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ID PMID Title PublicationDate abstract
30477552 Long-term, health-enhancing physical activity is associated with reduction of pain but not 2018 Nov 26 BACKGROUND: We aimed to evaluate the 1-year and 2-year outcome of a health-enhancing physical activity (HEPA) support program on global pain, pressure pain sensitivity, and exercise-induced segmental and plurisegmental hypoalgesia (EIH) in persons with rheumatoid arthritis (RA). METHODS: Thirty participants (27 women and 3 men) were recruited from a larger intervention cohort that engaged in strength training and moderate-intensity aerobic activity. Assessments were performed before the HEPA intervention and at 1-year and 2-year follow-ups. Global pain was assessed on a visual analogue scale (0-100). Pressure pain thresholds (PPTs) and suprathreshold pressure pain at rest corresponding to 4/10 (medium pain) (SP4) and 7/10 (strong pain) (SP7) on Borg CR 10 scale were assessed by algometry. In a subsample (n = 21), segmental and plurisegmental EIH were assessed during standardized submaximal static contraction (30% of the individual maximum), by algometry, alternately at the contracting right M. quadriceps and the resting left M. deltoideus. RESULTS: Global pain decreased from before the intervention to 2-year follow-up (median 11 to median 6, P = 0.040). PPTs and SP4 pressure pain at rest did not change from before the intervention to 2-year follow-up, while SP7 decreased from mean 647 kPa to mean 560 kPa (P = 0.006). Segmental EIH during static muscle contraction increased from the assessment before the intervention (from mean 1.02 to mean 1.42, P = 0.001), as did plurisegmental EIH (from mean 0.87 to mean 1.41, P <0.001). There were no statistically significant changes in segmental or plurisegmental EIH from before the intervention to 2-year follow-up. CONCLUSION: Participation in a long-term HEPA support program was associated with reduced global pain, whereas pressure pain sensitivity at rest was not reduced and EIH did not change. Thus, our results do not favor the hypothesis that long-term HEPA reduces pain by improving descending pain inhibition in persons with RA. TRIAL REGISTRATION: ISRCTN25539102 , ISRCTN registry, date assigned March 4, 2011. The trial was retrospectively registered.
30418120 Body mass index and persistence of conventional DMARDs and TNF inhibitors in rheumatoid ar 2019 May OBJECTIVES: Obese patients with rheumatoid arthritis (RA) may be more likely to discontinue therapy than non-obese patients, possibly signifying a more refractory phenotype. The purpose of this study was to examine the association between body mass index (BMI) and discontinuation rates for different RA treatments accounting for confounding factors. METHODS: Veterans Affairs administrative databases were used to define initial courses of methotrexate (MTX), hydroxychloroquine, sulfasalazine, prednisone, and self-injectable tumour necrosis factor inhibitors (TNFi). Discontinuation was defined as a lapse in drug refill >90 days. Using overweight BMI (25-30 kg/m2) as the referent group, multivariable Cox proportional hazards models were used to evaluate associations between BMI category and time to treatment discontinuation. RESULTS: There were 46,970 initial RA treatment courses identified from 2005-2014 among 23,669 Veterans with RA. In multivariable models, severe obesity (BMI >35 kg/m2), compared to overweight BMI, was not associated with treatment discontinuation with the exception of prednisone [HR 1.10 (1.04, 1.17) p<0.001]. Patients with low (<20 kg/m2) and normal BMI (20-25 kg/m2) were more likely to discontinue MTX, TNFi, and HCQ compared to overweight patients. Other factors associated with earlier MTX and/or TNFi discontinuation included female sex, black race, greater comorbidity, depression, malignancy, congestive heart failure, current smoking, and more recent calendar year. CONCLUSIONS: Obesity was not associated with therapy discontinuation among veterans with RA after accounting for confounding factors, suggesting that obesity is not a biological mediator of more refractory disease. Conversely, low BMI, comorbidity, and depression were identified as important predictors of drug discontinuation.
