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ID PMID Title PublicationDate abstract
34305925 Pathogenic Role of Circulating Citrullinated Antigens and Anti-Cyclic Monoclonal Citrullin 2021 We examined whether it is possible to directly detect citrullinated antigens in the serum of rheumatoid arthritis (RA) patients using a monoclonal antibody (mAb) designed to be specific for citrullinated peptides. In order to confirm the potential of the mAb as a direct arthritis-inducing substance through experimental model of RA, a monoclonal antibody (mAb) 12G1 was generated using by immunization of mice with a challenging cyclic citrullinated peptide. Immunohistochemical analysis of RA-affected synovial tissue showed that our mAb 12G1 could indeed detect citrullinated proteins in target tissues. Subsequently, serum levels of citrullinated type II collagen and filaggrin were measured in healthy volunteers, patients with RA, ankylosing spondylitis (AS), and systemic lupus erythematosus (SLE) using a 12G1-based sandwich ELISA. This showed that citrullinated filaggrin showed 78.9% sensitivity and 85.9% specificity for RA diagnosis with a cutoff optical density (OD) value of 1.013, comparable with the results from a second-generation anti-citrullinated protein antibody (ACPA) test. Circulating citrullinated collagen and filaggrin were detected even in sera of RA patients who were negative for both rheumatoid factor (RF) and ACPA. ELISA results also showed that RF and ACPA titers showed significantly positive correlation with both citrullinated collagen and filaggrin OD values in sera of RA patients. 12G1 challenging aggravated the severity of murine arthritis. In summary, mAb 12G1 can directly detect citrullinated proteins in RA target tissue and in sera of RA patients and 12G1 showed direct arthritogenic potential in vivo. This, 12G1 might be useful for diagnosis of RA including seronegative RA and may help to elucidate the pathophysiological role of citrullination in RA.
33048777 Yoga and its impact on chronic inflammatory autoimmune arthritis. 2021 Jan 1 Rheumatoid arthritis (RA) is one of the most common chronic inflammatory autoimmune diseases, which adversely affects the quality of life. RA is a disease of unknown etiology, however, both genetic and environmental factors appear to contribute to the susceptibility to this disease. The severity and progression of the disease are attributable to the release of a host of inflammatory cytokines, cytotoxic and immune regulatory factors. The treatments of RA are primarily limited to symptomatic alleviation of pain or other symptoms or to the use of cytotoxic drug treatment in severe forms of the disease which is commonly associated with significant side effects. Despite lack of a cure, the disease may be controlled by mind-body interventions. Holistic treatments such as Yoga significantly improve and reduce the psycho-somatic symptoms, pain perception, disability quotient, joint flexibility, range of motion, posture, muscle strength, coordination, and disease activity. Here, we discuss the features of RA and address how Yoga can be used as a therapeutic regimen to improve the quality of life of patients with RA.
34830268 The Genetic, Environmental, and Immunopathological Complexity of Autoantibody-Negative Rhe 2021 Nov 17 Differences in clinical presentation, response to treatment, and long-term outcomes between autoantibody-positive and -negative rheumatoid arthritis (RA) highlight the need for a better comprehension of the immunopathogenic events underlying the two disease subtypes. Whilst the drivers and perpetuators of autoimmunity in autoantibody-positive RA have started to be disclosed, autoantibody-negative RA remains puzzling, also due its wide phenotypic heterogeneity and its possible misdiagnosis. Genetic susceptibility appears to mostly rely on class I HLA genes and a number of yet unidentified non-HLA loci. On the background of such variable genetic predisposition, multiple exogeneous, endogenous, and stochastic factors, some of which are not shared with autoantibody-positive RA, contribute to the onset of the inflammatory cascade. In a proportion of the patients, the immunopathology of synovitis, at least in the initial stages, appears largely myeloid driven, with abundant production of proinflammatory cytokines and only minor involvement of cells of the adaptive immune system. Better understanding of the complexity of autoantibody-negative RA is still needed in order to open new avenues for targeted intervention and improve clinical outcomes.
