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ID PMID Title PublicationDate abstract
34488779 Biologic medicine inclusion in 138 national essential medicines lists. 2021 Sep 6 BACKGROUND: Essential medicines lists (EMLs) are intended to reflect the priority health care needs of populations. We hypothesized that biologic disease-modifying antirheumatic drugs (DMARDs) are underrepresented relative to conventional DMARDs in existing national EMLs. We aimed to survey the extent to which biologic DMARDs are included in EMLs, to determine country characteristics contributing to their inclusion or absence, and to contrast this with conventional DMARD therapies. METHODS: We searched 138 national EMLs for 10 conventional and 14 biologic DMARDs used in the treatment of childhood rheumatologic diseases. Via regression modelling, we determined country characteristics accounting for differences in medicine inclusion between national EMLs. RESULTS: Eleven countries (7.97%) included all 10 conventional DMARDs, 115 (83.33%) ≥5, and all countries listed at least one. Gross domestic product (GDP) per capita was associated with the total number of conventional DMARDs included (β(1)1.02 [95% CI 0.39, 1.66]; P = 0.00279). Among biologic DMARDs, 3 countries (2.2%) listed ≥10, 15 (10.9%) listed ≥5, and 47 (34.1%) listed at least one. Ninety-one (65.9%) of countries listed no biologic DMARDs. European region (β(1) 1.30 [95% CI 0.08, 2.52]; P = 0.0367), life expectancy (β(1)-0.70 [95% CI -1.22, - 0.18]; P = 0.0085), health expenditure per capita (β(1) 1.83 [95% CI 1.24, 2.42]; P < 0.001), and conventional DMARDs listed (β(1) 0.70 [95% CI 0.33, 1.07]; P < 0.001) were associated with the total number of biologic DMARDs included. CONCLUSION: Biologic DMARDs are excluded from most national EMLs. By comparison, conventional DMARDs are widely included. Countries with higher health spending and longer life expectancy are more likely to list biologics.
34691039 Anti-Carbamylated Fibrinogen Antibodies Might Be Associated With a Specific Rheumatoid Phe 2021 To identify the targets recognized by anti-carbamylated protein antibodies (anti-CarP) in patients with early Rheumatoid Arthritis (RA), to study the cross-reactivity between anti-CarP and anti-citrullinated protein antibodies (ACPA) and to evaluate their prognostic value. 331 patients (184 RA and 147 other rheumatisms) from the Very Early Arthritis (VErA) French cohort were analyzed. We performed mass spectrometry analysis of RA sera displaying anti-CarP activity and epitope mapping of the carbamylated fibrinogen γ chain to identify immunodominant peptides. The specificity of these targets was studied using competition assays with the major antigens recognized by ACPA. The prognostic value of anti-carbamylated fibrinogen IgG antibodies (ACa-Fib IgG) was compared to that of anti-cyclic citrullinated peptide antibodies (anti-CCP) and anti-CarP using an in-house ELISA. Besides the α chain, the γ chain of fibrinogen, particularly one immunodominant epitope that has a specific reactivity, was identified as a circulating carbamylated target in sera. The prevalence of ACa-Fib was 37% at baseline and 10.9% for anti-CCP-negative RA. In anti-CCP-negative patients, ACa-Fib positivity was associated with a more inflammatory and erosive disease at baseline but not with rapid radiological progression, which remains strongly related to anti-CCP antibodies. Fibrinogen seems to be one of the antigens recognized in vivo by the anti-CarP response, particularly 2 epitopes of the γ chain, one of which is not cross reactive with ACPA. This specificity might be associated with a distinct clinical phenotype since ACa-Fib IgG were shown to be linked to systemic inflammation in very early RA but not to rapid radiological progression.
