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ID PMID Title PublicationDate abstract
24261759 Early diagnosis and treatment of steroid-induced diabetes mellitus in patients with rheuma 2014 Jan PURPOSE: To reveal how often patients with rheumatoid arthritis (RA) or any of other connective tissue diseases (CTDs) who take prednisolone (PSL) manifest postprandial hyperglycemia, and to evaluate the effects of divided daily dose administration of PSL, and of acarbose and nateglinide, on RA patients. METHOD: The blood sugar (BS) levels of the patients were measured after meals. For in-patients who showed postprandial hyperglycemia, the daily dose of PSL was divided and nateglinide and/or acarbose were/was added if their BS levels did not improve sufficiently. The patients with BS levels that were well controlled for three months were compared with the patients with poorly controlled BS levels. RESULTS: The BS levels of 78 patients, including 16 patients with diabetes mellitus (DM), were measured after meals, and 27 of them were newly diagnosed with DM. Five of 14 patients who took a steady dose of PSL showed high BS levels after lunch (over 200 mg/dl) without elevated HbA1c. The combination therapy of divided-dose PSL and nateglinide and/or acarbose improved postprandial hyperglycemia significantly. The period from the start of PSL administration to intervention was significantly longer in patients with good control at three months than the corresponding period in those with poor control. CONCLUSION: The prevalence of postprandial hyperglycemia was high in patients with RA/CTD taking PSL; accordingly, measurement of the BS level after each meal was valuable. Combination therapy of divided-dose PSL and nateglinide and/or acarbose improved postprandial hyperglycemia.
23811296 Detection and isolation of auto-reactive human antibodies from primary B cells. 2013 Dec 1 The isolation of human monoclonal antibodies (hmAb) has emerged as a versatile platform in a wide variety of contexts ranging from vaccinology to therapeutics. In particular, the presence of high titers of circulating auto-antibodies is implicated in the pathology and outcome of autoimmune diseases. Therefore, the molecular characterization of these hmAb provides an avenue to understanding the pathogenesis of autoimmune diseases. Additionally, the phenotype of the auto-reactive B cells may have direct relevance for therapeutic intervention. In this report, we describe a high-throughput single-cell assay, microengraving, for the screening, characterization and isolation of anti-citrullinated protein antibodies (ACPA) from peripheral blood mononuclear cells (PBMC) of rheumatoid arthritis (RA) patients. Stimulated B cells are profiled at the single-cell level in a large array of sub-nanoliter nanowells (∼10(5)), assessing both the phenotype of the cells and their ability to secrete cyclic-citrullinated peptide (CCP)-specific antibodies. Single B cells secreting ACPA are retrieved by automated micromanipulation, and amplification of the immunoglobulin (Ig) heavy and light chains is performed prior to recombinant expression. The methodology offers a simple, rapid and low-cost platform for isolation of auto-reactive antibodies from low numbers of input cells and can be easily adapted for isolation and characterization of auto-reactive antibodies in other autoimmune diseases.
24795506 Lack of association between ABO, PPAP2B, ADAMST7, PIK3CG, and EDNRA and carotid intima-med 2014 INTRODUCTION: Rheumatoid arthritis (RA) is a polygenic disease associated with accelerated atherosclerosis and increased cardiovascular (CV) mortality. Recent studies have identified the ABO rs579459, PPAP2B rs17114036, and ADAMTS7 rs3825807 polymorphisms as genetic variants associated with coronary artery disease and the PIK3CG rs17398575 and EDNRA rs1878406 polymorphisms as the most significant signals related to the presence of carotid plaque in nonrheumatic Caucasian individuals. Accordingly, we evaluated the potential relationship between these 5 polymorphisms and subclinical atherosclerosis (assessed by carotid intima-media thickness (cIMT) and presence/absence of carotid plaques) and CV disease in RA. MATERIAL AND METHODS: 2140 Spanish RA patients were genotyped for the 5 polymorphisms by TaqMan assays. Subclinical atherosclerosis was evaluated in 620 of these patients by carotid ultrasonography technology. RESULTS: No statistically significant differences were found when each polymorphism was assessed according to cIMT values and presence/absence of carotid plaques in RA, after adjusting the results for potential confounders. Moreover, no significant differences were obtained when RA patients were stratified according to the presence/absence of CV disease after adjusting for potential confounders. CONCLUSION: Our results do not confirm association between ABO rs579459, PPAP2B rs17114036, ADAMTS7 rs3825807, PIK3CG rs17398575, and EDNRA rs1878406 and subclinical atherosclerosis and CV disease in RA.
