Browse

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

ID PMID Title PublicationDate abstract
34928418 [Radiosynoviorthesis of the thumb's carpometacarpal joint]. 2022 Jan Radiosynoviorthesis (RSO) is an established therapeutic method for the local treatment of pain in aseptic joint inflammation (e.g. arthritis, activated osteoarthritis, synovitis). RSO can be used for the treatment of synovial membrane inflammation of the finger joints such as the thumb's carpometacarpal joint. The beta emitter Erbium-169 (Er-169) is injected into the joint space, which irradiates the inflamed synovialis, thereby leading to fibrosis and obliteration of the pain receptors of the synovial membrane. The chances of success in the treatment of the thumb's carpometacarpal joint by RSO are estimated to be 54-100% within 2-6 weeks after therapy.
35013365 Clinical significance of quantitative bone SPECT/CT in the evaluation of hand and wrist pa 2022 Jan 10 We investigated the diagnostic value of the maximum standardized uptake value (SUV) at hand and wrist joints for differentiating rheumatic diseases via bone single-photon emission computed tomography (SPECT)/computed tomography (CT). A total of 84 patients manifesting hand and wrist pain (58 women; age, 49.8 ± 15.4 years) were finally diagnosed with rheumatoid arthritis (RA, n = 42), osteoarthritis (OA, n = 16), fibromyalgia (FM, n = 2), and other rheumatic diseases (n = 24). The SUV of each patient was measured in 32 joints including the distal interphalangeal (DIP), proximal interphalangeal (PIP), metacarpophalangeal (MCP), and wrist joints bilaterally. Differences in pain and SUVs between specific rheumatic diseases were assessed using the chi-squared test or one-way analysis of variance. Using the highest SUV (hSUV) in each patient, the diagnostic performance in differentiating specific diseases was evaluated by receiver operating characteristic (ROC) curve analysis. Pain symptoms were present in 886 (33.0%) sites in a total of 2688 joints. In four joint groups (DIP, PIP, MCP, and wrist), the SUVs of joints with pain were significantly higher than those of pain-free joints (all P < 0.001). Active joint sites with higher SUVs than the median value of each joint group were the most common in RA (55.1%). RA showed the greatest hSUV in the PIP (3.0 ± 2.4), MCP (3.5 ± 3.4), and wrist (3.3 ± 1.9) joint groups. FM was characterized by the lowest hSUV of all joint groups. In ROC curve analysis, the cumulative hSUV of the PIP, MCP, and wrist joint groups showed good performance for evaluating RA (area under the curve (AUC), 0.668; P = 0.005). The summation of the hSUVs at all joint groups had an excellent predictive performance for FM (AUC, 0.878; P < 0.001). Consequently, the arthritic activity of the hand and wrist joints based on SUV differed according to specific rheumatic diseases. Quantitative SPECT/CT may provide objective information related to arthritic activity for differentiating specific rheumatic diseases.
35263664 Interplay of redox imbalance with matrix gelatinases in neutrophils and their association 2022 Apr Rheumatoid arthritis (RA) etiopathogenesis still remains complex, but involvement of several immune cells is evident. Present study focusses on evaluation of polymorphonuclear neutrophils (PMNs) in RA patients and healthy controls. From generation of oxidative species, release of inflammatory cytokines and matrix-degrading proteases, PMNs possess the ability to mediate immunological responses. Intracellular and mitochondrial ROS in PMNs and other oxidative parameters including catalase, superoxide dismutase, glutathione peroxidase, reduced glutathione and lipid peroxidation were measured in PMNs and serum samples. Gene regulation studies involved in oxidative (Keap1 and Nrf2) and degradative pathways (MMP2 and MMP9) were done using DNA methylation analysis. Intracellular expression levels of Keap1, Nrf2, Dnmt1, MMP2, and MMP9 were analyzed using flowcytometry in patients and controls. Moreover, serum levels of pro-inflammatory cytokines IL-1β, IL-6, and TNF-α were also measured. Comparative measurements amongst patients and controls were statistically analyzed, and correlations were made with disease severity scores (DAS28 ESR).