30053896 A randomized controlled trial comparing PF-06438179/GP1111 (an infliximab biosimilar) and 2018 Jul 27 BACKGROUND: This double-blind, active-controlled, randomized, multinational study evaluated the efficacy, safety, pharmacokinetics (PK), and immunogenicity of PF-06438179/GP1111 (IxifiTM/Zessly®), an infliximab biosimilar, vs infliximab (Remicade®) reference product sourced from the European Union (infliximab-EU) in biologic-naïve patients with moderate to severe active rheumatoid arthritis (RA) despite methotrexate therapy. This paper reports results from the initial 30-week treatment period. METHODS: Patients (N = 650) were stratified by geographic region and randomized 1:1 to PF-06438179/GP1111 or infliximab-EU (3 mg/kg intravenous at weeks 0, 2, and 6, then every 8 weeks). Dose escalation to 5 mg/kg was allowed starting at week 14 for patients with inadequate RA response. The primary endpoint was American College of Rheumatology criteria for ≥ 20% clinical improvement (ACR20) response at week 14. Therapeutic equivalence was declared if the two-sided 95% CI for the treatment difference was within the symmetric equivalence margin of ± 13.5%. Statistical analysis was also performed with a two-sided 90% CI using an asymmetric equivalence margin (- 12.0%, 15.0%). RESULTS: Patients (80.3% female; 79.4% seropositive) had a mean RA duration of 6.9 years, and mean baseline Disease Activity Score in 28 joints, four components based on C-reactive protein was 6.0 in both arms. Week 14 ACR20 in the intention-to-treat population was 62.7% for PF-06438179/GP1111 and 64.1% for infliximab-EU. Week 14 ACR20 using nonresponder imputation was 61.1% for PF-06438179/GP1111 and 63.5% for infliximab-EU, and the 95% (- 9.92%, 5.11%) and 90% (- 8.75%, 4.02%) CIs for the treatment difference (- 2.39%) were entirely contained within the prespecified symmetric and asymmetric equivalence margins, respectively. No differences were observed between arms for secondary efficacy endpoints. Overall postdose antidrug antibody (ADA) rates through week 30 were 48.6% and 51.2% for PF-06438179/GP1111 and infliximab-EU, respectively. Efficacy and immunogenicity were similar between treatments for patients with dose escalation (at or after week 14), as well as between treatments for patients without dose escalation. Safety profiles of PF-06438179/GP1111 and infliximab-EU were similar, with no clinically meaningful differences observed between arms, including after ADA development. Serum drug concentrations were similar between arms at each time point during the initial 30-week treatment period. CONCLUSION: PF-06438179/GP1111 and infliximab-EU demonstrated similar efficacy, safety, immunogenicity, and PK with or without dose escalation in patients with moderate to severe active RA on background methotrexate. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02222493 . Registered on 21 August 2014. EudraCT, 2013-004148-49 . Registered on 14 July 2014.
29691971 Hydroxychloroquine may be associated with reduced risk of coronary artery diseases in pati 2018 May OBJECTIVES: The aim of this study was to determine whether hydroxychloroquine (HCQ) usage is associated with incidental risk of coronary artery diseases (CAD) in patients with rheumatoid arthritis (RA). METHODS: The Longitudinal Health Insurance Database in Taiwan was used. The study cohort comprised of 1104 newly diagnosed RA patients between 2001-2010, and patients were followed until 31 December 2011. Patients with history of CAD before RA diagnosis were excluded. We define as HCQ users if the usage duration of HCQ>180 days and non-users if less than 90 days. After propensity score matching of age, sex, index date and comorbidities, the study cohort was comprised of 346 patients: 173 HCQ users and 173 non-users. The study outcome was incidence of CAD. Cox regression model was used to estimate the hazard ratio (HR) of disease after controlling for demographic, other comorbidities and drugs. We also evaluate the effects of HCQ use and CAD events on different characteristics of RA patients. RESULTS: Kaplan-Meier curves comparing the HCQ users and non-users revealed a statistical significant difference (P value of log-rank test <.001). The adjusted HR for HCQ users versus non-users for CAD events was 0.32 (95% CI, 0.18-0.56, P value <.01) over up to 10 years of follow-up. The adjusted HR (95% CI) of CAD for different age group, gender and other subgroups showed no effect of interaction among each subgroup analysis parameter. CONCLUSIONS: This study revealed association of decreased CAD risk in RA patients taking HCQ. The protective effect of HCQ on CAD is consistent regarding subgroup analysis on age, gender and different comorbidities groups.
