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ID PMID Title PublicationDate abstract
24673997 Impact of patient-accessible electronic medical records in rheumatology: use, satisfaction 2014 Mar 26 BACKGROUND: To measure the use, satisfaction and impact of a web portal which provides patients with rheumatoid arthritis home access to their electronic medical records (EMR). METHODS: A pretest-posttest study was conducted among 360 patients. Questionnaires assessed socio-demographics, health literacy, Internet use, disease characteristics, patient-provider relationship and empowerment before and after launching a hospital-based patient web portal. To measure the impact of the portal, patients' satisfaction with care, trust in their rheumatologist, self-efficacy in patient-provider communication, illness perceptions, and medication adherence were assessed. The post-test included questions on portal use, satisfaction, and self-perceived impact due to portal use. RESULTS: 54% of respondents with Internet access had viewed their EMR. Respondents were positive about the ease of use and usefulness of the portal and reported very few problems. Age (P = .03), amount of Internet use (P = .01) and self-perceived Internet skills (P = .03) significantly predicted portal use. Of the respondents who had logged in, 44% reported feeling more involved in their treatment and 37% felt they had more knowledge about their treatment. Significant differences over time were not found on the empowerment-related instruments. CONCLUSIONS: The current portal succeeded in offering patients access to their EMR in a usable and understandable way. While its true impact is difficult to grasp, a relevant portion of the patients felt more involved in their treatment due to the web portal. Offering patients home EMR access, therefore, appears to be a valuable addition to the care process.
24326008 Key findings towards optimising adalimumab treatment: the concentration-effect curve. 2015 Mar OBJECTIVE: To determine a concentration-effect curve of adalimumab in rheumatoid arthritis (RA) patients taking into account the effect of methotrexate (MTX) on concentration and effect and to identify a therapeutic range for adalimumab concentrations. METHODS: In a prospective observational cohort study, 221 consecutive patients with RA were treated with 40 mg adalimumab subcutaneously every other week. The relationship between adalimumab trough level and clinical efficacy after 28 weeks of follow-up was determined in a concentration-effect curve. A receiver-operator characteristics (ROC) curve established a therapeutic cut-off concentration. The effect of MTX on adalimumab trough levels was shown by dividing patients that are and are not concomitantly using MTX in the concentration-effect curve and a concentration table. RESULTS: Clinical efficacy improved with increasing adalimumab concentration and reached a maximum (mean disease activity score in 28 joints improvement of 2) with levels between 5-8 μg/mL. Levels exceeding 8 μg/mL were illustrated to have no additional beneficial effect on disease activity. The ROC curve showed an area under the curve of 0.695 (95% CI 0.626 to 0.764) for European League Against Rheumatism response and adalimumab levels: good responders versus non-responders and moderate responders. A cut-off of 5 μg/mL had a sensitivity of 91% and a specificity of 43%. Adalimumab levels are influenced by concomitant MTX use: patients on adalimumab monotherapy had a median adalimumab level of 4.1 μg/mL (IQR 1.3-7.7), whereas patients concomitantly taking MTX had a median level of 7.4 μg/mL (IQR 5.3-10.6, p<0.001). CONCLUSIONS: Adalimumab trough levels in a range of 5-8 μg/mL are sufficient to reach adequate clinical response. These levels are influenced substantially by concomitant MTX use.
25172601 Prevalence of anterior knee pain among patients following total knee arthroplasty with non 2014 BACKGROUND AND OBJECTIVE: Anterior knee pain (AKP) may compromise the results of total knee arthroplasty in more than quarter of cases. The aim of the current work was to determine the prevalence of AKP and the severity of patellofemoral symptoms among patients who received a total knee arthroplasty with non-replaced patella in East-Tallinn Central Hospital from January 1, 2000 to December 31, 2009. MATERIALS AND METHODS: We carried out a retrospective study involving 1778 consecutive total knee arthroplasties with non-replaced patella. Mean follow-up time was 68 months. We collected data by two patient-reported measures: the knee pain questionnaire and the Kujala score. RESULTS: We diagnosed AKP among 20.2% of patients, 33.6% had pain in the knee from a source other than patellofemoral joint and 46.2% were pain free. In 87.3% of AKP cases the pain emerged within the first five years of knee replacement. AKP was more prevalent among patients with osteoarthritis compared to rheumatoid arthritis and among patients below 60 years. There was no difference in the prevalence of AKP in terms of gender or mobile and fixed bearing implants. The severity of patellofemoral symptoms in case of AKP was moderate. CONCLUSIONS: AKP is a frequent complication of total knee arthroplasty with non-replaced patella and patients undergoing this procedure should be apprised of the high probability of experiencing pain in the anterior part of the replaced knee.