33974929 Neutralizing anti-IL-1 receptor antagonist autoantibodies induce inflammatory and fibrotic 2022 Jan BACKGROUND: IgG4-related disease (IgG4-RD) is a fibroinflammatory condition involving loss of B-cell tolerance and production of autoantibodies. However, the relevant targets and role of these aberrant humoral immune responses are not defined. OBJECTIVE: Our aim was to identify novel autoantibodies and autoantigen targets that promote pathogenic responses in IgG4-RD. METHODS: We sequenced plasmablast antibody repertoires in patients with IgG4-RD. Representative mAbs were expressed and their specificities characterized by using cytokine microarrays. The role of anti-IL-1 receptor antagonist (IL-1RA) autoantibodies was investigated by using in vitro assays. RESULTS: We identified strong reactivity against human IL-1RA by using a clonally expanded plasmablast-derived mAb from a patient with IgG4-RD. Plasma from patients with IgG4-RD exhibited elevated levels of reactivity against IL-1RA compared with plasma from the controls and neutralized IL-1RA activity, resulting in inflammatory and fibrotic mediator production in vitro. IL-1RA was detected in lesional tissues from patients with IgG4-RD. Patients with anti-IL-1RA autoantibodies of the IgG4 subclass had greater numbers of organs affected than did those without anti-IL-1RA autoantibodies. Peptide analyses identified IL-1RA epitopes targeted by anti-IL-1RA antibodies at sites near the IL-1RA/IL-1R interface. Serum from patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) also had elevated levels of anti-IL-1RA autoantibodies compared with those of the controls. CONCLUSION: A subset of patients with IgG4-RD have anti-IL-1RA autoantibodies, which promote proinflammatory and profibrotic meditator production via IL-1RA neutralization. These findings support a novel immunologic mechanism underlying the pathogenesis of IgG4-RD. Anti-IL-1RA autoantibodies are also present in a subset of patients with SLE and RA, suggesting a potential common pathway in multiple autoimmune diseases.
33389218 Sialic Acid Conjugate-Modified Liposomal Dexamethasone Palmitate Targeting Neutrophils for Many anti-inflammatory therapies targeting neutrophils have been developed so far. A sialic acid (SA)-modified liposomal (SAL) formulation, based on the high expression of L-selectin in peripheral blood neutrophils (PBNs) and SA as its targeting ligand, has proved to be an effective neutrophil-mediated drug delivery system targeting rheumatoid arthritis (RA). The objective of this study was to investigate the influence of particle size of drug-carrying SALs transported and delivered by neutrophils on their anti-RA effect. Dexamethasone palmitate-loaded SALs (DP-SALs) of different particle sizes (300.2 ± 5.5 nm, 150.3 ± 4.3 nm, and 75.0 ± 3.9 nm) were prepared with DP as a model drug. Our study indicated that DP-SALs could efficiently target PBNs, with larger liposomes leading to higher drug accumulation in cells. However, a high intake of large DP-SALs by PBNs inhibited their migration ability and capacity to release the payload at the target site. In contrast, small DP-SALs (75.0 ± 3.9 nm) could maintain the drug delivery potential of PBNs, leading to their efficient accumulation at the inflammatory site, where PBNs would be excessively activated to form neutrophil extracellular traps along with efficient payload release (small DP-SALs) and finally to induce excellent anti-RA effect.
32453216 Metabolic Syndrome, Disease Activity, and Adipokines in Patients With Newly Diagnosed Infl 2021 Dec 1 OBJECTIVE: To investigate metabolic syndrome (MetS), disease activity, and adipokine levels among patients with rheumatoid arthritis (RA), spondyloarthritis (SpA), and undifferentiated arthritis (UA) at the time of diagnosis and after 1 year of follow-up. METHODS: Patients with inflammatory joint diseases participating in the Northern Savo 2010 population-based longitudinal epidemiological study were evaluated for components of MetS (by National Cholesterol Education Program's Adult Treatment Panel III) and clinical parameters of disease activity. The adipokines adiponectin, adipsin, resistin, and leptin were measured at baseline and after 1 year of treatment with disease-modifying antirheumatic drugs. RESULTS: Among 176 patients, MetS was detected in 42% of RA, 36% of SpA, and 51% of UA patients. Metabolic syndrome was associated with higher disease activity as measured by patient global assessment in RA and UA patients and increased pain in RA patients. Leptin levels were increased in patients with MetS, showing a linearly increasing trend with the number of components of MetS in SpA and UA, but not in RA. In RA patients, decrease in disease activity correlated with decrease in leptin levels. Resistin did not associate with MetS, but a decrease in resistin correlated with decrease in disease activity in RA and UA. In SpA, increased adiponectin level correlated with relief in disease activity, but not with MetS. CONCLUSIONS: Metabolic syndrome was common in patients with newly diagnosed arthritides and associated with higher disease activity and increased leptin levels. Resistin responded to treatment of arthritis in RA and UA, leptin in RA, and adiponectin in SpA.