34334362 Persistence to Biologic Therapy Among Patients With Ankylosing Spondylitis: An Observation 2022 Feb OBJECTIVE: To describe the treatment response and persistence to biologic disease-modifying antirheumatic drug (bDMARD) therapy in patients with ankylosing spondylitis (AS) in a real-world Australian cohort. METHODS: This was a retrospective, noninterventional cohort study that extracted data for patients with AS from the Optimising Patient outcomes in Australian RheumatoLogy (OPAL) dataset for the period of August 2006 to September 2019. Patients were classified as either bDMARD initiators if they commenced a bDMARD during the sampling window, or bDMARD-naïve if they did not. Results were summarized descriptively. Treatment persistence was calculated using Kaplan-Meier methods. Differences in treatment persistence were explored using log-rank tests. RESULTS: There were 5048 patients with AS identified. Of these, 2597 patients initiated bDMARDs and 2451 remained bDMARD-naïve throughout the study window. Treatment with first-, second-, and third-line bDMARDs significantly reduced disease activity. Median persistence on first-line bDMARDs was 96 months (95% CI 85-109), declining to 19 months (95% CI 16-22) in second-line therapy, and 15 months (95% CI 11-18) in third-line therapy. Median persistence was longest for the golimumab (GOL) group in all lines of therapy and shortest for the etanercept (ETN) group. Differences in persistence rates according to the time period that bDMARDs were prescribed (pre- and post-2012) were also seen for ETN and adalimumab. CONCLUSION: In this cohort, all bDMARDs effectively reduced AS disease activity. Treatment persistence was sustained for up to 8 years for patients remaining on their first bDMARD, longer than on subsequent agents. Further research is needed to determine its influence on treatment recommendations.
35426923 Association of Maternal Autoimmune Diseases With Risk of Mental Disorders in Offspring in 2022 Apr 1 IMPORTANCE: Maternal immune activation during pregnancy is associated with increased risks of several mental disorders in offspring during childhood, but little is known about how maternal autoimmune diseases during pregnancy are associated with mental health in offspring during and after childhood. OBJECTIVE: To investigate the association between maternal autoimmune diseases before childbirth and risk of mental disorders among offspring up to early adulthood. DESIGN, SETTING, AND PARTICIPANTS: This population-based nationwide cohort study used data from Danish national registers on singletons born in Denmark from 1978 to 2015 with up to 38 years of follow-up. Data analyses were conducted from March 1, 2020, through September 30, 2021. EXPOSURES: Maternal autoimmune disease diagnosed before or during pregnancy according to the Danish National Patient Register. MAIN OUTCOMES AND MEASURES: The main outcome was mental disorders, defined by hospital diagnoses, in offspring. Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% CIs for mental disorders. RESULTS: Of the 2 254 234 singleton infants included in the study (median age, 16.7 years [IQR, 10.5-21.7 years]; 51.28% male), 2.26% were born to mothers with autoimmune diseases before childbirth. Exposed participants had an increased risk of overall mental disorders compared with their unexposed counterparts (HR, 1.16; 95% CI, 1.13-1.19; incidence, 9.38 vs 7.91 per 1000 person-years). Increased risks of overall mental disorders in offspring were seen in different age groups for type 1 diabetes (1-5 years: HR, 1.35 [95% CI, 1.17-1.57]; 6-18 years: HR, 1.24 [95% CI, 1.15-1.33]; >18 years: HR, 1.19 [95% CI, 1.09-1.30]) and rheumatoid arthritis (1-5 years: HR, 1.42 [95% CI, 1.16-1.74]; 6-18 years: HR, 1.19 [95% CI, 1.05-1.36]; >18 years: HR, 1.28 [95% CI, 1.02-1.60]). Regarding specific mental disorders, increased risk after exposure to any maternal autoimmune disorder was observed for organic disorders (HR, 1.54; 95% CI, 1.21-1.94), schizophrenia (HR, 1.35; 95% CI, 1.21-1.51), obsessive-compulsive disorder (HR, 1.42; 95% CI, 1.24-1.63), mood disorders (HR, 1.12; 95% CI, 1.04-1.21), and a series of neurodevelopmental disorders (eg, childhood autism [HR, 1.21; 95% CI, 1.08-1.36] and attention-deficit/hyperactivity disorder [HR, 1.19; 95% CI, 1.12-1.26]). CONCLUSIONS AND RELEVANCE: In this cohort study in Denmark, prenatal exposure to maternal autoimmune diseases was associated with increased risks of overall and type-specific mental disorders in offspring. Maternal type 1 diabetes and rheumatoid arthritis during pregnancy were associated with offspring's mental health up to early adulthood. Individuals prenatally exposed to autoimmune disease may benefit from long-term surveillance for mental disorders.