33805383 Berberine Delays Onset of Collagen-Induced Arthritis through T Cell Suppression. 2021 Mar 29 There is evidence that berberine (BBR), a clinically relevant plant compound, ameliorates clinically apparent collagen-induced arthritis (CIA) in vivo. However, to date, there are no studies involving the use of BBR which explore its prophylactic potential in this model of rheumatoid arthritis (RA). The aim of this study was to determine if prophylactic BBR use during the preclinical phase of collagen-induced arthritis would delay arthritic symptom onset, and to characterize the cellular mechanism underlying such an effect. DBA/1J mice were injected with an emulsion of bovine type II collagen (CII) and complete Freund's adjuvant (day 0) and a booster injection of CII in incomplete Freund's adjuvant (day 18) to induce arthritis. Mice were then given i.p. injections of 1 mg/kg/day of BBR or PBS (vehicle with 0.01% DMSO) from days 0 to 28, were left untreated (CIA control), or were in a non-arthritic control group (n = 15 per group). Incidence of arthritis in BBR-treated mice was 50%, compared to 90% in both the CIA and PBS controls. Populations of B and T cells from the spleens and draining lymph nodes of mice were examined on day 14 (n = 5 per group) and day 28 (n = 10 per group). BBR-treated mice had significantly reduced populations of CD4(+)T(h) and CD4(+)CXCR5(+) T(fh) cells, and an increased proportion of Foxp3(+) T(reg) at days 14 and 28, as well as reduced expression of co-stimulatory molecules CD28 and CD154 at both endpoints. The effect seen on T cell populations and co-stimulatory molecule expression in BBR-treated mice was not mirrored in CD19(+) B cells. Additionally, BBR-treated mice experienced reduced anti-CII IgG2a and anti-CII total IgG serum concentrations. These results indicate a potential role for BBR as a prophylactic supplement for RA, and that its effect may be mediated specifically through T cell suppression. However, the cellular effector involved raises concern for BBR prophylactic use in the context of vaccine efficacy and other primary adaptive immune responses.
33810864 Structural damage in rheumatoid arthritis assessed by musculoskeletal ultrasound: A system 2021 Jun OBJECTIVES: To identify and synthesize the evidence for the use and measurement properties of musculoskeletal ultrasound in assessing structural joint damage in patients with rheumatoid arthritis (RA). METHODS: A systematic literature search (SLR) of the PubMed, Embase and Cochrane Library was performed. Original articles were included published in English reporting on ultrasound of bone erosion, cartilage damage and the measurement properties of ultrasound according to the OMERACT filter 2.1. RESULTS: Of the 1.495 identified articles 149 were included in the final review, most of which reported on cross-sectional studies and used the OMERACT definitions for ultrasonographic pathology. Among these, bone erosions were assessed in 139 (93.3%), cartilage damage in 24 (16.1%), enthesophytes in 8 (5.4%), osteophytes in 15 (10.1%) and malalignment and ankylosis in a single (0.9%) study, respectively. Most studies (126/149, 84.6%) assessed the joints of the hands. The overwhelming majority of studies (127/149, 85.2%) assessed structural joint damage bilaterally. Validity, reliability and responsiveness were assessed in 21 (14.1%), 34 (22.8%) and 17 (11.4%) studies, respectively. CONCLUSION: While the results of this SLR suggest that ultrasound is a sensitive, reliable and feasible tool to detect damage in RA, they also highlight the need for further research and validation. Findings of this SLR will inform the next steps of the OMERACT Ultrasound Working Group in developing an ultrasound score for assessing structural joint damage in patients with RA.
