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30952617 Latent autoimmunity across disease-specific boundaries in at-risk first-degree relatives o 2019 Apr BACKGROUND: Autoimmune disease prevention requires tools to assess an individual's risk of developing a specific disease. One tool is disease-associated autoantibodies, which accumulate in an asymptomatic preclinical period. However, patients sometimes exhibit autoantibodies associated with a different disease classification. When and how these alternative autoantibodies first appear remain unknown. This cross-sectional study characterizes alternative autoimmunity, and associated genetic and environmental factors, in unaffected first-degree relatives (FDRs) of patients, who exhibit increased future risk for the same disease. METHODS: Samples (n = 1321) from disease-specific autoantibody-positive (aAb+) systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and type 1 diabetes (T1D) patients; and unaffected aAb+ and autoantibody-negative (aAb-) SLE and RA FDRs were tested for SLE, RA, and T1D aAbs, as well as anti-tissue transglutaminase, anti-cardiolipin and anti-thyroperoxidase. FDR SLE and RA genetic risk scores (GRS) were calculated. FINDINGS: Alternative autoimmunity occurred in SLE patients (56%) and FDRs (57·4%), RA patients (32·6%) and FDRs (34·8%), and T1D patients (43%). Expanded autoimmunity, defined as autoantibodies spanning at least two other diseases, occurred in 18·5% of SLE patients, 16·4% of SLE FDRs, 7·8% of RA patients, 5·3% of RA FDRs, and 10·8% of T1D patients. SLE FDRs were more likely to have alternative (odds ratio [OR] 2·44) and expanded (OR 3·27) autoimmunity than RA FDRs. Alternative and expanded autoimmunity were associated with several environmental exposures. Alternative autoimmunity was associated with a higher RA GRS in RA FDRs (OR 1·41), and a higher SLE GRS in aAb+ RA FDRs (OR 1·87), but not in SLE FDRs. INTERPRETATION: Autoimmunity commonly crosses disease-specific boundaries in systemic (RA, SLE) and organ-specific (T1D) autoimmune diseases. Alternative autoimmunity is more common in SLE FDRs than RA FDRs, and is influenced by genetic and environmental factors. These findings have substantial implications for preclinical disease pathogenesis and autoimmune disease prevention studies. FUND: NIH U01AI101981, R01AR051394, U19AI082714, P30AR053483, P30GM103510, U54GM104938, U01AI101934, R01AI024717, U01AI130830, I01BX001834, & U01HG008666.
31414920 Macrophage migration inhibitory factor (MIF) as a therapeutic target for rheumatoid arthri 2019 Sep Introduction. Macrophage migration inhibitory factor (MIF) is a pleiotropic inflammatory cytokine with upstream regulatory roles in innate and adaptive immunity and is implicated in the pathogenesis of autoimmune diseases including rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Several classes of MIF inhibitors such as small molecule inhibitors and peptide inhibitors are in clinical development. Areas covered. The role of MIF in the pathogenesis of RA and SLE is examined; the authors review the structure, physiology and signaling characteristics of MIF and the related cytokine D-DT/MIF-2. The preclinical and clinical trial data for MIF inhibitors are also reviewed; information was retrieved from PubMed and ClinicalTrials.gov using the keywords MIF, D-DT/MIF-2, CD74, CD44, CXCR2, CXCR4, Jab-1, rheumatoid arthritis, systemic lupus erythematosus, MIF inhibitor, small molecule, anti-MIF, anti-CD74, and peptide inhibitor. Expert opinion. Studies in mice and in humans demonstrate the therapeutic potential of MIF inhibition for RA and SLE. MIF- directed approaches could be particularly efficacious in patients with high expression MIF genetic polymorphisms. In patients with RA and SLE and high expression MIF alleles, targeted MIF inhibition could be a precision medicine approach to treatment. Anti-MIF pharmacotherapies could also be steroid-sparing in patients with chronic glucocorticoid dependence or refractory autoimmune disease.