30446734 Paeoniflorin-6'-O-benzene sulfonate alleviates collagen-induced arthritis in mice by downr 2019 Jun Paeoniflorin-6'-O-benzene sulfonate (CP-25) is a new ester derivative of paeoniflorin with improved lipid solubility and oral bioavailability, as well as better anti-inflammatory activity than its parent compound. In this study we explored whether CP-25 exerted therapeutic effects in collagen-induced arthritis (CIA) mice through regulating B-cell activating factor (BAFF)-BAFF receptors-mediated signaling pathways. CIA mice were given CP-25 or injected with biological agents rituximab or etanercept for 40 days. In CIA mice, we found that T cells and B cells exhibited abnormal proliferation; the percentages of CD19(+) total B cells, CD19(+)CD27(+)-activated B cells, CD19(+)BAFFR(+) and CD19(+)TACI(+) cells were significantly increased in PBMCs and spleen lymphocytes. CP-25 suppressed the indicators of arthritis, alleviated histopathology, accompanied by reduced BAFF and BAFF receptors expressions, inhibited serum immunoglobulin levels, decreased the B-cell subsets percentages, and prevented the expressions of key molecules in NF-κB signaling. Furthermore, we showed that treatment with CP-25 reduced CD19(+)TRAF2(+) cell expressions stimulated by BAFF and decreased TRAF2 overexpression in HEK293 cells in vitro. Thus, CP-25 restored the abnormal T cells proliferation and B-cell percentages to the normal levels, and normalized the elevated levels of IgA, IgG2a and key proteins in NF-κB signaling. In comparison, rituximab and etanercept displayed stronger anti-inflammatory activities than CP-25; they suppressed the elevated inflammatory indexes to below the normal levels in CIA mice. In summary, our results provide evidence that CP-25 alleviates CIA and regulates the functions of B cells through BAFF-TRAF2-NF-κB signaling. CP-25 would be a soft immunomodulatory drug with anti-inflammatory effect.
30554586 [Establishment and application of quantitative detection of serum anti-carbamylated protei 2018 Oct Objective To develope a chemiluminescence immunoassay based on microarray protein chip technology for detecting the anti-carbamylated protein (CarP) antibody. We aimed to evaluate the detection performance of this method and to explore its preliminary clinical application value of this index in patients with rheumatoid arthritis (RA). Methods A quantitative detection method for anti-CarP antibody was established to evaluate the precision, minimum detection limit, linear range and specificity of the method. The 95th position of anti-CarP antibody level in serum of 120 healthy controls was defined as the cutoff value. The anti-CarP antibody level and positive rate in RA group and non-RA group were analyzed. And the correlation between anti-CarP antibody and disease activity index in RA group was analyzed. Results The precision of this method for detecting high-level sample and low-level sample was less than 15%; The linear range could reach (3.31~1448.18) AU/mL, and there was almost no cross-reaction between anti-CarP antibody and anti-CCP antibody. Compared with healthy control group, the level of anti-CarP antibody in RA group, anti-CCP antibody positive RA group and joint pain group was significantly higher, and that in undifferentiated connective tissue disease group was also higher. Compared with the 5% positive rate of anti-CarP antibody in healthy control group, the positive rate of RA patients was 28.21%, anti-CCP antibody positive RA patients was 32.2%, joint pain group was 38.89%, which were significantly higher. There was no statistical difference between other disease groups. The level of anti-CarP antibody was weakly correlated with level of rheumatoid factor (RF) and erythrocyte sedimentation rate (ESR) in RA patients, but it was moderately correlated with CRP and IgG level. Conclusion The protein chip chemiluminescence method for quantitative detection of anti-CarP antibody has good detection precision and wide linear range, and has good sensitivity and specificity. Anti-CarP antibody detection is valuable for RA diagnosis and disease activity evaluation.
