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ID PMID Title PublicationDate abstract
35192549 Dissecting the molecular control of immune cell accumulation in the inflamed joint. 2022 Apr 8 Mechanisms governing entry and exit of immune cells into and out of inflamed joints remain poorly understood. We sought herein to identify the key molecular pathways regulating such migration. Using murine models of inflammation in conjunction with mice expressing a photoconvertible fluorescent protein, we characterized the migration of cells from joints to draining lymph nodes and performed RNA-Seq analysis on isolated cells, identifying genes associated with migration and retention. We further refined the gene list to those specific for joint inflammation. RNA-Seq data revealed pathways and genes previously highlighted as characteristic of rheumatoid arthritis in patient studies, validating the methodology. Focusing on pathways associated with cell migration, adhesion, and movement, we identified genes involved in the retention of immune cells in the inflamed joint, namely junctional adhesion molecule A (JAM-A), and identified a role for such molecules in T cell differentiation in vivo. Thus, using a combination of cell-tracking approaches and murine models of inflammatory arthritis, we identified genes, pathways, and anatomically specific tissue signatures regulating cell migration in a variety of inflamed sites. This skin- and joint-specific data set will be an invaluable resource for the identification of therapeutic targets for arthritis and other inflammatory disorders.
35459151 Postoperative outcomes after degenerative lumbar spine surgery in rheumatoid arthritis pat 2022 Apr 22 BACKGROUND: Although treatment options for rheumatoid arthritis (RA) have evolved significantly since the introduction of biologic agents, degenerative lumbar disease in RA patients remains a major challenge. Well-controlled comparisons between RA patients and their non-RA counterparts have not yet been reported. The objective of the present study was to compare postoperative outcomes of lumbar spine surgery between RA and non-RA patients by a retrospective propensity score-matched analysis. METHODS: Patients who underwent primary posterior spine surgery for degenerative lumbar disease in our prospective multicenter study group between 2017 and 2020 were enrolled. Demographic data including age, sex, body mass index (BMI), American Society of Anesthesiologists (ASA) physical status classification, diabetes mellitus, smoking, steroid usage, number of spinal levels involved, and preoperative patient-reported outcome (PRO) scores (numerical rating scale [NRS] for back pain and leg pain, Short Form-12 physical component summary [PCS], EuroQOL 5-dimension [EQ-5D], and Oswestry Disability Index [ODI]) were used to calculate a propensity score for RA diagnosis. One-to-one matching was performed and 1-year postoperative outcomes were compared between groups. RESULTS: Among the 4567 patients included, 90 had RA (2.0%). RA patients in our cohort were more likely to be female, with lower BMI, higher ASA grade and lower current smoking rate than non-RA patients. Preoperative NRS scores for leg pain, PCS, EQ-5D, and ODI were worse in RA patients. Propensity score matching generated 61 pairs of RA and non-RA patients who underwent posterior lumbar surgery. After background adjustment, RA patients reported worse postoperative PCS (28.4 vs. 37.2, p = 0.008) and EQ-5D (0.640 vs. 0.738, p = 0.03), although these differences were not significant between RA and non-RA patients not on steroids. CONCLUSIONS: RA patients showed worse postoperative quality of life outcomes after posterior surgery for degenerative lumbar disease, while steroid-independent RA cases showed equivalent outcomes to non-RA patients.
34382069 CXCR5/CXCL13 pathway, a key driver for migration of regulatory B10 cells, is defective in 2022 May 5 OBJECTIVES: Chemokines (CKs) are key players of immune-cell homing and differentiation. CK receptors (CKRs) can be used to define T-cell functional subsets. We aimed to characterize the CKR profile of the regulatory B-cell subset B10+ cells and investigate the CKs involved in their migration and differentiation in healthy donors and patients with RA. METHODS: RNA sequencing and cytometry were used to compare CKR expression between B10+ and B10neg cells. Migration of B10+ and B10neg cells and IL-10 secretion of B cells in response to recombinant CKs or synovial fluid (SF) were assessed. RESULTS: CXCR5 was expressed at a higher level on the B10+ cell surface as compared with other B cells (referred to as B10neg cells). In line with this, its ligand CXCL13 preferentially attracted B10+ cells over B10neg cells. Interestingly, synovial fluid from RA patients contained high levels of CXCL13 and induced strong and preferential migration of B10+ cells. Besides its role in attracting B10+ cells, CXCL13 also promoted IL-10 secretion by B cells. In RA patients, the level of CXCR5 on B-cell surface was reduced. The preferential migration of RA B10+ cells toward CXCL13-rich SF was lost and CXCL13 stimulation triggered less IL-10 secretion than in healthy donors. CONCLUSION: Our results identify that the CXCR5/CXCL13 axis is essential for B10+ cell biology but is defective in RA. Restoring the preferential migration of B10+ within the affected joints to better control inflammation may be part of the therapeutic approach for RA.