34727862 TNF-induced Lupus. A Case-Based Review. 2022 Nowadays, tumor necrosis factor-alpha (TNFα) inhibitors have revolutionised the treatment of inflammatory arthritides by demonstrating efficacy with an acceptable toxicity profile. However, autoimmune phenomena and clinical entities have been reported ranging from an isolated presence of autoantibodies to full-blown autoimmune diseases, including drug-induced lupus (DIL). Case Presentation: A 62-year-old woman with rheumatoid arthritis (RA) refractory to methotrexate and prednisone was treated with adalimumab (ADA). 4 months later, she presented acute cutaneous eruptions after sun exposure, positive ANA (1/640 fine speckled pattern), Ro (SSA) and anti- Smith (Sm) antibodies with no other clinical or laboratory abnormalities. The diagnosis of DIL was made, ADA was discontinued, and she was treated successfully with prednisone plus local calcineurin inhibitors. Conclusion: Thus, we review the literature for cases of DIL development in patients treated with TNFα inhibitors. Rheumatologists should be aware of the possible adverse events and the requirement of careful clinical evaluation and monitoring.
35001548 Central Role of Semaphorin 3B in a Serum-Induced Arthritis Model and Reduced Levels in Pat 2022 Jun OBJECTIVE: Semaphorin 3B (Sema3B) decreases the migratory and invasive capacities of fibroblast-like synoviocytes (FLS) in rheumatoid arthritis (RA) and suppresses expression of matrix metalloproteinases. We undertook this study to examine the role of Sema3B in a mouse model of arthritis and its expression in RA patients. METHODS: Clinical responses, histologic features, and FLS function were examined in wild-type (WT) and Sema3B(-/-) mice in a K/BxN serum transfer model of arthritis. Protein and messenger RNA expression of Sema3B in mouse joints and murine FLS, as well as in serum and synovial tissue from patients with arthralgia and patients with RA, was determined using enzyme-linked immunosorbent assay, immunoblotting, quantitative polymerase chain reaction, and RNA sequencing. FLS migration was determined using a wound closure assay. RESULTS: The clinical severity of serum-induced arthritis was significantly higher in Sema3B(-/-) mice compared to WT mice. This was associated with increased expression of inflammatory mediators and increased migratory capacity of murine FLS. Administration of recombinant mouse Sema3B reduced the clinical severity of serum-induced arthritis and the expression of inflammatory mediators. Sema3B expression was significantly lower in the synovial tissue and serum of patients with established RA compared to patients with arthralgia. Serum Sema3B levels were elevated in patients with arthralgia that later progressed to RA, but not in those who did not develop RA; however, these levels drastically decreased 1 and 2 years after RA development. CONCLUSION: Sema3B expression plays a protective role in a mouse model of arthritis. In RA patients, expression levels of Sema3B in the serum depend on the disease stage, suggesting different regulatory roles in disease onset and progression.
35592686 Myostatin Levels and the Risk of Myopenia and Rheumatoid Cachexia in Women with Rheumatoid 2022 BACKGROUND: Myostatin is a regulator of muscle size. To date, there have been no published studies focusing on the relation between myostin levels and myopenia in rheumatoid arthritis (RA). OBJECTIVE: Evaluate the value of serum myostatin as a biomarker of cachexia and low skeletal muscle mass (LSMM) in RA patients, along with whether high serum myostatin is associated to these conditions after adjusting for potential confounders. METHODS: This cross-sectional study included 161 female RA patients and 72 female controls. In the RA group, we assessed several potential risk factors for LSMM and rheumatoid cachexia. Dual-energy X-ray absorptiometry was used to quantify the skeletal muscle mass index (SMMI) (considering LSMM ≤ 5.5 kg/m(2)) and the presence of rheumatoid cachexia (a fat-free mass index ≤ 10 percentile and fat mass index ≥ 25 percentile of the reference population). Serum myostatin concentrations were determined by ELISA. To identify a cut-off for high serum myostatin levels, we performed ROC curve analysis. Multivariable logistic regression analysis was used to identify the risk factors for LSMM and rheumatoid cachexia. The risk was expressed as odds ratios (ORs) and their 95% confidence intervals (95% CIs). RESULTS: Compared to the controls, the RA group had a higher proportion of LSMM and exhibited high serum myostatin levels (p < 0.001). ROC curve analysis showed that a myostatin level ≥ 17 ng/mL was the most efficient cut-off for identifying rheumatoid cachexia (sensitivity: 53%, specificity: 71%) and LSMM (sensitivity: 43%, specificity: 77%). In the multivariable logistic regression, RA with high myostatin levels (≥17 ng/mL) was found to increase the risk of cachexia (OR = 2.79, 95% CI: 1.24-6.29; p = 0.01) and LSMM (OR = 3.04, 95% CI: 1.17-7.89; p = 0.02). CONCLUSIONS: High serum myostatin levels increase the risk of LSMM and rheumatoid cachexia. We propose that high myostatin levels are useful biomarkers for the identification of patients in risk of rheumatoid cachexia and myopenia.