30251234 SB5: An Adalimumab Biosimilar. 2018 Oct SB5 (Imraldi(®)) is a biosimilar of the reference anti-TNF monoclonal antibody adalimumab. It is approved for use in the following indications for which reference adalimumab is approved: rheumatoid arthritis (RA), juvenile idiopathic arthritis [polyarticular juvenile idiopathic arthritis (pJIA) and enthesitis-related arthritis (ERA)], axial spondyloarthritis [ankylosing spondylitis (AS) and non-radiographic axial spondyloarthritis (nr-axSpA)], psoriatic arthritis (PsA), psoriasis, pediatric plaque psoriasis, hidradenitis suppurativa (HS), Crohn's disease, pediatric Crohn's disease, ulcerative colitis (UC), and non-infectious uveitis. SB5 has similar physicochemical and pharmacodynamic properties to those of reference adalimumab, and the pharmacokinetic similarity of these agents has been shown in healthy volunteers and patients with RA. SB5 demonstrated clinical efficacy considered equivalent to that of reference adalimumab in patients with RA, and was generally well tolerated in this population. The safety and tolerability profile of SB5 was similar to that of reference adalimumab, as was the immunogenicity profile. Switching from reference adalimumab to SB5 had no impact in terms of efficacy, safety or immunogenicity. The role of reference adalimumab in the management of RA, pJIA, ERA, AS, nr-axSpA, PsA, psoriasis, pediatric plaque psoriasis, HS, Crohn's disease, UC and non-infectious uveitis is well established and SB5 provides an effective biosimilar alternative for patients requiring adalimumab therapy.
27849414 Clinical Features and Complications of Scleritis in Chinese Patients. 2018 PURPOSE: To characterize the clinical features of scleritis in Chinese patients. METHODS: The history, demographics, ocular findings, auxiliary examination findings, complications, systemic diseases and therapeutic effects were analyzed retrospectively. RESULTS: The study included 124 male and 169 female patients with scleritis. Anterior and posterior scleritis were, respectively, found in 243 and 42 patients. The other eight patients had both anterior and posterior involvement. The mean age of scleritis onset was 39.4 years. Systemic diseases associated with scleritis mainly included rheumatoid arthritis (RA) (4.4%), ankylosing spondylitis (AS) (3.4%), and tuberculosis (1.7%). Anterior uveitis (23.7%), complicated cataract (16.7%), and intraocular hypertension (12.6%) were common complications of scleritis. Scleritis was controlled in 94.6% of the patients treated with corticosteroids combined with immunosuppressive agents. CONCLUSIONS: Diffuse anterior scleritis was the most common scleritis entity in China. RA and AS were relatively common diseases associated with scleritis. Corticosteroids combined with immunosuppressive agents effectively controlled the disease.
30116758 Analysis of Sodium Chloride Intake and Treg/Th17 Lymphocytes in Healthy Individuals and Pa 2018 We assessed different immune parameters in patients with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) with low (LSI) and high (HSI) sodium intake. Thirty-eight patients with RA, thirty-seven with SLE, and twenty-eight healthy subjects were studied and classified as LSI or HSI. Levels and suppressive function of CD4(+)CD25(+)Foxp3(+) and CD4(+)CD69(+)Foxp3(-) Treg cells were determined by flow cytometry in blood samples. Levels and in vitro differentiation of Th17 cells were also assessed. Similar levels of CD4(+)CD25(+)Foxp3(+) and CD4(+)CD69(+)Foxp3(-) Treg cells were observed in LSI and HSI patients or controls. However, a positive correlation was detected between sodium intake and levels of CD4(+)CD25(+)Foxp3(+) Treg cells in SLE and a negative association between CD4(+)CD69(+)Foxp3(-) Treg cells and sodium intake in RA. No other significant associations were detected, including disease activity and sodium intake. Moreover, the suppressor activity of CD4(+)CD25(+)Foxp3(+) and CD4(+)CD69(+)Foxp3(-) Treg cells was similar in LSI and HSI patients or controls. The levels and in vitro differentiation of Th17 cells were also similar in LSI and HSI individuals. Our results suggest that, in the population studied (Mexican mestizo), the level of sodium intake is not apparently associated with different relevant immune parameters in healthy subjects or patients with SLE or RA.
