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ID PMID Title PublicationDate abstract
33367912 Neutrophil extracellular traps mediate joint hyperalgesia induced by immune inflammation. 2021 Jul 1 OBJECTIVE: To evaluate the role of neutrophil extracellular traps (NETs) in the genesis of joint hyperalgesia using an experimental model of arthritis and transpose the findings to clinical investigation. METHODS: C57BL/6 mice were subjected to antigen-induced arthritis (AIA) and treated with Pulmozyme (PLZ) to degrade NETs or Cl-amidine to inhibit NET production. Oedema formation, the histopathological score and mechanical hyperalgesia were evaluated. NETs were injected intra-articularly in wild type (WT), Tlr4-/-, Tlr9-/-, Tnfr1-/- and Il1r-/- mice, and the levels of cytokines and Cox2 expression were quantified. NETs were also quantified from human neutrophils isolated from RA patients and individual controls. RESULTS: AIA mice had increased NET concentration in joints, accompanied by increased Padi4 gene expression in the joint cells. Treatment of AIA mice with a peptidyl arginine deiminase 4 inhibitor or with PLZ inhibited the joint hyperalgesia. Moreover, the injection of NETs into joints of naïve animals generated a dose-dependent reduction of mechanical threshold, an increase of articular oedema, inflammatory cytokine production and cyclooxygenase-2 expression. In mice deficient for Tnfr1, Il1r, Tlr4 and Tlr9, joint hyperalgesia induced by NETs was prevented. Last, we found that neutrophils from RA patients were more likely to release NETs, and the increase in synovial fluid NET concentration correlated with an increase in joint pain. CONCLUSION: The findings indicate that NETs cause hyperalgesia possibly through Toll-like receptor (TLR)-4 and TLR-9. These data support the idea that NETs contribute to articular pain, and this pathway can be an alternative target for the treatment of pain in RA.
34304373 Filgotinib in Rheumatoid Arthritis: A Profile of Its Use. 2021 Aug Filgotinib (Jyseleca(®)), an oral Janus kinase (JAK) inhibitor, is approved as monotherapy or in combination with methotrexate to treat moderate to severe active rheumatoid arthritis (RA) in adults who have an inadequate response or intolerance to one or more disease-modifying antirheumatic drugs (DMARDs). In phase 3 trials, once-daily filgotinib was generally well tolerated and associated with an improvement in RA signs and symptoms as well as physical function in patients with an inadequate response to ongoing methotrexate, an inadequate response to ongoing conventional synthetic DMARDs plus an inadequate response or intolerance to prior biologic DMARDs, or limited or no prior exposure to methotrexate. In addition, filgotinib was noninferior to adalimumab in terms of low disease activity response rate (DAS28-CRP ≤ 3.2) in patients with an inadequate response to methotrexate. Filgotinib also appeared to inhibit the radiographic progression of joint damage and led to low disease activity or disease remission (DAS28-CRP < 2.6). Filgotinib showed sustained efficacy, and the safety profile of filgotinib longer term was similar to that in the phase 2 and 3 trials.
33323577 Intracorneal scleral patch supported cyanoacrylate application for corneal perforations se 2021 Jan PURPOSE: To describe a new technique of intracorneal scleral patch (ICSP) supported cyanoacrylate tissue adhesive (CTA) application in corneal perforations, greater than 3.0 mm secondary to rheumatoid arthritis (RA). METHODS: This Prospective, non-randomized, non-comparative, interventional series included 14 eyes (14 patients). All patients had corneal perforations sized 3.5 to 4.5 mm due to RA, which were treated with ICSP supported CTA application. A partial thickness scleral patch 1.0 mm larger than diameter of corneal perforation was prepared. A lamellar corneal pocket 0.5 mm all around the corneal perforation was created. The partial thickness scleral patch was placed in the corneal perforation site and the edge was fitted into the lamellar intracorneal pocket. A minimum quantity of CTA was applied on the scleral patch to seal the perforation. RESULTS: The corneal perforations healed in 14 eyes (100%) in a mean 7.71 ± 1.14 (range, 6-9) weeks. One eye (7.14%) had inadvertent extrusion of ICSP due to premature removal of CTA but, Seidel's test was negative, and the corneal epithelial defect healed with BCL alone. One eye each (7.14%) developed steroid induced cataract and glaucoma. None of eyes developed infective keratitis, re-opening of corneal perforation (necessitating repeat procedure) or enlargement of corneal perforation requiring penetrating keratoplasty (PKP). CONCLUSION: ICSP supported CTA application is a successful alternative option to emergency PKP in treating corneal perforations sized 3.5 to 4.5 mm with associated RA.