35383869 Anti-cyclic Citrullinated Peptide Antibody-positive Girl with Chronic Polyarthritis Later 2022 Apr 20 BACKGROUND: Arthritis is one of the earliest symptoms of juvenile systemic lupus erythematosus (SLE) but is unusual in cases presenting with chronic arthritis or deforming/erosive arthritis. Overlap of juvenile idiopathic arthritis (JIA) and juvenile SLE is a rare clinical condition known as "rhupus" syndrome. The clinical and serological characteristics of rhupus syndrome in children remain to be established. In addition, no studies regarding anti-cyclic citrullinated peptide (CCP) antibody in juvenile SLE or juvenile rhupus syndrome have been reported. CASE REPORT: A 12-year-old girl suffered from polyarthralgia lasting for one week. She was tentatively diagnosed with polyarticular JIA because of her symptom of chronic arthritis and a positive result for anti-CCP antibody. After six months of follow-up for JIA, she presented with a fever, malar rash, and worsening of arthralgia. Laboratory examinations revealed hypocomplementemia and a positive result for anti-double-stranded DNA antibody. She was diagnosed with juvenile SLE. CONCLUSIONS: It is important to note that patients with chronic arthritis, as well as those with anti-CCP antibody-positive polyarthritis, should be carefully followed for their clinical and serological condition, considering the possibility of them developing juvenile SLE.
35587073 The impact of sleep disorders on the daily activity and quality of life in rheumatoid arth 2022 May OBJECTIVE: We aimed at determining the relationship between sleep disorders and daily activity and quality of life (QoL) of patients with rheumatoid arthritis (RA). MATERIALS AND METHODS: A systematic search of databases was carried out. We used the Cochrane guidelines to perform the meta-analysis following the PRISMA statement. Fifteen full-text papers were ultimately included in the subsequent statistical analyses. The study was registered in the PROSPERO database (No. CRD42021245664). RESULTS: In group 1, the mean sleep quality score measured with the Pittsburgh Sleep Quality Index (PSQI) was 6.93. The mean QoL score for the physical domain and the mental domain of the Short Form (36) Health Survey (SF-36) was 38.15 and 41.83, respectively. In group 2, the mean PSQI score was 7.21. The mean daily activity score measured with the Health Assessment Questionnaire (HAQ) was 0.80. A strong negative correlation was observed between the PSQI scores, and the SF-36 total score each unit increase in the SF-36 total score was associated with an average decrease of 0.35 points in the PSQI score. A one-point increase in the PSQI score was associated with an average decrease of 2.4 points in the QoL score measured with SF-36. CONCLUSIONS: RA patients have a low quality of sleep. Sleep disorders correlate negatively with the QoL scores in the physical and mental domains.
35396380 Dopamine receptor 1 expressing B cells exert a proinflammatory role in female patients wit 2022 Apr 8 Rheumatoid arthritis (RA) is a chronic rheumatic disease with a clear sex-bias. Recent data indicated a role for dopamine in RA pathogenesis, while dopaminergic pathways can be modulated by estrogens. As defined mechanism of action of dopamine on B cell function in RA are unclear, we aimed to elucidate this, with special focus on sex-differences. Healthy controls (HC, n = 64) and RA patients (n = 61) were recruited. Expression of D(1)-D(5) dopamine receptors (DRs) was investigated by flow cytometry on peripheral blood mononuclear cells (PBMCs). D(1)-like DRs were stimulated in vitro to assess effects on B cell activation and proliferation. Secretion of cytokines and dopamine content were measured by ELISA. All DRs were expressed on PBMCs of HC and RA patients. Dopamine content in PBMCs, and frequency of D(1)DR expressing B cells were significantly higher in RA females (p < 0.001). Expression of D(1)DR on RA B cells correlated positively with disease duration and severity only in women. Combined B cell and D(1)-like DR stimulation induced higher IL-8 and CCL-3 secretion from PBMCs of female RA patients compared to HC. These results indicate sex-specific differences in dopaminergic pathway in RA, with a proinflammatory feature of the D(1)DR pathway in women.