30001258 A Pilot Randomized Controlled Double-Blind Trial of High- Versus Low-Dose Weekly Folic Aci 2019 Oct BACKGROUND/OBJECTIVE: The aim of this study was to determine whether reducing the dose of supplemental folic acid used in conjunction with methotrexate (MTX) therapy in people with active rheumatoid arthritis (RA) improved disease control and/or increased MTX-related adverse effects. METHODS: A randomized double-blind randomized controlled trial comparing 5 mg/wk and 0.8 mg/wk folic acid was undertaken. Rheumatoid arthritis patients on MTX for 3 months or more at a stable dose for 1 month or more were recruited. All participants had DAS28 of 3.2 or greater or required a change in therapy determined by the treating clinician. Disease activity, full blood count, liver function tests, red blood cell (RBC) folate, and RBC MTX polyglutamates were assessed at weeks 0, 4, 8, 16, and 24 along with reports of adverse events. RESULTS: Forty participants were recruited. The mean (SD) change in RBC folate between week 0 and 24 was +87.9 (57.4) nmol/L in the high-dose group and -113.3 (65.7) nmol/L in the low-dose group (p < 0.05). There was no significant difference in the change in DAS28 between the high- and low-dose groups at 24 weeks (-0.13 [95% confidence interval, -0.69 to 0.43] vs -0.25 [-0.87 to 0.37], respectively [p = 0.78]). There was no significant difference in MTX-related adverse effects between the 2 groups. CONCLUSIONS: A reduction in RBC folate secondary to reduction in folic acid dose was not associated with a change in RA disease activity or MTX-related adverse effects. The prevention of MTX-related adverse effects remains the primary reason for coprescribing folic acid with MTX. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ANZCTR12610000739011).
30484352 Higher risk of hospitalized infection, cardiovascular disease, and fracture in patients wi 2019 Sep Objective: To evaluate the risk of hospitalized infection (HI), cardiovascular disease (CVD), stroke, and fracture in rheumatoid arthritis (RA) patients compared with non-RA patients using the Japanese health insurance database. Method: Among individuals aged ≥18 years, RA cases were defined to have one RA diagnostic code and receiving ≥1 disease-modifying antirheumatic drug between 2005 and 2013 (n = 6,712). Age-, sex-, calendar year of the observation start-, and observation length-matched non-RA cases were selected at 1:5 (n = 33,560). Hazard ratios (HRs) were calculated using the time-dependent Cox regression analysis. Results: Median age of the patients was 52.0 years. The incidence rates of HI, CVD, and fracture in the RA group were 2.42/100 person-years (PY), 4.94/1,000 PY, and 10.59/1,000 PY. The crude incidence rate ratios (95% CI) (RA vs. non-RA) for HI, CVD, and fracture were 2.47 (2.20-2.77), 1.89 (1.49-2.41), and 3.35 (2.80-4.02). The adjusted HR (95% CI) (RA vs. non-RA) was significantly elevated (HI, 1.74 [1.52-1.99], CVD, 1.38 [1.04-1.85], and fracture, 1.88 (1.54-2.31)]. Conclusion: The relatively young RA population had significantly higher risks of these complications than the non-RA, indicating importance of prevention of them even at young ages in clinical settings.
