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ID PMID Title PublicationDate abstract
35165166 The Purinergic Receptor P2X4 Promotes Th17 Activation and the Development of Arthritis. 2022 Mar 1 Purinergic signaling plays a major role in T cell activation leading to IL-2 production and proliferation. However, it is unclear whether purinergic signaling contributes to the differentiation and activation of effector T cells. In this study, we found that the purinergic receptor P2X4 was associated with human Th17 cells but not with Th1 cells. Inhibition of P2X4 receptor with the specific antagonist 5-BDBD and small interfering RNA inhibited the development of Th17 cells and the production of IL-17 by effector Th17 cells stimulated via the CD3/CD28 pathway. Our results showed that P2X4 was required for the expression of retinoic acid-related orphan receptor C, which is the master regulator of Th17 cells. In contrast, inhibition of P2X4 receptor had no effect on Th1 cells and on the production of IFN-γ and it did not affect the expression of the transcription factor T-bet (T-box transcription factor). Furthermore, inhibition of P2X4 receptor reduced the production of IL-17 but not of IFN-γ by effector/memory CD4(+) T cells isolated from patients with rheumatoid arthritis. In contrast to P2X4, inhibition of P2X7 and P2Y(11) receptors had no effects on Th17 and Th1 cell activation. Finally, treatment with the P2X4 receptor antagonist 5-BDBD reduced the severity of collagen-induced arthritis in mice by inhibiting Th17 cell expansion and activation. Our findings provide novel insights into the role of purinergic signaling in T cell activation and identify a critical role for the purinergic receptor P2X4 in Th17 activation and in autoimmune arthritis.
34170018 Chikungunya Fever: Comparison Study of Synovitis and Tenosynovitis of the Hands and Wrists 2022 Apr OBJECTIVES: To compare musculoskeletal changes on a physical examination (PE), ultrasound (US) and magnetic resonance imaging (MRI) of the hands and wrists of patients with Chikungunya fever (CF). METHODS: The sample consisted of 30 patients in the chronic phase of CF. The sites analyzed were the interphalangeal (IP), metacarpophalangeal (MCP) and wrist/mediocarpal (WMC) joints and periarticular soft tissue. The interval between the PE and imaging tests was 7 days, and the interval between US and MRI was 2 days. The kappa coefficient was calculated to estimate the agreement between the PE and US and MRI findings and between the US and MRI findings. RESULTS: Significant agreement was observed between PE and US in the diagnosis of synovitis. The only statistically significant agreement between US and MRI was the finding of flexor tenosynovitis; the agreement was moderate. CONCLUSIONS: US has great potential for use in diagnosing synovitis suspected based on a PE. The limited agreement observed between US and MRI, in turn, may suggest a complementary role of these methods.
35313978 Pooled safety results across phase 3 randomized trials of intravenous golimumab in rheumat 2022 Mar 21 BACKGROUND: Intravenous (IV) golimumab, a TNFi, is approved for treating rheumatoid arthritis (RA), psoriatic arthritis (PsA), and ankylosing spondylitis (AS). We analyzed pooled safety results from three phase 3 IV golimumab trials in these rheumatologic diseases and hypothesized that the safety profile of IV golimumab would be similar to that established for other TNFi, including subcutaneous golimumab. METHODS: Data from three double-blind, randomized trials of IV golimumab in patients with RA, PsA, and AS, each with a placebo-controlled period and an extension of active treatment, were included. Golimumab 2 mg/kg was administered at weeks 0 and 4, then every 8 weeks through week 100 (RA) or week 52 (PsA, AS). Concomitant low-dose, oral corticosteroids were permitted. Concomitant methotrexate was required in the RA trial and permitted in the PsA and AS trials; placebo patients crossed over to golimumab at weeks 24 (RA, PsA) and 16 (AS), respectively. Adverse events (AEs), including infections, serious infections, malignancies, and major adverse cardiovascular events (MACE), were assessed through week 112 (RA) or week 60 (PsA, AS). RESULTS: In total, 539 patients were randomized to placebo, and 740 patients were randomized to golimumab; 1248 patients received ≥ 1 golimumab administration. Among the placebo and golimumab patients, respectively, during the placebo-controlled periods, 40.6% and 50.3% had an AE, 2.4% and 3.8% had a serious AE, and 0.4% and 0.8% had a serious infection. Among all golimumab-treated patients, the numbers of events/100 patient-years (95% CI) were as follows: AEs, 175.2 (169.0, 181.6); serious AEs, 12.7 (11.0, 14.5); serious infections, 3.4 (2.5, 4.4); active tuberculosis, 0.4 (0.1, 0.8); opportunistic infection, 0.2 (0.1, 0.6); malignancies, 0.4 (0.2, 0.9), and MACE, 0.5 (0.2, 1.0). There were no cases of lymphoma. Three (0.6%) placebo-treated patients and 6 (0.5%) golimumab-treated patients died during the studies. Concomitant methotrexate was associated with increased occurrence of elevated alanine transaminase levels and lower incidence of antibodies to golimumab. During the placebo-controlled periods, serious infections in the placebo and golimumab groups were more common in patients receiving concomitant low-dose oral corticosteroids vs. those not receiving corticosteroids. CONCLUSIONS: IV golimumab demonstrated a safety profile that was broadly consistent across these rheumatologic indications and with other TNFi, including subcutaneous golimumab. Concomitant methotrexate or corticosteroids were associated with an increase in specific AEs. TRIAL REGISTRATIONS: ClinicalTrials.gov , NCT00973479 . Registered on September 9, 2009. CLINICALTRIALS: gov , NCT02181673 . Registered on July 4, 2014. CLINICALTRIALS: gov , NCT02186873 . Registered on July 10, 2014.
