Browse

Search for: rheumatoid arthritis    methotrexate    autoimmune disease    biomarker    gene expression    GWAS    HLA genes    non-HLA genes   

ID PMID Title PublicationDate abstract
32018293 [New aspects on autoantibodies for classification, diagnosis and therapy within rheumatolo 2020 Feb Recent advances in rheumatology indicate increased relevance of autoantibodies. In this regard, positive ANA are now required as entrance criterium for the first EULAR/ACR classification criteria of SLE. Importantly, ANA diagnostic with detection of isolated anti-dense fine speckled antibodies (DSF-70) need consideration since their unique detection has been identified to exclude largely an autoimmune disease. Thus, highly qualified ANA diagnostic preferably on Hep-2 cell lines is a prerequisite of reliable diagnostics.Recent recommendations for the management of antiphospholipid syndrome define high versus low risk seroprofiles which also guide primary and secondary prophylaxis. Importantly triple positive APS patients (positive for anticradiolipin, anti-ß2 GP I positive and carrying lupus anticoagulant) should be treated with vitamin K antagonists while direct oral anticoagulants have been shown to be inferior in terms of risk/benefit. Treatment of obstetric APS is mainly based on low dose aspirin and low molecular heparin. Notably, this treatment should be maintained for 6 weeks after delivery. Thus, serologic findings provide the basis for certain key clinical decisions and require their reliable detection.
32307918 Protective Role of Optineurin Against Joint Destruction in Rheumatoid Arthritis Synovial F 2020 Sep OBJECTIVE: Optineurin (OPTN) is an autophagy adaptor/receptor that acts as an intrinsic negative regulator of osteoclast differentiation. RANKL expressed by rheumatoid arthritis synovial fibroblasts (RASFs) is primarily responsible for the development of bone erosions in patients with RA. The aim of the present study was to explore the role of OPTN in the pathogenesis of joint destruction in RA. METHODS: RASFs were left untreated or incubated with tumor necrosis factor (TNF) or interferon-γ (IFNγ), and expression of OPTN by RASFs was analyzed by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and Western blotting. Expression of RANKL and osteoprotegerin (OPG) was evaluated in cultures of OPTN-reduced RASFs with or without TNF or IFNγ treatment. OPTN-reduced RASFs were cocultured with monocytes and stained for tartrate-resistant acid phosphatase (TRAP). IκBα, NF-κB1, and RelA protein levels were measured to evaluate NF-κB signaling. Expression of messenger RNA (mRNA) for matrix metalloproteinase 3 (MMP3), interleukin-6 (IL6), GATA binding protein 3 (GATA3), carbohydrate sulfotransferase 15 (CHST15), hyaluronan synthase 1 (HAS1), and GATA1 was analyzed by RT-qPCR. RESULTS: In RASFs incubated with TNF or IFNγ, OPTN expression was up-regulated and RANKL expression was increased, and these effects were further pronounced in OPTN-reduced RASFs (all P < 0.05 versus controls). OPG mRNA levels remained unchanged. Monocytes cocultured with OPTN-reduced RASFs differentiated to a greater extent into TRAP+ multinucleated cells compared to monocytes cocultured with control RASFs (P < 0.05). IκBα degradation and nuclear NF-κB1 expression following TNF treatment were both prolonged in OPTN-reduced RASFs (each P < 0.05 versus controls). MMP3 mRNA levels were up-regulated, while GATA3, CHST15, and HAS1 mRNA levels were down-regulated in OPTN-reduced RASFs (each P < 0.05 versus controls). CONCLUSION: OPTN plays a protective role in RA when it is up-regulated in RASFs in the presence of proinflammatory cytokines. Absence of OPTN might worsen RA by generating a joint-destructive state, as indicated by evidence of increased RANKL expression on RASFs and subsequent osteoclast differentiation.
32463156 Rapid monitoring of health services utilization following a shift in coverage from brand n 2020 Jul PURPOSE: We explored changes in health services utilization associated with the Biosimilars Initiative introduced in British Columbia on May 27, 2019. To maintain drug coverage, the policy requires users of originator infliximab or etanercept to transition to biosimilar versions. We present a three-month interim analysis of this initiative. METHODS: We conducted a rapid monitoring analysis to evaluate changes in health services utilization three months after the policy was introduced compared with a three-year period before the policy's introduction. Using the administrative claims data of the British Columbia Ministry of Health, we assembled three historical cohorts and one policy cohort of users of each originator drug (8 cohorts in total). Cumulative incidences of medication refills, switching, and visits to physicians were the outcome measures used to compare policy and historical cohorts. Likelihood ratios were used to quantify statistical differences between each policy cohort and its respective historical controls. Likelihood ratios above 7.1 were considered statistically significant. RESULTS: The four infliximab cohorts included 436 patients on average, mean age 56 to 59, 53% to 55% females. The four etanercept cohorts included 1826 patients on average, mean age 57 to 58, 60% to 63% females. Three months after the policy's introduction, 21% of patients treated in the policy cohorts transitioned to the biosimilar versions. Health services utilization in the policy cohorts were consistent with the historical cohorts. CONCLUSIONS: An increase in visits to physicians was expected but not detected in the first three months of the Biosimilars Initiative. The impacts of the policy will continue to be monitored.