30620293 Fibromyalgia in patients with rheumatoid arthritis. A 10-year follow-up study, results fro 2019 Jan OBJECTIVES: To examine cross-sectional and longitudinal relationships between fibromyalgia (FM) and rheumatoid arthritis (RA) disease activity. METHODS: 636 patients in the observational Oslo RA register (ORAR) were invited to a clinical examination in 1999. 28-tender and swollen joint counts (TJC, SJC) and 18-tender points were assessed, the RA disease activity score (DAS-28) calculated. Fibromyalgia (FM) was diagnosed according to 1990 (FM-1990) and modified 2011 (mFM-2011) ACR criteria. At the 10-year follow-up patients completed the RA Disease Activity Index (RADAI) and Routine Assessment of Patient Index Data 3 (RAPID-3). Baseline and 10-year RA disease activity were compared across presence/absence of FM. Linear regression models were constructed with 10-year RADAI and RAPID-3 as outcome. RESULTS: 502 patients participated at baseline data-collection and 10-year data was available in 236. At baseline, mean (SD) age was 59.5 (12.5) years and 87% were female. 9% and 30% had FM-1990 and mFM-2011 respectively. RA-FM patients were predominantly female with higher SJC, TJC, and DAS-28 at baseline. Baseline RA-FM predicted higher levels of RADAI and RAPID-3 at the 10-year follow-up. CONCLUSIONS: RA-FM was associated with significantly higher levels of cross-sectional and longitudinal RA disease activity. FM should be considered in patients with RA not reaching remission.
31661546 MiR-129-5p regulates cell proliferation and apoptosis via IGF-1R/Src/ERK/Egr-1 pathway in 2019 Dec 20 It is reported that miR-129-5p plays an important role in various diseases, but its effect on rheumatoid arthritis (RA) and the potential mechanism remain to be clarified. In the present research, we aimed to investigate the effect of miR-129-5p on RA and the special molecular mechanism. First, the expression of miR-129-5p was analyzed in RA patients and RA Fibroblast-like synoviocytes (RA-FLSs) by RT-PCR assay. The cell viability, apoptotic rate and the relative expression of caspase-3 and caspase-8 were measured by CCK-8, Annexin-FITC/propidium iodide (PI) and ELISA, respectively. Luciferase reporter assay was performed to investigate the target of miR-129-5p. The results revealed that the expression of miR-129-5p was down-regulated in RA patients and RA-FLSs. In addition, miR-129-5p inhibited cell proliferation and induced apoptosis of RA-FLS. Furthermore, luciferase reporter assay demonstrated that insulin-like growth factor-1 receptor (IGF-1R) was the direct target of miR-129-5p, and IGF-1R promoted cell proliferation and inhibited apoptosis by activating Src/ERK/Egr-1 signaling. Furthermoremore, the Src/ERK/Egr-1 signaling pathway was suppressed by miR-129-5p. Collectively, the results of the present study suggested that miR-129-5p regulated cell proliferation and apoptosis via IGF-1R/Src/ERK/Egr-1 signaling pathway in RA.
31791769 Relationship between polycyclic aromatic hydrocarbons and rheumatoid arthritis in US gener 2020 Feb 20 The purpose of this study was to explore the association between urinary concentrations of polycyclic aromatic hydrocarbon (PAH) metabolites and the prevalence of rheumatoid arthritis (RA). Cross-sectional data were analyzed from the National Health and Nutrition Examination Survey (NHANES) 2003-2012 using levels of nine monohydroxylated urinary PAH metabolites as exposure. Multivariable logistic regression was used to examine the association between urinary biomarkers of PAHs and RA. All of the models were adjusted for age, sex, race, education level, marital status, smoking, BMI, physical activity, energy, diabetes, and survey cycle. Ultimately, 6,072 adults (3,108 men and 2,964 women) 20 years of age or older were analyzed. In the quartile analyses, compared with the lowest quartile, increased RA prevalence was observed in the participants with the highest quartile of 2-hydroxynapthalene (OR = 1.89, 95% CI = 1.28-2.78), 3-hydroxyfluorene (OR = 1.55, 95% CI = 1.07-2.25), 2-hydroxyfluorene (OR = 1.51, 95% CI = 1.02-2.24), 3-hydroxyphenanthrene (OR = 1.50, 95% CI = 1.09-2.07), and 9-hydroxyfluorene (OR = 1.60, 95% CI = 1.10-2.33) in a fully adjusted model, respectively. In the subgroup analysis of current smokers, compared with the participants with lower urinary PAH scores, those with higher scores had a dramatically increased prevalence of RA (OR = 15.46, 95% CI = 3.11-76.75) in the adjusted model. There was a significant interaction between all of the urinary PAH metabolite levels and smoking status in the relationship with RA (P < 0.05). High levels of urinary PAH metabolites are positively associated with RA prevalence in the US general population. PAH exposure and smoking may potentially interact to increase the prevalence of RA. Further prospective studies are needed to clarify the possible effect of PAHs on RA.