33572273 Evaluation of Optical and Radar Based Motion Capturing Technologies for Characterizing Han 2021 Feb 9 In light of the state-of-the-art treatment options for patients with rheumatoid arthritis (RA), a detailed and early quantification and detection of impaired hand function is desirable to allow personalized treatment regiments and amend currently used subjective patient reported outcome measures. This is the motivation to apply and adapt modern measurement technologies to quantify, assess and analyze human hand movement using a marker-based optoelectronic measurement system (OMS), which has been widely used to measure human motion. We complement these recordings with data from markerless (Doppler radar) sensors and data from both sensor technologies are integrated with clinical outcomes of hand function. The technologies are leveraged to identify hand movement characteristics in RA affected patients in comparison to healthy control subjects, while performing functional tests, such as the Moberg-Picking-Up Test. The results presented discuss the experimental framework and present the limiting factors imposed by the use of marker-based measurements on hand function. The comparison of simple finger motion data, collected by the OMS, to data recorded by a simple continuous wave radar suggests that radar is a promising option for the objective assessment of hand function. Overall, the broad scope of integrating two measurement technologies with traditional clinical tests shows promising potential for developing new pathways in understanding of the role of functional outcomes for the RA pathology.
34596582 Evaluation of CD4+/CD25+/high/CD127low/- Regulatory T Cells in Rheumatoid Arthritis Patien 2021 Sep BACKGROUND: Rheumatoid arthritis (RA) is the most common rheumatoid disease of unknown etiology, determined by the articular cartilage destruction and bone loss. The hallmark of RA is the defect in immune tolerance. Regulatory T cells (Treg) play a critical role in the protection of peripheral tolerance. OBJECTIVE: To assess the percentage of CD4+/CD25+/high/CD127low/- Treg cells in peripheral blood of RA patients as compared with the healthy individuals. METHODS: The number of CD4+/CD25+/high/CD127low/- Treg cells was assessed by multicolor flow cytometry. The clinical disease activity of RA patients was determined by disease activity score 28 (DAS-28). The correlations of DAS-28 and erythrocyte sedimentation rate (ESR) with Treg cells were evaluated. RESULTS: The percentage of CD4+/CD25+/high/CD127low/- Treg cells in peripheral blood of RA patients significantly decreased as compared with the healthy individuals (P= 0.0002). The percentage of CD4+/CD25+/high/CD127low/- Treg cells negatively correlated with DAS-28 and ESR. CONCLUSION: This study concludes that the defect of Treg cells plays a vital role in the pathogenesis of this disease. Further studies are necessary to determine the role of Treg cells in the clinical course of rheumatoid arthritis.