33024253 Predictive factors for effective selection of Interleukin-6 inhibitor and tumor necrosis f 2020 Oct 6 Treatment of rheumatoid arthritis (RA) is aimed at long-term remission and inhibition of joint destruction by different biologic drugs. However, the choice of a particular biologic agent based on individual cases of RA remains unestablished. Interleukin-6 (IL-6) inhibitor and tumor necrosis factor (TNF) inhibitor are common biologics used for the treatment of RA. This study aimed to investigate predictive factors for effective selection of tocilizumab (IL-6 inhibitor) and etanercept (TNF inhibitor) in patients with RA. This is a retrospective cohort study. The 196 patients analyzed in this study were divided into four groups: tocilizumab treatment as the first biologic group (TCZ first, 42 patients), tocilizumab as second/ third biologic group (TCZ second, 34 patients), etanercept as the first biologic group (ETN first, 103 patients) and etanercept as second/third group (ETN second, 17 patients). Visual analog scale (VAS), clinical disease activity index (CDAI), and modified health assessment questionnaire (mHAQ) scores at the initiation of biologic treatment and after 6 months of tocilizumab and etanercept therapy were measured and compared to clinical parameters and radiographical parameters among the four groups. CRP, MMP-3, VAS, CDAI, and HAQ were improved after 6 months of treatment in all groups. Improvement of clinical outcomes was correlated with CRP value, duration of RA, and Sharp scores at the initiation of treatment. Multivariate analysis demonstrated improvement in CDAI was significantly associated with the yearly progression of erosion according to the Sharp score in TCZ first group (OR, 1.5; 95% CI, 1.03-2.07) and was negatively associated with the duration of RA (OR, 0.49; 95% CI, 0.29-0.86) at the initiation of treatment with ETN first group. We identified the predictive factors for effective selection of tocilizumab and etanercept treatment and established the effectiveness of tocilizumab for the patients with rapid progressive joint erosion and etanercept for the early administration from diagnosis of RA.
31837308 Leocarpinolide B attenuates LPS-induced inflammation on RAW264.7 macrophages by mediating 2020 Feb 5 Macrophages-mediated inflammation is involved in the regulation of rheumatoid arthritis (RA). Sigesbeckiae Herba (SH) has been traditionally used for rheumatism. However, the bioactive ingredients of SH are still unclear. Recently, we isolated a compound (Leocarpinolide B, LB) from SH and identified its potent anti-inflammatory and antioxidant effects on RAW264.7 macrophages for the first time. LB effectively inhibited excessive production of nitric oxide (NO), prostaglandin E2 (PGE(2)), cytokines (IL-6, TNF-α and MCP-1), and the expression of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthases (iNOS) in lipopolysaccharide (LPS)-induced RAW264.7 cells. LB blocked the degradation of inhibitor of kappa B (IκBα) and translocation of nuclear factor kappa B (NF-κB) p65. Additionally, LB reduced the intracellular reactive oxygen species, and increased the expression of heme oxygenase-1 (HO-1) and the translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) in the presence or absence of LPS. The results suggested that LB might be one of the bioactive components of SH, and be potential for the treatment of RA and valuable to be further investigated.
32621081 Understanding factors associated with vaccine uptake and vaccine hesitancy in patients wit 2021 Feb Due to higher risk of complications associated with vaccine-preventable infections (e.g., influenza, pneumococcus), patients with rheumatoid arthritis (RA) are a priority group for vaccination. However, vaccination rates among RA patients are low, indicating a need to understand the determinants of vaccine hesitancy in this group. This study conducted an evidence synthesis of various stakeholders' (patients, physicians/rheumatologists) perspectives about the determinants of vaccine hesitancy and uptake among patients with RA. We searched three bibliographic and reference databases (PUBMED, PsychINFO, and SCOPUS) for relevant English or French articles published in peer-reviewed journals through July 2019 that conducted either qualitative or quantitative assessments of vaccine hesitancy or uptake. Key themes associated with vaccination hesitancy themes according to different stakeholders were extracted and summarized. Of 783 unique citations, 16 articles met the inclusion criteria. Most studies (78%; n = 134,787 RA patients) examined barriers reported by patients, 13% (n = 114) by rheumatologists. Two principal themes and six sub-themes associated with vaccination hesitancy were identified among both patients and rheumatologists: 'social and contextual factors' (including healthcare policies, access to care/high patient loads, and social/media influences) and 'patient and provider factors' (including patient understanding of benefits and risks, provider awareness of guidelines and perceived responsibility for vaccination, and implementation challenges). Determinants of vaccine hesitancy and uptake in RA identified by different stakeholders implicate patient-, provider-, and healthcare system‑related factors. This information is relevant for the design of interventions that target improving vaccine uptake in RA patients.