24379267 [Prolactin as an immunomodulatory factor in psoriatic arthritis]. 2013 Dec 11 Prolactin (PRL) is a hormone synthesized and secreted by lactotroph cells in the anterior pituitary gland. There is also extrapituitary hormone secretion by many cells, including cells of the immune system. In physiological conditions PRL is responsible for lactogenesis and other processes associated with it. PRL plays a significant role during the immune response as a cytokine, affecting proliferation and differentiation of many immune system cells. The biological effect of the hormone depends on binding with the specific prolactin receptor PRL-R, and activation of the transcription factors of targeted genes. For T lymphocyte stimulated PRL, that factor is mainly the interferon regulatory factor (IRF-1), which gives the possibility of adjusting the prolactin immune response. Literature data indicate that hyperprolactinemia (HPRL) is one of the important factors in the pathogenesis and course of autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis, systemic sclerosis and Sjogren's syndrome. HPRL is diagnosed in nearly one-third of these patients. However, only a few data indicate the role of prolactin in psoriatic arthritis (PsA), whose etiology and disease progression are not fully elucidated, and the diagnosis is very difficult. Currently there is indicated a pronounced connection between the course of HPRL and activity of PsA. It seems also to be interesting that, regardless of the PRL levels in serum of patients with PsA, administration of bromocriptine--drug-lowering hormone--improves joint and skin symptoms, which indicates a decrease in disease activity, and is a promising way of alternative therapy for psoriatic arthritis. However, the effect of PRL on the pathogenesis and the severity of psoriatic arthritis has not yet been fully understood and further research will provide a possibility to assess the prognostic and diagnostic significance of prolactin in patients with PsA.
24394943 Trikatu, an herbal compound as immunomodulatory and anti-inflammatory agent in the treatme 2014 Jan In the present study, trikatu, an herbal compound was evaluated for its immunomodulatory and anti-inflammatory properties with reference to cell mediated immune responses (delayed type hypersensitivity reaction), humoral immune response (haemagglutination titer and plaque forming assay), macrophage phagocytic index, circulating immune complex and inflammatory mediators in rats. For comparison purposes, indomethacin was used as a reference drug for anti-inflammatory studies. The results obtained in our study showed a significant decrease in cell mediated immune responses, humoral immune responses (haemagglutination titre and plaque forming assay) and macrophage phagocytic index in trikatu treated rats (1000 mg/kg/b.wt.) compared to control animals implying its immunosuppressive property. In addition, significant anti-inflammatory effects were observed in trikatu treated adjuvant induced arthritic rats by a reduction in the levels of circulating immune complexes and inflammatory mediators (TNF-alpha and Interleukin-1beta). Thus, in conclusion, our data suggest that trikatu could be considered as a potential anti-inflammatory agent for treating autoimmune inflammatory disorders like rheumatoid arthritis with immunosuppressive property.
24065540 MMP-2, TNF-α and NLRP1 polymorphisms in Chinese patients with ankylosing spondylitis and 2013 Nov Rheumatoid arthritis (RA) and ankylosing spondylitis (AS) are autoimmune, inflammatory diseases with substantial genetic contributions. Matrix metalloproteinase (MMP)-2, tumor necrosis factor (TNF)-α and NLR family pyrin domain-containing 1 (NLRP1) play important roles in the immune response. We studied the MMP-2 rs243865 C/T, TNF-α rs1800629 A/G, NLRP1 rs878329 C/G and NLRP1 rs6502867 C/T polymorphisms in a Chinese cohort of 520 patients with RA, 100 with AS and 520 controls. Genotyping was performed using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Using the MMP-2 rs243865 CC homozygote genotype as the reference group, the CT and TT/CT genotypes were associated with significantly reduced risks of AS. However, logistic regression analyses revealed that the MMP-2 rs243865 C/T polymorphism was not associated with risk of RA. TNF-α rs1800629 A/G, NLRP1 rs878329 C/G and NLRP1 rs6502867 C/T polymorphisms were not associated with risk of RA or AS. These findings suggest that the MMP-2 rs243865 C/T polymorphism is associated with AS development.