30715670 SAMD9 is a (epi-) genetically regulated anti-inflammatory factor activated in RA patients. 2019 Jun To identify PBMC-expressed genes significant for RA, and to ascertain their upstream regulatory factors, as well as downstream functional effects relevant to RA pathogenesis. We performed peripheral blood mononuclear cells (PBMCs) transcriptome-wide mRNA expression profiling in a case-control discovery sample. Differentially expressed genes (DEGs) were identified and validated in PBMCs in independent samples. We also generated genome-wide SNP genotyping data, and collected miRNA expression data and DNA methylation data from PBMCs of the discovery sample. Pearson correlation analyses were conducted to identify miRNAs/DNA methylations influencing DEG expression. Association analyses were conducted to identify expression-regulating SNPs. The key DEG, SAMD9, which was reported to function as a tumor suppressor gene, was assessed for its effects on T cell proliferation, apoptosis, and inflammatory cytokine expression. A total of 181 DEGs (Fold Change ≥ 2.0, Bonferroni adjusted p ≤ 0.05) were discovered in PBMCs. Four DEGs (SAMD9, CKLF, PARP9, and GUSB), upregulated with RA, were validated independently in PBMCs. Specifically, SAMD9 mRNA expression level was significantly upregulated in PHA-activated Jurkat T cells in vitro, and correlated with 8 miRNAs and associated with 22 SNPs in PBMCs in vivo. Knockdown of SAMD9 could transiently promote Jurkat T cell proliferation within 48 h and significantly induce TNF-α and IL-8 expression in T cells. SAMD9 expression is (epi-) genetically regulated, and significantly upregulated in PBMCs in RA patients and in activated T cells in vitro. SAMD9 might serve as a T cell activation marker but act as an anti-inflammatory factor.
30729371 Exploring metabolic and inflammatory abnormalities in rheumatoid arthritis patients develo 2019 May OBJECTIVES: Intend to investigate the roles of serum lipids, inflammatory markers, and serological status in rheumatoid arthritis and stroke patients by using case-control study. MATERIALS AND METHODS: Clinical data were retrieved from the electronic medical record of the First Affiliated Hospital of China Medical University during January 2011 to March 2018. The obtained data were categorized into case groups and three control groups, in the ratios of 1:2, respectively, with all matching age and gender. Multinomial logistic regression analysis and restricted cubic spline were conducted examining the associations between serum lipids, inflammatory markers, serological status, and the risk of stroke among RA patients. RESULTS: The present studies included 1057 study subjects. The elevated ESR, LDL-C levels, and much higher CRP levels ≥ 230 mg/L were independent risk factors for RA patients in developing stroke. Furthermore, we found that ESR and LDL-C levels could exhibit a linear association with the risk of comorbid stroke while CRP level had a nonlinearity association with stroke risk among RA patients. CONCLUSIONS: A close monitoring is required for RA patients with dyslipidemia and elevated inflammatory markers, and the primary stroke preventive strategies should be directed against these risk factors.