32362074 Blockade of Discoidin Domain Receptor 2 as a Strategy for Reducing Inflammation and Joint 2020 Jun OBJECTIVE: This study was undertaken to uncover the pathophysiologic role of discoidin domain receptor 2 (DDR-2), a putative fibrillar collagen receptor, in inflammation promotion and joint destruction in rheumatoid arthritis (RA). METHODS: In synovial tissue from patients with RA and from mice with collagen antibody-induced arthritis (CAIA) (using Ddr2(-/-) and DBA/1 mice), gene and protein expression levels of DDR-2, interleukin-15 (IL-15), and Dkk-1 were measured by quantitative reverse transcription-polymerase chain reaction, Western blotting, and immunohistochemistry. Gene knockdown of DDR2 in human RA fibroblast-like synoviocytes (FLS) was conducted via small interfering RNA. Interaction between the long noncoding RNA H19 and microRNA 103a (miR-103a) was assessed in RA FLS using RNA pulldown assays. Cellular localization of H19 was examined using fluorescence in situ hybridization assays. Chromatin immunoprecipitation and dual luciferase reporter assays were applied to verify H19 transcriptional and posttranscriptional regulation by miR-103a. RESULTS: DDR2 messenger RNA (mRNA) expression was significantly associated with the levels of IL-15 and Dkk-1 mRNA in the synovial tissue of RA patients (r(2) = 0.2022-0.3293, all P < 0.05; n = 33) and with the serum levels of IL-15 and Dkk-1 in mice with CAIA (P < 0.05). In human RA FLS, activated DDR-2 induced the expression of H19 through c-Myc. Moreover, H19 directly interacted with and promoted the degradation of miR-103a. CONCLUSION: These results indicate a novel role for activated DDR-2 in RA FLS, showing that DDR-2 is responsible for regulating the expression of IL-15 and Dkk-1 in RA FLS and is involved in the promotion of inflammation and joint destruction during pathophysiologic development of RA. Moreover, DDR-2 inhibition, acting through the H19-miR-103a axis, leads to reductions in the inflammatory reaction and severity of joint destruction in mice with CAIA, suggesting that inhibition of DDR-2 may be a potential therapeutic strategy for RA.
32972460 Interleukin (IL)-25 suppresses IL-22-induced osteoclastogenesis in rheumatoid arthritis vi 2020 Sep 23 BACKGROUND: The present study aimed to evaluate the suppressive role of interleukin (IL)-25 in IL-22-induced osteoclastogenesis and receptor activator of nuclear factor κB ligand (RANKL) expression in rheumatoid arthritis (RA). METHODS: Serum from patients with RA and osteoarthritis (OA), and healthy controls, and synovial fluid from patients with RA and OA were collected, and the levels of IL-22 and IL-25 were measured. RA and OA synovial tissues were stained against IL-25. Fibroblast-like synoviocytes (FLSs) of patients with RA were cultured with IL-22, in the presence or absence of IL-25, and RANKL expression was measured by real-time PCR and enzyme-linked immunosorbent assay (ELISA). Human peripheral blood monocytes were cultured under IL-22/RANKL + M-CSF, with or without IL-25, and tartrate-resistant acid phosphatase (TRAP)-positive cells and osteoclast-related markers were investigated to determine osteoclastogenesis. RESULTS: Serum and synovial IL-25 levels in RA were upregulated compared to those in OA and healthy control, and elevated expression of IL-25 in RA synovial tissue was re-confirmed. IL-25 and IL-22 levels showed significant correlation in serum and synovial fluid. Pre-treatment of FLS with IL-25 reduced IL-22-induced RANKL expression at the RNA level. The suppressive effects of IL-25 were confirmed to occur through the STAT3 and p38 MAPK/IκBα pathways. IL-25 reduced osteoclast differentiation and suppressed the expression of osteoclast-related markers. CONCLUSION: In the current study, we demonstrated the regulatory effect of IL-25 on IL-22-induced osteoclastogenesis. Therapeutic approach involving augmentation of IL-25 regulatory response may serve as a novel treatment option for RA, especially by suppressing osteoclastogenesis.
