridoma cell (12G1) and introduced into two separate plant expression vectors under the control of the rice α-amylase 3D (RAmy3D) promoter system. The vectors were introduced into rice calli (Oryza sativa L. cv. Dongjin) using Agrobacterium tumefaciens mediated transformation. Integration of the CCP mAb genes into rice chromosomes was confirmed by a genomic DNA polymerase chain reaction and expression was verified by northern blot analysis of mRNA. The in vivo assembly and secretion of CCP mAb occurred in transgenic rice cell suspension culture under the RAmy3D expression system; accumulated CCP mAbs in the medium were purified by protein G affinity chromatography. Immunoblot assays and ELISA showed these plant-produced CCP mAbs successfully bound to a synthetic CCP antigen. Taken together, our results suggest that CCP mAb produced in a transgenic rice suspension culture were easily purified and biologically active against their antigen in the RA, and thus may be used a specific serological marker, which is present very early in the RA.
30690119 Possible involvement of the μ opioid receptor in the antinociception induced by sinomenin 2019 Apr 23 Sinomenine, an alkaloid originally isolated from the roots and the rhizome of Sinomenium acutum is used as a traditional Chinese herbal medicines for rheumatoid arthritis and neuralgia. The aims of this study were to investigate the effects of oral administration of shinomenine on formalin-induced nociceptive behavior in mice and the opioid receptor subtypes involved in the antinociceptive effects of sinomenine. Our findings showed that a single dose of oral-administrated sinomenine inhibited the formalin induced licking and biting responses in a dose-dependent manner. Intraperitoneal pretreatment with naloxone hydrochloride, an opioid receptor antagonist, and β-funaltrexamine hydrochloride (β-FNA), a selective μ-opioid receptor antagonist, significantly attenuated sinomenine induced antinociception, but not by naltrindole, a nonselective δ-opioid receptor antagonist and nor-binaltorphimine, a selective κ-opioid receptor antagonist. Furthermore, in western blot analysis, oral administration of sinomenine resulted in a significant blockage of spinal extracellular signal-regulated protein kinase (ERK1/2) activation induced by formalin. Naloxone hydrochloride and β-FNA significantly reversed the blockage of spinal ERK1/2 activation induced by sinomenine. These results suggest that sinomenine-induced anti nociceptive effect and blockage of spinal ERK1/2 activation may be triggered by activation of μ-opioid receptors.
32476695 Candida auris infection in the central catheter of a patient without sepsis symptoms. 2019 Dec 30 BACKGROUND: Candida auris is an emerging yeast frequently reported as resistant to multiple antifungal drugs commonly used to treat Candida infections. This specie can colonize the patient's skin and has great ability for producing outbreaks in hospitals. C. auris is phylogenetically related to other Candida species, can be misidentified using conventional biochemical or commercial methods and requires specific technology for its identification. CASE REPORT: We report the first isolate of C. auris in Cali, Colombia, from a central venous catheter in a 37-year-old patient with rheumatoid arthritis and endocarditis who did not have symptoms of sepsis. The yeast was initially misidentified as C. haemulonii using the Phoenix system and subsequently identified as C. auris by matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry (MALDI-TOF MS). The broth microdilution method was used to determine the minimum inhibitory concentration; the isolate was susceptible to fluconazole, itraconazole, voriconazole and amphotericin B. CONCLUSIONS: This report contributes to knowledge of the epidemiology of C. auris infections in individuals with underlying disease and describes an isolate with a behavior different from what is usually reported.