30924699 Effects of range of motion exercise of the metatarsophalangeal joint from 2-weeks after jo 2020 Mar Objectives: Joint-preserving rheumatoid forefoot surgery improves clinical outcomes, but postoperative range of motion (ROM) of the metatarsophalangeal (MTP) joint remains an issue. The objective of this study was to evaluate the effect of ROM exercise from the early period after lesser toe MTP joint-preserving surgery.Methods: A retrospective, observational study of 22 rheumatoid arthritis patients who underwent modified metatarsal shortening offset osteotomy was completed. Lesser toe scales were administered using the Japanese Society for Surgery of the Foot (JSSF) standard rating system, and the maximum distance of continuous walking was checked to evaluate clinical outcomes. Maximum passive ROM of the lesser toe MTP joints and the extension angle of the 2nd MTP joint at the terminal stance phase during gait were measured and evaluated.Results: Pain scores and ROM-related indices of the JSSF lesser toe scale improved significantly in the exercise group. The extension angle of the 2nd MTP joint at the terminal stance phase during gait was increased, and the maximum distance of continuous walking seemed longer.Conclusion: Passive/active ROM exercise from 2-weeks after surgery can improve a patient's activity and forefoot function through increasing ROM of the MTP joint at the terminal stance phase.
31639514 Failure of anti-TNF treatment in patients with rheumatoid arthritis: The pros and cons of 2019 Dec The five TNF inhibitors currently approved for the treatment of RA are characterised by differences in their molecular structures, half-lives, administration routes, dosing intervals, immunogenicity, and use in women who wish to become pregnant. TNF inhibitors still represent the first biologic after conventional synthetic DMARD (csDMARD) in the majority of patients according to registry data. This was possibly because they were historically the first biological agents available (biological DMARDS with a different mechanism of action or targeted synthetic DMARDs did not become available until 2006s), and so switching from one to another was frequent in the case of an inadequate response and/or side effects. TNF inhibitors are also efficacious for other inflammatory joint and spine diseases, and have been approved for inflammatory bowel disease, uveitis and psoriasis. In addition, national registries have provided long-term safety data and demonstrated their beneficial effect on cardiovascular morbidity and mortality. However, approximately 30-40% of patients discontinue anti-TNF treatment because of primary failure, secondary loss of response, or intolerance. The options for managing anti-TNF treatment failures include switching to an alternative anti-TNF (cycling) or to another class of targeted drug with a different mechanism of action (swapping). The aim of this review is to evaluate the pros and cons of whether it is more appropriate to choose a second anti-TNF biological agents after the failure of the first or swap treatment early.
30936285 Therapy with Biologic Agents After Diagnosis of Solid Malignancies: Results from the Corro 2019 Nov OBJECTIVE: Guidelines suggest that rheumatoid arthritis (RA) patients with previously treated solid malignancy may be treated as patients without such history. The recommendation is based on limited evidence, and rheumatologists and patients are frequently hesitant to start or continue biologic therapy after a cancer diagnosis. The objective of this study was to describe biologic use in real-world patients with RA following a malignancy diagnosis. METHODS: RA patients enrolled in the Corrona registry and diagnosed with solid malignancy with at least 1 followup visit within 12 months after diagnosis were included in this analysis. The proportion of patients continuing or initiating biological/targeted synthetic disease-modifying antirheumatic drug (bDMARD/tsDMARD) after diagnosis was estimated. Median time to initiation of bDMARD/tsDMARD after diagnosis was calculated using the Kaplan-Meier method and the proportion initiating biologic treatment in 6-month time intervals was estimated using the life-table method. RESULTS: There were 880 patients who met inclusion criteria with 2585 person-years total followup time postdiagnosis. Of those, 367 (41.7%) were treated with bDMARD/tsDMARD within 12 months preceding malignancy, of whom 270 (30.7%) were taking such agents at first postdiagnosis visit. Forty-four (5%) switched biologic agents within 36 months and an additional 90 patients (10.2%) started a biologic. The majority of bDMARD/tsDMARD initiations during followup was a tumor necrosis factor inhibitor (TNFi; 53.5%). CONCLUSION: In real-world practice, nearly one-third of RA patients with a cancer diagnosis were treated with systemic therapy in the immediate visit after malignancy diagnosis and a considerable percentage of malignancy survivors initiated biologic therapy within 3 years. The majority of bDMARD/tsDMARD initiations post-malignancy diagnosis was a TNFi.