33706664 Systematic review and meta-analysis of biosimilar for the treatment of rheumatoid arthriti 2022 Jan 5 OBJECTIVES: To evaluate the efficacy and safety of biosimilars compared with reference biological disease modifying antirheumatic drugs (bDMARDs) in patients with rheumatoid arthritis (RA) as a part of the process of developing the 2020 update of the Japan College of Rheumatology guidelines for the management of RA. METHODS: PubMed, Cochrane Library, and Japan Centra Revuo Medicina were searched for articles to conduct a systematic review (SR). The quality of evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation system. RESULTS: Twenty randomized controlled trials were included (biosimilars of infliximab, etanercept, and adalimumab). A meta-analysis revealed that the risk ratios (RRs) and 95% confidence intervals (CIs) of achieving the American College of Rheumatology 50% response (ACR50) at week 24 and serious adverse events (SAEs) for biosimilars compared with the reference bDMARDs were 1.04 (0.98-1.10) and 0.84 (0.61-1.18), respectively. The RRs of achieving ACR50 and SAEs at week 24 were respectively 0.93 (0.69-1.26) and 2.15 (0.55-8.35) in the patients who switched to biosimilars from the reference bDMARDs and 0.92 (0.76-1.12) and 1.41 (0.32-6.15) in those who continued the reference bDMARDs. CONCLUSION: Biosimilars and reference bDMARDs were equally useful for the management of RA.
35027248 Association between serum amyloid A and rheumatoid arthritis: A systematic review and meta 2022 Feb BACKGROUNDS: Consistent correlation of serum amyloid A (SAA) to rheumatoid arthritis (RA) is not completely established. The present study is to systematically summarize their relationship. METHODS: Publications up to may 2021 were examined using key terms in the PubMed, Cochrane Library, Embase and China national knowledge infrastructure (CNKI) databases. RESULTS: The total 33 studies, involving in 3524 RA cases and 3537 normal participants, were included. The pooled result indicated that the SAA level in the RA group was markedly higher than that in the control group [standardized mean difference (SMD) = 0.80, 95% CI (0.51, 1.08)]. By stratified analyses, the concentration of SAA was found to be gradually increased with the aggravation of RA. Additionally, the meta-analysis of correlation demonstrated that SAA levels were positively associated with the levels of disease activity score 28 (DAS28) [r = 0.55, 95% CI (0.15, 0.94)], erythrocyte sedimentation rate (ESR) [r = 0.65, 95% CI (0.53, 0.76)], C-reactive protein (CRP) [r = 0.92, 95% CI (0.57, 1.57)], rheumatoid factor (RF) [r = 0.24, 95% CI (0.09, 0.39)], interleukin 4 (IL-4) [r = 0.54, 95% CI (0.30, 0.78)], interleukin 6 (IL-6) [r = 0.46, 95% CI (0.27, 0.65)], interleukin 10 (IL-10) [r = 0.53, 95% CI (0.29, 0.77)], interleukin 17 (IL-17) [r = 0.52, 95% CI (0.27, 0.77)], and anti-cyclic citrullinated peptide antibody (A-CCP) [r = 0.32, 95% CI (0.15, 0.50)], but inversely linked with the levels of hemoglobin [r=-0.51, 95% CI (-0.84, -0.18)]. Furthermore, the allele of SAA 1.3 was actively related with increased risks of RA [OR=1.30, 95% CI (1.02, 1.65)] and of RA with amyloidosis [OR=2.06, 95% CI (1.63, 2.60)]. Besides, the genotype of SAA 1.3/1.3 was positively connected with the risks of RA [OR=1.56, 95% CI (1.00, 2.43)] and of RA with amyloidosis [OR=4.47, 95% CI (2.70, 7.41)]. CONCLUSIONS: High levels of SAA might be associated with elevated risk of RA, and the concentration of SAA might be gradually increased with the aggravation of RA. Moreover, high levels of SAA might play a vital role in RA by enhancing the levels of DAS28, ESR, CRP, RF, IL-4, IL-6, IL-10, IL-17 and A-CCP, or by attenuating hemoglobin levels. More importantly, the allele of SAA 1.3 and genotype of SAA 1.3/1.3 might be the risk factor of RA and of RA with amyloidosis.
35038641 Clinical features of methotrexate osteopathy in rheumatic musculoskeletal disease: A syste 2022 Feb BACKGROUND: There is growing evidence from case reports that methotrexate (MTX) therapy may impair bone metabolism in individual patients leading to low bone mass, atraumatic stress fractures and immobilizing bone pain - referred to as 'MTX osteopathy'. However, the clinical features, risk factors and treatment options of this condition are still elusive. METHODS: A systematic review was conducted according to PRISMA guidelines. Two databases (MEDLINE, Embase) were searched for published cases of MTX osteopathy in patients with rheumatic musculoskeletal diseases (RMD). Data from the included publications were extracted and descriptive statistical analysis was performed. RESULTS: We report data from 32 studies describing 80 adult RMD patients with stress fractures in MTX osteopathy. Most cases were found in elderly women with longstanding RMD, especially rheumatoid arthritis (72.5%). MTX osteopathy commonly presented as stress fracture of the distal tibia (51.3%), calcaneus (35.0%) and proximal tibia (27.5%), mimicking arthritis in some cases. Although a majority of the patients met the densitometric criteria for osteoporosis (58.1%), typical osteoporotic fractures (e.g., vertebral fractures) were rarely seen. Patients frequently suffered from bilateral (55.0%), multiple (71.3%) and recurrent fractures (25.0%). Fractures mainly occurred at low to moderate doses of MTX therapy (45.0%). It should be noted that half (48.8%) of the patients did not receive systemic steroid therapy for at least 3 years. CONCLUSIONS: Low-dose MTX therapy in RMD may result in atraumatic stress fractures of the lower extremity that can mimic arthritis. MTX osteopathy is characterized by a pathognomonic type of stress fractures with band- or meander-shaped appearance along the growth plate.