24470447 Identification of new citrulline-specific autoantibodies, which bind to human arthritic ca 2014 Jun OBJECTIVE: To investigate type II collagen (CII) as a joint-specific target of the anti-citrullinated protein antibody (ACPA) response in rheumatoid arthritis (RA). METHODS: Potential citrullinated neoepitopes were identified by high-resolution tandem mass spectrometry (MS/MS) of in vitro peptidylarginine deiminase 2 (PAD-2)-treated CII, and the relationship between citrullination and CII conformation was investigated by circular dichroism and conformation-dependent antibodies. Based on the MS analyses, synthetic peptides were designed and analyzed for serum IgG reactivity in the Epidemiological Investigation of RA (EIRA) case-control cohort of 1,949 RA patients and 278 healthy controls. Peptide-specific antibodies were purified from RA patient serum and used to stain RA cartilage specimens. RESULTS: We described the conformation-dependent citrullination pattern of CII after PAD-2 treatment at room temperature and 37°C and showed that CII could be citrullinated in its native triple-helical conformation. Screening of Arg and Cit pairs of synthetic peptides revealed new citrullinated B cell epitopes on CII. Antibodies directed to 2 proximal epitopes close to the C-terminus of the CII triple helix were recognized by autoantibodies in 21% and 17% of RA patients, respectively. Affinity-purified antibodies from RA sera directed to these 2 epitopes, but not antibodies directed to citrullinated α-enolase peptide 1, bound to RA cartilage. CONCLUSION: These findings suggest that cartilage-directed anticitrulline immunity contributes to the induction of joint inflammation in RA.
23817959 Unique protein signature of circulating microparticles in systemic lupus erythematosus. 2013 Oct OBJECTIVE: To characterize the unique qualities of proteins associated with circulating subcellular material in systemic lupus erythematosus (SLE) patients compared with healthy controls and patients with other chronic autoimmune diseases. METHODS: Using differential centrifugation and high-sensitivity nano-liquid chromatography tandem mass spectrometry, we systematically profiled proteins of microparticles (MPs) from SLE patients (n=12), systemic sclerosis (SSc) patients (n=6), and rheumatoid arthritis (RA) patients (n=6), as well as healthy controls (n=12). RESULTS: We identified 531 unique proteins and showed that the differences between healthy controls and patients with SLE with regard to the abundance of 248 proteins were highly statistically significant. Almost half of the proteins that were increased by >2-fold were complement proteins and Ig (increased by 100-4,000 times). MP Ig and complement loads also distinguished SLE from RA and SSc and correlated strongly with clinical SLE severity. Subsets of microtubule proteins, fibronectin, 14-3-3η, and desmosomal proteins as well as ficolin 2 and galectin 3 binding protein were also highly increased. In SLE MPs, levels of cytoskeletal, mitochondrial, and organelle proteins, including lysosome-associated membrane protein 1 and transforming growth factor β1, were decreased. CONCLUSION: The data show that SLE patients have increased numbers of MPs that are heavily tagged for removal and fewer MPs with normal protein composition. SLE MPs are unique and specific proteins that represent novel leads for our understanding of SLE and for the development of new treatments of the disease.