34605217 Antibody Responses to Epstein-Barr Virus in the Preclinical Period of Rheumatoid Arthritis 2022 Apr OBJECTIVE: Patients with established rheumatoid arthritis (RA) demonstrate altered immune responses to Epstein-Barr virus (EBV), but the presence and roles of EBV have not been fully explored during the pre-clinical disease period. This study was undertaken to determine if EBV infection, as evidenced by an altered anti-EBV antibody response, either plays an important role in driving the development of RA or is a result of expanded RA-related autoimmunity. METHODS: A total of 83 subjects with RA according to the 1987 American College of Rheumatology (ACR) criteria and 83 age-, sex-, and race-matched control subjects without RA were included in our study. We collected sera from RA subjects and matched controls during the pre-RA and post-RA diagnosis periods and tested the sera for the presence of 5 anti-EBV antibodies (anti-EBV nuclear antigen 1 IgG isotype, anti-viral capsid antigen [anti-VCA] isotypes IgG and IgA, and anti-early antigen [EA] isotypes IgG and IgA), 7 RA-related autoantibodies (rheumatoid factor measured by nephelometry [RF-Neph] as well as isotype-specific IgA-RF, IgM-RF, and IgG-RF, and anti-cyclic citrullinated peptide [anti-CCP] antibodies, including anti-CCP2, anti-CCP3, and anti-CCP3.1), 22 cytokines/chemokines, 36 individual anti-citrullinated protein antibodies, and IgG-cytomegalovirus (CMV) antibodies. Random forest classification, mixed modeling, and joint mixed modeling were used to determine differences in anti-EBV antibody levels between RA subjects and controls. RESULTS: Random forest analysis identified the presence of preclinical EBV antibodies in the serum that differentiated RA subjects from controls without RA. Specifically, IgG-EA antibody levels were higher in RA subjects (mean ± SD 0.82 ± 0.72 international standardized ratio [ISR]) compared to controls (mean ± SD 0.49 ± 0.28 ISR). In subjects with RA, elevated serum IgG-EA levels in the preclinical period before seroconversion were significantly correlated with increased serum IgM-RF levels (P = 0.007), whereas this correlation was not seen in control subjects without RA (P = 0.15). IgG-CMV antibody levels did not differ between groups. CONCLUSION: Subjects whose serum IgG-EA antibody levels are elevated in the preclinical period will eventually develop RA, which suggests that EBV reactivation cycles are increased during the preclinical period of RA. A combination of RF and EBV reactivation may play an important role in the development of RA.