32051226 JAK inhibition increases bone mass in steady-state conditions and ameliorates pathological 2020 Feb 12 Janus kinase (JAK)-mediated cytokine signaling has emerged as an important therapeutic target for the treatment of inflammatory diseases such as rheumatoid arthritis (RA). Accordingly, JAK inhibitors compose a new class of drugs, among which tofacitinib and baricitinib have been approved for the treatment of RA. Periarticular bone erosions contribute considerably to the pathogenesis of RA. However, although the immunomodulatory aspect of JAK inhibition (JAKi) is well defined, the current knowledge of how JAKi influences bone homeostasis is limited. Here, we assessed the effects of the JAK inhibitors tofacitinib and baricitinib on bone phenotype (i) in mice during steady-state conditions or in mice with bone loss induced by (ii) estrogen-deficiency (ovariectomy) or (iii) inflammation (arthritis) to evaluate whether effects of JAKi on bone metabolism require noninflammatory/inflammatory challenge. In all three models, JAKi increased bone mass, consistent with reducing the ratio of receptor activator of NF-κB ligand/osteoprotegerin in serum. In vitro, effects of tofacitinib and baricitinib on osteoclast and osteoblast differentiation were analyzed. JAKi significantly increased osteoblast function (P < 0.05) but showed no direct effects on osteoclasts. Additionally, mRNA sequencing and ingenuity pathway analyses were performed in osteoblasts exposed to JAKi and revealed robust up-regulation of markers for osteoblast function, such as osteocalcin and Wnt signaling. The anabolic effect of JAKi was illustrated by the stabilization of β-catenin. In humans with RA, JAKi induced bone-anabolic effects as evidenced by repair of arthritic bone erosions. Results support that JAKi is a potent therapeutic tool for increasing osteoblast function and bone formation.
32816071 [Successful treatment of adult Still's disease with tofacitinib in a HIV-2 positive femal 2020 Dec A 46-year-old female patient with a known HIV-2-infection suffered from adult onset Still's disease, which was initially complicated by a macrophage activation syndrome (MAS). The required glucocorticoid treatment induced a psychosis and the patient developed an aversion to glucocorticoids. After failure of treatment with anakinra, an alternative option with the JAK-inhibitor tofacitinib was introduced because of the short half-life and to reduce glucocorticoid exposure. A switch to tofacitinib was only successful after an overlapping treatment with anakinra and tofacitinib for 3 weeks. The patient is currently being treated with monotherapy with tofacitinib as well as NSAID on demand, is in stable remission and can continue working as normal.
31641751 Metabolomics analysis revealed significantly higher synovial Phe/Tyr ratio in reactive art 2020 Jul 1 OBJECTIVE: To compare the synovial phenylalanine/tyrosine (Phe/Tyr) ratio between ReA/uSpA and RA and OA by NMR spectroscopy. METHODS: Paired SF and serum of 30 patients with ReA/uSpA were collected and analysed using a 1D 1H Carr Purcell Meiboom Gill NMR spectra recorded on 800 MHz NMR spectrometer equipped with a TCI Cryoprobe (at 300 K). Phe and Tyr were quantified. SF from 25 patients with RA fulfilling ACR classification criteria and 21 patients with OA were taken as inflammatory and non-inflammatory controls. RESULTS: The synovial Phe/Tyr ratio was significantly higher in ReA/uSpA compared with RA and OA. Synovial Phe/Tyr ratios were comparable in RA and OA patients. Compared with serum, the Phe/Tyr was significantly higher in the SF in ReA/uSpA. The Phe/Tyr ratio was also found to be positively correlated between serum and SF samples, with a regression coefficient (r2) of 0.287. CONCLUSIONS: This NMR-based metabolomics study demonstrates that the synovial Phe/Tyr ratio is specifically elevated in ReA/uSpA.