25231904 Certolizumab pegol (CDP870) for rheumatoid arthritis in adults. 2014 Sep 18 BACKGROUND: Tumour necrosis factor (TNF)-alpha inhibitors are beneficial for the treatment of rheumatoid arthritis (RA) in terms of reducing the risk of joint damage, improving physical function and improving quality of life. This Cochrane review is an update of a review of the treatment of RA with certolizumab pegol that was first published in 2011. OBJECTIVES: To assess the clinical benefits and harms of certolizumab pegol (CDP870) in patients with RA who have not responded well to conventional disease-modifying anti-rheumatic drugs (DMARDs). SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (The Cochrane Library 2014, Issue 5), MEDLINE, EMBASE, Scopus, TOXLINE, Web of Knowledge; websites of the US Food and Drug Administration (FDA) and European Medicines Evaluation Agency (EMEA); reference lists of articles; and searched http/clinicaltrials.gov. The searches were updated from 2009 (date of last search for the original review) to 5 June 2014. SELECTION CRITERIA: Randomised controlled trials that compared certolizumab pegol with any other agent including placebo or methotrexate (MTX) in adult patients with active RA despite current or prior treatment with conventional disease-modifying anti-rheumatic drugs (DMARDs), such as MTX. DATA COLLECTION AND ANALYSIS: Two authors independently assessed search results, trial quality and extracted data. Disagreements were resolved by discussion or referral to a third author. MAIN RESULTS: Eleven trials were included in this update. Ten (4324 patients) were included in the pooled analysis for benefits, five more than previously, and 10 (3711 patients) in the pooled analysis for harms, four more trials (1930 patients) than previously. The duration of follow-up varied from 12 to 52 weeks and the range of doses of certolizumab pegol varied from 50 to 400 mg given subcutaneously (sc). In phase III trials, the control was placebo plus MTX in five trials and placebo in four trials. The risk of bias of the included studies was assessed as low but there may have been a risk of attrition bias.Statistically significant improvements were observed at 24 weeks with the approved dose of 200 mg certolizumab pegol every other week, in 1) American College of Rheumatology (ACR) 50% improvement: 27% absolute improvement (95% CI 20% to 33%), NNT of 4 (95% CI 3 to 8), risk ratio (RR) 3.80 (95% CI 2.42 to 5.95); 2) the Health Assessment Questionnaire (HAQ): -12% absolute improvement (95% CI -9% to -14%), NNT of 6 (95% CI 5 to 8), mean difference (MD) - 0.35 (95% CI -0.43 to -0.26) (scale 0 to 3); 3) Disease Activity Score (DAS) remission improvement: absolute improvement 11% (95% CI 8% to 15%), NNT of 9 (95% CI 4 to 20), RR 8.47 (95% CI 4.15-17.28); and 4) radiological changes: erosion score (ES) absolute improvement -0.29% (95% CI -0.42% to -0.17%), NNT of 6 (95% CI 4 to 10), MD -0.67 (95% CI -0.96 to -0.38) (scale 0 to 230). Serious adverse events were statistically significantly more frequent for certolizumab pegol (200 mg every other week) with an absolute rate difference of 4% (95% CI 2% to 6%), NNTH of 32 (95% CI 17 to 88), Peto odds ratio (OR) 1.77 (95% CI 1.27 to 2.46). There was a statistically significant increase in all withdrawals in the placebo groups (for all doses and all follow-ups) with an absolute rate difference of -34% (95% CI -18% to -50%), NNTH of 4 (95% CI 3 to 5), NNTH of 4 (95% CI 3 to 5), RR 0.42 (95% CI 0.36 to 0.50); and there was a statistically significant increase in all withdrawals due to adverse events in the certolizumab groups (for all doses and all follow-up) with an absolute rate difference of 2% (95% CI 1% to 3%), NNTH of 55 (95% CI 27 to 238), Peto OR 1.66 (95% CI 1.15 to 2.37).The risk of bias was low and the quality of evidence was downgraded to moderate because of high rates of dropouts (> 20%) in most of the trials. We did not find any problems with inconsistency, indirectness, imprecision or publication bias. AUTHORS' CONCLUSIONS: The results and conclusions did not change from the previous review. There is moderate-level evidence from randomised controlled trials that certolizumab pegol alone or combined with methotrexate is beneficial in the treatment of RA. Adverse events were more frequent with active treatment. We found a potential risk of serious adverse events.