25187198 Perioperative use of anti-rheumatic agents does not increase early postoperative infection 2015 Feb The aim of this study was to validate a novel technique that predicts stopping of disease-modifying anti-rheumatic drugs (DMARDs) and biologic agents (BA) from the Veterans Affairs (VA) database and compare infection risks of rheumatoid arthritis patients who stopped versus continued DMARDs/BA perioperatively. We identified 6,024 patients on 1 DMARD or BA in the perioperative period between 1999 and 2009. Time gap between medication stop date and the next start date predicted drug stoppage (X). Time gap between surgery date and stop date predicted whether stoppage was before surgery (Y). Chart review from Houston VA was used for validation. ROC analyses were performed on chart review data to obtain X and Y cutoffs. The primary endpoints were wound infections and other infections within 30 days. ROC analyses found X ≥ 33 (AUC = 0.954) and Y ≥ -11 (AUC = 0.846). Risk of postoperative infections was not different when stopping and continuing DMARDs/BA preoperatively. Stopping BA after surgery was associated with higher odds of postoperative wound (OR 14.15, 95 % CI 1.76-113.76) and general infection (OR 9.2, 95 % CI 1.99-42.60) compared to not stopping. Stopping DMARDs after surgery was associated with increased risk of postoperative general infection (OR 1.84, 95 % CI 1.07-3.16) compared with not stopping. There was positive association between stopping DMARDs after surgery and postoperative wound infection but failed to achieve statistical significance (OR 1.67, 95 % CI 0.96-2.91). There was no significant difference in postoperative infection risk when stopping or continuing DMARD/BA. Our new validated method can be utilized in the VA and other databases to predict drug stoppage.
24943093 Macrophage-derived delta-like protein 1 enhances interleukin-6 and matrix metalloproteinas 2014 Oct OBJECTIVE: We previously reported that blockade of the Notch ligand delta-like protein 1 (DLL-1) suppressed osteoclastogenesis and ameliorated arthritis in a mouse model of rheumatoid arthritis (RA). However, the mechanisms by which joint inflammation were suppressed have not yet been revealed. This study was undertaken to determine whether DLL-1 regulates the production of RA-related proinflammatory cytokines. METHODS: Joint cells from mice with collagen-induced arthritis (CIA) and mouse fibroblast-like synoviocytes (FLS) were cultured with or without stimuli in the presence of neutralizing antibodies against Notch ligands, and the production of proinflammatory cytokines was determined by enzyme-linked immunosorbent assay. The expression of Notch receptors and ligands on mouse joint cells was determined by flow cytometry. RESULTS: The production of interleukin-6 (IL-6) and granulocyte-macrophage colony-stimulating factor (GM-CSF) by mouse joint cells with or without stimulation was suppressed by DLL-1 blockade. DLL-1 blockade also suppressed the levels of IL-6 and matrix metalloproteinase 3 (MMP-3) in the joint fluid in a mouse model of RA. However, the production of tumor necrosis factor α and IL-1β was not suppressed by DLL-1 blockade. The production of IL-6 and MMP-3 by mouse FLS was enhanced by DLL-1 stimulation as well as Notch-2 activation. Among joint cells, DLL-1 was not expressed on mouse FLS but was expressed on macrophages. CONCLUSION: These results suggest that the interaction of DLL-1 on mouse joint macrophages with Notch-2 on mouse FLS enhances the production of IL-6 and MMP-3. Therefore, suppression of IL-6, GM-CSF, and MMP-3 production by DLL-1 blockade might be responsible for the amelioration of arthritis in a mouse model of RA.
25436214 TNFα promotes Th17 cell differentiation through IL-6 and IL-1β produced by monocytes in 2014 TNFα plays an important role in autoimmune pathogenesis and is the main therapeutic target of rheumatoid arthritis. However, its underlying mechanism is not completely understood. In this study, we described that Th17 cells were accumulated in synovial fluid, which was attributable to TNFα aberrantly produced in rheumatoid synovium. Interestingly, TNFα cannot induce IL-17 production of CD4(+) T cells directly, but through the monocytes high levels of IL-1β and IL-6 in a TNFRI and TNFRII dependent manner from the active RA patients are produced. TNFα was shown to enhance the phosphorylation level of STAT3 and the expression level of transcription factor RORC of CD4(+) T cells when cultured with CD14(+) monocytes. Treatment with an approved TNFα blocking antibody showed marked reduction in the levels of IL-6, IL-1β, and IL-17 and the expression level of STAT3 phosphorylation in relation to Th17 cell differentiation in patients with rheumatoid arthritis. The study provides new evidence supporting the critical role of TNFα in the pathogenic Th17 cell differentiation in rheumatoid arthritis.