32488768 Alterations and abnormal expression of A20 in peripheral monocyte subtypes in patients wit 2021 Jan As the precursors of macrophages and osteoclasts, monocytes play an important role in the pathogenesis of rheumatoid arthritis (RA). Since the deficiency of zinc-finger protein A20 in myeloid cells triggers erosive polyarthritis resembling RA, A20 in monocytes may play a protective role in RA. In the present study, we aimed to investigate the abnormality of monocyte subtypes and the expression of zinc-finger protein A20 in RA. Peripheral blood mononuclear cells and clinical data were collected from RA patients and healthy controls (HCs). Monocyte subtypes and A20 expression were determined through flow cytometry and compared between the two groups. Correlations between monocyte subtypes, A20 expression, and clinical data were analyzed. A total of 43 RA patients and 23 HCs were included in the present study. RA patients had higher absolute monocyte counts (p < 0.001) in the peripheral blood. The proportions and counts of intermediate monocytes (IMs) (both p < 0.001) and non-classical monocytes (NCMs) were higher (both p < 0.001) in RA patients. The expression of A20 in IMs (p < 0.001) was lower in RA patients compared with that in the HCs. Furthermore, the expression of A20 in IMs was negatively correlated with the anti-cyclic citrullinated peptide (CCP) antibody level in RA patients (r = - 0.409, p = 0.01). The expression of A20 in NCMs was positively correlated with modified total Sharp score (mTSS) in RA patients (r = 0.471, p = 0.02). Collectively, we proved that IMs and NCMs were increased in RA patients, suggesting that they played a suggestive role in the pathogenesis of RA. Furthermore, the downregulation of A20 in IMs might be correlated with anti-CCP antibody production. The A20 expression in NCMs might affect bone erosion in RA. Key Points • IMs and NCMs were increased in the peripheral blood of RA patients, suggesting their pathogenic role in RA. • The decreased expression of zinc-finger protein A20 in IMs of RA patients suggested the protective role of A20 in RA. • The negative correlation between the A20 expression in IMs and anti-CCP antibody revealed that A20 in IMs might be related to the formation of anti-CCP antibodies. • The positive correlation between the A20 expression in NCMs and mTSS revealed that A20 in NCMs might affect the bone erosion in RA.
32268958 Paeoniflorin-6'-O-benzene sulfonate down-regulates CXCR4-Gβγ-PI3K/AKT mediated migration 2020 Jun 4 OBJECTIVE: This study aims to explore the effect of paeoniflorin-6'-O-benzene sulfonate (CP-25) on the migration of fibroblast-like synoviocytes (FLS) in rheumatoid arthritis (RA) and the mechanism focused on CXCR4-Gβγ-PI3K/AKT signaling. METHODS: Human synovial tissues were collected from RA and osteoarthritis (OA) patients. Immunohistochemistry (IHC) and Western blot were used to detect the protein expression of CXCR4, GRK2, Gβγ, PI3K, p-PI3K, AKT and p-AKT. Transwell was adopted to analyse the migration of fibroblast-like synoviocytes (FLS). Co-immunoprecipitation (Co-IP) and laser scanning confocal microscopy (LSCM) were used to detect the combination of GRK2 and Gβγ, the combination of PI3K and Gβγ. RESULTS: The expression level of CXCR4, GRK2, Gβγ, p-p85 and p-AKT were increased in RA synovial tissue according to the results of IHC and Western blot. In vitro, the migration of FLS was increased after stimulation of CXCL12, inhibition of Gβγ suppressed the migration and phosphorylation of p85 and AKT induced by CXCL12 in FLS, and CP-25 had the same effect as inhibition of Gβγ. The membrane expression of GRK2, Gβγ, PI3K and the combination of GRK2 and Gβγ, the combination of PI3K and Gβγ in FLS were increased after the stimulation of CXCL12, and CP-25 had an ability in reducing the membrane expression and the combination of these proteins. CONCLUSION: Excessive migration of FLS in RA was associated with over-activation of PI3K/AKT signaling, and the activity of Gβγ was involved in the over-activation of PI3K/AKT. CP-25 down-regulated CXCR4-Gβγ-PI3K/AKT signals by inhibiting GRK2-Gβγ complex membrane translocation.
32314175 Profile of common inflammatory markers in treatment-naïve patients with systemic rheumati 2020 Oct OBJECTIVES: To evaluate and compare the clinical implications of common inflammatory markers in systemic rheumatic diseases (SRDs). METHOD: We investigated the profiles of erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and white blood cell (WBC) count in treatment-naïve patients with SRDs, osteoarthritis and pneumonia diagnosed at Seoul National University Hospital during 2004-2016. SRDs included rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), ankylosing spondylitis (AS), systemic sclerosis (SSc), idiopathic inflammatory myopathy (IIM) and adult-onset Still's disease (AOSD). Associations between inflammatory markers were evaluated using Pearson's correlation and regression analysis. ROC curve analysis was performed to examine the predictive value of inflammatory markers for SRD diagnosis. RESULTS: We identified a total of 1191 patients. Leukocytosis was present in < 20% SRD patients. There was marked variability in ESR and CRP levels among different SRDs. The highest mean CRP levels (mean ± SD, mg/dL) were observed in AOSD (11.3 ± 7.9), followed by RA (2.0 ± 3.3), IIM (1.8 ± 3.5), SLE (1.5 ± 3.1), SSc (0.6 ± 1.3) and AS (0.08 ± 0.1). Mean ESR (mm/h) was also highest in AOSD (71.2 ± 31.0), followed by SLE (47.3 ± 34.2), RA (45.5 ± 30.6), IIM (40.8 ± 24.8) and SSc (27.8 ± 26.0). All SRDs showed significant positive correlations between ESR and CRP: greatest in RA (r = 0.53, p < 0.001) and weakest in SLE (r = 0.20, p = 0.03). WBC correlated weakly with CRP but not with ESR in most SRDs. While the AUC for WBC count was less than that of ESR or CRP, the AUC for ESR and CRP were similar in SRD. The optimal cuff-off values for inflammatory markers predicting SRD were within or slightly above the normal limit. CONCLUSIONS: ESR, CRP and WBC are not always elevated in treatment-naïve patients with SRD. Individual SRDs have a unique profile of inflammatory markers. However, routine inflammatory markers should still be interpreted with caution when diagnosing and assessing disease activity in those with SRD. Key Points •Leukocytosis and elevation of ESR and CRP are not always present in all systemic rheumatic diseases. •Inflammatory markers are often dissociated and they are not specific for disease diagnosis. •Better biomarkers, which measure disease-specific local and systemic inflammation, are needed.