35439173 Soluble CD13 induces inflammatory arthritis by activating the bradykinin receptor B1. 2022 Jun 1 CD13, an ectoenzyme on myeloid and stromal cells, also circulates as a shed, soluble protein (sCD13) with powerful chemoattractant, angiogenic, and arthritogenic properties, which require engagement of a G protein-coupled receptor (GPCR). Here we identify the GPCR that mediates sCD13 arthritogenic actions as the bradykinin receptor B1 (B1R). Immunofluorescence and immunoblotting verified high expression of B1R in rheumatoid arthritis (RA) synovial tissue and fibroblast-like synoviocytes (FLSs), and demonstrated binding of sCD13 to B1R. Chemotaxis, and phosphorylation of Erk1/2, induced by sCD13, were inhibited by B1R antagonists. In ex vivo RA synovial tissue organ cultures, a B1R antagonist reduced secretion of inflammatory cytokines. Several mouse arthritis models, including serum transfer, antigen-induced, and local innate immune stimulation arthritis models, were attenuated in Cd13-/- and B1R-/- mice and were alleviated by B1R antagonism. These results establish a CD13/B1R axis in the pathogenesis of inflammatory arthritis and identify B1R as a compelling therapeutic target in RA and potentially other inflammatory diseases.
35601739 Association Study of Anticitrullinated Peptide Antibody Status with Clinical Manifestation 2022 INTRODUCTION: Rheumatoid arthritis (RA) is an autoimmune disease of unknown etiology that leads to disability due to articular and extra-articular damage. RA prevalence is variable. The disease is most common among females with a 3 : 1 ratio. The interaction of environmental and host factors contributes to RA development. Currently, the genome-wide association studies (GWAS) give the opportunity to uncover the RA genetic background. Anticitrullinated peptide antibody (ACPA) is a highly specific RA antibody, associated with poor prognosis and severe course of RA, and regulated by numerous genes. Our study is aimed at investigating whether there are any clinical and genetic aspects correlate with ACPA presence in Kazakhstani patients with RA. Indeed, the available studies on this subject are focused on Caucasian and East Asian populations (mainly Japanese and Chinese), and there are scarce data from Central Asia. METHODS: Our study included 70 RA patients. Patients' blood samples were collected and genotyped for 14 SNPs by real-time polymerase chain reaction (RT-PCR). General examination, anamnestic, and clinical and laboratory data collection were carried out. Statistical analysis was performed using R statistics. Results and Conclusion. Our study revealed a significant association of ACPA positivity with Fc receptor-like 3 (FCRL3) and ACPA negativity with signal transducer and activator of transcription 4 (STAT4) genes, but not with T cell activation Rho GTPase activating protein (TAGAP). In addition, ACPA positivity was associated with radiographic progression, rheumatoid factor (RF), erythrocyte sedimentation rate (ESR), age of RA onset, the patient global assessment, body mass index (BMI), and Gamma globulin. CONCLUSION: Remained 11 earlier identified significantly associated in Caucasian and Asian population SNPs were not replicated in our cohort. Further studies on larger cohorts are needed to confirm our findings with higher confidence levels and stronger statistical power.