34251303 Comparison of the efficacy and safety of LBAL, a candidate adalimumab biosimilar, and adal 2022 May OBJECTIVES: To evaluate the similarities between LBAL (adalimumab biosimilar candidate) and the adalimumab reference product (ADL) in terms of efficacy and safety, including immunogenicity, in patients with active rheumatoid arthritis despite methotrexate treatment. METHODS: This phase III, multicentre, randomised, double-blind, parallel-group, 56-week study was conducted in Japan and Korea. During the first 24 weeks, patients subcutaneously received 40 mg of LBAL or ADL every two weeks (LBAL and ADL groups). During the subsequent 28 weeks, the LBAL group patients and half of the ADL group patients received LBAL (L-L and A-L arms). The remaining ADL group patients continued to receive ADL (A-A arm). The primary efficacy endpoint was the change from baseline in disease activity score 28-erythrocyte sedimentation rate (DAS28-ESR) at Week 24. American College of Rheumatology (ACR) response rates, adverse events (AEs), and anti-drug antibody (ADA) were also assessed. RESULTS: In total, 383 patients were randomised. The least squares (LS) mean changes from baseline in DAS28-ESR at Week 24 were -2.45 and -2.53 in the LBAL (n=191) and ADL (n=190) groups, respectively. The 95% confidence interval (CI; -0.139, 0.304) of the difference (0.08) was within the pre-specified equivalence margin (-0.6, 0.6). Up to Week 52, the decreases in DAS28-ESR were maintained in all three arms. No notable differences in ACR20/50/70 were observed. The AE and ADA incidences were comparable between the arms. CONCLUSIONS: LBAL was equivalent in efficacy and comparable in safety, including immunogenicity, to ADL. Switching from ADL to LBAL did not impact on efficacy and safety.
33179071 Mortality over 14 years in MTX-refractory patients randomized to a strategy of addition of 2021 May 14 OBJECTIVE: To compare mortality risk over up to 14 years of follow-up in methotrexate-refractory patients with early RA randomized to a strategy starting with addition of infliximab vs addition of SSZ and HCQ. METHODS: Data was from the two-arm, parallel, randomized, active-controlled, open-label Swefot trial in which patients with early RA (symptom duration <1 y) were recruited from 15 rheumatology clinics in Sweden (2002-2005). Patients who did not achieve low disease activity after 3-4 months of MTX were randomized to addition of infliximab (n = 128) or SSZ and HCQ (n = 130). Participants were followed until death, emigration, or end of follow-up, whichever came first. Analyses were by intention-to-treat. RESULTS: Over an average follow-up of 13 years, there were 13 and 16 deaths, respectively [8.8 vs 10.6 deaths per 1000 person-years; mortality hazard ratio 1.2 (95% CI: 0.6, 2.5); P =0.62]. The 1-year mortality was 0.8% in both treatment arms, the 5-year mortality was 2.3% for the infliximab arm compared with 1.5% for the conventional combination treatment arm, while the 10-year mortality was 7.8% and 7.7%, respectively. After 5 years, ∼50% of patients in the conventional combination therapy arm had switched to biologic treatment, and 50% in the biologic arm had discontinued treatment with a biologic DMARD. CONCLUSION: No difference in mortality risk could be observed over up to 14 years of follow-up between treatment strategy groups. At 5 years (3 years after trial cessation), 50% of patients remained on their assigned therapy, reflecting that DMARD combination is an adequate treatment strategy in 50% of patients. TRIAL REGISTRATION: clinicaltrials.gov, identifier: NCT00764725.
32607803 Perfusion in hand arthritis on dynamic contrast-enhanced computed tomography: a randomized 2021 Jan OBJECTIVE: To evaluate the performance of dynamic contrast-enhanced CT (DCE-CT) in detecting and quantitatively assessing perfusion parameters in patients with arthritis of the hand compared with dynamic contrast-enhanced MRI (DCE-MRI) as a standard of reference. MATERIALS AND METHODS: In this IRB-approved randomized prospective single-centre study, 36 consecutive patients with suspected rheumatoid arthritis underwent DCE-CT (320-row, tube voltage 80 kVp, tube current 8.25 mAs) and DCE-MRI (1.5 T) of the hand. Perfusion maps were calculated separately for mean transit time (MTT), time to peak (TTP), relative blood volume (rBV), and relative blood flow (rBF) using four different decomposition techniques. Region of interest (ROI) analysis was performed in metacarpophalangeal joints II-V and in the wrist. Pairs of perfusion parameters in DCE-CT and DCE-MRI were compared using a two-tailed t test for paired samples and interpreted for effect size (Cohen's d). According to the Rheumatoid Arthritis Magnetic Resonance Imaging Score (RAMRIS) scoring results, differentiation of synovitis-positive and synovitis-negative joints with both modalities was assessed with the independent t test. RESULTS: The two modalities yielded similar perfusion parameters. Identified differences had small effects (d 0.01-0.4). DCE-CT additionally differentiates inflamed and noninflamed joints based on rBF and rBV but tends to underestimate these parameters in severe inflammation. The total dose-length product (DLP) was 48 mGy*cm with an estimated effective dose of 0.038 mSv. CONCLUSION: DCE-CT is a promising imaging technique in arthritis. In patients with a contraindication to MRI or when MRI is not available, DCE-CT is a suitable alternative to detect and assess arthritis.