33249645 Anti-citrullinated protein antibodies are associated with neutrophil extracellular trap fo 2021 Mar OBJECTIVES: We evaluated the associations of anti-citrullinated protein antibodies (ACPAs) and serological and cytological levels of neutrophil extracellular trap (NET) formation in rheumatoid arthritis (RA) patients. METHODS: Serum levels of myeloperoxidase-DNA and elastase-DNA complexes (NET remnants) were examined in 51 patients with RA and 40 healthy controls using a modified enzyme-linked immunosorbent assay. Neutrophils were isolated by density gradient centrifugation. IgG antibodies were purified by affinity chromatography. NET formation in RA and control neutrophils was assessed by microscopy in vitro. NETs were purified and co-incubated with fibroblast-like synoviocyte (FLS) cells. Interleukin (IL)-6 and IL-8 mRNA expression and protein levels in FLS cells were determined by real-time polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. RESULTS: In RA patients, NET remnants in the peripheral circulation were higher in extremely high ACPA titers when compared to in moderate ACPA titers. And IgG antibodies containing ACPA can stimulate neutrophils to form NETs in a concentration-dependent manner. Furthermore, significantly higher expression of the pro-inflammatory cytokines IL-6 and IL-8 is detected after FLS cells interacted with NETs which derived from neutrophils stimulated with ACPA-containing IgG antibodies. CONCLUSIONS: Anti-citrullinated protein antibodies may enhance NET formation and contribute to inflammation development in RA by stimulating NET formation, such as by subsequent activation of FLS cells by NETs.
34882369 The effect of Helicobacter pylori seropositivity and activity on disease outcome in patien 2021 Oct The association between infection with Gram-negative bacteria and autoimmune diseases has been investigated with controversies about the role of the organisms especially, Helicobacter pylori (H. pylori). To evaluate the impact of the presence and activity of H. pylori on the disease activity in patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and ankylosing spondylitis (AS). This study was carried out on one hundred adult patients and 50 controls. Patients included 40 RA, 40 SLE, and 20 AS. Participants were subjected to clinical examination and laboratory investigations; ESR (spectrophotometric assay), CRP (turbidimetric method), serum H.pylori IgG antibody test (enzyme immunoassay), and H. pylori antigen test (lateral flow immunoassay, rapid one-step test) in stool. Positive test in stool indicated active current H. pylori infection. Mean age of patients was 36.95±10.34; 51.2±6.91, 35.5±3.71, and 48.82±5.81 in SLE, RA, AS, and control groups respectively. Serum H. pylori IgG antibodies was 0.803±0.497 U/mL in SLE group, 1.48±0.637 U/mL in RA group and 0.75±0.68 U/mL in AS group while it was 0.2±0.61U/mL in the control group with a significant difference (P=0.000). The H. pylori antigen in stool was found positive in 30%, 70% and 20% of patients of the three groups respectively while it was positive in 10% of the control group with P>0.001. Patients with active SLE (SLEDAI >3) and RA (DAS-28 >3.2) demonstrated higher frequency of positive test for H. pylori antigen in stool than patients at remission (66.7% P= 0.02 and 83.3% P= 0.01 respectively). In contrast, 22.2% of patients with active AS (BASDAI > 4) were positive for H. pylori in stool. In conclusion, H. pylori infection is associated with increased disease activity in patients with SLE and RA but not AS.
32967573 Subcutaneous immunoglobulin therapy in statin-induced necrotizing autoimmune myopathy. 2021 Jan We report a case of statin-associated necrotising autoimmune myopathy successfully treated with subcutaneous immunoglobulin therapy (SCIG) monotherapy without corticosteroids. This is a 51-year old female with seronegative rheumatoid arthritis, who had been on statins for several years, who developed proximal muscle weakness and elevated creatine kinase after resuming her statin post sleeve gastrectomy for weight loss. Our patient had a history of severe side effects to prednisone. She did not respond to mycophenolate, cyclophosphamide, and rituximab treatment. She had responded to partial treatment with intravenous immunoglobulin (IVIG) but had a severe headache after IVIG infusion. IVIG treatment was discontinued. We tried SCIG treatment, and she was able to tolerate the SCIG treatment with intermittent headaches that were less intense. After treatment with SCIG, creatine kinase levels decreased significantly, with an improvement of muscle strength. She continues to do well on SCIG treatment. To our knowledge, no other cases of statin-associated necrotising autoimmune myopathy treated with SCIG have been reported in the literature. More studies and reports are needed to confirm the utility and efficacy of SCIG in statin-associated necrotising autoimmune myopathy, as well as to provide information about dosing, tolerability, and durability of SCIG in the treatment of statin-associated necrotising autoimmune myopathy.