35129860 proBDNF/p75NTR promotes rheumatoid arthritis and inflammatory response by activating proin 2022 Mar P75 pan-neurotrophin receptor (p75NTR) is an important receptor for the role of neurotrophins in survival and death of neurons during development and after nerve injury. Our previous research found that the precursor of brain-derived neurotrophic factor (proBDNF) regulates pain as an inflammatory mediator. The current understanding of the role of proBDNF/p75NTR signaling pathway in inflammatory arthritis pain and rheumatoid arthritis (RA) is unclear. We recruited 20 RA patients, 20 healthy donors (HDs), and 10 osteoarthritis (OA) patients. Hematoxylin and eosin (H&E) staining and immunohistochemistry (IHC) of proBDNF and p75NTR in synovial membrane were performed and evaluated. We next examined the mRNA and protein expression of proBDNF/p75NTR signaling pathway in peripheral blood mononuclear cells (PBMCs) and synovial tissue. ELISA and flow cytometry were assessed between the blood of RA patients and HD. To induce RA, collagen-induced arthritis (CIA) were induced in mice. We found over-synovitis of RA synovial membrane compared to OA controls in histologic sections. P75NTR and sortilin mRNA, and proBDNF protein level were significantly increased in PBMCs of RA patients compared with the HD. Consistently, ELISA showed that p75NTR, sortilin, tumor necrosis factor α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), and interleukin-10 (IL-10) levels in the serum of RA patients were increased compared with HD and p75NTR, sortilin were positively correlated with Disease Activity Score in 28 joints (DAS28). In addition, using flow cytometry we showed that the increased levels of proBDNF and p75NTR characterized in CD4(+) and CD8(+) T cells of RA patients were subsequently reversed with methotrexate (MTX) treatment. Furthermore, we found pathological changes, inflammatory pain, upregulation of the mRNA and protein expression of proBDNF/p75NTR signaling pathway, and upregulation of inflammatory cytokines in spinal cord using a well-established CIA mouse model. We showed intravenous treatment of recombinant p75ECD-Fc that biologically blocked all inflammatory responses and relieved inflammatory pain of animals with CIA. Our findings showed the involvement of proBDNF/p75NTR pathway in the RA inflammatory response and how blocking it with p75ECD-Fc may be a promising therapeutic treatment for RA.
35179632 Cytokines and chemokines multiplex analysis in patients with low disease activity rheumato 2022 Apr Rheumatoid arthritis is a severe chronic autoimmune disorder that results from pathological activation of immune cells and altered cytokine/chemokine network. The aim of our study was to evaluate concentrations of chosen cytokines and chemokines in blood sera and synovial fluid samples isolated from low disease activity rheumatoid arthritis (RA) patients and osteoarthritis (OA) sufferers. Blood sera and synovial fluid samples have been obtained from 24 OA and 14 RA patients. Cytokines/chemokines levels have been determined using a Milliplex(®) Map 38-plex human cytokine/chemokine magnetic bead-based panel (Merck Millipore, Germany) and Luminex(®) MAGPIX(®) platform (Luminex USA). Low disease activity RA patients showed altered concentration of numerous cytokine/chemokine when compared to OA controls-they were characterized by, inter alia, increased: eotaxin/CCL11 (p = 0.037), GRO/CXCL1 (p = 0.037), IL-2 (p = 0.013), IL-4 (p = 0.017), IL-7 (p = 0.003), IL-8 (p = 0.0007) and GM-CSF (p = 0.037) serum levels, whilst MDC/CCL22 concentration was decreased in this group (p = 0.034). Eotaxin/CCL11 (p = 0.001), GRO/CXCL1 (p = 0.041), IL-10 (p = 0.003), GM-CSF (p = 0.01), IL-1RA (p = 0.0005) and VEGF (p = 0.01) concentrations in synovial fluid of RA females were also increased. Even with low disease activity score, RA patients exhibited increased concentrations of cytokines with pro- and anti-inflammatory activities, as well as numerous chemokines, growth factors and regulators of angiogenesis. Surprisingly, RA subjects also shown decreased concentration of CCL22 chemokine. The attempt to restore cytokine balance and tolerogenic environment is ineffective in RA sufferers even with good disease management. Distinguished factors could serve as possible indicators of disease progression even in low disease activity patients.