35164829 Tumor necrosis factor alpha neutralization attenuates immune checkpoint inhibitor-induced 2022 Feb 14 OBJECTIVE: During treatment with immune checkpoint inhibitors (ICI) such as the anti-PD-1 antibody pembrolizumab, half of patients with pre-existing inflammatory arthritis experience disease flares. The underlying immunological mechanisms have not been characterized. Here, we investigate the effect of pembrolizumab on cells involved in inflammation and destruction in the synovial joint and how immunosuppressive treatments affect the pembrolizumab-induced immune reactions. METHODS: We included synovial fluid mononuclear cells (SFMCs, n = 28) and peripheral blood mononuclear cells (PBMCs, n = 6) from patients with rheumatoid arthritis and peripheral spondyloarthritis and PBMCs from healthy controls (n = 6). Fibroblast-like synovial cells (FLSs) were grown from SFMCs. The in vitro effect of pembrolizumab was tested in SFMCs cultured for 48 h, FLS-PBMC co-cultures and in SFMCs cultured for 21 days (inflammatory osteoclastogenesis). Cells and supernatants were analyzed by ELISA, flow cytometry, and pro-inflammatory multiplex assay. Finally, the effect of the disease-modifying anti-rheumatic drugs (DMARDs) adalimumab (TNFα inhibitor), tocilizumab (IL-6R inhibitor), tofacitinib (JAK1/JAK3 inhibitor), and baricitinib (JAK1/JAK2 inhibitor) on pembrolizumab-induced immune reactions was tested. RESULTS: Pembrolizumab significantly increased monocyte chemoattractant protein-1 (MCP-1) production by arthritis SFMCs (P = 0.0031) but not by PBMCs from patients or healthy controls (P = 0.77 and P = 0.43). Pembrolizumab did not alter MMP-3 production in FLS-PBMC co-cultures (P = 0.76) or TRAP secretion in the inflammatory osteoclastogenesis model (P = 0.28). In SFMCs, pembrolizumab further increased the production of TNFα (P = 0.0110), IFNγ (P = 0.0125), IL-12p70 (P = 0.0014), IL-10 (P = 0.0100), IL-13 (P = 0.0044), IL-2 (P = 0.0066), and IL-4 (P = 0.0008) but did not change the production of IL-6 (P = 0.1938) and IL-1 (P = 0.1022). The SFMCs treated with pembrolizumab showed an increased frequency of intermediate monocytes (P = 0.044), and the MCP-1 production increased only within the intermediate monocyte subset (P = 0.028). Lastly, adalimumab, baricitinib, and tofacitinib treatment were able to attenuate the pembrolizumab-induced MCP-1 production (P = 0.0004, P = 0.033, and P = 0.025, respectively), while this was not seen with tocilizumab treatment (P = 0.75). CONCLUSION: Pembrolizumab specifically activated intermediate monocytes and induced the production of several cytokines including TNFα but not IL-6. These findings indicate that flares in patients with pre-existing inflammatory arthritis involve monocyte activation and could be managed with TNFα neutralization.
35022393 Danger signal extracellular calcium initiates differentiation of monocytes into SPP1/osteo 2022 Jan 12 The danger signal extracellular calcium is pathophysiologically increased in the synovial fluid of patients with rheumatoid arthritis (RA). Calcium activates the NLRP3-inflammasome via the calcium-sensing receptor in monocytes/macrophages primed by lipopolysaccharide, and this effect is mediated by the uptake of calciprotein particles (CPPs) formed out of calcium, phosphate, and fetuin-A. Aim of the study was to unravel the influence of calcium on monocytes when the priming signal is not present. Monocytes were isolated from the blood of healthy controls and RA patients. Macrophages were characterized using scRNA-seq, DNA microarray, and proteomics. Imaging flow cytometry was utilized to study intracellular events. Here we show that extracellular calcium and CPPs lead to the differentiation of monocytes into calcium-macrophages when the priming signal is absent. Additional growth factors are not needed, and differentiation is triggered by calcium-dependent CPP-uptake, lysosomal alkalization due to CPP overload, and TFEB- and STAT3-dependent increased transcription of the lysosomal gene network. Calcium-macrophages have a needle-like shape, are characterized by excessive, constitutive SPP1/osteopontin production and a strong pro-inflammatory cytokine response. Calcium-macrophages differentiated out of RA monocytes show a stronger manifestation of this phenotype, suggesting the differentiation process might lead to the pro-inflammatory macrophage response seen in the RA synovial membrane.