31810226 The Innate Immune Cell Profile of the Cornea Predicts the Onset of Ocular Surface Inflamma 2019 Dec 2 Ocular surface inflammatory disorder (OSID) is a spectrum of disorders that have features of several etiologies whilst displaying similar phenotypic signs of ocular inflammation. They are complicated disorders with underlying mechanisms related to several autoimmune disorders, such as rheumatoid arthritis (RA), Sjögren's syndrome, and systemic lupus erythematosus (SLE). Current literature shows the involvement of both innate and adaptive arms of the immune system in ocular surface inflammation. The ocular surface contains distinct components of the immune system in the conjunctiva and the cornea. The normal conjunctiva epithelium and sub-epithelial stroma contains resident immune cells, such as T cells, B cells (adaptive), dendritic cells, and macrophages (innate). The relative sterile environment of the cornea is achieved by the tolerogenic properties of dendritic cells in the conjunctiva, the presence of regulatory lymphocytes, and the existence of soluble immunosuppressive factors, such as the transforming growth factor (TGF)-β and macrophage migration inhibitory factors. With the presence of both innate and adaptive immune system components, it is intriguing to investigate the most important leukocyte population in the ocular surface, which is involved in immune surveillance. Our meta-analysis investigates into this with a focus on both infectious (contact lens wear, corneal graft rejection, Cytomegalovirus, keratitis, scleritis, ocular surgery) and non-infectious (dry eye disease, glaucoma, graft-vs-host disease, Sjögren's syndrome) situations. We have found the predominance of dendritic cells in ocular surface diseases, along with the Th-related cytokines. Our goal is to improve the knowledge of immune cells in OSID and to open new dimensions in the field. The purpose of this study is not to limit ourselves in the ocular system, but to investigate the importance of dendritic cells in the disorders of other mucosal organs (e.g., lungs, gut, uterus). Holistically, we want to investigate if this is a common trend in the initiation of any disease related to the mucosal organs and find a unified therapeutic approach. In addition, we want to show the power of computational approaches to foster a collaboration between computational and biological science.
31780370 Butyrate alleviates inflammatory response and NF-κB activation in human degenerated inter 2020 Jan Butyrate has multiple protective effects in inflammation-related intestinal diseases. Previous studies have found that butyrate could inhibit inflammation in rheumatoid arthritis. Inflammation is a pivotal inducement in the degeneration progress of the intervertebral disc. The anti-inflammatory treatment has an apparent curative effect in the symptomatic treatment of spine-related disease. Herein we investigated whether butyrate plays a protective role in degenerated intervertebral disc model. To mimic the lumbar disc local inflammatory environment, human primary nucleus pulposus cells were cultured with interleukin-1β (IL-1β, 10 ng/ml) to build a nucleus pulposus cell inflammation model. Butyrate was added to the cell culture medium to test the effect of butyrate on disc inflammation. Furthermore, a cultured nucleus pulposus tissue model was treated with butyrate (1 mM) to simulate the local treatment of intervertebral disc disease. Herein, we found that butyrate could downregulate the production of the inflammatory mediator caused by IL-1β stimulation in the cell culture model. Additionally, butyrate inhibits the secretion of pro-inflammatory cytokines or graded enzymes in disc tissues from lumbar disc herniation patients. Furthermore, the anti-inflammatory function of butyrate in lumbar disc degenerated model may be caused by inhibiting the activation of the nuclear factor kappa B (NF-κB) signal pathway. This study presents butyrate as a candidate therapeutic method to treat lumbar disc degenerative disease.