35297195 A Case of Rice Body Synovitis of the Knee Joint. 2022 Mar BACKGROUND: Rice body synovitis (RBS) is a rare disease. It is prone to be developed due to rheumatoid disorder or tuberculosis infection. Additional infectious arthritis (non-tuberculous mycobacterial infection and fungal infection), juvenile arthritis, the onset of adult Still's disease, systemic lupus erythematosus (SLE), seronegative arthritis, and non-specific arthritis. The clinical imaging, histopathological features, and surgical treatment process of a patient were documented combined with literature. Furthermore, differentiation was performed with additional synovitis diseases so that the cognition of synovitis could be enhanced for clinical reference. CASE PRESENTATION: The present study reported a 50-year-old female patient who suffered from intermittent left knee pain with limited movement for 9  years. The conditions were aggravated after long-term standing or walking and remitted after taking a rest, accompanied by noose and jamming. The specialist range of motion (ROM) examinations of the left knee revealed: 30° - 0° - 110° and left McMurray sign (+). Plain MRI scanning revealed that in the left knee cavity and the popliteal fossa area, a large number of low signals on free rice-like bodies were visible inside and the lower femur and the upper tibia exhibited abnormally high signals of patchy lipography. Surgical exploration revealed numerous rice-like free bodies in the suprapatellar bursa, the intercondylar fossa, and the posterior articular capsule. The patient presently has resolution of symptoms after surgical treatment. CONCLUSIONS: The RBS of the knee joint is very rare in the clinic. As MRI examination can provide valuable information, clinicians should actively perform MRI examination. Once the disease is diagnosed by examination, surgery is the optimal treatment.
34929309 Erteng Tongbi Decoction ameliorates collagen-induced arthritis in mice via modulating T ce 2022 Mar 25 ETHNOPHARMACOLOGICAL RELEVANCE: Herbs have been commonly used for the treatment of rheumatoid arthritis (RA). It has been verified that Erteng Tongbi Decoction has good therapeutic effects on RA, while, relatively few studies on the relationship between its components and anti-rheumatoid efficacy were carried out. AIM OF THE STUDY: To discuss the anti-RA effects of Erteng Tongbi Decoction on collagen-induced arthritis (CIA) in mice and the influence of T cell differentiation and cytokines balance. MATERIALS AND METHODS: Separate researches on the two traditional Chinese medicines of the Erteng Tongbi Decoction were conducted. First, a murine peritoneal macrophage model was established, and then the cytokines levels and macrophage maturity were measured to select the best extraction solvent. Furthermore, ethanol extracts were partitioned successively with four kinds of solvents, and the anti-inflammatory parts were selected by the same vitro model. Subsequently, mice were arbitrarily divided into control, CIA model, positive control, effective parts alone or in combination. After 20 days of oral administration, the weight, hind paw volume, rheumatism index value, and the pathological changes were checked to assess the obvious level of arthritis. Furthermore, the levels of IL-6, TNF-α, IL-10, and IL-17A in serum and the balance of Th17/Treg and Th1/Th2 cells in spleen and mesenteric lymph nodes (MLN) was detected. Finally, the major active constituents were identified. RESULTS: In vitro, the anti-inflammatory effects of ethanol extracts was much better than water extract. In addition, the effective parts of Celastrus orbiculatus Thunb. ethanol extract were petroleum ether parts and dichloromethane parts. The effective parts of Spatholobus suberectus Dunn. ethanol extracts was petroleum ether parts and ethyl acetate parts screened. In vivo, effective parts compatibility could inhibit the progression of inflammation by modulating T cell differentiation and cytokines balance. Constituent analysis revealed that effective parts contained sesquiterpenes alkaloids, phenolic acids, and flavanols. CONCLUSIONS: Erteng Tongbi Decoction could notably ameliorate CIA mice by modulating T cell differentiation and cytokines balance and support its application in folk medicine.