33651342 Systematic Review and Meta-analysis on the Association of Occupational Exposure to Free Cr 2022 Apr • Occupational exposure to free crystalline silica and tobacco smoking are associated with an increased risk rheumatoid arthritis, with the evidence of an interaction in seropositive subjects. • Further studies in the field are needed to support such association We carried out a systematic search for all published epidemiological studies concerning the association between occupational exposure to free crystalline silica (FCS) and subsequent development of rheumatoid arthritis (RA). A meta-analysis was conducted on relevant studies. We searched PubMed and Embase, search engines, for original articles published (from 1960 to November 2019) in any language. In addition, we also searched reference lists of included studies manually for additional relevant articles. Finally, twelve studies were included in the meta-analysis (seven case-control cases and five cohort studies). The odds risks and 95% confidence interval (CI) were calculated using a random effect meta-analysis. A primary meta-analysis (using a random effect model)-regarding RA risk in subjects exposed to FCS-yelled to an overall OR of 1.94 (95% CI 1.46-2.58). We also conducted three further meta-analysis, taking into account the presence of autoantibodies (anti-RF or anti-ACPA) and smoking habits and found a significant association between FCS and RA in both seropositive and seronegative subjects (OR 1.74, 95% CI 1.35-2.25 and OR 1.23, 95% CI 1.06-1.4, respectively) and in seropositive subjects which were smokers (OR 3.30, 95% CI 2.40-4.54). The studies that have investigated the association between RA and occupatational exposure to FCS are still scarce and the heterogeneity between the studies remains high. Some critical limitations have been identified within studies, among which, the methods for assessing exposure stand out. Although with due caution, our results confirm the hypothesis of an association between occupational exposure to FCS and RA development. There was an interaction between FCS and tobacco smoking in RA seropositive workers.
33815416 Human PD-1(hi)CD8(+) T Cells Are a Cellular Source of IL-21 in Rheumatoid Arthritis. 2021 BACKGROUND: Rheumatoid arthritis (RA) is a prototypical autoantibody-driven autoimmune disease in which T-B interactions play a critical role. Recent comprehensive analysis suggests that PD-1(+)CD8(+) T cells as well as two distinct IL-21-producing PD-1(+)CD4(+) T cell subsets, follicular helper T (Tfh) and peripheral helper T (Tph) cells, are involved in the pathogenesis of RA. Herein, we aimed to clarify a generation mechanism of IL-21-producing CD8(+) T cells in humans, and to characterize this novel subset in patients with RA. METHODS: CD8(+) T cells in the peripheral blood (PB) and synovial fluid (SF) of healthy control (HC) and patients with RA were subject to the analysis of IL-21 mRNA and protein. We evaluated the surface marker, cytokine and transcription profiles of IL-21-producing CD8(+) T cells in HCPB, RAPB and RASF. RESULTS: IL-21-producing CD8(+) T cells were enriched in the CD45RA(-)(memory) PD-1(+), especially PD-1(hi) subpopulation, and IL-12 and IL-21 synergistically induced IL-21 production by naïve CD8(+) T cells. Memory PD-1(hi)CD8(+) T cells in HCPB facilitated plasmablast differentiation and IgG production in an IL-21-dependent manner. In addition, PD-1(hi)CD8(+) T cells in RASF and RAPB produced large amounts of IL-21 and were characterized by high levels of CD28, ICOS, CD69, HLA-DR, and CCR2 but not CXCR5. Furthermore, PD-1(hi)CD8(+) T cells expressed high levels of transcripts of MAF and PRDM1, a feature observed in Tph cells. CONCLUSIONS: Identification of IL-21-producing PD-1(hi)CD8(+) T cells expands our knowledge of T cell subsets with B helper functions in RA. Selective targeting of these subsets could pave an avenue for the development of novel treatment strategies for this disease.
32990114 Simplified disease activity index and clinical disease activity index before and during pr 2021 Jul OBJECTIVES: We explored rheumatoid arthritis (RA) disease activity before, during, and after pregnancy in patients treated with tight control and investigated the association between disease activity in the postpartum period and those before and during pregnancy. METHODS: We retrospectively reviewed disease activity and medications of 27 patients before pregnancy, at every trimester, and in the postpartum period. RESULTS: Prednisolone was administered to 33% of patients with a median dose of 0 (0-2.5) mg/day and biologic agents was 78% in the third trimester. The median remission rates during all periods were the Disease Activity Score-28-C-reactive Protein assessed with three variables (DAS28-CRP-3) 85%, Simplified Disease Activity Index (SDAI) 55%, and Clinical Disease Activity Index (CDAI) 54%. Although SDAI and CDAI decreased significantly from before pregnancy to the first trimester and increased from the third trimester to the postpartum period, DAS28-CRP-3 did not change during all periods. Although SDAI and CDAI before and during pregnancy were significantly correlated with those in the postpartum period, DAS28-CRP-3 was not. CONCLUSIONS: Tight control before pregnancy suppressed RA disease activity during pregnancy and in the postpartum period. SDAI/CDAI before and during pregnancy were predictive for disease activity in the postpartum period.