35212005 SARS-CoV-2 (COVID-19)-specific T cell and B cell responses in convalescent rheumatoid arth 2022 May Rheumatoid arthritis (RA) patients present higher risk of SARS-CoV-2 infection (COVID-19), and proper management of the disease in this population requires a better understanding of how the immune system controls the virus. We analyzed the T cell and B cell phenotypes, and their repertoire in a pair of monozygotic twins with RA mismatched for COVID-19 infection. Twin- was not infected, while Twin+ was infected and effectively controlled the infection. We found no significant changes on the αβ T cell composition, while γδ T cells and B cells presented considerable expansion of memory population in Twin+ and robust T/B cell responses to several SARS-CoV-2 peptides. T cell receptor β/γ-chain and immunoglobulin heavy chain next-generation sequencing depicted a remarkable higher diversity in Twin+ compared with Twin-, despite no significant changes being found in variable/joining family usage. Repertoire overlap analyses showed that, although being identical twins, very few clones were shared between them, indicating that COVID-19 may lead to deep changes on the immune cell repertoire in RA patients. Altogether, our results indicate that RA patients may develop robust and persistent COVID-19-specific T/B cell responses; γδ T cells and B cells may play a key role in the management of COVID-19 in RA, and the infection may lead to a profound reshaping of immune cell receptor specificities.
35414711 Dynamic synovial fibroblasts are modulated by NBCn1 as a potential target in rheumatoid ar 2022 Apr Rheumatoid arthritis (RA) is an autoimmune disease characterized by aggressive fibroblast-like synoviocytes (FLSs) and pannus formation. Various therapeutic strategies have been developed against inflammatory cytokines in RA in recent decades. Based on the migratory features of FLSs, we examined whether modulation of the migratory module attenuates RA severity. In this study, inflamed synovial fluid-stimulated FLSs exhibited enhanced migration and migratory apparatus expression, and sodium bicarbonate cotransporter n1 (NBCn1) was identified in primary cultured RA-FLSs for the first time. The NBC inhibitor S0859 attenuated the migration of FLSs induced with synovial fluid from patients with RA or with TNF-α stimulation. Inhibition of NBCs with S0859 in a collagen-induced arthritis (CIA) mouse model reduced joint swelling and destruction without blood, hepatic, or renal toxicity. Primary FLSs isolated from the CIA-induced mouse model also showed reduced migration in the presence of S0859. Our results suggest that inflammatory mediators in synovial fluid, including TNF-α, recruit NBCn1 to the plasma membrane of FLSs to provide dynamic properties and that modulation of NBCn1 could be developed into a therapeutic strategy for RA.
35309353 Pro Nerve Growth Factor and Its Receptor p75NTR Activate Inflammatory Responses in Synovia 2022 We have recently provided new evidence for a role of p75NTR receptor and its preferential ligand proNGF in amplifying inflammatory responses in synovial mononuclear cells of chronic arthritis patients. In the present study, to better investigate how activation of the p75NTR/proNGF axis impacts synovial inflammation, we have studied the effects of proNGF on fibroblast-like synoviocytes (FLS), which play a central role in modulating local immune responses and in activating pro-inflammatory pathways. Using single cell RNA sequencing in synovial tissues from active and treatment-naïve rheumatoid arthritis (RA) patients, we demonstrated that p75NTR and sortilin, which form a high affinity receptor complex for proNGF, are highly expressed in PRG4(pos) lining and THY1(pos)COL1A1(pos) sublining fibroblast clusters in RA synovia but decreased in RA patients in sustained clinical remission. In ex vivo experiments we found that FLS from rheumatoid arthritis patients (RA-FLS) retained in vitro a markedly higher expression of p75NTR and sortilin than FLS from osteoarthritis patients (OA-FLS). Inflammatory stimuli further up-regulated p75NTR expression and induced endogenous production of proNGF in RA-FLS, leading to an autocrine activation of the proNGF/p75NTR pathway that results in an increased release of pro-inflammatory cytokines. Our data on the inhibition of p75NTR receptor, which reduced the release of IL-1β, IL-6 and TNF-α, further confirmed the key role of p75NTR activation in regulating inflammatory cytokine production. In a set of ex vivo experiments, we used RA-FLS and cultured them in the presence of synovial fluids obtained from arthritis patients that, as we demonstrated, are characterized by a high concentration of proNGF. Our data show that the high levels of proNGF present in inflamed synovial fluids induced pro-inflammatory cytokine production by RA-FLS. The blocking of NGF binding to p75NTR using specific inhibitors led instead to the disruption of this pro-inflammatory loop, reducing activation of the p38 and JNK intracellular pathways and decreasing inflammatory cytokine production. Overall, our data demonstrate that an active proNGF/p75NTR axis promotes pro-inflammatory responses in synovial fibroblasts, thereby contributing to chronic synovial inflammation, and point to the possible use of p75NTR inhibitors as a novel therapeutic approach in chronic arthritis.