31762221 Identifying damage clusters in patients with systemic lupus erythematosus. 2020 Jan AIM: Systemic lupus erythematosus (SLE) causes irreversible damage to organ systems. Recently, evidence has been obtained for subphenotypes of SLE. This study aimed to identify damage clusters and compare the associated clinical manifestations, SLE disease activity, mortality, and genetic risk scores (GRS). METHODS: The study was conducted on the Hanyang BAE lupus cohort. Patients with disease duration <5 years were excluded to minimize confounding effects of disease duration. They were grouped into 3 clusters based on the Systemic Lupus International Collaborating Clinics Damage Index using k-means cluster analysis. RESULTS: Among the 1130 analyzed patients, musculoskeletal damage was most prevalent (20.2%), followed by ocular (11.4%), renal (10.5%), and neuropsychiatric damage (10.2%). Three significantly different damage clusters were identified. Patients in cluster 1 (n = 824) showed the least damage. Cluster 2 (n = 195) was characterized by frequent renal (55.4%) and ocular (58.0%) damage, and cluster 3 (n = 111) was dominated by neuropsychiatric (100%) and musculoskeletal damage (35.1%). Cluster 2 had the highest adjusted mean AMS (adjusted mean SLE Disease Activity Index score; mean ± SD: 5.4 ± 2.9), while cluster 3 had the highest mortality (14.4%). Weighted GRS did not differ significantly between the clusters. CONCLUSION: Patients in prevalent renal and ocular damage cluster had the highest AMS scores, while the cluster with frequent neuropsychiatric damage had the highest mortality.
31730889 Physicochemical characterization of Suvarna Bhasma, its toxicity profiling in rat and beha 2020 Mar 1 ETHNOPHARMACOLOGICAL RELEVANCE: Suvarna Bhasma is a gold-based Ayurved medicine that has a wide range of therapeutic indications like tuberculosis, diabetes mellitus, rheumatoid arthritis and nervous diseases. Suvarna Bhasma is also used in Suvarnaprashana, an Ayurved advocated therapy being practised to improve immunity in children. AIM OF THE STUDY: To augment traditional understanding, here we present an evidence-based study on Suvarna Bhasma regarding its physicochemical properties, toxicity and efficacy. MATERIALS AND METHODS: Suvarna Bhasma was characterised by physicochemical characterization techniques such as scanning electron microscope (SEM), transmission electron microscopy (TEM), X-ray diffraction (XRD) and atomic emission spectroscopy (ICP-AES). Toxicity of Suvarna Bhasma was studied in Holtzman rats with daily oral dose from 3 mg/kg (therapeutic dose, TD) up to 30 mg/kg (10 TD) body weight for 90 days. Behavioural study, such as motor and geotactic behaviour were examined in zebrafish model to find out any sign of neurotoxicity or behavioural changes due to Suvarna Bhasma administration. RESULTS: Suvarna Bhasma has two types of gold particles, large ones (~60 μm) having irregular shapes, and nano-sized spherical particles (starting from ~10 nm), the latter coated with Fe, Si, O, P and Na. XRD study revealed that all the peaks of Suvarna Bhasma match well with pure gold (face centred cube) with crystallites size 45 ± 2.8 nm. In rat studies, some change in biochemical parameters such as urea, creatinine and alanine aminotransferase (ALT) was observed mainly at the higher therapeutic dose; however, those parameters were within the normal range. There were no significant macroscopic as well as microscopic treatment-related alteration observed, in any of the organs and tissues evaluated. In zebrafish behavioural study, the motor parameters of Suvarna Bhasma treated fish showed normal behaviour analogous to the vehicle control group. Interestingly, the geotactic behaviour showed anxiolytic effects of Suvarna Bhasma as evidenced by the time spent in the upper zone, and average swimming height. The anxiolytic effects persisted for more than 30 days after withdrawing the Suvarna Bhasma treatment. CONCLUSIONS: Suvarna Bhasma contained spherical gold nanoparticles. It was nontoxic in rat model at the does tested. Suvarna Bhasma has anxiolytic effects in zebrafish behavioural model.
31690793 Synthesis of new isoquinoline-base-oxadiazole derivatives as potent inhibitors of thymidin 2019 Nov 5 Here in this study regarding the over expression of TP, which causes some physical, mental and socio problems like psoriasis, chronic inflammatory disease, tumor angiogenesis and rheumatoid arthritis etc. By this consideration, the inhibition of this enzyme is vital to secure life from serious threats. In connection with this, we have synthesized twenty derivatives of isoquinoline bearing oxadiazole (1-20), characterized through different spectroscopic techniques such as HREI-MS, (1)H- NMR and (13)C-NMR and evaluated for thymidine phosphorylase inhibition. All analogues showed outstanding inhibitory potential ranging in between 1.10 ± 0.05 to 54.60 ± 1.50 µM. 7-Deazaxanthine (IC(50) = 38.68 ± 1.12 µM) was used as a positive control. Through limited structure activity relationships study, it has been observed that the difference in inhibitory activities of screened analogs are mainly affected by different substitutions on phenyl ring. The effective binding interactions of the most active analogs were confirmed through docking study.