33706472 Baseline use of hydroxychloroquine or immunosuppressive drugs and the risk of coronavirus 2022 May BACKGROUND/AIMS: The preventive role of hydroxychloroquine (HCQ) on coronavirus disease 2019 (COVID-19) remains unclear. The aim of this study was to examine the effects of HCQ and other immunosuppressive drugs on the incidence of COVID-19. METHODS: The data were collected from the South Korea National Health Insurance Sharing-COVID-19 database. All individuals who underwent nasopharyngeal and oropharyngeal swab tests for COVID-19 from January 2020 to May 2020 are included. The association between COVID-19 risk and HCQ use was examined in a propensity score-matched population. Factors associated with COVID-19 were identified using multiple logistic regression analysis. RESULTS: Total 8,070 patients with COVID-19 and 121,050 negative controls were included from the database. Among all participants, 381 were HCQ users. In a propensity score-matched population, the incidence of COVID-19 was 7.1% in HCQ users and 6.8% in non-users. The odds ratio (OR) for HCQ use was 1.05 with a 95% confidence interval (CI) of 0.58 to 1.89. Among the subpopulation of patients with rheumatoid arthritis (RA), 33 were diagnosed with COVID-19 and 478 were not. Use of HCQ, glucocorticoids, or other immunosuppressive drugs was not associated with COVID-19 risk, whereas abatacept use was. Chronic lung disease was an independent risk factor for COVID-19 diagnosis in patients with RA (adjusted OR, 6.07; 95% CI, 1.10 to 33.59). CONCLUSION: The risk of COVID-19 did not differ between HCQ users and non-users. Glucocorticoids, conventional disease-modifying antirheumatic drugs (DMARDs), and biological DMARDs other than abatacept did not increase the risk of COVID-19.
33327830 The Clinical Utility of Autoantibodies in Patients with Idiopathic Granulomatous Mastitis. 2022 Feb BACKGROUND: Although the etiopathogenesis of idiopathic granulomatous mastitis (IGM) is still controversial, recently autoimmunity and immune dysregulation have been emphasized. The aim of this study is to investigate the clinical utility of autoantibodies in IGM. MATERIAL AND METHODS: Rheumatoid factor (RF), antinuclear antibody (ANA), anti-double stranded DNA antibody (anti-ds-DNA), anti-cyclic citrullinated peptides antibody (anti-CCP) and perinuclear anti-neutrophil cytoplasmic antibody (pANCA) levels were investigated in pathologically diagnosed IGM patients (Group IGM) and healthy women (Group C). IGM patients were divided into two groups as those with active symptoms and signs (Group IGM(A)) and those without clinical and radiological findings (Group IGM(R)). RESULTS: While, in Group IGM, the positivity of RF, ANA, anti-ds-DNA, pANCA and anti-CCP was 13.1%, 3.3%, 1.6%, 0%, and 3.3%, respectively, in Group C, they were 13.3%, 0%, 0%, 0%, and 0%, respectively. The differences were not statistically significant (p > .05). In Groups IGM(A), IGM(R) and C, RF positivity was 10%, 16.1%, and 13.3%, respectively. The ANA positivity of Groups IGM(A), IGM(R) and C was 0%, 6.5%, and 0%, respectively. Groups IGM(A), IGM(R) and C's anti-ds-DNA positivity were 0%, 3.2%, and 0%, respectively. In all groups, pANCA was negative. The anti-CCP positivity of Groups IGM(A), IGM(R) and C was 6.7%, 0%, and 0%, respectively. CONCLUSION: Our findings did not support the clinical utility of autoantibodies including RF, ANA, anti-ds-DNA, pANCA and anti-CCP in IGM.
35015571 Cytoplasmic zinc promotes IL-1β production by monocytes and macrophages through mTORC1-in 2022 Jan 11 The essential micronutrient zinc regulates immune responses by affecting signaling pathways. In activated monocytes and macrophages, signaling networks mediate the metabolic reprogramming that meets the demands of participation in immune responses. Here, we demonstrated that cytoplasmic, bioavailable zinc was essential for promoting IL-1β production in activated human monocytes and macrophages downstream of glycolysis induced by the kinase-containing multiprotein complex mTORC1. The concentration of cytoplasmic zinc was determined by that of extracellular zinc, which was brought into cells through the zinc-specific importer Zip8. The abundance of Zip8 was increased in monocytes from patients with rheumatoid arthritis (RA), as well as in LPS-stimulated monocytes and macrophages from healthy individuals. The mTORC1-mediated phosphorylation of S6 kinase (S6K) was enhanced by zinc-mediated inhibition of PP2A, a phosphatase that targets S6K. As a result, IL-1β production was increased due to the activation of mTORC1-induced glycolysis. In monocytes of patients with RA, the expression of Zip8 and the zinc-inducible metallothionein isoform MT2A and the phosphorylation of S6K were enhanced compared with those of healthy controls. Furthermore, Zip8 expression correlated with more severe RA clinical parameters, suggesting that Zip8-mediated zinc influx is related to inflammatory conditions. These results provide insight into the role of cytoplasmic, bioavailable zinc in the metabolic reprogramming of human monocytes and macrophages in inflammatory responses.