35125110 Spontaneous regression of breast lymphoproliferative disorders after withdrawal of methotr 2022 Feb 7 BACKGROUND: Lymphoproliferative disorder (LPD) has been shown to occur after treatment with methotrexate (MTX). Currently, MTX-LPD has become widely recognized, but its mechanism and prognostic factors remain unclear. CASE PRESENTATION: We report the first case of Epstein-Barr virus (EBV)-associated MTX-LPD of the breast. A 63-year-old Asian woman with long-term rheumatoid arthritis presented to our facility with intermittent fever. A physical examination revealed a 3-cm lump in her left breast. She had been taking MTX for the past 15 years. Laboratory studies revealed slightly elevated levels of EBV-viral capsid antigen antibody immunoglobulin G and EBV nuclear antibody. Contrast-enhanced computer tomography revealed a mass in the left breast, a subcutaneous nodule in the abdomen, a mass in the left lung, and a nodule in the left retroperitoneum. The definitive diagnosis was consistent with MTX-LPD merging into an EBV-positive, diffuse large B-cell lymphoma. Six months following the withdrawal of MTX, the breast mass had markedly shrunk and the patient remained in good health for 1 year with no evidence of relapse of LPD. CONCLUSION: MTX-LPD rarely occurs in the breast, and it is difficult to diagnose because there have only been six reported cases of breast MTX-LPD reported in the literature. EBV-positive MTX-LPD tends to regress spontaneously after MTX withdrawal, and our case also had similar results. It is important to make an appropriate diagnosis of MTX-LPD of the breast based on imaging and pathology to determine the appropriate treatment protocol for this rare disorder.
34980246 Unraveling heterogeneity within ACPA-negative rheumatoid arthritis: the subgroup of patien 2022 Jan 3 BACKGROUND: Rheumatoid arthritis (RA) is a heterogeneous disease, as evidenced by the differences in long-term outcomes. This applies especially to anti-citrullinated protein antibodies (ACPA)-negative RA, where a proportion achieves sustained DMARD-free remission (SDFR; sustained absence of synovitis after DMARD cessation). Differentiation of RA patients who will achieve SDFR can guide personalized treatment/tapering strategies. Although this subgroup remains scarcely discerned, previous research demonstrated that these RA patients are characterized by an early clinical response (DAS remission after 4 months) after DMARD start. We studied whether, in addition to this clinical response, a specific biomarker response can further distinguish the subgroup of RA patients most likely to achieve SDFR. METHODS: In 266 RA patients, levels of 12 biomarkers (SAA/CRP/MMP-1/MMP-3/resistin/leptin/IL-6/TNF-R1/YKL-40/EGF/VEGF/VCAM-1), in the first 2 years after diagnosis, were studied in relation to SDFR, stratified for ACPA status. Subsequently, biomarkers associated with SDFR development were combined with early DAS remission to study its additional value in defining subgroups. Since most biomarker levels are not routinely measured in clinical practice, we explored how this subgroup can be clinically recognized. RESULTS: ACPA-negative RA patients achieving SDFR were characterized by high baseline levels and stronger decline in MMP-1/MMP-3/SAA/CRP after DMARD-start, respectively 1.30×/1.44×/2.12×/2.24× stronger. This effect was absent in ACPA-positive RA. In ACPA-negative RA, a strong biomarker decline is associated with early DAS remission. The combination of both declines (clinical, biomarker) was present in a subgroup of ACPA-negative RA patients achieving SDFR. This subgroup can be clinically recognized by the combination of high baseline CRP levels (≥ 3 times ULN), and early DAS remission (DAS(4 months) < 1.6). This latter was replicated in independent ACPA-negative RA patients. CONCLUSIONS: ACPA-negative RA patients with early DAS remission and a strong biomarker response (or baseline CRP levels ≥ 3× ULN) are most likely to achieve SDFR later on. This could guide personalized decisions on DMARD tapering/cessation in ACPA-negative RA.
35289351 Anti-inflammatory activity of nicotine isolated from Brassica oleracea in rheumatoid arthr 2022 Apr 29 OBJECTIVES: Rheumatoid arthritis (RA) is an autoimmune disease, associated with chronic inflammation of synoviocytes. Tumor necrosis factor α (TNF-α) plays a crucial role in the pathogenesis of RA through pro-inflammatory cytokines. Nicotine, an alkaloid used as herbal medicine, often worked as an anti-inflammatory agent. In the present study, we tried to uncover the anti-inflammatory impact of nicotine against RA. MATERIALS AND METHODS: Nicotine was isolated from Brassica oleracea, purified by high profile/phase liquid chromatography (HPLC). In-silico docking was carried out using bioinformatics tools SwissADME (absorption, distribution, metabolism and excretion), PASS, and Drug-induced Gene Expression Profile (DIGEP)-Pred to determine drug likeliness of nicotine. The in-vitro study was performed in TNFα-induced SW982 synoviocytes by qPCR. mRNA expression of pro-inflammatory cytokines (TNF, IL6, IL1β) and proteins (TRAF2, P50, P65) were analyzed followed by validation of P65 (RELA), pP65, IkBα by Western blot analysis. RESULTS: Nicotine compound was extracted from Brassica oleracea and purified by HPLC method (Rt values at 2.67 min). The physicochemical, pharmacokinetic properties and drug-likeliness of nicotine were studied by in-silico analysis. In-vitro studies revealed that nicotine lowers the expression of inflammatory cytokines (TNF, IL6, IL1β) and proteins (TNF receptor-associated factor 2 (TRAF2), P50, P65) at 1 µg/ml in TNFα-induced SW982 cells. CONCLUSION: Nicotine from natural sources (Brassica oleracea) has been found to be an effective anti- inflammatory compound at a low dosage; thus, identifying the role of nicotine present in the natural sources as a therapeutic option for RA, may be recommended as remedial drug instead of synthetic drug.