34479638 Cross-reactivity of IgM anti-modified protein antibodies in rheumatoid arthritis despite l 2021 Sep 3 BACKGROUND: Anti-modified protein antibodies (AMPA) targeting citrullinated, acetylated and/or carbamylated self-antigens are hallmarks of rheumatoid arthritis (RA). Although AMPA-IgG cross-reactivity to multiple post-translational modifications (PTMs) is evident, it is unknown whether the first responding B cells, expressing IgM, display similar characteristics or if cross-reactivity is crucially dependent on somatic hypermutation (SHM). We now studied the reactivity of (germline) AMPA-IgM to further understand the breach of B cell tolerance and to identify if cross-reactivity depends on extensive SHM. Moreover, we investigated whether AMPA-IgM can efficiently recruit immune effector mechanisms. METHODS: Polyclonal AMPA-IgM were isolated from RA patients and assessed for cross-reactivity towards PTM antigens. AMPA-IgM B cell receptor sequences were obtained by single cell isolation using antigen-specific tetramers. Subsequently, pentameric monoclonal AMPA-IgM, their germline counterparts and monomeric IgG variants were generated. The antibodies were analysed on a panel of PTM antigens and tested for complement activation. RESULTS: Pentameric monoclonal and polyclonal AMPA-IgM displayed cross-reactivity to multiple antigens and different PTMs. PTM antigen recognition was still present, although reduced, after reverting the IgM into germline. Valency of AMPA-IgM was crucial for antigen recognition as PTM-reactivity significantly decreased when AMPA-IgM were expressed as IgG. Furthermore, AMPA-IgM was 15- to 30-fold more potent in complement-activation compared to AMPA-IgG. CONCLUSIONS: We provide first evidence that AMPA-IgM are cross-reactive towards different PTMs, indicating that PTM (cross-)reactivity is not confined to IgG and does not necessarily depend on extensive somatic hypermutation. Moreover, our data indicate that a diverse set of PTM antigens could be involved in the initial tolerance breach in RA and suggest that AMPA-IgM can induce complement-activation and thereby inflammation.
32583971 Randomized Controlled Trial of Patient Education Tools for Patients With Rheumatoid Arthri 2021 Oct OBJECTIVE: The present study was undertaken to evaluate the efficacy of 2 educational tools for patients with rheumatoid arthritis (RA) by comparing a newly developed video tool, including storylines and testimonials, combined with a written booklet to the same written booklet alone. METHODS: We conducted a randomized controlled trial. Our primary outcome was disease knowledge. Secondary outcomes were decisional conflict, self-efficacy, effective health care management, and satisfaction. Outcomes were measured before and after reviewing the materials, and 3 and 6 months later. Linear mixed-effects models were performed to evaluate changes over time. RESULTS: In total, 221 participants received an educational video and booklet (n = 111) or a booklet alone (n = 110). The mean age was 50.8 years, mean disease duration was 4.8 years, 85% were female, and 24% had limited health literacy levels. Within groups, most outcomes improved between baseline and follow-up, but there were no statistically significant differences across groups. Patients receiving the video and booklet were more likely than those receiving the booklet alone to rate the presentation as excellent for providing information about the impact of RA, medication options, evidence about medications, benefits of medication, and self-care options. Factors significantly associated with greater improvements in knowledge and decisional conflict from baseline to 6 months included limited health literacy, lower educational level, and shorter disease duration. CONCLUSION: Regardless of the delivery method, outcomes were improved up to 6 months after educational materials were delivered. Our findings support the implementation of self-administered educational materials in clinical settings, as they can result in sustained improvements in disease knowledge and decisional conflict.