31654328 Development of In Vitro-In Vivo Correlation for Upadacitinib Extended-Release Tablet Formu 2019 Oct 25 Upadacitinib is a selective Janus Kinase 1 inhibitor which is being developed for the treatment of several inflammatory diseases including rheumatoid arthritis. Upadacitinib was evaluated in Phase 3 studies as an oral extended-release (ER) formulation administered once daily. The purpose of this study was to develop a level A in vitro-in vivo correlation (IVIVC) for upadacitinib ER formulation. The pharmacokinetics of four upadacitinib extended-release formulations with different in vitro release characteristics and an immediate-release capsule formulation of upadacitinib were evaluated in 20 healthy subjects in a single-dose, randomized, crossover study. In vivo pharmacokinetic data and in vitro dissolution data (USP Dissolution Apparatus 1; pH 6.8; 100 rpm) were used to establish a level A IVIVC. Three formulations were used to establish the IVIVC, and the fourth formulation was used for external validation. A non-linear IVIVC best described the relationship between upadacitinib in vitro dissolution and in vivo absorption profiles. The absolute percent prediction errors (%PE) for upadacitinib C(max) and AUC were less than 10% for all three formulations used to establish the IVIVC, as well as for the %PE for the external validation formulation and the overall mean internal validation. Model was cross-validated using the leave-one-out approach; all evaluated cross-validation runs met the regulatory acceptance criteria. A level A IVIVC was successfully developed and validated for upadacitinib ER formulation, which meets the FDA and EMA regulatory validation criteria and can be used as surrogate for in vivo bioequivalence.
31539553 The protective effects of the GPR39 agonist TC-G 1008 against TNF-α-induced inflammation 2019 Dec 15 Rheumatoid arthritis (RA) is a common immune-mediated chronic inflammatory joint disease of unknown etiology. While tumor necrosis factor-α(TNF-α) blockers have proven to be a beneficial treatment option for many patients, not all respond to such treatments. In the present study, we investigate the role of the recently discovered zinc-sensing G protein-couple receptor GPR39. To our knowledge, this study is the first to investigate the role of GPR39 in the context of RA using human fibroblast-like synoviocytes (FLS). We found that agonism of GPR39 using its specific agonist TC-G 1008 significantly ameliorated important markers of RA, including oxidative stress, mitochondrial dysfunction, expression of proinflammatory cytokines including interleukin-1β (IL-1β), IL-6, and monocyte chemoattractant protein 1 (MCP-1), and secretion of key matrix metalloproteinases (MMPs) including MMP-1, MMP-3 and MMP-13. Furthermore, we demonstrate that these may be mediated via the Janus-kinase (JNK), activating protein 1 (AP-1), and nuclear factor-κB (NF-κB) cellular signaling pathways. Our findings demonstrate for the first time the potential of GPR39 to mediate synovial inflammation, pannus invasion, and enzymatic degradation of articular extracellular matrix.