31030956 A20: A multifunctional tool for regulating immunity and preventing disease. 2019 Jun A20, also known as TNFAIP3, is a potent regulator of ubiquitin (Ub) dependent signals. A20 prevents multiple human diseases, indicating that the critical functions of this protein are clinically as well as biologically impactful. As revealed by mouse models, cell specific functions of A20 are linked to its ability to regulate diverse signaling pathways. Aberrant expression or functions of A20 in specific cell types underlie divergent disease outcomes. Discernment of A20's biochemical functions and their phenotypic outcomes will contribute to our understanding of how ubiquitination is regulated, how Ub mediated functions can prevent disease, and will pave the way for future therapeutic interventions.
30793998 Effects of forefoot arthroplasty on plantar pressure, pain, gait and disability in rheumat 2020 Mar Objectives: The purpose of this study was to clarify the effect of forefoot arthroplasty on plantar pressure, pain, gait, and disability within 1 year after arthroplasty in patients with RA.Methods: Eleven patients with RA who underwent forefoot arthroplasty completed this quasi-experimental study. Outcome measures were in-shoe plantar pressure, visual analog scale (VAS) for pain, temporal gait parameters, and modified Health Assessment Questionnaire (mHAQ), obtained preoperatively and at 4 and 12 months postoperatively.Results: The average peak plantar pressure under the 2nd metatarsal head decreased at 4 months postoperatively, compared to preoperative values (p < .05) and the decreased plantar pressure was sustained at 12 months postoperatively. Similar changes were observed under the 3rd to 5th metatarsal heads. The median VAS for foot pain decreased from 25 mm preoperatively to 1 mm at 4 months postoperatively and the lower score was sustained at 12 months postoperatively (p < .05). The median mHAQ score remained lower (<1.0) at all measurement points. Regarding gait, there were no significant differences from the preoperative assessment to postoperative follow-up.Conclusion: Plantar pressure and forefoot pain decreased at 4 and 12 months after forefoot arthroplasty in patients with RA. No adverse effects on gait parameters or disability were observed.
31036624 Association of response to TNF inhibitors in rheumatoid arthritis with quantitative trait 2019 Aug OBJECTIVES: We sought to investigate whether genetic effects on response to TNF inhibitors (TNFi) in rheumatoid arthritis (RA) could be localised by considering known genetic susceptibility loci for relevant traits and to evaluate the usefulness of these genetic loci for stratifying drug response. METHODS: We studied the relation of TNFi response, quantified by change in swollen joint counts ( Δ SJC) and erythrocyte sedimentation rate ( Δ ESR) with locus-specific scores constructed from genome-wide assocation study summary statistics in 2938 genotyped individuals: 37 scores for RA; scores for 19 immune cell traits; scores for expression or methylation of 93 genes with previously reported associations between transcript level and drug response. Multivariate associations were evaluated in penalised regression models by cross-validation. RESULTS: We detected a statistically significant association between Δ SJC and the RA score at the CD40 locus (p=0.0004) and an inverse association between Δ SJC and the score for expression of CD39 on CD4 T cells (p=0.00005). A previously reported association between CD39 expression on regulatory T cells and response to methotrexate was in the opposite direction. In stratified analysis by concomitant methotrexate treatment, the inverse association was stronger in the combination therapy group and dissipated in the TNFi monotherapy group. Overall, ability to predict TNFi response from genotypic scores was limited, with models explaining less than 1% of phenotypic variance. CONCLUSIONS: The association with the CD39 trait is difficult to interpret because patients with RA are often prescribed TNFi after failing to respond to methotrexate. The CD39 and CD40 pathways could be relevant for targeting drug therapy.