33057725 Assessment of radiographic progression in patients with rheumatoid arthritis treated with 2021 Apr 6 OBJECTIVES: Tofacitinib is an oral Janus kinase inhibitor for the treatment of RA. We evaluated radiographic progression in tofacitinib-treated patients with RA for up to 3 years in two pooled long-term extension (LTE) studies (ORAL Sequel; A3921041) (primary analysis), and for up to 5 years using data integrated from one phase (P)2 (A3921068), two P3 (ORAL Start; ORAL Scan) and two LTE studies (exploratory analysis). METHODS: In LTE studies, patients received tofacitinib 5 mg twice daily (BID) or 10 mg BID as monotherapy or with conventional synthetic (cs)DMARDs. Radiographic outcomes up to 3 years: least squares mean (LSM) change from baseline in van der Heijde modified Total Sharp Score (ΔmTSS), erosion score (ΔES) and joint space narrowing (ΔJSN) score; proportion of patients with no radiographic progression (ΔmTSS ≤0.5); proportion of patients with no new erosions (ΔES ≤0.5). ΔmTSS was evaluated for up to 5 years in an exploratory analysis. RESULTS: For all tofacitinib-treated patients with radiographic data available at LTE month 36 (n = 414), LSM ΔmTSS was 1.14, LSM ΔES was 0.66, LSM ΔJSN was 0.74, and 74.3% and 86.2% of patients showed no radiographic progression and no new erosions, respectively. Similar values were observed regardless of tofacitinib dose, or whether patients received tofacitinib as monotherapy or with csDMARDs. In an exploratory analysis of integrated P2/P3/LTE studies, LSM ΔmTSS was 3.34 at month 60 (n = 269). CONCLUSION: Limited progression of structural damage was observed in tofacitinib-treated patients up to 5 years, with similar results for tofacitinib used as monotherapy or combination therapy up to 3 years. TRIAL REGISTRATION: ClinicalTrials.gov (http://clinicaltrials.gov): NCT01164579; NCT01039688; NCT00847613; NCT00413699; NCT00661661.
34573331 Thousands of CpGs Show DNA Methylation Differences in ACPA-Positive Individuals. 2021 Aug 29 High levels of anti-citrullinated protein antibodies (ACPA) are often observed prior to a diagnosis of rheumatoid arthritis (RA). We undertook a replication study to confirm CpG sites showing evidence of differential methylation in subjects positive vs. negative for ACPA, in a new subset of 112 individuals sampled from the population cohort and biobank CARTaGENE in Quebec, Canada. Targeted custom capture bisulfite sequencing was conducted at approximately 5.3 million CpGs located in regulatory or hypomethylated regions from whole blood; library and protocol improvements had been instituted between the original and this replication study, enabling better coverage and additional identification of differentially methylated regions (DMRs). Using binomial regression models, we identified 19,472 ACPA-associated differentially methylated cytosines (DMCs), of which 430 overlapped with the 1909 DMCs reported by the original study; 814 DMRs of relevance were clustered by grouping adjacent DMCs into regions. Furthermore, we performed an additional integrative analysis by looking at the DMRs that overlap with RA related loci published in the GWAS Catalog, and protein-coding genes associated with these DMRs were enriched in the biological process of cell adhesion and involved in immune-related pathways.