32687015 Rapidly progressive glomerulonephritis after introduction of certolizumab pegol: a case re 2021 Jan Tumour necrosis factor (TNF) inhibitors are used against a variety of connective tissue diseases, including rheumatoid arthritis. Contrarily, although rare, TNF inhibitors are known to induce autoimmune diseases, such as systemic lupus erythematosus and psoriasis as a paradoxical reaction. We experienced a case of rapidly progressive glomerulonephritis after introduction of certolizumab pegol. The patient was a 30-year-old woman who was previously diagnosed with rheumatoid arthritis in X-8. She received treatment with methotrexate (8 mg/week) and infliximab (3 mg/kg/8 weeks), following which she showed low disease activity and remission. In September X-1, methotrexate and infliximab were discontinued and certolizumab pegol was introduced because she desired to bear children. In March X, the patient experienced renal dysfunction, and urinary protein analysis revealed positivity for myeloperoxidase anti-neutrophil cytoplasmic autoantibody. Renal biopsy showed crescentic glomerulonephritis, and the patient was diagnosed with rapidly progressive glomerulonephritis due to TNF inhibitor-induced microscopic polyangiitis. As she desired to bear children, rituximab was introduced in addition to corticosteroids, which led to remission of the symptoms. TNF inhibitors should be discontinued in patients who develop rapidly progressive glomerulonephritis, and these patients should be treated with immunosuppressive drugs, such as massive corticosteroids and cyclophosphamide. In the present case, rituximab was useful for not only the treatment, but also for the preservation of fertility.
34678240 Icariin arrests cell cycle progression and induces cell apoptosis through the mitochondria 2021 Dec 5 Rheumatoid arthritis (RA) is a highly disabling autoimmune disorder, characterized by the proliferation of Fibroblast-like Synoviocytes (FLSs). Icariin is a prenylated flavonol glycoside extracted from the medical plant Epimedium, which can inhibit the proliferation and migration of FLSs. However, the potential mechanism of icariin to alleviate RA remains unclear. In this study, icariin inhibited the migration and proliferation of FLSs in a concentration-dependent manner, by inducing G2/M phase arrest and apoptosis. Icariin reduced the mitochondrial transmembrane potential, upregulated cytosolic cytochrome c and increased the level of intracellular reactive oxygen species (ROS). In conclusion, icariin inhibited the proliferation of FLSs by interfering with the cell cycle process and inducing cell apoptosis, suggesting its potential use for the treatment of RA.
34013364 Astragaloside regulates lncRNA LOC100912373 and the miR‑17‑5p/PDK1 axis to inhibit the 2021 Jul Previous studies have confirmed that astragaloside (AST) exerts a positive effect on alleviating synovial and joint injury in rheumatoid arthritis (RA). However, the precise mechanisms through which AST acts in the treatment of RA remain unclear. Long non‑coding RNA (lncRNA) LOC100912373 was identified as a key gene related to RA and has been proven to interact with miR‑17‑5p, in order to regulate the pyruvate dehydrogenase kinase 1 and protein kinase B axis (PDK1/AKT axis). The present study aimed to determine whether AST may treat RA through the interaction between lncRNA LOC100912373 and the miR‑17‑5p/PDK1 axis. MTT assays and flow cytometry were used to detect the proliferation and cell cycle progression of AST‑treated fibroblast‑like synoviocytes (FLSs). The expression of lncRNA LOC100912373 and miR‑17‑5p, as well as relative the mRNA expression of the PDK1 and AKT genes following AST intervention was detected by reverse transcription‑quantitative PCR (RT‑qPCR), immunofluorescence and western blot analysis. The results revealed that AST inhibited FLS proliferation, reduced lncRNA LOC100912373 expression levels, increased miR‑17‑5p expression levels, and decreased the PDK1 and p‑AKT expression levels. Additionally, consecutive rescue experiments revealed that AST counteracted the effects of lncRNA LOC100912373 overexpression on FLS proliferation and cell cycle progression. On the whole, the present study demonstrates that AST inhibits FLS proliferation by regulating the expression of lncRNA LOC100912373 and the miR‑17‑5p/PDK1 axis.