34666547 Erosive arthritis in systemic lupus erythematosus: not only Rhupus. 2021 Nov Systemic lupus erythematosus (SLE)-related arthritis has been traditionally defined as non-erosive and is therefore considered a minor manifestation requiring a mild treatment. However, the concept of non-erosive arthritis in SLE has been challenged with the advent of sensitive imaging techniques, such as high-resolution ultrasound with power Doppler or magnetic resonance. The application of these new imaging tools has demonstrated that up to 40% of SLE patients with joint involvement can develop erosive damage. Thus, this more aggressive phenotype can be identified not only in patients overlapping with rheumatoid arthritis (RA). This issue has been considered for the first time in the classification criteria proposed by Systemic Lupus International Collaborating Clinics in 2012, in which the old definition of "non-erosive arthritis" was replaced with either synovitis or tenderness in two or more joints with morning stiffness, suggesting the possible presence of an erosive phenotype. Accordingly, the 2019 EULAR/ACR's SLE recommendations advise treatment with immunosuppressant or biological drugs for patients with RA-like moderate arthritis. As a result, several studies have investigated the presence of biomarkers associated with SLE erosive damage. A relevant role seems to be played by the autoantibodies directed against post-translational modified proteins: above all, a significant association has been observed with antibodies directed against citrullinated and carbamylated proteins. Conversely, the rheumatoid factor was not associated with this more aggressive SLE-related arthritis. Nonetheless, some pro-inflammatory factors have been associated with erosive damage in SLE patients. These results suggest new pathogenic mechanisms underlining erosive arthritis, only partially shared with RA. Hence, in the present narrative review, we summarized available data about erosive arthritis in SLE patients, in the light of its impact on therapeutic decisions.
31811708 Roles of Postdiagnosis Accumulation of Morbidities and Lifestyle Changes in Excess Total a 2021 Feb OBJECTIVE: To elucidate how postdiagnosis multimorbidity and lifestyle changes contribute to the excess mortality of rheumatoid arthritis (RA). METHODS: We performed a matched cohort study among women in the Nurses' Health Study (1976-2018). We identified women with incident RA and matched each by age and year to 10 non-RA comparators at the RA diagnosis index date. Specific causes of death were ascertained via death certificates and medical record review. Lifestyle and morbidity factors were reported biennially; 61 chronic conditions were combined into the Multimorbidity Weighted Index (MWI). After adjusting for baseline confounders, we used inverse probability weighting analysis to examine the mediating influence of postindex MWI scores and lifestyle factors on total, cardiovascular, and respiratory mortality, comparing women with RA to their matched comparators. RESULTS: We identified 1,007 patients with incident RA and matched them to 10,070 non-RA comparators. After adjusting for preindex confounders, we found that hazard ratios (HRs) and 95% confidence intervals (95% CIs) were higher for total mortality (HR 1.46 [95% CI 1.32, 1.62]), as well as cardiovascular (HR 1.54 [95% CI 1.22, 1.94]) and respiratory (HR 2.75 [95% CI 2.05, 3.71]) mortality in patients with RA compared to non-RA comparators. Adjusting for postindex lifestyle factors (physical activity, body mass index, diet, smoking) attenuated but did not substantially account for this excess RA mortality. After additional adjustment for postindex MWI scores, patients with RA had HRs of 1.18 (95% CI 1.05, 1.32) for total, 1.19 (95% CI 0.94, 1.51) for cardiovascular, and 1.93 (95% CI 1.42, 2.62) for respiratory mortality. CONCLUSION: We found that MWI scores substantially accounted for the excess total and cardiovascular mortality among women with RA. This finding underscores the importance of monitoring for the total disease burden as a whole in monitoring patients with RA.