32173059 All-cause and cause-specific mortality in persons with fibromyalgia and widespread pain: A 2020 Dec PURPOSE: Studies of the relation of fibromyalgia (FM) and widespread pain (WSP) to mortality have differed as to the presence or absence of an association and the extent of cause-specific mortality. However, no studies have investigated which definitions of FM and WSP associate with mortality, nor of FM mortality in other diseases. We investigated these issues and the meaning of mortality in patients with FM. METHODS: We used Cox regression to study 35,248 rheumatic disease patients with up to 16 years of mortality follow-up in all patients and separately in those with diagnoses of rheumatoid arthritis (RA) (N = 26,458), non-inflammatory rheumatic disorders (NIRMD) (N = 5,167) and clinically diagnosed FM (N = 3,659). We applied 2016 FM criteria and other FM and WSP criteria to models adjusted for age and sex as well as to models that included a full range of covariates, including comorbid disease and functional status. We estimated the degree of explained of variance (R2) as a measure of predictive ability. RESULTS: We found positive associations between al`l definitions of FM and WSP and all-cause mortality, with relative risks (RR)s ranging from 1.19 (95%CI 1.15-1.24) for American College of Rheumatology (ACR) 1990 WSP to 1.38 (1.31-1.46) in age and sex adjusted revised 2016 criteria (FM 2016). However, in full covariate models the FM 2016 RR reduced further to 1.15 (1.09-1.22). The association with mortality was noted with RA (1.52 (1.43-1.61)), NIRMD (1.43 (1.24-1.66)) and clinical FM (1.41 (1.14-1.75) - where 37% of FM diagnosed patients did not satisfy FM 2016 criteria. In the all-patient analyses, the age and sex explained variation (R2) was 0.255, increasing to 0.264 (4.4%) when FM 2016 criteria were added, and to 0.378 in a full covariate model. Death causes related to FM 2016 status included accidents, 1.45 (1.11-1.91); diabetes 1.78 (1.16-2,71); suicide, 3.01 (1.55-5.84) and hypertensive related disorders, 3.01 (1.55-5.84). Cancer deaths were less common 0.77 (0.68-0.88). CONCLUSIONS: FM is weakly associated with mortality within all criteria definitions of FM and WSP examined (3.4% of explained variance), and across all diseases (RA, NIRMD, clinical FM) equally. Clinical and criteria-defined FM had different mortality outcomes. We found no evidence for a positive association of cancer and FM or WSP.
32039570 Association of a Type 2-Polarized T Cell Phenotype With Methotrexate Nonresponse in Patien 2020 Jul OBJECTIVE: Rheumatoid arthritis (RA) is a chronic inflammatory disease mediated through complex immunologic pathways. Among RA patients receiving low-dose methotrexate (MTX) monotherapy, approximately one-half exhibit a meaningful clinical response within the first 6 months of starting treatment. Whether baseline immune phenotypes differ between subsequent MTX responders and nonresponders is unknown. This study utilized comprehensive T cell immunophenotyping to identify specific immunologic pathways associated with MTX-nonresponsive joint inflammation in patients with RA. METHODS: In total, 32 patients with recent-onset RA were treated with MTX therapy. After 6 months, 15 patients were categorized as responders and 17 as nonresponders. Comprehensive blood T cell immunophenotyping, using multiparameter immunofluorescence flow cytometry analyses, was performed at baseline and following 6 months of treatment. RESULTS: Baseline measures of disease activity (Disease Activity Score in 28 joints [DAS28], C-reactive protein level, and erythrocyte sedimentation rate) did not differ between MTX responders and nonresponders following MTX treatment. Frequencies of CD4+ and CD8+ T cells were skewed to favor higher CD4:CD8 T cell ratios in MTX responders compared to nonresponders (P < 0.05). The proportion of inducible costimulator-expressing Treg cells was significantly greater among MTX nonresponders. Interleukin-13 (IL-13)-producing, but not interferon-γ- or IL-17-producing, CD4+ effector memory T (Tem) cells were significantly more frequent in MTX nonresponders (P < 0.05). The ratio of IL-13+:IL-17+ Tem cells among CD4+ Tem cells was 1.9-fold higher in MTX nonresponders compared to responders (P < 0.05). Both the CD4:CD8 T cell ratio and the frequency of IL-13+CD4+ Tem cells correlated with changes in the DAS28 score following MTX treatment, whereas T cell expression of immune checkpoint inhibitor markers (CTLA-4, programmed death 1, and T cell immunoglobulin and mucin domain-containing protein 3) did not differ between MTX responders and nonresponders. CONCLUSION: We observed a bias toward type 2-polarized T cell inflammatory responses in the peripheral blood of MTX-nonresponsive RA patients. Targeting the IL-13+CD4+ T cell pathway could be a new therapeutic strategy in RA patients whose disease remains resistant to MTX.