33459349 Atypical phenotype and response of B cells in patients with seropositive rheumatoid arthri 2021 May Patients with rheumatoid arthritis (RA) may be classified as seropositive or seronegative according to the presence of autoantibodies. An abnormal B cell phenotype and function could be one of the main components of the immunopathology of seropositive patients; however, there is little information regarding B cell defects in these patients. This study shows a broad characterization of the B cell phenotype and function in patients with seropositive RA. We focused mainly on the evaluation of subsets, the expression of modulatory molecules of cell activation (CD22, FcɣRIIb and FcµR), calcium mobilization, global tyrosine phosphorylation, expression of activation markers, cytokine and immunoglobulin (Ig) production, proliferation and the in-vitro generation of plasma cells. Increased frequency of CD27(-) IgM(-) IgD(-) and CD21(-) B cells was observed in patients with seropositive RA compared with healthy donors (HD). Decreased expression of CD22 was primarily found in memory B cells of patients with RA regardless of seropositivity. B cells from seropositive patients exhibited normal proliferation, calcium mobilization kinetics and global tyrosine phosphorylation, but showed an increased frequency of CD86(+) B cells compared with HD. B cells of seropositive patients secrete less interleukin-10 after in-vitro activation and showed a decreased frequency of plasma cell differentiation and IgM production compared with HD. Our data indicate that patients with seropositive RA have an increased frequency of atypical B cell populations previously associated with chronic activation and antigen exposure. This may result in the observed low responsiveness of these cells in vitro.
34437305 Orthopaedic Gene Therapy: Twenty-Five Years On. 2021 Aug 26 »: Orthopaedics pioneered the expansion of gene therapy beyond its traditional scope of diseases that are caused by rare single-gene defects. Orthopaedic applications of gene therapy are most developed in the areas of arthritis and regenerative medicine, but several additional possibilities exist. »: Invossa, an ex vivo gene therapeutic for osteoarthritis, was approved in South Korea in 2017, but its approval was retracted in 2019 and remains under appeal; a Phase-III clinical trial of Invossa has restarted in the U.S. »: There are several additional clinical trials for osteoarthritis and rheumatoid arthritis that could lead to approved gene therapeutics for arthritis. »: Bone-healing and cartilage repair are additional areas that are attracting considerable research; intervertebral disc degeneration and the healing of ligaments, tendons, and menisci are other applications of interest. Orthopaedic tumors, genetic diseases, and aseptic loosening are additional potential targets. »: If successful, these endeavors will expand the scope of gene therapy from providing expensive medicines for a few patients to providing affordable medicines for many.