31520790 The GTF2I rs117026326 polymorphism is associated with neuromyelitis optica spectrum disord 2019 Dec 15 Multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) are common demyelinating disorders of the central nervous system. The etiology and pathogenesis of MS and NMOSD remain unclear. The pathogenesis of these two diseases involves a genetic predisposition as well as environmental factors. NMOSD sometimes co-exists with Sjögren's syndrome, systemic lupus erythematosus (SLE), and rheumatoid arthritis (RA), and these diseases are frequently associated with central nervous system disorder involvement, as manifest in MS- and NMOSD-like clinical features. Genetic variant rs117026326 upstream of the general transcription factor II-I (GTF2I) has been associated with primary Sjögren's syndrome, SLE and RA in East Asian populations. In this study, we genotyped single nucleotide rs117026326 polymorphisms of the GTF2I gene in 168 patients with MS, 144 patients with NMOSD, and 1403 healthy controls. We observed a significant genetic association between the variant rs117026326 and NMOSD (P = 1.09 × 10(-11), OR = 2.535), however, the association with MS was not significant (P = .4289, OR = 1.129). Gene expression analyses showed that there was no significant association between the messenger RNA expression of GTF2I and genotypes at the variant. We conclude that the risk T allele of rs117026326 increases the risk of NMOSD, suggesting that NMOSD and MS may have different genetic risk factors.
31443821 Physical health burden of PTSD, depression, and their comorbidity in the U.S. veteran popu 2019 Sep OBJECTIVE: Although it is well-established that posttraumatic stress disorder (PTSD) and major depressive disorder (MDD) are associated with physical health difficulties among U.S. veterans, the incremental burden of having both disorders relative to either one alone remains largely unknown. The goal of this study was to provide the first population-based characterization of the burden of medical illness associated with PTSD, MDD, and their comorbidity among U.S. veterans. METHODS: Data were from National Health and Resilience in Veterans Study, a nationally representative survey of U.S. veterans (n = 2732). Analyses (a) examined the magnitude of medical comorbidity and disability associated with PTSD, MDD, and co-occurring PTSD/MDD; and (b) compared physical functioning by PTSD/MDD status. RESULTS: After adjusting for sociodemographic characteristics and substance use disorders, veterans with comorbid PTSD/MDD were more likely to be diagnosed with heart disease, migraine, fibromyalgia, and rheumatoid arthritis compared to those with MDD-only. Conversely, they were at greater odds of being diagnosed with hypercholesterolemia and hypertension relative to those with PTSD-only. Comorbid PTSD/MDD status was associated with approximately three times greater odds of disability compared to MDD alone. Veterans with co-occurring PTSD/MDD and PTSD-only exhibited worse physical functioning than those with MDD-only. CONCLUSION: Findings indicate that veterans with co-occurring PTSD/MDD represent a high-risk group for cardiovascular disease and other health problems, and therefore deserve careful attention from healthcare systems. Further research is needed to investigate mechanisms underlying associations between PTSD/MDD and physical health morbidities, as well as whether treatment of PTSD/MDD can reduce risk for comorbid medical conditions.
31430946 Viruses and Autoimmunity: A Review on the Potential Interaction and Molecular Mechanisms. 2019 Aug 19 For a long time, viruses have been shown to modify the clinical picture of several autoimmune diseases, including type 1 diabetes (T1D), systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), Sjögren's syndrome (SS), herpetic stromal keratitis (HSK), celiac disease (CD), and multiple sclerosis (MS). Best examples of viral infections that have been proposed to modulate the induction and development of autoimmune diseases are the infections with enteric viruses such as Coxsackie B virus (CVB) and rotavirus, as well as influenza A viruses (IAV), and herpesviruses. Other viruses that have been studied in this context include, measles, mumps, and rubella. Epidemiological studies in humans and experimental studies in animal have shown that viral infections can induce or protect from autoimmunopathologies depending on several factors including genetic background, host-elicited immune responses, type of virus strain, viral load, and the onset time of infection. Still, data delineating the clear mechanistic interaction between the virus and the immune system to induce autoreactivity are scarce. Available data indicate that viral-induced autoimmunity can be activated through multiple mechanisms including molecular mimicry, epitope spreading, bystander activation, and immortalization of infected B cells. Contrarily, the protective effects can be achieved via regulatory immune responses which lead to the suppression of autoimmune phenomena. Therefore, a better understanding of the immune-related molecular processes in virus-induced autoimmunity is warranted. Here we provide an overview of the current understanding of viral-induced autoimmunity and the mechanisms that are associated with this phenomenon.