33492907 Development and Validity Testing of a Morning Stiffness Assessment Scale for Patients with 2021 Jan Morning stiffness is known to exert a significant impact on functional ability, quality of life, and employment status. There is an increasing need for a valid, reliable tool to comprehensively assess morning stiffness. The purpose of this study was to develop and verify a Morning Stiffness Assessment Scale. Items were developed on the basis of a framework of the conceptual attributes of morning stiffness. Validity and reliability tests were conducted on the devised scale. Eighty-five patients with rheumatoid arthritis were included to verify the devised scale. A 10-item Morning Stiffness Assessment Scale was developed. Its content and construct validities were well supported. The scale was found to have good reliability. The devised scale is simple and brief, but it provides a more comprehensive means of evaluation for morning stiffness. We believe this scale offers a clinically useful means of properly assessing morning stiffness and has potential utility for evaluating the effects of morning stiffness treatments.
34817776 A molecular insight of inflammatory cascades in rheumatoid arthritis and anti-arthritic po 2022 Mar Rheumatoid arthritis (RA) is an auto-immune inflammatory disorder of the synovial lining of joints marked by immune cells infiltration and hyperplasia of synovial fibroblasts which results in articular cartilage destruction and bone erosion. The current review will provide comprehensive information and results obtained from the recent research on the phytochemicals which were found to have potential anti-arthritic activity along with the molecular pathway that were targeted to control RA progression. In this review, we have summarized the scientific data from various animal studies about molecular mechanisms, possible side effects, associations with conventional therapies, and the role of complementary and alternative medicines (CAM) for RA such as ayurvedic medicines in arthritis. In the case of RA, phytochemicals have been shown to act through different pathways such as regulation of inflammatory signaling pathways, T cell differentiation, inhibition of angiogenic factors, induction of the apoptosis of fibroblast-like synoviocytes (FLS), inhibition of autophagic pathway by inhibiting High-mobility group box 1 protein (HMGB-1), Akt/ mTOR pathway and HIF-1α mediated Vascular endothelial growth (VEGF) expression. Also, osteoclasts differentiation is inhibited by down-regulating the VEGF expression by decreasing the accumulation of the ARNT (Aryl Hydrocarbon Receptor Nuclear Translocator)-HIF-1α complex Although phytochemicals have shown to exert potential anti-arthritic activity in many animal models and further clinical data is needed to confirm their safety, efficacy, and interactions in humans.
33040843 Suppressive effect of vitamin K2 against mitogen-activated peripheral blood mononuclear ce 2021 Jan OBJECTIVE: To investigate the immunosuppressive effect of vitamin K2 against mitogen-activated peripheral blood mononuclear cells (PBMCs) of rheumatoid arthritis (RA) patients. MATERIALS AND METHODS: Concanavalin A-stimulated PBMC culture procedure was used to evaluate the pharmacodynamics of vitamin K2 in vitro. Methotrexate was set up as the positive control. The proliferation of PBMCs was detected by MTT assay. Relationship between IC(50) values of drugs on PBMC proliferation and patient-related factors including laboratory data was analyzed by nonparametric Spearman correlation test. RESULTS: Vitamin K2 inhibited the proliferation of mitogen-activated PBMCs of RA patients with an IC(50) value of 3,288.47 ± 4,910.02 ng/mL (mean ± SD). There was a significant correlation between IC(50) values of vitamin K2 and patient-related factors of RA patients (p < 0.05), such as C-reactive protein (CRP), rheumatoid factor, anti-cyclic citrullinated peptide antibody (ACPA), matrix metalloproteinase-3, Pre-DAS-28 (CRP), and ∆DAS-28 (CRP). It would be possible to predict the pharmacodynamics of vitamin K2 in RA patients according to the above factors. Methotrexate inhibited the proliferation of mitogen-activated PBMCs of RA patients with a IC(50) value of 22.83 ± 12.47 ng/mL (mean ± SD). IC(50) values of methotrexate only showed significant correlation with ACPA (p = 0.0158, r = 0.6905), which suggests that ACPA might be a suitable predictor of the pharmacodynamics of methotrexate. CONCLUSION: The above information suggests that vitamin K2 could provide a benefit for the treatment of RA patients via its immunosuppressive function.