34594343 ImmunosuppressiveTherapies Differently Modulate Humoral- and T-Cell-Specific Responses to 2021 OBJECTIVE: To assess in rheumatoid arthritis (RA) patients, treated with different immunosuppressive therapies, the induction of SARS-CoV-2-specific immune response after vaccination in terms of anti-region-binding-domain (RBD)-antibody- and T-cell-specific responses against spike, and the vaccine safety in terms of clinical impact on disease activity. METHODS: Health care workers (HCWs) and RA patients, having completed the BNT162b2-mRNA vaccination in the last 2 weeks, were enrolled. Serological response was evaluated by quantifying anti-RBD antibodies, while the cell-mediated response was evaluated by a whole-blood test quantifying the interferon (IFN)-γ-response to spike peptides. FACS analysis was performed to identify the cells responding to spike stimulation. RA disease activity was evaluated by clinical examination through the DAS28crp, and local and/or systemic clinical adverse events were registered. In RA patients, the ongoing therapeutic regimen was modified during the vaccination period according to the American College of Rheumatology indications. RESULTS: We prospectively enrolled 167 HCWs and 35 RA patients. Anti-RBD-antibodies were detected in almost all patients (34/35, 97%), although the titer was significantly reduced in patients under CTLA-4-inhibitors (median: 465 BAU/mL, IQR: 103-1189, p<0.001) or IL-6-inhibitors (median: 492 BAU/mL, IQR: 161-1007, p<0.001) compared to HCWs (median: 2351 BAU/mL, IQR: 1389-3748). T-cell-specific response scored positive in most of RA patients [24/35, (69%)] with significantly lower IFN-γ levels in patients under biological therapy such as IL-6-inhibitors (median: 33.2 pg/mL, IQR: 6.1-73.9, p<0.001), CTLA-4-inhibitors (median: 10.9 pg/mL, IQR: 3.7-36.7, p<0.001), and TNF-α-inhibitors (median: 89.6 pg/mL, IQR: 17.8-224, p=0.002) compared to HCWs (median: 343 pg/mL, IQR: 188-756). A significant correlation between the anti-RBD-antibody titer and spike-IFN-γ-specific T-cell response was found in RA patients (rho=0.432, p=0.009). IFN-γ T-cell response was mediated by CD4(+) and CD8(+) T cells. Finally, no significant increase in disease activity was found in RA patients following vaccination. CONCLUSION: This study showed for the first time that antibody-specific and whole-blood spike-specific T-cell responses induced by the COVID-19 mRNA-vaccine were present in the majority of RA patients, who underwent a strategy of temporary suspension of immunosuppressive treatment during vaccine administration. However, the magnitude of specific responses was dependent on the immunosuppressive therapy administered. In RA patients, BNT162b2 vaccine was safe and disease activity remained stable.
33310728 Large-scale meta-analysis across East Asian and European populations updated genetic archi 2021 May OBJECTIVES: Nearly 110 susceptibility loci for rheumatoid arthritis (RA) with modest effect sizes have been identified by population-based genetic association studies, suggesting a large number of undiscovered variants behind a highly polygenic genetic architecture of RA. Here, we performed the largest-ever trans-ancestral meta-analysis with the aim to identify new RA loci and to better understand RA biology underlying genetic associations. METHODS: Genome-wide RA association summary statistics in three large case-control collections consisting of 311 292 individuals of Korean, Japanese and European populations were used in an inverse-variance-weighted fixed-effects meta-analysis. Several computational analyses using public omics resources were conducted to prioritise causal variants and genes, RA variant-implicating features (tissues, pathways and transcription factors) and potentially repurposable drugs for RA treatment. RESULTS: We identified 11 new RA susceptibility loci that explained 6.9% and 1.8% of the single-nucleotide polymorphism-based heritability in East Asians and Europeans, respectively, and confirmed 71 known non-human leukocyte antigens (HLA) susceptibility loci, identifying 90 independent association signals. The RA variants were preferentially located in binding sites of various transcription factors and in cell type-specific transcription-activation histone marks that simultaneously highlighted the importance of CD4(+) T-cell activation and the potential role of non-immune organs in RA pathogenesis. A total of 615 plausible effector genes, based on gene-based associations, expression-associated variants and chromatin interaction, included targets of drugs approved for RA treatments and potentially repurposable drugs approved for other indications. CONCLUSION: Our findings provide useful insights regarding RA genetic aetiology and variant-driven RA pathogenesis.
34800087 The composition of the lung microbiome differs between patients with dermatomyositis and r 2022 Jan Dermatomyositis and rheumatoid arthritis are inflammatory diseases that affect the skeletal muscles and joints, respectively. A common systemic complication of these diseases is interstitial lung disease (ILD), which leads to a poor prognosis and increased mortality. However, the mechanism for the initiation and development of ILD in patients with dermatomyositis is currently unknown. In the present study, we used 16S rRNA high-throughput sequencing to profile the bacterial community composition of bronchoalveolar lavage fluid of patients with dermatomyositis associated with ILD (DM-ILD; shortened to DM below), rheumatoid arthritis associated with ILD (RA-ILD; shortened to RA below) and healthy controls (N) aiming to understand the differences in their lung microbiota and to predict gene function. We found that there were more operational taxonomic units (OTUs) in the lung microbiota of both RA and DM compared to N, although there was no significant difference in the number of OTUs between RA and DM. Similarly, the diversity in alphaproteobacteria differed between RA and DM compared to N, but not between RA and DM. The lung microbiota of RA, DM and N was mainly comprised of five phyla: Firmicutes, Bacteroidetes, Proteobacteria, Actinobacteria and Fusobacteria, with 10 dominant genera. Despite the similarity in microbiota composition, we also identified 41 OTUs of lung microbiota that differed among RA, DM and N. Additionally, linear discriminant analysis effect size and linear discriminant analysis genus scores confirmed that 31 microbial biomarkers were clearly distinguished among RA, DM and N. The functional and metabolic alterations of the lung microbiota among RA, DM and N were predicted using picrust, and differentially abundant KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways were identified. Research on the lung microbiota of patients with DM and RA may open new opportunities for developing biomarkers to identify high-risk patients.