35523814 Optimization of IL-1RA structure to achieve a smaller protein with a higher affinity to it 2022 May 6 Interleukine-1 family cytokines are key orchestrators of innate and adaptive immunity. In particular, up-regulation of IL-1R1 via its agonistic ligands consisting of IL-1β and IL-1α is implicated in a variety of human diseases, such as rheumatoid arthritis, psoriasis, type I diabetes, amyotrophic lateral sclerosis, and dry-eye disease. Until now, there are no small-molecule inhibitors of the IL-1R1 with increased antagonistic potency to be used for the treatment of peripheral inflammation. The objective of this study was to engineer a low-molecular-weight version of IL-1RA with increased affinity and enhanced antagonistic activity for potential therapeutic use. To develop a smaller protein-ligand with a better affinity to IL-1R, we used bioinformatics studies and in silico simulations to anticipate non-binding areas on IL-1RA. In this study, we have identified a 41aa (F57-F98) non-binding site of IL-1RA. Overall RMSF of the Truncated complex (1.5 nm) was lower than the Native complex (2 nm), which could prove higher stability of the Truncated complex. The free binding energy of the T-IL-1RA (- 1087.037 kJ/mol) was significantly lower than the IL-1RA (- 836.819 kJ/mol) which could demonstrate a higher binding affinity of the truncated ligand with its receptor as a result of new important interactions. These findings have demonstrated a higher binding affinity of the T-IL-1RA with its receptor than the native protein. These results should: have an impact on the development of new treatments that block IL-1 signaling, although more research is needed in vitro and in vivo.
35309354 Role of the CXCL13/CXCR5 Axis in Autoimmune Diseases. 2022 CXCL13 is a B-cell chemokine produced mainly by mesenchymal lymphoid tissue organizer cells, follicular dendritic cells, and human T follicular helper cells. By binding to its receptor, CXCR5, CXCL13 plays an important role in lymphoid neogenesis, lymphoid organization, and immune responses. Recent studies have found that CXCL13 and its receptor CXCR5 are implicated in the pathogenesis of several autoimmune diseases, such as rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, primary Sjögren's syndrome, myasthenia gravis, and inflammatory bowel disease. In this review, we discuss the biological features of CXCL13 and CXCR5 and the recent findings on the pathogenic roles of the CXCL13/CXCR5 axis in autoimmune diseases. Furthermore, we discuss the potential role of CXCL13 as a disease biomarker and therapeutic target in autoimmune diseases.
34585327 Autologous ATG-free hematopoietic stem cell transplantation for refractory autoimmune rheu 2022 Mar Autologous hematopoietic stem cell transplantation (HSCT) has been recognized as treatment alternative for patients with severe, refractory autoimmune rheumatic diseases (ARDs). Usually, anti-thymocyte globulin (ATG)-containing conditioning regimens are employed; however, ATG is unavailable in some developing nations. We report our 15-year clinical experience autografting patients with ARDs with an ATG-free conditioning regimen and a brief assessment of patient-reported outcomes post-HSCT. All patients had active disease and were resistant to multiple lines of treatment. Event-free survival (EFS) was assessed using the Kaplan-Meier method. Eight patients underwent autologous HSCT. Diagnoses included juvenile idiopathic arthritis (n = 3), systemic lupus erythematosus (n = 2), systemic sclerosis (n = 2), and rheumatoid arthritis (n = 1). Median time from diagnosis to HSCT was 3 years (0.75-19). Hematological recovery was documented in all recipients, and 4 patients (50%) completed the procedure in a completely ambulatory setting. Five (62.5%) patients achieved complete response and 3 (37.5%) partial response. The median EFS was 7 months (95% CI, 4.97-9.02), and the 1-year EFS rate was 21.9% (95% CI, 18.25-25.76). Transplant-related mortality was 0%, and 1 recipient died 8 years post-HSCT due to chronic kidney disease. Six (75%) patients presented steroid dosage reduction post-HSCT, and 2 (25%) perceived improvement in functionality despite having relapsed. HSCT is a viable treatment alternative for selected patients with severe therapy-resistant ARDs, as an improvement in disease management and quality of life was documented. The need remains to elucidate the characteristics of the optimal HSCT candidate, as well as the adequate conditioning regimen when ATG is not available. Key Points • Despite advances in the treatment of autoimmune rheumatic diseases, some patients remain refractory. In this context, autologous hematopoietic stem cell transplantation (HSCT) rises as a viable alternative. • Of 8 HSCT recipients with autoimmune rheumatic diseases, 5 (62.5%) patients achieved complete response and 3 (37.5%) partial response, with a 1-year event-free survival of 21.9%. • Transplant-related mortality was 0%, with 4 (50%) patients autografted in a completely outpatient setting. • Even when relapse presented, patients reported an improvement in functionality and quality of life; also, a better response to DMARDs and a reduction in steroid dependency post-HSCT were documented.