29652202 Effect of sulfasalazine use on the presence of Pneumocystis organisms in the lung among pa 2019 May OBJECTIVE: To evaluate the effect of sulfasalazine (SSZ) on the presence of Pneumocystis jirovecii (P. jirovecii) in the lungs of rheumatoid arthritis (RA) patients. METHODS: We retrospectively studied episodes of suspected P. jirovecii pneumonia (PJP) which were examined for P. jirovecii with polymerase chain reaction (PCR). We employed a test negative design case-control study; the cases were episodes of suspected PJP that were positive for PCR, and the controls were episodes of suspected PJP that were negative for PCR. The odds ratio for the positive PCR result associated with SSZ use was estimated by Firth's logistic regression. RESULTS: Between 2003 and 2017, 36 cases and 83 controls were identified. While none of the cases received SSZ before the episode, 18 of the controls received the drug. In the primary analysis involving all the episodes, SSZ use was negatively associated with PCR positivity (adjusted odds ratio, 0.087; confidence interval, <0.001-0.789). The sensitivity analysis, excluding those who received PJP prophylaxis, showed the same association as the primary analysis (adjusted odds ratio 0.085, 95% CI <0.001-0.790). CONCLUSION: This study demonstrated that SSZ use is associated with the absence of P. jirovecii in the lung, suggesting the preventive efficacy of the drug against PJP.
31949424 Concomitant Treatment with Etanercept and Tacrolimus Synergistically Attenuates Arthritis 2019 In the present study, we investigated the effects and mechanisms of action of a combined treatment with etanercept, a soluble tumor necrosis factor receptor (p75) Fc fusion protein, and tacrolimus, a calcineurin inhibitor on the progression of arthritis in human tumor necrosis factor-α (TNF-α) transgenic (hTNF-Tg) mice. Single-drug treatments with etanercept and tacrolimus attenuated the clinical signs but not the radiographic changes associated with the development of arthritis in mice. On the contrary, combined treatment significantly suppressed the radiographic progression and also improved the clinical signs. The combined treatment exhibited synergistic effects of the two drugs in reducing the serum matrix metalloproteinase-3 level and the number of peripheral CD11b(high) osteoclast precursor cells. Moreover, tacrolimus inhibited the cytokine-induced osteoclast differentiation in synergy with etanercept in an in vitro assay. Interestingly, tacrolimus did not inhibit the production of antidrug antibodies (ADAs) against etanercept in the hTNF-Tg mice. This result implies that the synergistic effects of etanercept and tacrolimus are not due to secondary effects derived from the suppression of ADA production by tacrolimus but are due to their primary effects. These findings suggest that concomitant treatment with etanercept and tacrolimus may be one of preferable treatment options to control disease activities for patients with rheumatoid arthritis, especially for those with bone resorption.
31370727 ER-stressed MSC displayed more effective immunomodulation in RA CD4(+)CXCR5(+)ICOS(+) foll 2020 May Objectives: To analyze the further immunomodulatory effects of endoplasmic reticulum (ER)-stressed umbilical cord-derived mesenchymal stem cells MSCs (UC-MSCs) on rheumatoid arthritis (RA) CD4(+)CXCR5(+)ICOS(+) T (follicular helper-like T, Tfh) cells.Methods: MSCs were isolated from umbilical cord and surface markers were identified by flow cytometry. CD4(+) T cells were purified from RA patients' peripheral blood mononuclear cells (PBMCs) using immunomagnetic beads. Thapsigargin (Tg)-stimulated or unstimulated MSCs were co-cultured with RA CD4(+) T cells. CD4(+)CXCR5(+)ICOS(+) T cells were analyzed with fluorescence activating cell sorter (FACS) and major soluble factors secreted by MSCs were detected by qRT-PCR as well as ELISA. Receptors of prostanoid E2 (PGE2), known as EP1-4, on CD4(+) T cells were tested with RT-PCR and FACS. Proportion of CD4(+)CXCR5(+)ICOS(+) T cells was determined after EP2/EP4 antagonists and anti-IL-6R antibody was added into co-cultured system, respectively.Results: ER-stressed MSCs further down-regulated peripheral CD4(+)CXCR5(+)ICOS(+) T cells compared with Tg-stimulated MSCs and CD4(+) T co-cultured group. PGE2 and IL-6 increased obviously in the supernatants. EP2/EP4 could be detected on CD4(+) T cells and frequencies of CD4(+)CXCR5(+)ICOS(+) T cells were upregulated when EP2 and/or EP4 antagonists rather than anti-IL-6R antibody were added.Conclusions: ER-stressed MSCs exhibited better inhibition effect on RA CD4(+)CXCR5(+)ICOS(+) T cells by releasing PGE2, indicating the immunosuppressive effect of MSCs could be enhanced by induction of ER stress.