33626293 Guizhi-Shaoyao-Zhimu decoction attenuates bone erosion in rats that have collagen-induced 2021 Dec CONTEXT: Guizhi-Shaoyao-Zhimu decoction (GSZD) is commonly used to treat rheumatoid arthritis (RA), but its mechanism is unclear. OBJECTIVE: To investigate the effect of GSZD on bone erosion in type II collagen (CII)-induced arthritis (CIA) in rats and to identify the underlying mechanism. MATERIALS AND METHODS: The CIA model was prepared in male Wistar rats by two subcutaneous injections of CII, 1 mg/mL. Fifty CIA rats were randomized equally into the control group given saline daily, the positive group given saline daily and methotrexate 0.75 mg/kg once a week, and three GSZD-treated groups gavaged daily with 800, 1600 and 3200 mg/kg of GSZD for 21 days. GSZD effects were assessed by paw volume, arthritic severity index and histopathology. Cytokine levels were determined by ELISA. The effects of GSZD on RAW264.7 cells were evaluated by receptor activator of NF-κB ligand (RANKL)-induced osteoclastogenesis and bone resorption assay. Expression of IκB-α and p65 was measured by Western blotting. Major components of GSZD were identified by HPLC. RESULTS: Arthritis index score, paw volume and bone destruction score showed that GSZD improved inflammatory symptoms and reduced joint tissue erosion (p < 0.01). GSZD decreased RANKL, and the number of osteoclasts (OCs) in joint tissues (p < 0.01) and increased osteoprotegerin levels (p < 0.01). GSZD inhibited RANKL-induced RAW264.7 differentiation and reduced bone resorption by OCs. GSZD upregulated IκB (p < 0.01) and p65 (p < 0.01) in the cytoplasm and downregulated p65 (p < 0.01) in the cell nucleus. CONCLUSIONS: Guizhi-Shaoyao-Zhimu decoction has an anti-RA effect, suggesting its possible use as a supplement and alternative drug therapy for RA.
33795279 ANCA-associated vasculitis can present with episodic attacks of joint pain consistent with 2021 Apr 1 A 64-year-old man with a 2-year history of palindromic rheumatoid arthritis, presented with recurrent flares of arthritis, weight loss, new onset Raynaud's phenomenon and one previous episode of small-volume haemoptysis. Investigations, including renal biopsy, revealed antineutrophil cytoplasmic antibodies-mediated vasculitis. This case highlights the need to consider vasculitis in patients in whom there is an atypical history of arthritis.
33205906 Etanercept or Methotrexate Withdrawal in Rheumatoid Arthritis Patients in Sustained Remiss 2021 May OBJECTIVE: Patients with rheumatoid arthritis (RA) in whom remission is achieved following combination therapy with methotrexate plus etanercept face an ongoing medication burden. This study was undertaken to investigate whether sustained remission achieved on combination therapy can be maintained with either methotrexate or etanercept monotherapy, as assessed following discontinuation of one or the other medication from the combination. METHODS: Of the 371 adult patients with RA who received combination therapy with methotrexate plus etanercept, remission (defined as a Simplified Disease Activity Index [SDAI] score of ≤3.3) was sustained in 253 patients through a 24-week open-label period. These 253 patients then entered a 48-week, double-blind period and were randomized to receive either 1) methotrexate monotherapy (n = 101), 2) etanercept monotherapy (n = 101), or 3) methotrexate plus etanercept combination therapy (n = 51). Patients who subsequently experienced disease-worsening received rescue therapy with the combination regimen at the same dosages as used in the initial run-in period. The primary end point was the proportion of patients in whom SDAI-defined remission was maintained without disease-worsening at week 48 in the etanercept monotherapy group as compared to the methotrexate monotherapy group. Secondary end points included time to disease-worsening, and the proportion of patients in whom SDAI-defined remission was recaptured after initiation of rescue therapy. RESULTS: Baseline demographic and clinical characteristics of the RA patients were similar across the treatment groups. At week 48, SDAI-defined remission was maintained in significantly more patients in the etanercept monotherapy group than in the methotrexate monotherapy group (49.5% versus 28.7%; P = 0.004). Moreover, as a secondary end point, sustained SDAI-defined remission was achieved in significantly more patients who received combination therapy than in those who received methotrexate monotherapy (52.9% versus 28.7%; P = 0.006). Time to disease-worsening was shorter in those who received methotrexate monotherapy than in those who received etanercept monotherapy or those who received combination therapy (each P < 0.001 versus methotrexate monotherapy). Among the patients who received rescue therapy, SDAI-defined remission was recaptured in 70-80% in each treatment group. No new safety signals were reported. CONCLUSION: The efficacy of etanercept monotherapy was superior to that of methotrexate monotherapy and similar to that of combination therapy in maintaining remission in patients with RA. SDAI-defined remission was recaptured in most of the patients who were given rescue therapy. These data could inform decision-making when withdrawal of therapy is being considered to reduce treatment burden in patients with well-controlled RA.