23338540 Certolizumab pegol: a review of its use in the management of rheumatoid arthritis. 2013 Jan Certolizumab pegol (Cimzia(®)) is a recombinant, polyethylene glycolylated, antigen-binding fragment of a humanized monoclonal antibody that selectively targets and neutralizes tumour necrosis factor (TNF)-α. The drug is indicated for subcutaneous use every 2 or 4 weeks (q2w or q4w) for the treatment of adults with moderate to severe active rheumatoid arthritis (RA). The efficacy of subcutaneous certolizumab pegol in adults with active RA has been investigated in several well designed, placebo-controlled trials. In four pivotal studies of ≤52 weeks duration, patients with moderate to severe disease receiving recommended dosages of certolizumab pegol (200 mg q2w or 400 mg q4w), either as monotherapy (after failing prior disease-modifying anti-rheumatic drug [DMARD] therapy) or in combination with methotrexate (after responding inadequately to methotrexate alone), experienced rapid clinical improvement, with some combination trials also demonstrating inhibition of radiographic progression. The beneficial effects of certolizumab pegol therapy were generally maintained for up to ≈5 years in clinical trial extensions in which the drug was administered at dosages of 400 mg q4w or q2w. Additional studies suggest certolizumab pegol is also effective in patients who are Asian or have low to moderate disease activity, as well as more clinically representative patient populations. The tolerability profile of certolizumab pegol was acceptable, with infections/infestations the most common adverse events. Thus, certolizumab pegol is an effective option for the management of active RA in adults, although additional long-term and comparative efficacy and tolerability data are needed to help definitively position certolizumab pegol relative to other biological DMARDs, particularly other anti-TNF agents.
23802849 Neurological events with tumour necrosis factor alpha inhibitors reported to the Food and 2013 Aug BACKGROUND: The association between inhibition of tumour necrosis factor alpha (TNF-α) and new onset of neurological adverse events (AEs) is unclear. AIMS: To evaluate neurological AEs with TNF-α inhibitors reported to the Food and Drug Administration Adverse Event Reporting System (FAERS) utilising a standardised scoring tool for drug-induced AEs. METHODS: A search of FAERS for neurological AEs (January 1, 2000 to December 31, 2009) reported with infliximab, adalimumab, certolizumab and etanercept was performed. Full-text reports were accessed using the Freedom of Information Act and scored using Naranjo score, while accounting for temporal association, previous conclusive reports of the neurological AE with any TNF-α inhibitor, and alternate explanations including underlying disease, concomitant medications and comorbidities, such as diabetes mellitus. RESULTS: There were 772 reports. Most were in patients who had rheumatoid arthritis (393, 50.9%) followed by inflammatory bowel disease (140, 18.1%). No significant differences in age or gender were seen between IBD patients compared with rheumatological diseases (P = 0.584 and P = 0.055 respectively). Etanercept was reported most (327, 42.4%) followed by infliximab (276, 35.8%) (P = 0.008). Peripheral neuropathy was the most common neurological AE (296 reports, 38.3%) followed by central nervous system and/or spinal cord demyelination (153 reports, 19.8%). Majority (551, 71.4%) of the reports were of 'possible' AE with the remaining 'probable' AE and none identified as 'definite' AE. CONCLUSION: While several neurological AEs have been described, definite association between de novo development of these AEs and exposure to TNF-α inhibitors was not established using the Naranjo score.