33999944 Association between ischemic stroke and seropositive rheumatoid arthritis in Korea: A nati 2021 The purpose of this longitudinal follow-up study was to investigate the risk of ischemic stroke nationwide in patients with seropositive rheumatoid arthritis (RA) and controls who were matched in age and sex. Patient data were collected from the National Health Insurance Service (NHIS) Health Screening (HEALS) cohort. Using the International Classification of Diseases code M05 (seropositive RA), with a prescription of any disease-modifying anti-rheumatic drug (DMARD), RA was identified. A total of 2,765 patients and 13,825 control subjects were included in our study. The 12-year incidence of ischemic stroke in each group was calculated using the Kaplan-Meier method. The risk ratio of ischemic stroke was estimated using Cox proportional hazards regression. Sixty-four patients (2.31%) in the seropositive RA group and 512 (3.70%) in the control group experienced ischemic stroke (P < 0.001) during the follow-up period. The hazard ratio of ischemic stroke in the seropositive RA group was 1.32 (95% confidence interval (CI), 1.02-1.73) after adjusting for age and sex. The adjusted hazard ratio of ischemic stroke in the seropositive RA group was 1.40 (95% CI, 1.07-1.82) after adjusting for demographics and comorbid medical disorders. According to the subgroup analysis, the hazard ratios of ischemic stroke risks in the female and hypertensive subgroups were 1.44 (95% CI, 1.05-1.97) and 1.66 (95% CI, 1.16-2.38), respectively. In the non-diabetes and non-dyslipidemia subgroups, the corresponding hazard ratios of ischemic stroke were 1.47 (95% CI, 1.11-1.95) and 1.43 (95% CI, 1.07-1.91). Seropositive RA patients have an increased risk of ischemic stroke. In female, hypertension, non-diabetes, and non-dyslipidemia RA subgroups, even without the traditional risk factors for stroke (except for hypertension), increased the risk, which could be potentially attributed to RA.
34176840 Development of Intravascular Large B-cell Lymphoma during Methotrexate Treatment for Rheum 2022 Jan 1 A 56-year-old woman with rheumatoid arthritis who had been taking methotrexate (MTX) for six years visited our hospital with dyspnea and dizziness. Abdominal ultrasonography revealed mild splenomegaly. Laboratory examinations showed a marked elevation in soluble interleukin-2 receptor and lactate dehydrogenase levels. These abnormalities revealed a spontaneous regression after MTX discontinuation, however, they worsened again four months later. Skin biopsies revealed a diagnosis of intravascular large B-cell lymphoma (IVLBCL), and we diagnosed MTX-associated IVLBCL (MTX-IVLBCL) based on its characteristic course. Despite the recurrence of IVLBCL, it showed a good response to chemotherapy. MTX-IVLBCL should therefore be treated with consideration since it has different characteristics from that of de novo IVLBCL.
32891814 A mechanistic study of Solenostemma argel as anti-rheumatic agent in relation to its metab 2021 Jan 30 ETHNOPHARMACOLOGICAL RELEVANCE: Solenostemma argel (Argel) is a traditional perennial edible herb that is commonly used in folkloric medicine for the treatment of rheumatic pain, inflammation, bronchitis, cold, diabetes, gastrointestinal cramps, and urinary tract infections. No previous reports traced the mechanistic activity of this plant for treatment of rheumatoid arthritis in relation to its chemical constituents. AIM OF THE STUDY: The present study was designed to substantiate the anti-arthritic potential of S. argel and identification of its secondary metabolites responsible for the action using ultra-performance liquid chromatography coupled to high resolution mass spectrometry (UPLC/HRMS). MATERIALS AND METHODS: The air-dried powder of S. argel was subjected to liquid-liquid fractionation method to yield polar metabolites fraction (PMF) and nonpolar metabolites fraction (NPMF) where the metabolites that represent each fraction were identified using UPLC/HRMS. The in-vitro anti-arthritic effects of both fractions were tested using protein denaturation, membrane stabilization and proteinase inhibition assays, in addition to in-vitro enzyme inhibition assays of COXs, LOX and collagenases. Adjuvant-induced arthritis (AIA) model was also established to evaluate their anti-arthritic effects in-vivo at two doses (200 and 400 mg/kg) in compared to the standard ibuprofen (5 mg/kg). Physical changes with hind paw edema and body weight gain as well as the assessment of serum rheumatoid biomarkers, inflammatory cytokines, oxidative stress markers, and the activity of hyaluronidase and β-glucouronidase enzymes were studied. The histopathological study of ankle and knee joints and immunohistochemistry of caspase-3 and TNF-α in joint synovium were also examined. RESULTS: The PMF significantly (P < 0.05) reduced paw edema, serum rheumatoid markers, pro-inflammatory mediators, degeneration enzymes of cartilage and bone, and oxidative stress biomarkers. Interestingly, flavonoid glycosides and phenolic acids dominated the polar fraction, which showed the promising anti-arthritic activity of Argel compared to the NPMF which was dominated by pregnane glycosides. CONCLUSIONS: Since arthritis is a chronic disease and there are imperative needs for a lifelong treatment with desirable pharmacological action and lower cost than the currently approved synthetic drugs having severe side effects, the PMF of Argel could be used as a potent anti-rheumatic agent.