34530431 Influence of Janus Kinase Inhibitors on the Neuronal Activity as a Proof-of-Concept Model 2022 BACKGROUND: Itching is considered to be a subjective symptom of the activation of neurosensory structures by different signal molecules and trigger factors. The signaling cascades responsible for it are closely linked to inflammatory processes. This explains why itching also occurs in many inflammatory diseases. One of these signaling cascades is mediated by Janus kinases (JAKs). Recently, it could be shown on a molecular level that Janus kinase 1 (JAK1) directly activates frontal cortex neurons and thus can cause chronic itching. OBJECTIVES: This study deals with the influence of different JAK inhibitors (JAKi) on the activity of chip-based neural networks of cultured frontal cortex neurons by investigating neurophysiological activity parameters. This in vitro model provides information on dose-dependent effects of model substances with different specificity regarding the inhibition of different JAKs. METHODS: Tofacitinib (pan-JAKi), baricitinib (JAK1/2i), and upadacitinib (JAK1i) in a concentration range from 10 nmol/L to 50 μmol/L were tested in a microelectrode array neurochip culture system. RESULTS: The results show that the inhibition of the neuronal activity of frontal cortex neurons increases with JAK1 selectivity and is dependent on concentration. CONCLUSION: These observations are supported by data from clinical studies in atopic dermatitis and psoriasis. The clinical relevance of these results must be proven by further clinical studies with subjective and objective parameters for itching.
34251326 Role of adiponectin in non-diabetic patients with rheumatoid arthritis undergoing anti-IL- 2022 May OBJECTIVES: Adiponectin is an adipokine that plays a relevant role in the development of metabolic syndrome (MetS), a complication that increases the risk of cardiovascular (CV) disease in patients with rheumatoid arthritis (RA). Accordingly, we assessed for the first time the short-term effect of anti-IL-6 receptor tocilizumab (TCZ) administration on adiponectin serum levels in RA patients and explored the potential association of adiponectin levels with MetS features, other CV risk factors and demographic and clinical characteristics of these patients. METHODS: Adiponectin serum levels were evaluated in 50 non-diabetic RA patients, undergoing TCZ treatment, immediately prior to (pre-infusion) and 60 minutes after the end of a TCZ intravenous infusion (post-infusion). RESULTS: No significant differences in adiponectin levels pre- and post-TCZ infusion were found in RA patients (p=0.69). Patients with obesity exhibited decreased basal levels of adiponectin with respect to those non-obese (p=0.03). Additionally, a negative association of adiponectin basal levels with body mass index, insulin, insulin/glucose index, C-peptide and leptin levels (p<0.01; p=0.02; p=0.03; p=0.03 and p=0.01, respectively), as well as a positive correlation with HDL-cholesterol levels (p<0.001) was seen. CONCLUSIONS: Our results support the claim that low adiponectin may contribute to the development of MetS and, consequently, CV disease in RA. Anti-IL-6 therapy does not seem to exert a short-term effect on adiponectin levels.
35292659 Dopamine D3 receptor signaling alleviates mouse rheumatoid arthritis by promoting Toll-lik 2022 Mar 15 Dopamine receptors are involved in several immunological diseases. We previously found that dopamine D3 receptor (D3R) on mast cells showed a high correlation with disease activity in patients with rheumatoid arthritis, but the mechanism remains largely elusive. In this study, a murine collagen-induced arthritis (CIA) model was employed in both DBA/1 mice and D3R knockout mice. Here, we revealed that D3R-deficient mice developed more severe arthritis than wild-type mice. D3R suppressed mast cell activation in vivo and in vitro via a Toll-like receptor 4 (TLR4)-dependent pathway. Importantly, D3R promoted LC3 conversion to accelerate ubiquitin-labeled TLR4 degradation. Mechanistically, D3R inhibited mTOR and AKT phosphorylation while enhancing AMPK phosphorylation in activated mast cells, which was followed by autophagy-dependent protein degradation of TLR4. In total, we found that D3R on mast cells alleviated inflammation in mouse rheumatoid arthritis through the mTOR/AKT/AMPK-LC3-ubiquitin-TLR4 signaling axis. These findings identify a protective function of D3R against excessive inflammation in mast cells, expanding significant insight into the pathogenesis of rheumatoid arthritis and providing a possible target for future treatment.