25431052 Safety and efficacy of baricitinib at 24 weeks in patients with rheumatoid arthritis who 2015 Feb OBJECTIVES: To investigate baricitinib (LY3009104, formerly INCB028050), a novel, oral inhibitor of JAK1/JAK2 in patients with moderate to severe rheumatoid arthritis (RA) despite treatment with methotrexate. METHODS: In this phase IIb study, 301 patients were randomised 2:1:1:1:1 to receive once daily doses of placebo or 1, 2, 4 or 8 mg baricitinib for 12 weeks. Patients assigned to 2, 4 and 8 mg baricitinib continued blinded treatment for an additional 12 weeks. Patients assigned to placebo or 1 mg baricitinib were reassigned to 2 mg twice daily or 4 mg once daily baricitinib between weeks 12-24. The primary endpoint was the proportion of patients in the combined 4 and 8 mg groups achieving an American College of Rheumatology 20% (ACR20) response versus placebo at week 12. RESULTS: Significantly more patients in the combined baricitinib 4 and 8 mg groups compared with placebo achieved an ACR20 response at week 12 (76% vs 41%, p<0.001). At week 12, significant differences versus placebo were also observed in patients achieving ACR50, ACR70 and remission as measured by Disease Activity Score for 28-joint counts, Clinical Disease Activity Index and Simplified Disease Activity Index. Patients receiving 2, 4, or 8 mg baricitinib maintained or improved in all measures through 24 weeks. Similar proportions of patients experienced at least one adverse event in the placebo and baricitinib groups. Serious infections developed in three patients receiving baricitinib. No cases of tuberculosis, herpes zoster, opportunistic infections or deaths were reported. Dose-dependent decreases in haemoglobin were observed with baricitinib. CONCLUSIONS: Baricitinib improved the signs and symptoms of RA in methotrexate inadequate responders with active disease. Baricitinib was well tolerated with no unexpected safety findings through week 24. TRIAL REGISTRATION NUMBER: NCT01185353.
23983401 Angiogenesis and its therapeutic opportunities. 2013 Angiogenesis plays critical roles in human physiology that range from reproduction and fetal growth to wound healing and tissue repair. The sophisticated multistep process is tightly regulated in a spatial and temporal manner by "on-off switch signals" between angiogenic factors, extracellular matrix components, and endothelial cells. Uncontrolled angiogenesis may lead to several angiogenic disorders, including vascular insufficiency (myocardial or critical limb ischemia) and vascular overgrowth (hemangiomas, vascularized tumors, and retinopathies). Thus, numerous therapeutic opportunities can be envisaged through the successful understanding and subsequent manipulation of angiogenesis. Here, we review the clinical implications of angiogenesis and discuss pro- and antiangiogenic agents that offer potential therapy for cancer and other angiogenic diseases.
23869798 Transforming growth factor (TGF)-β signalling is increased in rheumatoid synovium but TGF 2013 Nov The aim of this study was to analyse the distribution of regulatory and inhibitory mothers against decapentaplegic homologue (Smad) proteins as markers of active transforming growth factor (TGF)-β signalling in rheumatoid arthritis (RA) synovial tissue and to investigate the effect of TGF-β blockade in the development and progression of collagen-induced arthritis. The expression of Smad proteins in synovial tissues from RA, osteoarthritic and healthy controls was analysed by immunohistochemistry. Arthritis was induced in DBA/1 mice by immunization with chicken type-II collagen (CII). TGF-β was blocked in vivo with the specific peptide p17 starting at the time of immunization or on the day of arthritis onset. T cell population frequencies and specific responses to CII were analysed. The expression of cytokines and transcription factors was quantified in spleen and joint samples. Statistical differences between groups were compared using the Mann-Whitney U-test or one-way analysis of variance (anova) using the Kruskal-Wallis test. p-Smad-2/3 and inhibitory Smad-7 expression were detected in RA and control tissues. In RA, most lymphoid infiltrating cells showed nuclear p-Smad-2/3 without Smad-7 expression. Treatment with TGF-β antagonist did not affect clinical severity, joint inflammation and cartilage damage in collagen-induced arthritis. Frequency of T cell subsets, mRNA levels of cytokines and transcription factors, specific proliferation to CII, serum interleukin (IL)-6 and anti-CII antibodies were comparable in p17 and phosphate-buffered saline (PBS)-treated groups. The pattern of Smad proteins expression demonstrates active TGF-β signalling in RA synovium. However, specific TGF-β blockade does not have a significant effect in the mice model of collagen-induced arthritis.