33017281 Potential of B-cell-targeting therapy in overcoming multidrug resistance and tissue invasi 2021 Sep Rheumatoid arthritis (RA) is a systemic autoimmune mediated inflammatory disease characterized by progressive joint damage and extra-articular organ manifestations. Among the effector pathways and cells involved in the development of RA, activated B cells play a pivotal role in the pathological process of RA. P-glycoprotein (P-gp), a member of ATP-binding cassette transporters, is induced on the cell membrane by certain stimuli. P-gp transports various drugs from the cytoplasm to the cell exterior, resulting in the development of drug resistance. P-gp expression on B cells appears in patients with RA as the disease activity increases, and treatment of these patients' results in modification of over-expression of P-gp on activated B cells. Evidence suggests that P-gp expressing-activated B cells play important roles in the pathogenesis and treatment resistance in RA through the efflux of intracellular drugs and progression of infiltration in inflammatory lesions. Therapies designed to target activated B cells might overcome refractory RA. Identification of the subsets of peripheral activated B cells that express P-gp in RA patients might help the selection of suitable treatment strategy.
34225810 Inhibition of histone deacetylase 6 suppresses inflammatory responses and invasiveness of 2021 Jul 5 BACKGROUND: To investigate the effects of inhibiting histone deacetylase (HDAC) 6 on inflammatory responses and tissue-destructive functions of fibroblast-like synoviocytes (FLS) in rheumatoid arthritis (RA). METHODS: FLS from RA patients were activated with interleukin (IL)-1β in the presence of increasing concentrations of M808, a novel specific HDAC6 inhibitor. Production of ILs, chemokines, and metalloproteinases (MMPs) was measured in ELISAs. Acetylation of tubulin and expression of ICAM-1 and VCAM-1 were assessed by Western blotting. Wound healing and adhesion assays were performed. Cytoskeletal organization was visualized by immunofluorescence. Finally, the impact of HDAC6 inhibition on the severity of arthritis and joint histology was examined in a murine model of adjuvant-induced arthritis (AIA). RESULTS: HDAC6 was selectively inhibited by M808. The HDAC6 inhibitor suppressed the production of MMP-1, MMP-3, IL-6, CCL2, CXCL8, and CXCL10 by RA-FLS in response to IL-1β. Increased acetylation of tubulin was associated with decreased migration of RA-FLS. Inhibiting HDAC6 induced cytoskeletal reorganization in RA-FLS by suppressing the formation of invadopodia following activation with IL-1β. In addition, M808 tended to decrease the expression of ICAM-1 and VCAM-1. In the AIA arthritis model, M808 improved the clinical arthritis score in a dose-dependent manner. Also, HDAC6 inhibition was associated with less severe synovial inflammation and joint destruction. CONCLUSION: Inhibiting HDAC6 dampens the inflammatory and destructive activity of RA-FLS and reduces the severity of arthritis. Thus, targeting HDAC6 has therapeutic potential.