34999146 System pharmacology analysis to decipher the effect and mechanism of active ingredients co 2022 Apr 24 ETHNOPHARMACOLOGICAL RELEVANCE: Traditional herb couple Angelicae pubescentis radix (APR) and Notopterygii rhizoma et radix (NRR), composition of two traditional Chinese medicinal herbs, has been used clinically in China for the treatment of rheumatoid arthritis (RA) over years. APR and NRR contain coumarins and phenolic acids, which have been reported to have analgesic and anti-inflammatory activities. AIM OF THE STUDY: The active ingredients combination (AIC) and potential therapeutic mechanism of APR and NRR (AN) herb couple remain unclear. Therefore, the present study aimed to identify the AIC and elucidate the underlying mechanism of AIC on RA. MATERIALS AND METHODS: Firstly, a novel strategy of in vitro experiments, computational analysis, UPLC-QTOF-MS and UPLC-QQQ-MS was established to confirm the optimum ratio of AN herb couple samples and identified the AIC. Then, the anti-arthritis effects of the optimal herb couple and AIC were studied with Collagen II induced rheumatoid arthritis (CIA) rats in vivo. Finally, an integrated model of network pharmacology, metabolomics, gut microbiota analysis and biological techniques were applied to clarify the underlying mechanism through a comprehensive perspective. RESULTS: AN7:3 herb couple was regarded as the optimal ratio of AN herbal samples, and AIC was screened as osthole, columbianadin, notopterol, isoimperatorin, psoralen, xanthotoxin, bergapten, nodakenin and bergaptol respectively. Additionally, AIC exerted similar therapeutic effects as AN 7:3 in CIA rats. Moreover, AIC ameliorated RA might via regulating MAPK signaling pathway, altering metabolic disorders and gut microbiome involved autoimmunity. CONCLUSIONS: our findings provided scientific evidence to support that AIC of AN herb couple could be used as a prebiotic agent for RA. Importantly, this research provided a systematic and feasible strategy to optimize the proportion of medicinal materials and screen AIC from multi-component traditional Chinese herb couples or Chinese medicine formulae. Moreover, it provided a comprehensive perspective to discover AIC, clarify the overall effects and understand the mechanisms for natural products through the perspective of database and multi-omics integration.
35001558 Rheumatoid Factor and Anti-Modified Protein Antibody Reactivities Converge on IgG Epitopes 2022 Jun OBJECTIVE: Rheumatoid arthritis (RA) patients often develop rheumatoid factors (RFs), antibodies that bind IgG Fc, and anti-modified protein antibodies (AMPAs), multireactive autoantibodies that commonly bind citrullinated, homocitrullinated, and acetylated antigens. Recently, antibodies that bind citrulline-containing IgG epitopes were discovered in RA, suggesting that additional undiscovered IgG epitopes could exist and that IgG could be a shared antigen for RFs and AMPAs. This study was undertaken to reveal new IgG epitopes in rheumatic disease and to determine if multireactive AMPAs bind IgG. METHODS: Using sera from patients with RA, systemic lupus erythematosus, Sjögren's disease (SjD), or spondyloarthropathy, IgG binding to native, citrulline-containing, and homocitrulline-containing linear epitopes of the IgG constant region was evaluated by peptide array, with highly bound epitopes further evaluated by enzyme-linked immunosorbent assay (ELISA). Binding of monoclonal AMPAs to IgG-derived peptides and IgG Fc was also evaluated by ELISA. RESULTS: Seropositive RA sera showed high IgG binding to multiple citrulline- and homocitrulline-containing IgG-derived peptides, whereas anti-SSA+ sera from SjD patients showed consistent binding to a single linear native epitope of IgG in the hinge region. Monoclonal AMPAs bound citrulline- and homocitrulline-containing IgG peptides and modified IgG Fc. CONCLUSION: The repertoire of epitopes bound by AMPAs includes modified IgG epitopes, positioning IgG as a common antigen that connects the otherwise divergent reactivities of RFs and AMPAs.