30145050 Discovery and structural characterization of peficitinib (ASP015K) as a novel and potent J 2018 Oct 1 Janus kinases (JAKs) are considered promising targets for the treatment of autoimmune diseases including rheumatoid arthritis (RA) due to their important role in multiple cytokine receptor signaling pathways. Recently, several JAK inhibitors have been developed for the treatment of RA. Here, we describe the identification of the novel orally bioavailable JAK inhibitor 18, peficitinib (also known as ASP015K), which showed moderate selectivity for JAK3 over JAK1, JAK2, and TYK2 in enzyme assays. Chemical modification at the C4-position of lead compound 5 led to a large increase in JAK inhibitory activity and metabolic stability in liver microsomes. Furthermore, we determined the crystal structures of JAK1, JAK2, JAK3, and TYK2 in a complex with peficitinib, and revealed that the 1H-pyrrolo[2,3-b]pyridine-5-carboxamide scaffold of peficitinib forms triple hydrogen bonds with the hinge region. Interestingly, the binding modes of peficitinib in the ATP-binding pockets differed among JAK1, JAK2, JAK3, and TYK2. WaterMap analysis of the crystal structures suggests that unfavorable water molecules are the likely reason for the difference in orientation of the 1H-pyrrolo[2,3-b]pyridine-5-carboxamide scaffold to the hinge region among JAKs.
29715455 Regulatory effect of nicotine on the differentiation of Th1, Th2 and Th17 lymphocyte subse 2018 Jul 15 Previous research has demonstrated that nicotine have protective role in rheumatoid arthritis (RA). However, the immunologic mechanisms of nicotine's effect have not been fully elucidated. Herein, the effects of nicotine on the differentiation of Th1, Th2, and Th17 cells were assessed. Peripheral blood mononuclear cells (PBMCs) and CD4+T cells were separated from patients with RA. PBMCs were stimulated with anti-CD3/anti-CD28 in the absence or presence of nicotine. CD4+T cells were cultured in the Th cell differentiation condition in the absence of nicotine or nicotine and alpha- bungarotoxin (αBgt) (the antagonist of nicotine) combined. Levels of T cell cytokines were detected with ELISA and flow cytometry. The expression of specific transcription factors (retinoic orphan re- ceptor c (RORc), T-box transcription factor (T-bet), and GATA Binding Protein 3 (GATA-3)) and signaling molecules (P-ERK1/2 and T-ERK1/2) were determined by Western blot. The results showed nicotine reduced IL-17A and increased IL-4 produced by stimulated PBMCs. During Th17 differentiation conditions, nicotine reduced the levels of IL-17A and RORc, induced the phosphorylation of ERK1/2. Meanwhile, nicotine increased the levels of IL-4 and GATA3 during Th2 differentiation. α-Bgt blocked the effects of nicotine on Th2 and Th17 differentiation. However, nicotine had no effect on the expression of IFN-γ and T-bet in CD4+T cells during Th1differentiation. These results demonstrate that nicotine suppresses Th17 differentiation, promotes Th2 differentiation and improves Th1/Th2 imbalance in RA patients, providing a new justification for its application in the treatment of rheumatoid arthritis.
29774031 IL-10 Producing B Cells Ability to Induce Regulatory T Cells Is Maintained in Rheumatoid A 2018 Despite growing evidence highlighting the relevance of increasing IL-10-producing B cells (B10(+)cells) in autoimmune diseases, their functions in patients are still unknown. The aim of this study was to evaluate the functions of CpG-induced B10(+) cells isolated from healthy controls (HC) and rheumatoid arthritis (RA) patients, on naïve T cell differentiation. We demonstrated that CpG-induced B10(+) cells from HC drove naïve T cell differentiation toward regulatory T cells (Treg cells) and IL-10-producing T cells (Tr1) through IL-10 secretion and cellular contacts. B10(+) cells from HC did not decrease T helper 1 (Th1) nor and tumor necrosis factor α producing T cell (TNFα(+) T cell) differentiation. We showed that in RA, B10(+) cells could also induce Treg cells and Tr1 from naïve T cells. Contrary to HC, B10(+) cells from RA patients increased naïve T cell conversion into Th1. Interestingly, PD-L2, a programmed death-1 (PD-1) ligand that inhibits PD-L1 and promotes Th1 differentiation, was overexpressed on RA B10(+) cells compared to HC B10(+) cells. Together, our findings showed that CpG-induced B10(+) cells may be used to increase Treg cells in patients with RA. However, CpG may not be the most adequate stimuli as CpG-induced B10(+) cells also increased inflammatory T cells in those patients.