33674373 Strategies for developing and implementing a rheumatoid arthritis healthcare quality frame 2021 Mar 5 OBJECTIVES: To obtain stakeholder perspectives to inform the development and implementation of a rheumatoid arthritis (RA) healthcare quality measurement framework. DESIGN: Qualitative study using thematic analysis of focus groups and interviews. SETTING: Arthritis stakeholders from across Canada including healthcare providers, persons living with RA, clinic managers and policy leaders were recruited for the focus groups and interviews. PARTICIPANTS: Fifty-four stakeholders from nine provinces. INTERVENTIONS: Qualitative researchers led each focus group/interview using a semistructured guide; the digitally recorded data were transcribed verbatim. Two teams of two coders independently analysed the transcripts using thematic analysis. RESULTS: Perspectives on the use of different types of measurement frameworks in healthcare were obtained. In particular, stakeholders advocated for the use of existing healthcare frameworks over frameworks developed in the business world and adapted for healthcare. Persons living with RA were less familiar with specific measurement frameworks, however, they had used existing online public forums for rating their experience and quality of healthcare provided. They viewed a standardised framework as potentially useful for assisting with monitoring the care provided to them individually. Nine guiding principles for framework development and 13 measurement themes were identified. Perceived barriers identified included access to data and concerns about how measures in the framework were developed and used. Effective approaches to framework implementation included having sound knowledge translation strategies and involving stakeholders throughout the measurement development and reporting process. Clinical models of care and health policies conducive to outcome measurement were highlighted as drivers of successful measurement initiatives. CONCLUSION: These important perspectives will be used to inform a healthcare quality measurement framework for RA.
34227243 Circulating CD4(+)  FoxP3(-)  CXCR5(-)  CXCR3(+)  PD-1(hi) cells are elevated in activ 2021 Aug OBJECTIVE: To examine the expression and clinical significance of circulating CD4(+)  FoxP3(-)  CXCR5(-)  CXCR3(+)  PD-1(hi) cells in rheumatoid arthritis (RA). METHODS: CD4(+)  FoxP3(-)  CXCR5(-)  CXCR3(+)  PD-1(hi) cells in peripheral blood of 35 patients with active RA, 17 with RA in stable remission, and 24 healthy controls were analyzed by flow cytometry. Serum IgG and circulating plasmablast percentages were measured and correlations with CD4(+)  FoxP3(-)  CXCR5(-)  CXCR3(+)  PD-1(hi) cells were systematically analyzed. Disease Activity Scale 28 (DAS28) scores were also calculated and correlation analysis with CD4(+)  FoxP3(-)  CXCR5(-)  CXCR3(+)  PD-1(hi) cells was conducted. The levels of CD4(+)  FoxP3(-)  CXCR5(-)  CXCR3(+)  PD-1(hi) cells were compared before and after disease-modifying anti-rheumatic drug treatment. Cytokine levels in plasma and cytokine secretion in CD4 cells were measured and their correlations with CD4(+)  FoxP3(-)  CXCR5(-)  CXCR3(+)  PD-1(hi) cells were further analyzed. RESULTS: The levels of CD4(+)  FoxP3(-)  CXCR5(-)  CXCR3(+)  PD-1(hi) cells in the peripheral blood of patients with active RA were significantly increased compared with healthy controls. CD4(+)  FoxP3(-)  CXCR5(-)  CXCR3(+)  PD-1(hi) cells in patients with active RA were positively correlated with serum IgG and DAS28 scores. CD4(+)  FoxP3(-)  CXCR5(-)  CXCR3(+)  PD-1(hi) cells were significantly decreased in patients after treatment. Plasma interleukin-10 concentrations and interleukin-10-positive CD4 cell percentages were significantly positively correlated with CD4(+)  FoxP3(-)  CXCR5(-)  CXCR3(+)  PD-1(hi) cell levels. CONCLUSION: Circulating CD4(+)  FoxP3(-)  CXCR5(-)  CXCR3(+)  PD-1(hi) cells in patients with active RA are increased and could reflect the severity of the disease, which may play a potential role in the pathogenesis of RA.