33381897 HLA-B*08 Identified as the Most Prominently Associated Major Histocompatibility Complex Lo 2021 Jun OBJECTIVE: Previously, only the HLA-DRB1 alleles have been assessed in rheumatoid arthritis (RA). The aim of the present study was to identify the key major histocompatibility complex (MHC) susceptibility factors showing a significant association with anti-carbamylated protein antibody-positive (anti-CarP+) RA. METHODS: Analyses were restricted to RA patients who were anti-cyclic citrullinated peptide antibody negative (anti-CCP-), because the anti-CCP status dominated the results otherwise. Therefore, we studied samples from 1,821 anti-CCP- RA patients and 6,821 population controls from Spain, Sweden, and the Netherlands. The genotypes for ~8,000 MHC biallelic variants were assessed by dense genotyping and imputation. Their association with the anti-CarP status in RA patients was tested with logistic regression and combined with inverse-variance meta-analysis. Significance of the associations was assessed according to a study-specific threshold of P < 2.0 × 10(-5) . RESULTS: The HLA-B*08 allele and its correlated amino acid variant Asp-9 showed a significant association with anti-CarP+/anti-CCP- RA (P < 3.78 × 10(-7) ; I(2) = 0). This association was specific when assessed relative to 3 comparator groups: population controls, anti-CarP-/anti-CCP- RA patients, and anti-CCP- RA patients who were positive for other anti-citrullinated protein antibodies. Based on these findings, anti-CarP+/anti-CCP- RA patients could be separated from other antibody-defined subsets of RA patients in whom an association with the HLA-B*08 allele has been previously demonstrated. No other MHC variant remained associated with anti-CarP+/anti-CCP- RA after accounting for the presence of the HLA-B*08 allele. Specifically, the reported association of HLA-DRB1*03 was observed at a level comparable to that reported previously, but it was attributable to linkage disequilibrium. CONCLUSION: These results identify HLA-B*08 carrying Asp-9 as the MHC locus showing the strongest association with anti-CarP+/anti-CCP- RA. This knowledge may help clarify the role of the HLA in susceptibility to specific subsets of RA, by shaping the spectrum of RA autoantibodies.
33934077 Safety of the Methotrexate-leflunomide Combination in Rheumatoid Arthritis: Results of a M 2021 Oct OBJECTIVE: To evaluate the safety of the methotrexate (MTX)-leflunomide (LEF) combination in rheumatoid arthritis (RA), comparing it with other therapeutic schemes involving conventional synthetic (cs-) and biologic (b-) disease-modifying antirheumatic drugs (DMARDs) or Janus kinase inhibitors (JAKi). METHODS: Patients with RA starting a treatment course with a csDMARD (without previous use of bDMARD or JAKi) or their first bDMARD/JAKi were followed up in a registry-based, multicentric cohort study in Brazil (BiobadaBrasil). The primary outcome was the incidence of serious adverse events (SAEs); secondary outcomes included serious infections. Multivariate Cox proportional hazards models and propensity score matching analysis (PSMA) were used for statistical comparisons. RESULTS: In total, 1671 patients (5349 patient-years [PY]) were enrolled; 452 patients (1537 PY) received MTX + LEF. The overall incidence of SAEs was 5.6 per 100 PY. The hazard of SAEs for MTX + LEF was not higher than for MTX or LEF (adjusted HR [aHR] 1.00, 95% CI 0.76-1.31, P = 0.98). MTX + LEF presented a lower hazard of SAEs (aHR 0.56, 95% CI 0.36-0.88, P = 0.01) and infectious SAEs (aHR 0.48, 95% CI 0.25-0.94, P = 0.03) than bDMARDs/JAKi with MTX or LEF. MTX + LEF presented lower hazard of SAEs than MTX + sulfasalazine (SSZ; aHR 0.33, 95% CI 0.16-0.65, P = 0.002). Analysis using PSMA confirmed the results obtained with traditional multivariate Cox analysis. CONCLUSION: In our study, MTX + LEF presented a relatively good overall safety profile in comparison to MTX + SSZ and schemes involving advanced therapies in RA.