24344160 Golimumab 3-year safety update: an analysis of pooled data from the long-term extensions o 2015 Mar OBJECTIVE: To assess pooled golimumab safety up to year 3 of rheumatoid arthritis (RA), psoriatic arthritis (PsA) and ankylosing spondylitis (AS) trials. METHODS: Golimumab 50 and 100 mg, administered subcutaneously (SC) every 4 weeks (q4wk), were assessed in patients with active RA (methotrexate-naïve, methotrexate-experienced and anti-TNF (tumour necrosis factor)-experienced), PsA or AS, despite conventional therapy. Placebo control continued up to week (wk) 24 (wk 52, methotrexate-naïve), with early escape at wk 16 (wk 28, methotrexate-naïve); subsequently, all patients received golimumab 50 or 100 mg q4wk. After the blinded controlled period, golimumab doses could be adjusted per investigator discretion. Pooled safety analyses reported herein include data from placebo-controlled and uncontrolled study periods up to wk 160. Determinations of incidences/100 patient-years (pt-yrs) for rare events also included RA patients from a phase IIb trial. RESULTS: Across five phase III trials of SC golimumab, 639 patients received placebo and 2226 received golimumab 50 mg (n=1249) and/or 100 mg (n=1501) up to wk 160 (patients may be included in more than one group because non-responders were allowed early escape); 1179 patients were treated for ≥156 weeks. For placebo, golimumab 50 mg and golimumab 100 mg, respective adverse event incidences/100 pt-yrs (95% CIs) up to wk 160 were: 0.28 (0.01 to 1.56), 0.30 (0.12 to 0.62), 0.41 (0.23 to 0.69) for death; 5.31 (3.20 to 8.30), 3.03 (2.36 to 3.82), 5.09 (4.36 to 5.90) for serious infection; 0.00 (0.00 to 0.84), 0.17 (0.05 to 0.44), 0.35 (0.18 to 0.62) for tuberculosis; 0.00 (0.00 to 0.84), 0.13 (0.03 to 0.38), 0.24 (0.10 to 0.46) for opportunistic infection; 0.00 (0.00 to 0.84), 0.00 (0.00 to 0.13), 0.12 (0.03 to 0.30) for demyelination; and 0.00 (0.00 to 0.84), 0.04 (0.00 to 0.24), 0.18 (0.06 to 0.38) for lymphoma. CONCLUSIONS: SC golimumab safety up to 3 years remained consistent with that of other TNF antagonists. Golimumab 100 mg showed numerically higher incidences of serious infections, demyelinating events and lymphoma than 50 mg; safety follow-up up to year 5 continues.
25003765 PTPN22: the archetypal non-HLA autoimmunity gene. 2014 Oct PTPN22 encodes a tyrosine phosphatase that is expressed by haematopoietic cells and functions as a key regulator of immune homeostasis by inhibiting T-cell receptor signalling and by selectively promoting type I interferon responses after activation of myeloid-cell pattern-recognition receptors. A single nucleotide polymorphism of PTPN22, 1858C>T (rs2476601), disrupts an interaction motif in the protein, and is the most important non-HLA genetic risk factor for rheumatoid arthritis and the second most important for juvenile idiopathic arthritis. PTPN22 exemplifies a shared autoimmunity gene, affecting the pathogenesis of systemic lupus erythematosus, vasculitis and other autoimmune diseases. In this Review, we explore the role of PTPN22 in autoimmune connective tissue disease, with particular emphasis on candidate-gene and genome-wide association studies and clinical variability of disease. We also propose a number of PTPN22-dependent functional models of the pathogenesis of autoimmune diseases.