29101675 Red blood cell distribution width: a potential laboratory parameter for monitoring inflamm 2018 Jan Correlation analysis of red blood cell distribution width (RDW) and C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), tumor necrosis factor α (TNF-α), interleukin (IL)-6, and IL-10 in rheumatoid arthritis (RA) to investigate whether RDW can serve as a potential parameter for indicating inflammation in RA patients. A total of 670 RA patients from October 2014 to April 2016 were enrolled in our study. The white blood cell (WBC), red blood cell (RBC), platelet (PLT), hemoglobin (HGB), RDW, CRP, and ESR in peripheral blood of patients with RA were retrospectively analyzed. The relative expression of TNF-α, IL-6, and IL-10 was detected by RT-qPCR. Correlation analysis between RDW and CRP, ESR, TNF-α, IL-6, and IL-10 in RA was conducted by Microsoft Excel. RDW level was significantly increased in RA patients compared to osteoarthritis (OA) patients (P < 0.001) and healthy donors (HDs) (P < 0.001), and RDW was positively associated with inflammatory markers, such as CRP and ESR. In ROC curve analysis, the area under the curve (AUC) of RDW for the identification of RA was 0.881, with a 95% confidence interval (CI) from 0.864 to 0.898. Moreover, correlation analysis showed that RDW level was positively associated with TNF-α and IL-6, however negatively associated with IL-10. RDW was increased in patients with RA which was associated with inflammation in RA, suggesting that RDW may be a potential auxiliary marker for indicating inflammation process in RA conveniently.
29628928 Impaired CD27(+)IgD(+) B Cells With Altered Gene Signature in Rheumatoid Arthritis. 2018 Natural antibodies, particularly natural IgM, are proved to play indispensable roles in the immune defenses against common infections. More recently, the protective roles of these natural IgM were also recognized in autoimmune diseases. They are mainly produced by B-1 and innate-like B cells (ILBs). Human CD19(+)CD27(+)IgD(+) B cells, also termed as un-switched memory B cells, were proposed to be a kind of ILBs. However, functional features and characteristics of these cells in rheumatoid arthritis (RA) remained poorly understood. In this study, we found that human CD27(+)IgD(+) B cells could produce natural antibody-like IgM. Under RA circumstance, the frequencies of these cells were significantly decreased. Moreover, the IgM-producing capacities of these cells were also dampened. Interestingly, the BCR repertoire of these cells was altered in RA, demonstrating decreased diversity with preferential usage alteration from VH3-23D to VH1-8. Single cell sequencing further revealed the proinflammatory biased features of these cells in RA. These CD27(+)IgD(+) B cells were negatively correlated with RA patient disease activities and clinical manifestations. After effective therapy with disease remission in RA, these cells could be recovered. Taken together, these results have revealed that CD27(+)IgD(+) B cells were impaired in RA with dysfunctional features, which might contribute to the disease perpetuation.
29119225 Piperlongumine inhibits the proliferation, migration and invasion of fibroblast-like synov 2018 Mar OBJECTIVES: Recent studies have indicated that piperlongumine (PLM) may exert anti-inflammatory effects. In the present study, we determined the effect of PLM on the proliferation, apoptosis, migration and invasion of fibroblast-like synoviocytes (FLS) from patients with rheumatoid arthritis (RA) (referred to herein as RA FLS). We further explored the mechanisms by which the studied compound inhibits the functions of RA FLS. METHODS: RA FLS viability and apoptosis were tested using MTT and Annexin V/PI assays, respectively. We performed an EDU assay to examine the proliferation of RA FLS. The migration and invasion of these cells were measured using a transwell chamber method and wound closure assay. The MMP-1, MMP-3, and MMP-13 levels in the culture supernatants of RA FLS were detected using a Luminex Assay kit. The intracellular ROS levels were detected using DCFH-DA. The expression levels of signal transduction proteins were measured using western blot. RESULTS: We found that PLM induced apoptosis in RA FLS at concentrations of 15 and 20 μM. The proliferation of RA FLS was downregulated by PLM at concentrations of 1, 5 and 10 μM. Migration and invasion of RA FLS were reduced by PLM at concentrations of 1, 5 and 10 μM. PLM also inhibited cytoskeletal reorganization in migrating RA FLS and decreased TNF-α-induced intracellular ROS production. Moreover, we demonstrated the inhibitory effect of PLM on activation of the p38, JNK, NF-κB and STAT3 pathways. CONCLUSIONS: Our findings suggest that PLM can inhibit proliferation, migration and invasion of RA FLS. Moreover, these data suggests that PLM might have therapeutic potential for the treatment of RA.