35334058 Trabecular Bone Score in Rheumatic Disease. 2022 Apr PURPOSE OF REVIEW: Patients with rheumatic disease are at high risk of low bone mass and osteoporotic fracture. Trabecular bone score (TBS), derived from lumbar spine dual-energy x-ray absorptiometry (DXA), is a novel measure of bone texture that independently predicts fracture risk. This review examines the role of TBS in rheumatic disease including fracture prediction. RECENT FINDINGS: Most studies concerning TBS and rheumatic disease are cross-sectional, with consistent evidence of lower TBS in patients with rheumatic disease compared to controls. Recent studies have shown association and predictive ability of TBS for prevalent fracture, and the few longitudinal studies showed predictive ability of TBS for incident fracture. TBS in ankylosing spondylitis is of interest given the high rates of vertebral fracture and technical difficulty with lumbar spine bone mineral density. TBS degradation has been associated with disease activity in ankylosing spondylitis, systemic sclerosis, and rheumatoid arthritis. Glucocorticoid exposure is associated with lower TBS, and predicts prevalent fracture, in patients with rheumatic conditions.
35185927 Progesterone Inhibits the Establishment of Activation-Associated Chromatin During T(H)1 Di 2022 T(H)1-mediated diseases such as multiple sclerosis (MS) and rheumatoid arthritis (RA) improve during pregnancy, coinciding with increasing levels of the pregnancy hormone progesterone (P4), highlighting P4 as a potential mediator of this immunomodulation. Here, we performed detailed characterization of how P4 affects the chromatin and transcriptomic landscape during early human T(H)1 differentiation, utilizing both ATAC-seq and RNA-seq. Time series analysis of the earlier events (0.5-24 hrs) during T(H)1 differentiation revealed that P4 counteracted many of the changes induced during normal differentiation, mainly by downregulating key regulatory genes and their upstream transcription factors (TFs) involved in the initial T-cell activation. Members of the AP-1 complex such as FOSL1, FOSL2, JUN and JUNB were particularly affected, in both in promoters and in distal regulatory elements. Moreover, the changes induced by P4 were significantly enriched for disease-associated changes related to both MS and RA, revealing several shared upstream TFs, where again JUN was highlighted to be of central importance. Our findings support an immune regulatory role for P4 during pregnancy by impeding T-cell activation, a crucial checkpoint during pregnancy and in T-cell mediated diseases, and a central event prior to T-cell lineage commitment. Indeed, P4 is emerging as a likely candidate involved in disease modulation during pregnancy and further studies evaluating P4 as a potential treatment option are needed.
35583542 Observational studies: Ambient air pollution and hospitalization for RA-ILD in a heavily p 2022 May 13 Little is known within the medical community about the impact of air pollution on hospital admissions due to rheumatoid arthritis associated with interstitial lung disease (RA-ILD). Our research aimed to explore whether there is a correlation and to estimate how the association was distributed across various lags in Jinan, China.The relationships between ambient air pollutant concentrations, including PM2.5, PM10, sulfur dioxide (SO2), ozone (O3), and nitrogen dioxide (NO2), and monthly hospitalizations for RA-ILD were studied by employing a general linear model with a Poisson distribution. This time-series study was performed from January 1st, 2015 to December 31st, 2019.In the 5-year study, there were 221 hospitalizations for RA-ILD in Jinan city. The levels of PM2.5, PM10, SO2, and NO2 were significantly related to the number of admissions for RA-ILD. PM2.5, PM10, and SO2 showed the most significant effect on the month (lag 0), and NO2 was most related to RA-ILD at a lag of two months (lag 2). The monthly admissions of RA-ILD increased by 0.875% (95% CI: 0.375-1.377%), 0.548% (95% CI: 0.148-0.949%), 1.968% (95% CI: 0.869-3.080%), and 1.534% (95% CI: 0.305-2.778%) for each 10 μg/m3 increase in PM2.5, PM10, SO2 and NO2, respectively.This study might add more detailed evidence that higher levels of PM2.5, PM10, SO2 and NO2 increase the risk of hospitalizations for RA-ILD. Further study of the role of air pollution in the pathogenesis of RA-ILD is warranted.