24642072 Participation of interleukin 17A in neuroimmune interactions. 2014 Oct Inflammation involving the helper T cell 17 (Th17) subset of lymphocytes has been implicated in a number of diseases that affect the nervous system. As the canonical cytokine of Th17 cells, interleukin 17A (IL-17A) is thought to contribute to these neuroimmune interactions. The main receptor for IL-17A is expressed in many neural tissues. IL-17A has direct effects on neurons but can also impact neural function via signaling to satellite cells and immune cells. In the central nervous system, IL-17A has been associated with neuropathology in multiple sclerosis, epilepsy syndromes and ischemic brain injury. Effects of IL-17A at the level of dorsal root ganglia and the spinal cord may contribute to enhanced nociception during neuropathic and inflammatory pain. Finally, IL-17A plays a role in sympathetic axon growth and regeneration of damaged axons that innervate the cornea. Given the widespread effects of IL-17A on neural tissues, it will be important to determine whether selectively mitigating the damaging effects of this cytokine while augmenting its beneficial effects is a possible strategy to treat inflammatory damage to the nervous system.
25515957 Design, synthesis and evaluation of novel 5-phenylpyridin-2(1H)-one derivatives as potent 2015 Jan 15 A series of novel reversible Btk inhibitors has been designed based on the structure of the recently reported preclinical drug RN486. The synthesis and SAR of these compounds are described. Among these derivatives, compound 16b was identified to be a potent and orally available reversible agent with satisfactory Btk enzymatic and cellular inhibition in vitro, as well as favorable PK properties and inhibition of arthritis in vivo.
25398374 The JAK inhibitor tofacitinib suppresses synovial JAK1-STAT signalling in rheumatoid arthr 2015 Jun OBJECTIVE: Tofacitinib is an oral Janus kinase (JAK) inhibitor for the treatment of rheumatoid arthritis (RA). The pathways affected by tofacitinib and the effects on gene expression in situ are unknown. Therefore, tofacitinib effects on synovial pathobiology were investigated. METHODS: A randomised, double-blind, phase II serial synovial biopsy study (A3921073; NCT00976599) in patients with RA with an inadequate methotrexate response. Patients on background methotrexate received tofacitinib 10 mg twice daily or placebo for 28 days. Synovial biopsies were performed on Days -7 and 28 and analysed by immunoassay or quantitative PCR. Clinical response was determined by disease activity score and European League Against Rheumatism (EULAR) response on Day 28 in A3921073, and at Month 3 in a long-term extension study (A3921024; NCT00413699). RESULTS: Tofacitinib exposure led to EULAR moderate to good responses (11/14 patients), while placebo was ineffective (1/14 patients) on Day 28. Tofacitinib treatment significantly reduced synovial mRNA expression of matrix metalloproteinase (MMP)-1 and MMP-3 (p<0.05) and chemokines CCL2, CXCL10 and CXCL13 (p<0.05). No overall changes were observed in synovial inflammation score or the presence of T cells, B cells or macrophages. Changes in synovial phosphorylation of signal transducer and activator of transcription 1 (STAT1) and STAT3 strongly correlated with 4-month clinical responses (p<0.002). Tofacitinib significantly decreased plasma CXCL10 (p<0.005) at Day 28 compared with placebo. CONCLUSIONS: Tofacitinib reduces metalloproteinase and interferon-regulated gene expression in rheumatoid synovium, and clinical improvement correlates with reductions in STAT1 and STAT3 phosphorylation. JAK1-mediated interferon and interleukin-6 signalling likely play a key role in the synovial response. TRIAL REGISTRATION NUMBER: NCT00976599.