35095831 CD209/CD14(+) Dendritic Cells Characterization in Rheumatoid and Psoriatic Arthritis Patie 2021 Dendritic cells (DC) have a key role in the initiation and progression of inflammatory arthritis (IA). In this study, we identified a DC population that derive from monocytes, characterized as CD209/CD14(+) DC, expressing classical DC markers (HLADR, CD11c) and the Mo-DC marker (CD209), while also retaining the monocytic marker CD14. This CD209/CD14(+) DC population is present in the circulation of Healthy Control (HC), with increased frequency in Rheumatoid Arthritis (RA) and Psoriatic arthritic (PsA) patients. We demonstrate, for the first time, that circulatory IA CD209/CD14(+) DC express more cytokines (IL1β/IL6/IL12/TNFα) and display a unique chemokine receptor expression and co-expression profiles compared to HC. We demonstrated that CD209/CD14(+) DC are enriched in the inflamed joint where they display a unique inflammatory and maturation phenotype, with increased CD40 and CD80 and co-expression of specific chemokine receptors, displaying unique patterns between PsA and RA. We developed a new protocol of magnetic isolation and expansion for CD209(+) DC from blood and identified transcriptional differences involved in endocytosis/antigen presentation between RA and PsA CD209(+) DC. In addition, we observed that culture of healthy CD209(+) DC with IA synovial fluid (SF), but not Osteoarthritis (OA) SF, was sufficient to induce the development of CD209/CD14(+) DC, leading to a poly-mature DC phenotype. In addition, differential effects were observed in terms of chemokine receptor and chemokine expression, with healthy CD209(+) DC displaying increased expression/co-expression of CCR6, CCR7, CXCR3, CXCR4 and CXCR5 when cultured with RA SF, while an increase in the chemokines CCR3, CXCL10 and CXCL11 was observed when cultured with PsA SF. This effect may be mediated in part by the observed differential increase in chemokines expressed in RA vs PsA SF. Finally, we observed that the JAK/STAT pathway, but not the NF-κB pathway (driven by TNFα), regulated CD209/CD14(+) DC function in terms of activation, inflammatory state, and migratory capacity. In conclusion, we identified a novel CD209/CD14(+) DC population, which is active in the circulation of RA and PsA, an effect potentiated once they enter the joint. Furthermore, we demonstrated that JAK/STAT inhibition can be used as a therapeutic strategy to decrease the inflammatory state of the pathogenic CD209/CD14(+) DC.
35143824 Co-treatment of Nimbolide augmented the anti-arthritic effects of methotrexate while prote 2022 Apr 15 Prolonged exposure to the pharmacological doses of disease-modifying anti-rheumatic drugs (DMARDs) often results in major organ toxicities resulting in poor patient compliance. Methotrexate (MTX) is one of the commonly prescribed DMARDs for the treatment of arthritis, which results in vital organ dysfunction. To retain the anti-arthritic activity of MTX with the reduction in toxicities, combination therapies are warranted. Nimbolide (NMB) is a potent anticancer, anti-inflammatory and anti-fibrotic agent whose potential has been demonstrated in various pre-clinical models. Monoarthritis was developed with Complete Freund's Adjuvant in the knees of Wistar rats and treatment was given with either NMB (3 mg/kg/day) or MTX (2 mg/kg/week) alone or combination therapy (NMB + MTX). The anti-arthritic effects were evaluated by arthritic scoring, radiological imaging, synovial tissue proteins analysis, and histopathological staining. While hepato-renal toxicity was assessed in serum by evaluating the kidney and liver functional parameters, in tissues by oxidative-nitrosative stress markers, and pro-inflammatory cytokines levels. Histopathological analysis was performed to study the extent of tissue damage. Molecular studies like immunoblotting and immunohistochemistry were performed to understand the effect of combination therapy. We thereby report that monotherapy with either NMB or MTX exhibited significant anti-arthritic effects, while combination therapy resulted in augmented anti-arthritic effects with significant reduction in hepato-renal toxicity produced by MTX probably through anti-inflammatory and anti-oxidant effects. Therefore, our proposed combination of NMB and MTX may serve as a potential strategy for the effective management of arthritis.