31359117 Stress, sex hormones, inflammation, and major depressive disorder: Extending Social Signal 2019 Oct Social Signal Transduction Theory of Depression is a biologically plausible, multi-level theory that describes neural, physiologic, molecular, and genomic mechanisms that link experiences of social-environmental adversity with internal biological processes that drive depression pathogenesis, maintenance, and recurrence. Central to this theory is the hypothesis that interpersonal stressors involving social threat (e.g., social conflict, evaluation, rejection, isolation, and exclusion) upregulate inflammatory processes that can induce several depressive symptoms, including sad mood, anhedonia, fatigue, psychomotor retardation, and social-behavioral withdrawal. The original article describing this formulation (Psychol Bull 140:774-815, 2014) addressed critical questions involving depression onset and recurrence, as well as why depression is strongly predicted by early life stress and comorbid with anxiety disorders and certain physical disease conditions, such as asthma, rheumatoid arthritis, chronic pain, and cardiovascular disease. Here, we extend the theory to help explain sex differences in depression prevalence, which is a defining feature of this disorder. Central to this extension is research demonstrating that ovarian hormone fluctuations modulate women's susceptibility to stress, brain structure and function, and inflammatory activity and reactivity. These effects are evident at multiple levels and are highly context-dependent, varying as a function of several factors including sex, age, reproductive state, endogenous versus exogenous hormones, and hormone administration mode and dose. Together, these effects help explain why women are at greater risk for developing inflammation-related depressed mood and other neuropsychiatric, neurodevelopmental, and neurodegenerative disorders during the reproductive years, especially for those already at heightened risk for depression or in the midst of a hormonal transition period.
31349745 One-Step ARMS-PCR for the Detection of SNPs-Using the Example of the PADI4 Gene. 2019 Jul 25 In eukaryotes, cellular functions are tightly controlled by diverse post-translational modifications (PTMs) of proteins. One such PTM affecting many proteins is the deimination of arginine to citrulline. This process, called citrullination is catalyzed by a group of hydrolases called protein arginine deiminases (PADs), of which five isoforms have been identified. Hypercitrullination, as a result of increased PAD expression or activity, is associated with autoimmune diseases e.g., rheumatoid arthritis, lupus, Alzheimer's disease, ulcerative colitis, multiple sclerosis, and certain cancers. Three common single nucleotide polymorphisms (SNPs) in the PADI4 gene have been described, namely rs874881, rs11203366, and rs11203367, which are thought to affect PAD4 expression and activity. We here compared the suitability of four methods for the screening of SNPs in the PADI4 gene: (i) SYBR-green based real-time polymerase chain reaction followed by high resolution melting curve analysis (HRM-PCR); (ii) PCR followed by detection of restriction fragment length polymorphisms (PCR-RFLP); (iii) conventional tetra-primer amplification refractory mutation system PCR (ARMS-PCR); and (iv) real-time PCR based on the one-step ARMS-PCR. Of these, ARMS-PCR proved to be the most suitable method regarding handling, duration, and cost of experiments. Using the method with SYBR-green based real-time PCR reagents further diminished handling steps and thus potential sources of error.