31203226 Does Abatacept Increase Postoperative Adverse Events in Rheumatoid Arthritis Compared with 2020 Apr OBJECTIVE: To investigate whether abatacept (ABA) causes more adverse events (AE) than conventional synthetic disease-modifying antirheumatic drugs (csDMARD) after orthopedic surgery in patients with rheumatoid arthritis (RA). METHODS: A retrospective multicenter nested case-control study was performed in 18 institutions. Patients receiving ABA (ABA group) were matched individually with patients receiving csDMARD and/or steroids (control group). Postoperative AE included surgical site infection, delayed wound healing, deep vein thrombosis or pulmonary embolism, flare, and death. The incidence rates of the AE in both groups were compared with the Mantel-Haenszel test. Risk factors for AE were analyzed by logistic regression model. RESULTS: A total of 3358 cases were collected. After inclusion and exclusion, 2651 patients were selected for matching, and 194 patients in 97 pairs were chosen for subsequent comparative analyses between the ABA and control groups. No between-group differences were detected in the incidence rates of each AE or in the incidence rates of total AE (control vs ABA: 15.5% vs 20.7% in total, 5.2% vs 3.1% in death). CONCLUSION: Compared with csDMARD and/or steroids without ABA, adding ABA to the treatment does not appear to increase the incidence rates of postoperative AE in patients with RA undergoing orthopedic surgery. Large cohort studies should be performed to add evidence for the perioperative safety profile of ABA.
33327830 The Clinical Utility of Autoantibodies in Patients with Idiopathic Granulomatous Mastitis. 2022 Feb BACKGROUND: Although the etiopathogenesis of idiopathic granulomatous mastitis (IGM) is still controversial, recently autoimmunity and immune dysregulation have been emphasized. The aim of this study is to investigate the clinical utility of autoantibodies in IGM. MATERIAL AND METHODS: Rheumatoid factor (RF), antinuclear antibody (ANA), anti-double stranded DNA antibody (anti-ds-DNA), anti-cyclic citrullinated peptides antibody (anti-CCP) and perinuclear anti-neutrophil cytoplasmic antibody (pANCA) levels were investigated in pathologically diagnosed IGM patients (Group IGM) and healthy women (Group C). IGM patients were divided into two groups as those with active symptoms and signs (Group IGM(A)) and those without clinical and radiological findings (Group IGM(R)). RESULTS: While, in Group IGM, the positivity of RF, ANA, anti-ds-DNA, pANCA and anti-CCP was 13.1%, 3.3%, 1.6%, 0%, and 3.3%, respectively, in Group C, they were 13.3%, 0%, 0%, 0%, and 0%, respectively. The differences were not statistically significant (p > .05). In Groups IGM(A), IGM(R) and C, RF positivity was 10%, 16.1%, and 13.3%, respectively. The ANA positivity of Groups IGM(A), IGM(R) and C was 0%, 6.5%, and 0%, respectively. Groups IGM(A), IGM(R) and C's anti-ds-DNA positivity were 0%, 3.2%, and 0%, respectively. In all groups, pANCA was negative. The anti-CCP positivity of Groups IGM(A), IGM(R) and C was 6.7%, 0%, and 0%, respectively. CONCLUSION: Our findings did not support the clinical utility of autoantibodies including RF, ANA, anti-ds-DNA, pANCA and anti-CCP in IGM.