34523675 Identification of causal metabolites related to multiple autoimmune diseases. 2022 Feb 21 Observational studies provide evidence that metabolites may be involved in the development of autoimmune diseases (ADs), but whether it is causal is still unknown. Based on the large-scale genome-wide association studies (GWAS) summary statistics, we performed two-sample Mendelian randomization (MR) to evaluate the causal associations between human blood metabolites and multiple ADs, which were inflammatory bowel disease (IBD), ulcerative colitis (UC), crohns disease (CD), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), type 1 diabetes (T1D), multiple sclerosis (MS), primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC). After Bonferroni adjustment, we identified 6 causal features of metabolites, i.e., glycerol 2-phosphate for T1D, hexadecanedioate, phenylacetylglutamine and laurylcarnitine for RA, glycine and arachidonate (20:4n6) for CD. Comprehensive sensitive analysis was further performed to validate the robustness of associations. We also observed some overlaps of metabolites among different ADs, implying similar or shared underlying mechanisms in such pathogenic processes. Multivariable MR analysis was then conducted to avoid potential pleiotropic effect of other complex traits. After controlling for several common traits, multivariable MR analysis ruled out most of potential pleiotropic effects and validated independence of identified metabolites. Finally, metabolic pathway analysis was performed based on suggestive metabolites for each AD respectively and a total of seven metabolic pathways were identified. In conclusion, this study provided novel insights into investigating causal role of blood metabolites in development of multiple ADs through a comprehensive genetic pathway.
35265077 Update on Tenosynovial Giant Cell Tumor, an Inflammatory Arthritis With Neoplastic Feature 2022 Rheumatoid arthritis (RA) is a chronic inflammatory disease that leads to joint destruction and bone erosion. Even if many treatments were developed with success in the last decades, some patients fail to respond, and disease chronicity is still a burden. Mechanisms involved in such resistance may include molecular changes in stromal cells. Other explanations can come from observations of tenosynovial giant cell tumor (TGCT), first considered as an inflammatory arthritis, but with unusual neoplastic features. TGCT leads to synovium hypertrophy and hyperplasia with hemosiderin deposition. It affects young adults, resulting in secondary osteoarthritis and increased morbidity. TGCT shows clinical, histological and genetic similarities with RA but affecting a single joint. However, the monoclonality of some synoviocytes, the presence of translocations and rare metastases also suggest a neoplastic disease, with some features common with sarcoma. TGCT is more probably in an intermediate situation between an inflammatory and a neoplastic process, with a main involvement of the proinflammatory cytokine CSF-1/CSF1R signaling axis. The key treatment option is surgery. New treatments, derived from the RA and sarcoma fields, are emerging. The tyrosine kinase inhibitor pexidartinib was recently FDA-approved as the first drug for severe TGCT where surgery is not an option. Options directly targeting the excessive proliferation of synoviocytes are at a preclinical stage.
34980223 The impact of filgotinib on patient-reported outcomes and health-related quality of life f 2022 Jan 3 BACKGROUND: The effects of filgotinib on patient-reported outcomes (PROs) from 3 trials in patients with active rheumatoid arthritis were investigated. METHODS: Methotrexate (MTX)-naïve patients received filgotinib 200 or 100 mg plus MTX (FIL200+MTX, FIL100+MTX), filgotinib 200 mg monotherapy (FIL200), or MTX monotherapy through 52 weeks (NCT02886728). Patients with inadequate response (IR) to MTX (MTX-IR) received FIL200+MTX, FIL100+MTX, adalimumab 40 mg +MTX (ADA+MTX), or placebo (PBO)+MTX (rerandomized to FIL200+MTX or FIL100+MTX at week 24) through 52 weeks (NCT02889796). Patients with IR to biologic disease-modifying antirheumatic drugs (bDMARD-IR) received FIL200 or FIL100 or PBO with background stable conventional synthetic (cs) DMARDs for up to 24 weeks (NCT02873936). PROs included Health Assessment Questionnaire-Disability Index (HAQ-DI), Medical Outcomes Study 36-Item Short Form Health Survey (SF-36) physical/mental component summary (PCS/MCS), Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue), Work Productivity and Activity Impairment Questionnaire-Rheumatoid Arthritis (WPAI-RA), and Patient Global Assessment of Disease Activity (PtGA). Data are reported as least-squares mean changes from baseline with standard error to the timepoint representing each study's primary endpoint. All statistical comparisons are of filgotinib groups vs their respective control groups. RESULTS: At week 24, among MTX-naïve patients, change from baseline (standard deviation) in HAQ-DI was - 1.00 (0.03; P < 0.001) with FIL200+MTX, - 0.94 (0.04; P < 0.01) with FIL100+MTX, and - 0.91 (0.04; P < 0.05) with FIL200 alone compared with - 0.81 (0.03) with MTX alone. At week 12, among MTX-IR patients, change from baseline in HAQ-DI was - 0.69 (0.04; P < 0.001 vs PBO+MTX, P < 0.05 vs ADA) with FIL200+MTX, - 0.57 (0.04; P < 0.001 vs placebo) with FIL100+MTX, and - 0.60 (0.04) with ADA vs - 0.40 (0.04) with PBO+MTX. At week 12, among bDMARD-IR patients, change from baseline in HAQ-DI was - 0.50 (0.06; P < 0.001) with FIL200+csDMARD and - 0.46 (0.05; P < 0.001) with FIL100+csDMARD vs - 0.19 (0.06) with placebo+csDMARD. Changes in SF-36 PCS and MCS, FACIT-Fatigue, WPAI, and PtGA tended to favor filgotinib over PBO, MTX, and ADA. Greater proportions of patients experienced clinically meaningful differences with either dosage of FIL in combination with csDMARDs (including MTX) and with FIL200 monotherapy vs comparators. CONCLUSIONS: Filgotinib provided improvements in PROs across patient populations. These findings suggest filgotinib can be an effective treatment option for patients with insufficient response to MTX or bDMARDs and patients who are MTX-naïve. TRIAL REGISTRATION: ClinicalTrials.gov , FINCH 1, NCT02889796 , first posted September 7, 2016; FINCH 2, NCT02873936 , first posted August 22, 2016, retrospectively registered; FINCH 3, NCT02886728 , first posted September 1, 2016, retrospectively registered.