34638736 Interleukin-9 Facilitates Osteoclastogenesis in Rheumatoid Arthritis. 2021 Sep 27 In rheumatoid arthritis (RA), inflammatory cytokines play a pivotal role in triggering abnormal osteoclastogenesis leading to articular destruction. Recent studies have demonstrated enhanced levels of interleukin-9 (IL-9) in the serum and synovial fluid of patients with RA. In RA, strong correlation has been observed between tissue inflammation and IL-9 expression in synovial tissue. Therefore, we investigated whether IL-9 influences osteoclastogenesis in patients with RA. We conducted the study in active RA patients. For inducing osteoclast differentiation, mononuclear cells were stimulated with soluble receptor activator of NF-kB ligand (sRANKL) and macrophage-colony-stimulating factor (M-CSF) in the presence or absence of recombinant (r) IL-9. IL-9 stimulation significantly enhanced M-CSF/sRANKL-mediated osteoclast formation and function. Transcriptome analysis revealed differential gene expression induced with IL-9 stimulation in the process of osteoclast differentiation. IL-9 mainly modulates the expression of genes, which are involved in the metabolic pathway. Moreover, we observed that IL-9 modulates the expression of matrix metalloproteinases (MMPs), which are critical players in bone degradation. Our results indicate that IL-9 has the potential to influence the structural damage in the RA by promoting osteoclastogenesis and modulating the expression of MMPs. Thus, blocking IL-9 pathways might be an attractive immunotherapeutic target for preventing bone degradation in RA.
33621881 Subgroup analysis of the relationship between polycyclic aromatic hydrocarbons and rheumat 2021 Jun 25 The present study examined potential effect modifiers between polycyclic aromatic hydrocarbon (PAH) exposure and the development of rheumatoid arthritis (RA) and elucidated the relationship between PAHs and RA in subgroups using data from the National Health and Nutrition Examination Survey (NHANES) (2003-2014). The relatedness between eight PAH metabolites and RA in the whole population and different subgroups was tested using multivariable logistic regression analyses. This study included 6297 participants, including 400 RA patients and 5897 non-RA control participants, with full data. Compared to the lowest quartiles, risk of RA was increased in population with the highest quartiles of 1-hydroxynaphthalene (1-NAP), 2-NAP, 2-hydroxyfluorene (2-FLU), and 3-FLU in a bias factor corrected model. The associations between urinary PAH metabolites and RA were prominent in female, young and middle-aged, obese, smoking and alcohol-consuming populations in the subgroup analysis. Our results demonstrated that PAH exposure was related to RA, and the relationship between urinary PAH metabolites and RA differed between subgroups and depended on specific PAH metabolites.
33523580 Assessment of the anti-rheumatoid arthritis activity of Gastrodia elata (tian-ma) and Radi 2021 Mar AIM: Gastrodia elata and Radix aconiti lateralis preparrata are respectively named as Tian-Ma and Fu-Zi (TF) in Chinese. We explored the active components against rheumatoid arthritis (RA) from an extensively used couplet of Chinese herbs, Gastrodia elata and Radix aconiti lateralis preparata (TF) via untargeted metabolomics and network pharmacological approaches. METHODS: Water extracts of TF were mixed at ratios 1:1, 3:2 and 2:3 (w/w). Ultra-performance liquid chromatography/tandem mass spectrometry (UPLC-MS/MS) was then utilized as metabolomics screening. Human Metabolome (http://www.hmdb.ca/) and Lipidmaps (http://www.lipidmaps.org/) databases were used to annotate detected compounds. Further identification of vital genes and important pathways associated with the anti-RA properties of the TF preparations was done via network pharmacology, and verified by real-time quantitative polymerase chain reaction (RT-qPCR). RESULTS: Four key compounds involved in unsaturated fatty acid biosynthesis and isoflavonoid biosynthesis were identified through metabolomics analyses. Three key components of TF associated with anti-RA activity were linoleic acid, daidzein, and daidzin. Results of RT-qPCR revealed that all 3 tested TF couplets (1:1, 3:2, and 2:3) markedly suppressed the transcription of PTGS2. These results were consistent with our network pharmacological predictions. CONCLUSIONS: The anti-RA properties of Tian-Ma and Fu-Zi are associated with the inhibition of arachidonic acid metabolism pathway.