30915650 Efficacy and safety profile of intravenous tocilizumab versus intravenous abatacept in tre 2019 Aug OBJECTIVES: To compare the efficacy and safety of tocilizumab with those of abatacept in patients with active rheumatoid arthritis not responding to anti-tumor necrosis factor therapy. METHODS: A prospective, open-label study was carried out on adult females with moderate-to-severe rheumatoid arthritis. Patients were randomly assigned to receive either intravenous tocilizumab or abatacept treatment. History taking, clinical examination, and laboratory evaluation were done at baseline and during a 24-week period of follow-up. Disease activity was calculated using the DAS28-ESR score. The incidence of accompanying adverse events was evaluated and all statistical analyses were performed by InStat. RESULTS: One hundred thirty-two patients were enrolled and classified randomly into the tocilizumab (n = 68) and abatacept (n = 64) groups. By week 24, the mean DAS28-ESR was significantly reduced in both groups (P < 0.0001) in association with significant reductions in CRP, ESR, and HAQ scores. No significant difference in the incidence rate of adverse effects appeared between both study groups. However, there were marked declines in the hemoglobin levels (P = 0.003) and neutrophil count (P = 0.002) together with significant elevations in systolic blood pressure (P = 0.002), liver enzymes (P = 0.001), total cholesterol (P = 0.001), and high-density lipoproteins (P = 0.002) in the tocilizumab group compared with the abatacept group. CONCLUSION: Both intravenous abatacept and tocilizumab significantly decreased the disease activity and improved the physical function in rheumatoid arthritis patients who failed to respond to anti-tumor necrosis factor therapy. Although the efficacy of both drugs was similar, abatacept showed a more promising short-term safety profile since it was associated with less adverse effects and better laboratory outcomes.
30997154 Neural networks for automatic scoring of arthritis disease activity on ultrasound images. 2019 BACKGROUND: The development of standardised methods for ultrasound (US) scanning and evaluation of synovitis activity by the OMERACT-EULAR Synovitis Scoring (OESS) system is a major step forward in the use of US in the diagnosis and monitoring of patients with inflammatory arthritis. The variation in interpretation of disease activity on US images can affect diagnosis, treatment and outcomes in clinical trials. We, therefore, set out to investigate if we could utilise neural network architecture for the interpretation of disease activity on Doppler US images, using the OESS scoring system. METHODS: Two state-of-the-art neural networks were used to extract information from 1342 Doppler US images from patients with rheumatoid arthritis (RA). One neural network divided images as either healthy (Doppler OESS score 0 or 1) or diseased (Doppler OESS score 2 or 3). The other to score images across all four of the OESS systems Doppler US scores (0-3). The neural networks were hereafter tested on a new set of RA Doppler US images (n=176). Agreement between rheumatologist's scores and network scores was measured with the kappa statistic. RESULTS: For the neural network assessing healthy/diseased score, the highest accuracies compared with an expert rheumatologist were 86.4% and 86.9% with a sensitivity of 0.864 and 0.875 and specificity of 0.864 and 0.864, respectively. The other neural network developed to four class Doppler OESS scoring achieved an average per class accuracy of 75.0% and a quadratically weighted kappa score of 0.84. CONCLUSION: This study is the first to show that neural network technology can be used in the scoring of disease activity on Doppler US images according to the OESS system.