23905390 [Effects of danshen injection on the proliferation of rheumatoid arthritis fibroblast-like 2013 May OBJECTIVE: To investigate the effects of Danshen Injection (DSI) on the proliferation of rheumatoid arthritis fibroblast-like synoviocytes (RA FLSs) cultured in RA patients' serum. METHODS: The RA FLSs harvested from RA patients' synovial fluid were primarily cultured by routines. The cells were cultured with 10% inactivated human serum (the healthy human serum and the RA patients' serum) for 24 h. Then DSI at the final concentration of 0. 4 mg/mL was added in the cells for further 24 h culture. By taking 10% fetal calf serum as the control, the morphological changes were observed under optical microscope. The proliferation was analyzed by MTT. The apoptosis was detected by flow cytometry. The total RNA was extracted and reverse transcription was performed. The Bax mRNA expression was detected by fluorescent quantitative PCR. RESULTS: (1) After human serum was added in the healthy human serum and RA patients' serum, cells could grow adhering to the wall. Compared with the fetal calf serum group (FCS), the cell density was higher in the healthy human serum group than in the fetal calf serum group, with no obvious morphological changes. (2) MTT results showed that, compared with the fetal calf serum group, the absorbance value (OD) obviously increased in the healthy human serum group and the RA patients' serum group, showing statistical difference (P <0.01). After adding DSI at the final concentration of 0.4 mg/mL, cells from different serums were inhibited to various degrees (with OD significantly decreased, P <0.05). The OD value significantly increased more in the healthy human serum group and the RA patients' serum group than in the fetal calf serum group, showing statistical difference (P <0.01). There was statistical difference between the healthy human serum group and the RA patients' serum group (P <0.01). (3) The apoptosis rate in the RA patients' serum group obviously decreased with statistical difference, when compared with the Salvia miltiorrhiza free fetal calf serum group (P >0. 01). The apoptosis rate in the fetal calf serum group and the RA patients' serum group significantly increased after adding 0.4 mg/mL Salvia miltiorrhiza, showing statistical difference when compared with the Salvia miltiorrhiza free fetal calf serum group and the Salvia miltiorrhiza free RA patients' serum group (P <0.05). The FLSs were effected by 0.4 mg/mL Salvia miltiorrhiza, the apoptosis rate significantly decreased in the healthy human serum group and the RA patients' serum group, showing statistical difference when compared with the fetal calf serum group (P <0. 05, P <0.01). (4) The expression of Bax gene significantly increased in the RA patients' serum group and the fetal calf serum group after action of 0.4 mg/mL Salvia miltiorrhiza, showing statistical difference (P <0. 01). When 0.4 mg/mL Salvia miltiorrhiza was added, the expression of Bax mRNA obviously increased in the healthy human serum group and the RA patients' serum group, showing statistical difference when compared with the fetal calf serum group (P <0.01). CONCLUSIONS: (1) Although healthy human serum can be favorable to the growth of RA FLSs, the fetal calf serum could reflect the actual results better in the cyto biological research on specific diseases (if there is no serum from patients with corresponding disease). (2) DSI could inhibit the proliferation of RA FLSs through promoting their apoptosis.
25452562 Ex vivo-expanded but not in vitro-induced human regulatory T cells are candidates for cell 2015 Jan 1 Regulatory T cell (Treg) therapy is a promising approach for transplant rejection and severe autoimmunity. Unfortunately, clinically meaningful Treg numbers can be obtained only upon in vitro culture. Functional stability of human expanded (e)Tregs and induced (i)Tregs has not been thoroughly addressed for all proposed protocols, hindering clinical translation. We undertook a systematic comparison of eTregs and iTregs to recommend the most suitable for clinical implementation, and then tested their effectiveness and feasibility in rheumatoid arthritis (RA). Regardless of the treatment, iTregs acquired suppressive function and FOXP3 expression, but lost them upon secondary restimulation in the absence of differentiation factors, which mimics in vivo reactivation. In contrast, eTregs expanded in the presence of rapamycin (rapa) retained their regulatory properties and FOXP3 demethylation upon restimulation with no stabilizing agent. FOXP3 demethylation predicted Treg functional stability upon secondary TCR engagement. Rapa eTregs suppressed conventional T cell proliferation via both surface (CTLA-4) and secreted (IL-10, TGF-β, and IL-35) mediators, similarly to ex vivo Tregs. Importantly, Treg expansion with rapa from RA patients produced functionally stable Tregs with yields comparable to healthy donors. Moreover, rapa eTregs from RA patients were resistant to suppression reversal by the proinflammatory cytokine TNF-α, and were more efficient in suppressing synovial conventional T cell proliferation compared with their ex vivo counterparts, suggesting that rapa improves both Treg function and stability. In conclusion, our data indicate Treg expansion with rapa as the protocol of choice for clinical application in rheumatological settings, with assessment of FOXP3 demethylation as a necessary quality control step.