35125345 Multipathway In Vitro Pharmacological Characterization of Specialized Proresolving G Prote 2022 Apr Specialized proresolving mediators (SPMs) and their cognate G protein-coupled receptors are implicated in autoimmune disorders, including chronic inflammation, rheumatoid arthritis, systemic scleroderma, and lupus erythematosus. To date, six G protein-coupled receptors (GPCRs) have been paired with numerous endogenous and synthetic ligands. However, the function and downstream signaling of these receptors remains unclear. To address this knowledge gap, we systematically expressed each receptor in a human embryonic kindney 293 (HEK293)-Flp-In-CD8a-FLAG cell system. Each receptor was pharmacologically characterized with both synthetic and putative endogenous ligands across different signaling assays, covering both G protein-dependent (G(s), G(i), and G(q)) and independent mechanisms (β-arrestin2 recruitment). Three orphan GPCRs previously identified as SPM receptors (GPR 18, GPR32 and GPR37) failed to express in HEK 293 cells. Although we were unsuccessful in identifying an endogenous ligand for formyl peptide receptor 2 (FPR2)/lipoxin A4 receptor (ALX), with only a modest response to N-formylmethionine-leucyl-phenylalanine (fMLP), we did reveal clear signaling bias away from extracelluar signal-related kinase (ERK) 1/2 phosphorylation for the clinically tested agonist N-(2-{[4-(1,1-difluoroethyl)-1,3-oxazol-2-yl]methyl}-2H-1,2,3-triazol-4-yl)-2-methyl-5-(3-methylphenyl)-1,3-oxazole-4-carboxamide (ACT-389949), adding further evidence for its poor efficacy in two phase I studies. We also identified neuroprotectin D1 as a new leukotriene B4 receptor 1 (BLT(1)) agonist, implying an alternative target for the neuroprotective effects of the ligand. We confirmed activity for resolvin E1 (RvE1) at BLT(1) but failed to observe any response at the chemerin(1) receptor. This study provides some much-needed clarity around published receptor-ligand pairings but indicates that the expression and function of these SPM GPCRs remains very much context-dependent. In addition, the identification of signaling bias at FPR2/ALX may assist in guiding design of new FPR2/ALX agonists for the treatment of autoimmune disorders. SIGNIFICANCE STATEMENT: To our knowledge, this is the first study to comprehensibly show how several natural mediators and synthetic ligands signal through three specialized proresolving mediator GPCRs using multiple ligands from different classes across four-six endpoint signaling assays. This study discovers new ligand pairings, refutes others, reveals poly-pharmacology, and identifies biased agonism in formyl peptide receptor 2/lipoxin A4 receptor pharmacology. This study highlights the potential of these receptors in treating specific autoimmune diseases, including rheumatoid arthritis, systemic scleroderma, and systemic lupus erythematosus.
35365321 High Utility of the 1st Metatarsal Phalangeal Joint Fusion. 2022 Apr Fusion of the first metatarsophalangeal joint has been used by foot and ankle surgeons as a reproducible and useful means of treating end-stage arthritis of the great toe. However, the overall utility and successful outcomes of this procedure have led to its incorporation into the treatment of more significant bunion deformities, reconstruction forefoot, and salvage procedures. The authors review surgical fixation methods, offer insightful technical pearls for challenging cases and share examples of complex reconstructive and salvage procedures.
33993221 Pulmonary fibrosis in relation to genetic loci in an inception cohort of patients with ear 2022 Mar 2 OBJECTIVES: Pulmonary manifestations in RA are common comorbidities. Interstitial lung disease (ILD), both idiopathic and in RA, has been associated with several genetic variants. We assessed pulmonary fibrosis (PF) in an inception cohort of RA patients in relation to genetic variants and disease-related factors. METHODS: A total of 1466 early RA patients were consecutively included and followed prospectively from the index date until death or 31 December 2016. Clinical and laboratory data and treatment were continuously registered according to the Swedish Rheumatology Quality Register. DNA was available from 1184 patients and 571 151 genome-wide single-nucleotide polymorphisms (SNPs) were analysed. Thirteen identified genetic variants were extracted. At follow-up, the patients answered a questionnaire regarding disease progression and lung involvement that was validated by reviewing medical records and analysing radiological examinations. RESULTS: The prevalence of PF was 5.6% and the annualized incidence rate was 5.0/1000 (95% CI 3.80, 6.54). Four SNPs were associated with PF in RA: rs35705950 [MUC5B; OR 2.5 (95% CI 1.5, 4.0), adjusted P-value = 0.00016, q-value = 0.0021]; rs111521887 [TOLLIP; OR 1.9 (95% CI 1.3, 2.8), adjusted P-value = 0.0014, q-value = 0.0092]; rs2609255 [FAM13A; OR 1.7 (95% CI 1.1, 2.5), adjusted P-value = 0.013, q-value = 0.055] and rs2736100 [TERT; OR 1.5 (95% CI 1.0, 2.2), adjusted P-value = 0.046, q-value = 0.15]. Older age and RF positivity were associated with increased risk, while MTX treatment was associated with a lower risk of PF. CONCLUSIONS: Development of PF in an inception cohort of RA patients was associated with 4 of 12 ILD risk genes. RA-related factors except for age at diagnosis and RF positivity were of limited importance in PF development.