33047630 Short-term transcutaneous non-invasive vagus nerve stimulation may reduce disease activity 2021 Jan Objective: Rheumatoid arthritis (RA) is a chronic, autoimmune, inflammatory disease. Studies suggest that pro-inflammatory cytokines may be attenuated by the vagus nerve through the cholinergic anti-inflammatory pathway. We aimed to evaluate the anti-inflammatory effects of short-term transcutaneous non-invasive vagus nerve stimulation (n-VNS) applied to the cervical vagus nerve in patients with RA. Method: We conducted a single-centre, open-label, preliminary proof-of-concept study of n-VNS in two cohorts of participants with RA: one with high disease activity (n = 16) and one with low disease activity (n = 20). Disease Activity Score based on 28-joint count-C-reactive protein (DAS28-CRP), cardiac vagal tone, and pro-inflammatory cytokines were measured at baseline and after 1 and 4 days of n-VNS. Results: In the high disease activity group, n-VNS resulted in reductions in DAS28-CRP (4.1 to 3.8, p = 0.02), CRP (8.2 to 6 mg/mL, p = 0.01), and interferon-γ (29.8 to 22.5 pg/mL, p = 0.02). In the low disease activity group, there was no effect on DAS28-CRP, and n-VNS was associated with a decrease in cardiac vagal tone (p = 0.03) and a reduction in interleukin-10 (0.8 to 0.6 pg/mL, p = 0.02). Participants with high disease activity had lower baseline cardiac vagal tone than those with low disease activity (3.6 ± 2 vs 4.9 ± 3 linear vagal scale, p = 0.03). Cardiac vagal tone was negatively associated with DAS28-CRP (r = -0.37, p = 0.03). Overall, n-VNS was well tolerated. Conclusion: This study provides preliminary support for an anti-inflammatory effect of n-VNS in patients with RA. These findings warrant further investigation in larger placebo-controlled trials.
33462611 Prevalence, incidence and cause-specific mortality of rheumatoid arthritis-associated inte 2021 Aug 2 OBJECTIVE: We aimed to investigate the prevalence, incidence and cause-specific mortality of RA-associated interstitial lung disease (RA-ILD) among older US patients with RA. METHODS: We performed a nationwide cohort study using Medicare claims data (parts A, B and D for 2008-2017). RA was identified with a validated algorithm using RA diagnosis codes and DMARD prescription. RA-ILD was identified with a validated algorithm using ILD diagnosis codes by a rheumatologist/pulmonologist. RA-ILD was categorized as prevalent or incident relative to the initial RA observation (baseline/index date). We compared the total mortality of RA-ILD to RA without ILD using multivariable Cox regression, adjusting for baseline covariates. For cause-specific mortality, Fine and Gray subdistribution hazard ratios (sdHRs) were estimated to handle competing risks of alternative mortality causes. RESULTS: Among 509 787 RA patients (mean age 72.6 years, 76.2% female), 10 306 (2.0%) had prevalent RA-ILD at baseline. After baseline, 13 372 (2.6%) developed RA-ILD during 1 873 127 person-years of follow-up (median 3.0 years/person). During follow-up, 38.7% of RA-ILD patients died compared with 20.7% of RA patients without ILD. After multivariable adjustment, RA-ILD had an HR of 1.66 (95% CI 1.60, 1.72) for total mortality. Accounting for competing risk of other causes of death, RA-ILD had an sdHR of 4.39 (95% CI 4.13, 4.67) for respiratory mortality and an sdHR of 1.56 (95% CI 1.43, 1.71) for cancer mortality compared with RA without ILD. CONCLUSIONS: RA-ILD was present or developed in nearly 5% of patients in this nationwide study of older patients with RA. Compared with RA without ILD, RA-ILD was associated with excess total, respiratory and cancer mortality that was not explained by measured factors.