29979807 Shoulder Arthroplasty in Patients with Rheumatoid Arthritis: A Population-Based Study Exam 2018 Jun It has been suggested that the utilization of joint arthroplasty in patients with rheumatoid arthritis (RA) is decreasing; however, this observation is largely based upon evidence pertaining to lower-extremity joint arthroplasty. It remains unknown if these observed trends also hold true for shoulder arthroplasty. The purpose of this study is to utilize a nationally representative population database in the US to identify trends in the utilization of shoulder arthroplasty among patients with RA. Secondarily, we sought to determine the rate of early adverse events, length of stay, and hospitalization costs associated with RA patients undergoing shoulder arthroplasty and to compare these outcomes to those of patients without a diagnosis of RA undergoing shoulder arthroplasty. Using a large population database in the US, we determined the annual rates of shoulder arthroplasty (overall and individual) in RA patients between 2002 and 2011. Early adverse events, length of stay, and hospitalization costs were determined and compared with those of non-RA patients undergoing shoulder arthroplasty. Overall, we identified 332,593 patients who underwent shoulder arthroplasty between 2002 and 2011, of whom 17,883 patients (5.4%) had a diagnosis of RA. Over the study period, there was a significant increase in the utilization of shoulder arthroplasty in RA patients, particularly total shoulder arthroplasty. Over the same period, there was a significant increase in the number of RA patients who underwent shoulder arthroplasty with a diagnosis of rotator cuff disease. There were no significant differences in adverse events or mean hospitalization costs between RA and non-RA patients. Non-RA patients had a significantly shorter length of stay; however, the difference did not appear to be clinically significant. In conclusion, the utilization of shoulder arthroplasty in patients with RA significantly increased from 2002 to 2011, which may partly reflect a trend toward management of rotator cuff disease with arthroplasty rather than repair.
30467094 Functional MIF promoter haplotypes modulate Th17-related cytokine expression in peripheral 2019 Mar Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease characterized by elevated levels of pro-inflammatory cytokines, such as interleukin (IL)-6, IL-17, and macrophage migration inhibitory factor (MIF). MIF induces IL-17 secretion and MIF promoter polymorphisms influence the expression of selected downstream mediators. The aim of this study was to investigate the relationship between known functional MIF haplotypes and Th17-related cytokine secretion profile in peripheral blood mononuclear cells (PBMC) from control subjects (CS) and RA patients stimulated with lipopolysaccharide (LPS) and recombinant human MIF (rhMIF). The -794 CATT(5-8) and -173G > C polymorphisms of the MIF gene were determined by conventional PCR and PCR-RFLP, respectively. The most frequent haplotypes of the MIF polymorphism and PBMC were identified from three subjects homozygous for each haplotype and in both study groups, the PBMC were obtained and stimulated with LPS or rhMIF. The secretion of cytokines related to the Th17 profile was determined by a multiplex immunoassay (MAGPIX). LPS stimulation induced the secretion of cytokines related to the Th17 profile in PBMC from CS and RA patients, whereas, rhMIF only stimulated this response in PBMC from RA patients. PBMC from CS carriers of the MIF 7C haplotype showed more IL-17A, IL-17F, IL-22, and IL-23 secretion than non-7C carriers after LPS stimulation. In the case of rhMIF stimulation, the PBMC from CS carriers of the 7C haplotype secreted more IL-17A and IL-23 than non-7C carriers. In conclusion, genetic variants of the MIF promoter modulate the secretion of cytokines related to the Th17 profile in PBMC from CS inducing a differential response in comparison to PBMC from RA patients.