33739886 Pinocembrin Reduces Arthritic Symptoms in Mouse Model via Targeting Sox4 Signaling Molecul 2021 Mar Rheumatoid arthritis (RA) is a chronic autoimmune, multifactorial, inflammatory disorder characterized by hyperplasia and infiltration of inflammatory cells at the synovial lining leading to destruction of cartilage and bone tissues. Pinocembrin (PCB) is a natural flavonoid extracted as a pure molecule from honey, propolis, and some plants. In this study, we evaluated the antiarthritic effect of PCB in adjuvant induced arthritis (AIA) mice. Treating the AIA mouse model with PCB reduced the arthritis symptoms/score, including edema size, extent of hind paw redness, abnormal movement, and holding inability. At the pathological level, PCB significantly decreased the joint erosion and percentages of infiltrated inflammatory cells. Biochemically, PCB interacts with the transcription factor, SRY-related HMG-box 4 (Sox4), and then modulates its dysregulated expression and the expression of Sox4/Stat3 signaling molecules in AIA mice. These molecules include tumor necrosis factor-α, nuclear transcription factor kappaB, and cyclooxygenase-2, besides the microRNAs; miR-132, miR-202-5p, and miR-7235, which are dysregulated in adjuvant-induced arthritis model relative to the control mice. The possible PCB interaction with Sox4 transcriptional protein was confirmed through molecular docking where three hydrogen bonds were formed at ARG and LYS residues at a stable binding energy of -4.72. Taken together, our data demonstrate that PCB could serve as a therapeutic drug in treatment of RA.
33799223 Wutou decoction ameliorates experimental rheumatoid arthritis via regulating NF-kB and Nrf 2021 May BACKGROUND: Thousands of years of clinical application of Wutou decoction (WTD) support its reliable efficacy and safety in treating rheumatoid arthritis (RA). However, the underlying molecular mechanism remains unclear, and the synergistic involvement of assistant herbs in WTD in enhancing the sovereign herb in treating RA is unknown. PURPOSE: This study aimed to investigate the efficacy-oriented compatibility of five herbs in WTD and the underlying mechanisms. METHODS: The anti-arthritic effects of WTD and the compatibilities of the five herbs in WTD were studied in vivo with adjuvant-induced arthritis (AIA) rat model and in vitro with LPS-induced RAW264.7 macrophage. Network pharmacology analysis was conducted to identify the dominant pathways involved in the anti-arthritis mechanisms of WTD and how the five herbs work synergistically. The results were further verified by in vivo and in vitro experiments. RESULTS: Our data revealed that the five herbs in WTD exert synergistic anti-arthritic effects on RA. Moreover, Radix Aconite (AC) is the principal anti-inflammatory component in WTD according to the extent of therapeutic effects exerted on the AIA rats. In vivo and in vitro experiments demonstrated that WTD inhibited NF-κB phosphorylation and simultaneously increased the expression of Nrf2, which were the major pathways identified by the network pharmacology analysis. The major assistant component, Herba Ephedrae (EP), evidently inhibited NF-κB mediated inflammatory response. The other assistant component, Radix Astragali (AS), considerably enhanced the expression of Nrf2 when used alone or in combination with AC. These combinations improved the anti-arthritis effects on the AIA rats better than that of AC alone. Nevertheless, WTD always achieved the best effects than any combinations both in vivo and in vitro. CONCLUSION: The ministerial herbs EP and AS intensify the anti-arthritic effects of AC by regulating the NF-κB-mediated inflammatory pathway and the Nrf2-mediated anti-oxidation pathway which are the major pathways of WTD for alleviating the symptoms of RA.