32956604 Risk for Serious Infection With Low-Dose Glucocorticoids in Patients With Rheumatoid Arthr 2020 Dec 1 BACKGROUND: Low-dose glucocorticoids are frequently used for the management of rheumatoid arthritis (RA) and other chronic conditions, but the safety of long-term use remains uncertain. OBJECTIVE: To quantify the risk for hospitalized infection with long-term use of low-dose glucocorticoids in patients with RA receiving stable disease-modifying antirheumatic drug (DMARD) therapy. DESIGN: Retrospective cohort study. SETTING: Medicare claims data and Optum's deidentified Clinformatics Data Mart database from 2006 to 2015. PATIENTS: Adults with RA receiving a stable DMARD regimen for more than 6 months. MEASUREMENTS: Associations between glucocorticoid dose (none, ≤5 mg/d, >5 to 10 mg/d, and >10 mg/d) and hospitalized infection were evaluated using inverse probability-weighted analyses, with 1-year cumulative incidence predicted from weighted models. RESULTS: 247 297 observations were identified among 172 041 patients in Medicare and 58 279 observations among 44 118 patients in Optum. After 6 months of stable DMARD use, 47.1% of Medicare patients and 39.5% of Optum patients were receiving glucocorticoids. The 1-year cumulative incidence of hospitalized infection in Medicare patients not receiving glucocorticoids was 8.6% versus 11.0% (95% CI, 10.6% to 11.5%) for glucocorticoid dose of 5 mg or less per day, 14.4% (CI, 13.8% to 15.1%) for greater than 5 to 10 mg/d, and 17.7% (CI, 16.5% to 19.1%) for greater than 10 mg/d (all P < 0.001 vs. no glucocorticoids). The 1-year cumulative incidence of hospitalized infection in Optum patients not receiving glucocorticoids was 4.0% versus 5.2% (CI, 4.7% to 5.8%) for glucocorticoid dose of 5 mg or less per day, 8.1% (CI, 7.0% to 9.3%) for greater than 5 to 10 mg/d, and 10.6% (CI, 8.5% to 13.2%) for greater than 10 mg/d (all P < 0.001 vs. no glucocorticoids). LIMITATION: Potential for residual confounding and misclassification of glucocorticoid dose. CONCLUSION: In patients with RA receiving stable DMARD therapy, glucocorticoids were associated with a dose-dependent increase in the risk for serious infection, with small but significant risks even at doses of 5 mg or less per day. Clinicians should balance the benefits of low-dose glucocorticoids with this potential risk. PRIMARY FUNDING SOURCE: National Institute of Arthritis and Musculoskeletal and Skin Diseases.
32248829 Effectiveness of TOcilizumab in comparison to Prednisone In Rheumatoid Arthritis patients 2020 Apr 5 BACKGROUND: Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease, predominantly affecting joints, which is initially treated with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs). In RA patients with insufficient response to csDMARDs, the addition of prednisone or tocilizumab, a biological DMARD (bDMARD), to the medication has been shown to be effective in reducing RA symptoms. However, which of these two treatment strategies has superior effectiveness and safety is unknown. METHODS: In this multicenter, investigator-initiated, open-label, randomized, pragmatic trial, we aim to recruit 120 RA patients meeting the 2010 ACR/EULAR classification criteria for RA, with active disease defined as a Clinical Disease Activity Index (CDAI) > 10 and at least one swollen joint of the 28 assessed. Patients must be on stable treatment with csDMARDs for ≥ 8 weeks prior to screening and must have been treated with ≥ 2 DMARDs, of which a maximum of one tumor necrosis factor inhibitor (a class of bDMARDs) is allowed. Previous use of other bDMARDs or targeted synthetic DMARDs is not allowed. Patients will be randomized in a 1:1 ratio to receive either tocilizumab (subcutaneously at 162 mg/week) or prednisone (orally at 10 mg/day) as an addition to their current csDMARD therapy. Study visits will be performed at screening; baseline; and months 1, 2, 3, 6, 9, and 12. Study medication will be tapered in case of clinical remission (CDAI ≤ 2.8 and ≤ 1 swollen joint at two consecutive 3-monthly visits) with careful monitoring of disease activity. In case of persistent high disease activity at or after month 3 (CDAI > 22 at any visit or > 10 at two consecutive visits), patients will switch to the other strategy arm. Primary outcome is a change in CDAI from baseline to 12 months. Secondary outcomes are additional clinical response and quality of life measures, drug retention rate, radiographically detectable progression of joint damage, functional ability, and cost utility. Safety outcomes include tocilizumab-associated adverse events (AEs), glucocorticoid-associated AEs, and serious AEs. DISCUSSION: This will be the first randomized clinical trial comparing addition of oral prednisone or of tocilizumab head to head in RA patients with insufficient response to csDMARD therapy. It will yield important information for clinical rheumatology practice. TRIAL REGISTRATION: This trial was prospectively registered in the Netherlands Trial Register on October 7, 2019 (NL8070). The Netherlands Trial Register contains all items from the World Health Organization Trial Registration Data Set.