24938855 Neurological adverse events in patients receiving anti-TNF therapy: a prospective imaging 2014 Jun 17 INTRODUCTION: The aim was to investigate the frequency of neurological adverse events in patients with rheumatoid arthritis (RA) and spondylarthropathies (SpA) treated with tumor necrosis factor (TNF) α antagonists. METHODS: Seventy-seven patients eligible for anti-TNFα therapy were evaluated. There were 36 patients with RA, 41 with SpA [24 psoriatic arthritis (PsA) and 17 with ankylosing spondylitis (AS)]. All patients had a complete physical and neurological examination. Brain and cervical spine magnetic resonance imaging (MRI) and neurophysiological tests were performed in all patients before the initiation of anti-TNFα therapy and after a mean of 18 months or when clinical symptoms and signs indicated a neurological disease. Exclusion criteria included hypertension, diabetes mellitus, dyslipidemia, heart arrhythmias, atherothrombotic events, vitamin B12 and iron deficiency, head and neck trauma and neurological surgeries. RESULTS: Two patients did not receive anti-TNFα therapy because brain MRIs at baseline revealed lesions compatible with demyelinating diseases. Thus, 75 patients received anti-TNFα (38 infliximab, 19 adalimumab and 18 etanercept). Three patients developed neurological adverse events. A 35-year-old man with PsA after 8 months of infliximab therapy presented with paresis of the left facial nerve and brain MRI showed demyelinating lesions. Infliximab was discontinued and he was treated with pulses of corticosteroids recovering completely after two months. The second patient was a 45-year-old woman with RA who after 6 months of adalimumab therapy presented with optic neuritis. The third patient was a 50-year-old woman with AS, whom after 25 months of infliximab therapy, presented with tingling and numbness of the lower extremities and neurophysiological tests revealed peripheral neuropathy. In both patients anti-TNF were discontinued and they improved without treatment after 2 months. The rest of our patients showed no symptoms and MRIs showed no abnormalities. The estimated rate of neurological adverse events in patients treated with anti-TNF therapy is 4% (3/75). CONCLUSIONS: Neurological adverse events after anti-TNFα therapy were observed in our patient. Brain MRI and neurophysiological tests are essential tools to discriminate neurological diseases.
24419251 Simvastatin inhibits cytokines in a dose response in patients with rheumatoid arthritis. 2014 Apr OBJECTIVE AND DESIGN: To evaluate the effects of simvastatin in peripheral blood mononuclear cell (PBMC) cytokines profiles and correlate with the disease state of rheumatoid arthritis (RA) patients. METHODS: The PBMC from 22 RA patients were purified and stimulated or not stimulated with phorbol myristate acetate/ionomycin and were treated with simvastatin in different doses. Cytokine levels were quantified by ELISA and patients were assessed for clinical and laboratory variables. This assessment included disease activity measures [Clinical Disease Activity Index (CDAI), Disease Activity Score for 28 joints (DAS28)] and a Health Assessment Questionnaire. RESULTS: The IL-17A, IL-6, IL-22 and IFN-γ were significantly reduced in a dose response after simvastatin treatment (50 μM, p = 0.0005; p < 0.0001; p < 0.02; p = 0.0005, respectively). The IL-17A and IL-6 cytokines were also significantly reduced in lower concentrations of simvastatin (10 μM) compared to controls (p = 0.018; p = 0.04) and compared to the standard drug (p = 0.007; p = 0.0001). The results also showed that only RA patients with severe disease (DAS28 >5.1 and CDAI >22) had poor response to simvastatin in reducing cytokines levels, mainly for IL-17A and IL-22 cytokines (p = 0.03; p = 0.039, respectively). CONCLUSION: The RA patients in clinical remission, mild or moderate had lower levels of all cytokines analyzed after simvastatin treatment, showing that these patients have better response to treatment. Our findings suggest that the simvastatin therapy modulates different cytokines in a dose dependent manner and its effect is associated with stratification of patients according to disease activity.