35107653 Erosive Hand OsteoArthritis (EHOA): analysis of consecutive patients presenting with EHOA 2022 Jun INTRODUCTION: Erosive Hand OsteoArthritis (EHOA) is a common rheumatological problem. We aim to determine characteristics of EHOA patients: comorbidities, radiographic erosivity and pain experienced after being diagnosed, in order to find which of these are potentially relevant in upcoming interventional trials. METHOD: Retrospective analysis of EHOA patients within the electronic database in one centre, with a telephone interview on pain as experienced even exceeding 12 months after being diagnosed. RESULTS: Eighty-four non-academic EHOA patients were found: 89% females (median age 69 years), 11% males (similar age distribution). Kellgren-Lawrence (KL) erosivity scores in both sexes were comparable; DIPs scored higher than PIP's. Comorbid conditions were crystal-induced arthritis, rheumatoid arthritis (RA) and psoriatic arthritis (PsA) in 8%, 5% and 1%, respectively; seropositivity for rheumatoid factor and anti-citrullinated protein antibodies in 8% and 1% respectively. Pain worst experienced often exceeded a visual analogue score of 5.0, but was unrelated to the total KL score. Some pain reduction was reached with non-steroidals (perorally/transcutaneously) as deduced from continued use in 1 in 3. CONCLUSIONS: In many EHOA patients, there is an unmet need regarding the treatment of pain, which per se was not directly correlated with erosivity score. Future studies may be designed considering the aforementioned characteristics, acting on the inflammatory process resulting in PIP/DIP erosions, with the exclusion of RA and PsA in order to get a clean study on EHOA. Several studies with monoclonal antibodies have been performed but demonstrated ineffectivity on the outcome of pain. Hope glooms with the arrival of innovative small molecules that may reach EHOA target cells. Key Points • Erosive handOA is a common problem in non-academic rheumatology; it is often associated with significant pain in both sexes exceeding a VASpain of 5.0 even years after being diagnosed; 1 in 3 found some relief in non-steroidals perorally/transcutaneously. • Future studies will have to focus on (episodic) inflammatory hand OA resulting in proven erosivity (EHOA) located in PIP plus DIP joints and may have to exclude comorbid active crystal-induced arthritis as well as rheumatoid/psoriatic arthritis and possibly even RF/ACPA seropositivity in order to get a clean study on EHOA. • As several big monoclonals have failed in EHOA, we may have to search for promising new drugs within the group of small molecules. These will have to show a significant pain-reducing effect and preferably also a disease-modifying osteoarthritis drug (DMOAD) effect.
34670991 Development of a COVID-19 Vaccine Readiness Kit for Veterans With Rheumatologic Diseases o 2022 Mar 1 BACKGROUND: The advent of multiple safe and effective vaccines to prevent SARS-CoV-2 infection represents a major step in resolving the COVID-19 global pandemic. Vaccination of individuals with rheumatologic diseases on immunomodulators represents an additional challenge because data suggest that certain immunomodulators may impact vaccine efficacy. METHODS: At a large, predominantly rural Midwestern Veterans Affairs rheumatology clinic, an interprofessional group of investigators conducted a quality improvement project to develop a COVID-19 vaccine readiness kit, consisting of patient education materials and a readiness questionnaire to help guide veteran decision-making. Using a Lean Six Sigma approach and the DMAIC (Define-Measure-Analyze-Improve-Control) framework, the investigators identified customer values, needs, and barriers to participation. Return rates and responses from the questionnaire were tracked over 28 days. RESULTS: One hundred seventy-nine veterans were identified and mailed kits; 129 (73%) returned the questionnaire within 28 days. Ninety-seven percent of those opted to hold immunomodulators after at least 1 administration of the vaccine; 3.1% were not interested in vaccination. Veterans voiced satisfaction at the simplicity of the process, comprehensibility of materials, and the clarity of communication. CONCLUSIONS: The Lean Six Sigma approach, systematically focusing on identifying the values, needs, and barriers of veterans on immunomodulators, was critical to high participation rates from veterans. This approach is cost-effective for resource-poor settings, audiences without access or familiarity to digital content, and rural settings separated by large geographic distances.