23455633 CIP2A facilitates apoptotic resistance of fibroblast-like synoviocytes in rheumatoid arthr 2013 Sep The aim of this study is to investigate the effects of CIP2A (Cancerous inhibitor of protein phosphatase 2A) on the apoptosis of RA FLS. Proliferation and apoptotic activity of RA FLS following treatment with CIP2A siRNA or control siRNA were analyzed using MTT assays and Cell Death Detection kit. RA FLS was treated with CIP2A siRNA or control siRNA in 3-, 6-, and 9-day intervals for a Western blot analysis to determine C-Myc expression. To evaluate the signal transduction pathways engaged in apoptosis, caspase-3 activity, caspase-9 activity, PARP, and phosphorylation of the Akt kinase were analyzed by Western blot. Cell viability of RA FLS was significantly lower in the CIP2A siRNA-treated group compared with the control after 7 days (p = 0.022). Apoptosis of RA FLS was significantly higher in the CIP2A siRNA-treated group compared with the control when incubated for 3, 6, and 9 days (p = 0.029, p = 0.021, p = 0.043, respectively). C-Myc expression did not change with the different incubation periods. CIP2A siRNA-treated FLS expressed higher level of activated caspase-3, caspase-9, and PARP (p = 0.014, p = 0.020, p = 0.021, respectively) and lower level of phosphorylated Akt (p = 0.001) compared with those treated with the control siRNA. Our data show that CIP2A expression in RA FLS is an important mediator of dysfunctional apoptosis independent of c-Myc stabilization. Expression of CIP2A may contribute to apoptotic resistance of RA FLS through the activation of Akt and deactivation of caspase-3, caspase-9, and PARP. Inhibition of CIP2A may therefore constitute a novel, promising therapeutic target in RA.
23300329 Autonomous online health assessment questionnaire registry in daily clinical practice. 2013 May OBJECTIVE: Tight control in RA necessitates frequent disease monitoring; patients might participate by self-assessment of their functional status. Therefore, we assessed the feasibility and acceptability of autonomous online registry of physical functioning. METHODS: In two tertiary-care centres (in The Netherlands and France), consecutive RA patients were approached to perform autonomous registry of the HAQ in an electronic medical record. Feasibility and acceptability of autonomous HAQ registry was assessed through: (i) the percentage of acceptances; (ii) the time needed to register the HAQ (the Netherlands); (iii) patient satisfaction with autonomous registry; and (iv) willingness for future home-based HAQ completion, either self-declared (The Netherlands) or actual file access from home within 6 months (France). RESULTS: In all, 214 patients were approached; 163 agreed to participate; 137 (64% of 214) had complete data that were analysed. Median age was 56 years (range 20-78 years), 80% were female, median disease duration was 9 years. The median time needed to fill in the HAQ in the waiting room was 5.8 min; patient satisfaction was high (mean score 4.1 out of 5), self-declared willingness for autonomous registry at home was 73%. In the 6-month follow-up period, 46% of patients accessed their medical file from home at least once. CONCLUSION: Many RA patients reported willingness to self-monitor their disease online, but fewer than half of the patients actually did. To enhance patient autonomous monitoring, progress is needed in terms of Internet access, continuous patient support and, importantly, convincing patients that they will benefit from autonomous monitoring.
23327567 Are two readers more reliable than one? A study of upper neck ligament scoring on magnetic 2013 Jan 17 BACKGROUND: Magnetic resonance imaging (MRI) studies typically employ either a single expert or multiple readers in collaboration to evaluate (read) the image results. However, no study has examined whether evaluations from multiple readers provide more reliable results than a single reader. We examined whether consistency in image interpretation by a single expert might be equal to the consistency of combined readings, defined as independent interpretations by two readers, where cases of disagreement were reconciled by consensus. METHODS: One expert neuroradiologist and one trained radiology resident independently evaluated 102 MRIs of the upper neck. The signal intensities of the alar and transverse ligaments were scored 0, 1, 2, or 3. Disagreements were resolved by consensus. They repeated the grading process after 3-8 months (second evaluation). We used kappa statistics and intraclass correlation coefficients (ICCs) to assess agreement between the initial and second evaluations for each radiologist and for combined determinations. Disagreements on score prevalence were evaluated with McNemar's test. RESULTS: Higher consistency between the initial and second evaluations was obtained with the combined readings than with individual readings for signal intensity scores of ligaments on both the right and left sides of the spine. The weighted kappa ranges were 0.65-0.71 vs. 0.48-0.62 for combined vs. individual scoring, respectively. The combined scores also showed better agreement between evaluations than individual scores for the presence of grade 2-3 signal intensities on any side in a given subject (unweighted kappa 0.69-0.74 vs. 0.52-0.63, respectively). Disagreement between the initial and second evaluations on the prevalence of grades 2-3 was less marked for combined scores than for individual scores (P ≥ 0.039 vs. P ≤ 0.004, respectively). ICCs indicated a more reliable sum score per patient for combined scores (0.74) and both readers' average scores (0.78) than for individual scores (0.55-0.69). CONCLUSIONS: This study was the first to provide empirical support for the principle that an additional reader can improve the reproducibility of MRI interpretations compared to one expert alone. Furthermore, even a moderately experienced second reader improved the reliability compared to a single expert reader. The implications of this for clinical work require further study.