28741808 Reconciling disparate data to determine the right answer: A grounded theory of meta analys 2018 Mar While the systematic review process is intended to maximize objectivity and limit researchers' biases, examples remain of discordant recommendations from meta-analyses. Current guidelines to explore discrepancies assume the variation is produced by methodological differences and thus focus only on the study process. Because heterogeneity of interpretation also occurs when experts examine the same data, our purpose was to examine if there are reasoning differences, ie, in how information is processed and valued. We created simulated meta-analyses based on idealized randomized studies (ie, perfect studies with no bias) to ensure differences in interpretations could only be due to reasoning. We recruited published meta-analysts using purposeful variables. We conducted 3 audio-recorded interviews per participant using structured and semi-structured interviews, with paraphrasing and reflective listening to enhance and verify responses. Recruitment and analysis of transcripts and field notes followed the principles of grounded theory (eg, theoretical saturation, constant comparative analysis). Results show the complexity of meta-analytic reasoning. At each step of the process, participants attempted to reconcile disparate forms of knowledge to determine a right answer (moral concern) and accurately draw a treatment effect (epistemological concern). The reasoning processes often shifted between considering the meta-analysis as if the data were whole, and as if the data were discrete components (individual studies). These findings highlight paradigmatic tensions regarding the epistemological premises of meta-analysis, resembling previous historical investigations of the functioning of scientific communities. In understanding why different meta-analysts interpret data differently, it may be unrealistic to expect objective homogenous recommendations based on meta-analyses.
29266801 Antibody Responses to Citrullinated and Noncitrullinated Antigens in the Sputum of Subject 2018 Apr OBJECTIVE: The location and mechanisms involved in the initial generation of autoantibodies to citrullinated and noncitrullinated proteins/peptides during the natural history of rheumatoid arthritis (RA) development is incompletely understood. This study sought to explore individual antibody responses to citrullinated and noncitrullinated proteins/peptides in the sputum and associations with neutrophil extracellular traps (NETs) in subjects at risk for the future development of RA. METHODS: Serum and sputum samples were obtained from 41 RA-free subjects who were considered at risk for the development of RA based on familial or serologic risk factors, from 20 subjects classified as having RA, and from 22 healthy control subjects. Samples were evaluated using a bead-based array for IgG reactivity to 29 citrullinated proteins/peptides and 21 noncitrullinated proteins/peptides. Cutoff levels for antibody positivity were established in a separate control group. NET levels in the sputum were measured using sandwich enzyme-linked immunosorbent assays that quantitate DNA-myeloperoxidase and DNA-neutrophil elastase complexes. RESULTS: In at-risk subjects, antibody responses to the citrullinated forms of fibrinogen, apolipoprotein E, and fibronectin were highly prevalent. The most citrulline-specific antibodies in the sputum of at-risk subjects were those to fibrinogen, vimentin, and peptides of fibrinogen A and apolipoprotein A1. Patterns of sputum autoantibody positivity differed between at-risk subjects and subjects with RA. In at-risk subjects, increasing sputum NET levels significantly correlated with several citrullinated and some noncitrullinated antibody reactivities. CONCLUSION: These findings suggest that sputum antibody reactivity to particular citrullinated and noncitrullinated proteins/peptides is specific for RA and for subjects at risk of RA, and the association of these proteins/peptides with NETs may be a key feature of early RA-related autoimmunity in the lung. These results further support the hypothesis that the lung plays a role in early RA-related autoimmunity.
30339841 Central role of RIPK1-VDAC1 pathway on cardiac impairment in a non-human primate model of 2018 Dec Rheumatoid arthritis (RA) is a chronic inflammatory disorder characterized by destructive polyarthritis and systemic complications. It increases cardiovascular morbidity and mortality. However, the mechanism underlying RA-related cardiac damage remains largely unknown. Here, we found and characterized a non-human primate (NHP) model with spontaneous RA similar to the human conditions. Compared with the control group, the cardiac function in RA monkeys showed progressively deterioration; histologically, we found significantly increased inflammatory cell infiltration, cell death, and fibrosis in RA monkey heart tissue. Mechanistically, the upregulated receptor-interacting protein kinase 1 (RIPK1) in RA monkey heart tissue bound to voltage-dependent anion-selective channel 1 (VDAC1), increased VDAC1 oligomerization, and subsequently induced cardiac cell death and functional impairment. These findings identified that RIPK1-VDAC1 pathway is a promising target to treat cardiac impairment in RA. This unique model of RA will provide a valuable tool for mechanistic and translational studies.