35642152 [Correlation between circRNA0003353 in Peripheral Blood Mononuclear Cells and Immune Infla 2022 May OBJECTIVE: To investigate the expression of circRNA 0003353 in the peripheral blood mononuclear cells (PBMCs) of rheumatoid arthritis (RA) patients with dampness heat obstruction syndrome and to examine its effect on inflammatory response of fibroblast-like synoviocytes (FLS). METHODS: The PBMCs and serum samples of 55 RA patients with dampness heat obstruction syndrome and 30 healthy volunteers were collected. The expression of circRNA 0003353 and its correlation with clinical indexes were examined. The circRNA 0003353 overexpression plasmid and siRNA were constructed and transfected into RA-FLS cell line. RT-qPCR was used to determine the expression of circRNA 0003353 mRNA. The expressions of interleukin (IL)-4, IL-10 and IL-17 were examined by ELISA. The expressions of Janus kinase 2 (JAK2), p-JAK2, signal transducers and activators of transcription 3 (STAT3) and p-STAT3 were exmained by Western blot. CCK-8 assay was used to assess cell viability. Cell migration was assessed with Transwell migration assay. RESULTS: 1) Compared with that of the normal group, the expression of circRNA 003353 in the PBMCs of RA patients with damp heat obstruction syndrome was significantly increased ( P<0.05). 2) Pearson correlation analysis showed that circRNA 0003353 was positively correlated with erythrocyte sedimentation rate (ESR), rheumatoid factor (RF), receptor activator of nuclear factor-κ B ligand (RANKL) and DAS28, and circRNA 0003353 was negatively correlated with IL-10 ( P<0.05). 3) The findings on the association patterns showed that the increase in circRNA 0003353 was significantly correlated with the increase of ESR, IL-17, CRP and immunoglobulin (Ig) G. 4) Logistic regression analysis showed that circRNA 0003353 was a risk factor for RANKL, CRP and ESR. 5) RT-qPCR results showed that the expression of circRNA 003353 mRNA in pcDNA3.1-circRNA 0003353 group was significantly higher than that in pcDNA3.1-NC group ( P<0.05), and that the expression of circRNA 003353 mRNA in si-circRNA 0003353 group was significantly lower than that in si-NC group ( P<0.05). 6) ELISA and Western blot results showed that, compared with those of pcDNA3.1-NC group, the expression of IL-10 in pcDNA3.1-circRNA 0003353 group significantly decreased, the expression of IL-17 increased, and p-JAK2/JAK2 and p-STAT3/STAT3 ratios significantly increased ( P<0.05). Compared with those of si-NC group, the expression of IL-10 in si-circRNA 0003353 group significantly increased, the expression of IL-17 and JAK2 decreased, and p-JAK2/JAK2 and p-STAT3/STAT3 ratios significantly decreased ( P<0.05). 7) The results of CCK-8 and Transwell assays showed that the viability and migration of RA-FLS in pcDNA3.1-circRNA 0003353 group were higher than those in pcDNA3.1-NC group ( P<0.05). Compared with those of si-NC group, the viability and migration ability of RA-FLS in si-circRNA 0003353 group decreased ( P<0.05). CONCLUSION: The expression of circRNA 0003353 is up-regulated in RA patients with damp heat obstruction syndrome, and it is involved in the pathogenesis of RA by activating the JAK2/STAT3 signaling pathway and promoting the inflammatory response.