31263994 Study of familial aggregation of autoimmune rheumatic diseases in Asian Indian patients wi 2019 Dec Systemic lupus erythematosus (SLE) and other autoimmune rheumatic diseases (AIRD) tend to co-aggregate in families, making positive familial history a risk factor. We aimed to estimate familial aggregation of AIRD in SLE patients and to compare between ones having a positive and negative family history of autoimmunity in our cohort. We included families of 157 consecutive SLE patients in a hospital-based, cross-sectional design for a three-generation pedigree study. Clinical and laboratory parameters of these patients were recorded. AIRD was seen in families of 39 SLE patients amounting to a familial prevalence of 24.8% [95% confidence interval (CI) 18.1, 31.6] with a relative risk (λ) of 4.3 for first-degree relatives (FDRs) and 1.1 for second-degree relatives (SDRs). SLE was the commonest AIRD seen in families of 19 patients with a familial prevalence of 12.1% (95% CI 7.0, 17.2) and λ of 78.2 for FDRs and 18.1 for SDRs. AIRD as a whole and SLE alone were seen more commonly with parental consanguinity (p < 0.05). Familial aggregation in SLE patients also showed a relatively higher percentage of affected males and lesser presentation with constitutional features (p < 0.05) than sporadic SLE patients. Rheumatoid arthritis (RA) was the second most common AIRD seen in 16/39 (41%) families with a RR of 3.1 in FDRs of SLE patients. In conclusion, Asian Indian SLE patients seem to have a high familial aggregation of AIRD, which is more pronounced in the background of parental consanguinity. SLE is the commonest AIRD seen amongst FDRs and SDRs of SLE patients, followed by RA, with FDRs being at highest risk.
30920455 Pathogenesis and treatment of autoimmune rheumatic diseases. 2019 May PURPOSE OF REVIEW: Autoimmune diseases are of unknown origin, and they represent significant causes of morbidity and mortality. Here, we review new developments in the understanding of their pathogenesis that have led to development of well tolerated and effective treatments. RECENT FINDINGS: In addition to the long-recognized genetic impact of the HLA locus, interferon regulatory factors, PTPN22, STAT4, and NOX have been implicated in pathogenesis of systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). Smoking, ultraviolet light, diet, and microbiota exert strong environmental influence on development of RA and SLE. Metabolism has been recognized as a critical integrator of genetic and environmental factors, and it controls immune cell differentiation both under physiological and pathological conditions. SUMMARY: With the advent of high-throughput genetic, proteomic, and metabolomic technologies, the field of medicine has been shifting towards systems-based and personalized approaches to diagnose and treat common conditions, including rheumatic diseases. Regulatory checkpoints of metabolism and signal transduction, such as glucose utilization, mitochondrial electron transport, JAK, mTOR, and AMPK pathway activation, and production of pro-inflammatory cytokines IL-1, IL-6, and IL-17 have presented new targets for therapeutic intervention. This review amalgamates recent discoveries in genetics and metabolomics with immunological pathways of pathogenesis in rheumatic diseases.
30847768 Prevention of Infection in the Perioperative Setting in Patients with Rheumatic Disease Tr 2019 Mar 8 PURPOSE OF REVIEW: Patients with autoimmune rheumatic disease are at increased risk of infection after surgery. The goal of this manuscript is to review current evidence on important contributors to infection risk in these patients and the optimal management of immunosuppression in the perioperative setting. RECENT FINDINGS: Recent studies have confirmed that patients with autoimmune rheumatic disease, including rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), are at increased risk of infection after surgery, with most evidence coming from studies of joint replacement surgery. Immunosuppression, disease activity, comorbidities, demographics, and surgeon and hospital volume are all important contributors to post-operative infection risk. Recently published guidelines regarding immunosuppression management before joint replacement recommend continuing the conventional disease-modifying drugs used to treat RA (e.g., methotrexate) without interruption, holding more potent conventional therapies for 1 week unless the underlying disease is severe, and holding biologic therapies for one dosing interval before surgery. Recent observational data suggests that holding biologics may not have a substantial impact on infection risk. These data also implicate glucocorticoids as a major contributor to post-operative infection risk. Observational data supports recent recommendations to continue many therapies in the perioperative period with only short interruptions of biologics and other potent immunosuppression. Even brief interruptions may not significantly lower risk, although the field continues to evolve. Clinicians should also consider other risk factors and should focus on minimizing glucocorticoids before surgery when possible to limit the risk of post-operative infection.
30789148 Novel biomarkers containing citrullinated peptides for diagnosis of systemic lupus erythem 2019 Nov OBJECTIVES: Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterised by autoantibody production. This study aims to identify biomarkers involving citrullinated peptides that can be used for SLE diagnosis. METHODS: After a negative selection step with serum from healthy controls (HCs), a phage library of 12 peptides was used for three rounds of screening with sera from 30 SLE patients. After four rounds of biopanning, 21 positive peptides were sequenced. We produced 37-feature arrays containing 16 recombinant citrullinated peptides. The microarrays were tested with an independent validation set of serum samples from 50 HCs, 60 SLE patients, and 60 rheumatoid arthritis (RA) patients. RESULTS: Microarray analysis showed that the positive rates of 13S1212Cit3-IgM (60.0%), 13S1210-IgG (43.33%), and 13S1212Cit3-IgG (41.67%) were increased in SLE patients compared with HCs and RA patients. The area under the receiver operating characteristic curve (AUC) was 0.770, 0.687 and 0.698, respectively. The combination of 13S1212Cit3-IgM and 13S1210-IgG (termed COPSLE, for combination of peptides for SLE) was more efficient for SLE diagnosis, with a larger AUC (0.830) and a positive rate of 73.33%. COPSLE could be used to identify 80.0% of SLE patients who were negative for anti-Smith (Sm), anti-double-stranded DNA (ds-DNA), and anticardiolipin (ACA). The Spearman rank correlation indicated that COPSLE increased with albumin, serum level of C3 and platelet distribution width, but had negative correlations with decreased C3 and discoid lupus. CONCLUSIONS: A citrullinated/non-citrullinated peptide panel is a valuable diagnostic marker of SLE, even for patients who are negative for anti-Sm, anti-ds-DNA and ACA.
30687329 Ethyl Pyruvate Stimulates Regulatory T Cells and Ameliorates Type 1 Diabetes Development i 2018 Type 1 diabetes (T1D) is an autoimmune disease in which a strong inflammatory response causes the death of insulin-producing pancreatic β-cells, while inefficient regulatory mechanisms allow that response to become chronic. Ethyl pyruvate (EP), a stable pyruvate derivate and certified inhibitor of an alarmin-high mobility group box 1 (HMGB1), exerts anti-oxidant and anti-inflammatory properties in animal models of rheumatoid arthritis and encephalomyelitis. To test its therapeutic potential in T1D, EP was administered intraperitoneally to C57BL/6 mice with multiple low-dose streptozotocin (MLDS)-induced T1D. EP treatment decreased T1D incidence, reduced the infiltration of cells into the pancreatic islets and preserved β-cell function. Apart from reducing HMGB1 expression, EP treatment successfully interfered with the inflammatory response within the local pancreatic lymph nodes and in the pancreas. Its effect was restricted to boosting the regulatory arm of the immune response through up-regulation of tolerogenic dendritic cells (CD11c(+)CD11b(-)CD103(+)) within the pancreatic infiltrates and through the enhancement of regulatory T cell (Treg) levels (CD4(+)CD25(high)FoxP3(+)). These EP-stimulated Treg displayed enhanced suppressive capacity reflected in increased levels of CTLA-4, secreted TGF-β, and IL-10 and in the more efficient inhibition of effector T cell proliferation compared to Treg from diabetic animals. Higher levels of Treg were a result of increased differentiation and proliferation (Ki67(+) cells), but also of the heightened potency for migration due to increased expression of adhesion molecules (CD11a and CD62L) and CXCR3 chemokine receptor. Treg isolated from EP-treated mice had the activated phenotype and T-bet expression more frequently, suggesting that they readily suppressed IFN-γ-producing cells. The effect of EP on Treg was also reproduced in vitro. Overall, our results show that EP treatment reduced T1D incidence in C57BL/6 mice predominantly by enhancing Treg differentiation, proliferation, their suppressive capacity, and recruitment into the pancreas.