24909454 Management of patients with overt or resolved hepatitis B virus infection undergoing ritux 2014 Jul INTRODUCTION: Rituximab (RTX), a chimeric mouse anti-human CD20 monoclonal antibody, is indicated for the treatment of patients with non-Hodgkin's lymphoma, chronic lymphocytic leukemia, granulomatosis with polyangiitis and microscopic polyangiitis, and rheumatoid arthritis, but nowadays it is increasingly used for the treatment of many other immune-mediated disorders. Hepatitis B virus (HBV) reactivation in RTX-treated patients, eventually leading to fatal liver failure, has been reported more often among hepatitis B surface antigen (HBsAg)-positive patients (overt infection) than in HBsAg-negative, antibody to hepatitis B core antigen (anti-HBc) seropositive patients (resolved infection). AREAS COVERED: This paper reviews the safety of RTX in patients with overt or resolved HBV infection, providing recommendations for its safe use in such patients. EXPERT OPINION: Prior to starting RTX treatment, all patients should be screened for HBV infection. While HBsAg-positive active carriers should receive long-term antiviral treatment with entecavir (ETV) or tenofovir, inactive carriers are candidates for universal prophylaxis with lamivudine, or ETV or tenofovir in selected cases, to prevent hepatitis reactivation. Conversely, for HBsAg-negative anti-HBc positive carriers, that is, those with resolved HBV infection, universal prophylaxis with lamivudine is recommended for those with onco-hematological diseases, whereas watchful monitoring of HBsAg/HBV DNA levels is advisable for all the other indications.
24981319 Efficacy and safety of certolizumab pegol without methotrexate co-administration in Japane 2014 Jul OBJECTIVE: This 24-week, placebo-controlled, double-blind, randomized study (NCT00791921) investigated efficacy and safety of certolizumab pegol (CZP) in Japanese rheumatoid arthritis (RA) patients in whom methotrexate (MTX) cannot be administered. METHODS: A total of 230 patients were randomized to subcutaneous CZP 200 mg (induction dosing: 400 mg at Weeks 0, 2 and 4) or placebo every 2 weeks. RESULTS: ACR20 responses with CZP were rapid and significant versus placebo at Week 1, sustained to Week 12 (67.2% vs. 14.9%) and Week 24 (63.8% vs. 11.4%). Week 24-modified Total Sharp Score (mTSS) change from baseline (CFB) was 0.48 (CZP) versus 2.45 (placebo). CZP treatment was associated with higher Week 12 ACR20 responses versus placebo (with non-MTX disease modifying antirheumatic drugs [DMARDs], 74.2% vs. 20.0%; without [monotherapy], 59.3% vs. 8.2%) and inhibition of radiographic progression at Week 24 (mTSS CFB; with non-MTX DMARDs, 0.24 vs. 1.61; monotherapy, 0.68 vs. 3.65). Incidences of serious adverse events were 11.2% (CZP) and 2.6% (placebo); one CZP patient died of dissecting aortic aneurysm. CONCLUSION: CZP treatment with and without non-MTX DMARDs in Japanese patients in whom MTX cannot be administered resulted in rapid, sustained reductions in RA signs and symptoms. Notably, CZP monotherapy showed significant inhibition of radiographic progression.
24490617 Generation of disease-specific induced pluripotent stem cells from patients with rheumatoi 2014 Feb 4 INTRODUCTION: Since the concept of reprogramming mature somatic cells to generate induced pluripotent stem cells (iPSCs) was demonstrated in 2006, iPSCs have become a potential substitute for embryonic stem cells (ESCs) given their pluripotency and "stemness" characteristics, which resemble those of ESCs. We investigated to reprogram fibroblast-like synoviocytes (FLSs) from patients with rheumatoid arthritis (RA) and osteoarthritis (OA) to generate iPSCs using a 4-in-1 lentiviral vector system. METHODS: A 4-in-1 lentiviral vector containing Oct4, Sox2, Klf4, and c-Myc was transduced into RA and OA FLSs isolated from the synovia of two RA patients and two OA patients. Immunohistochemical staining and real-time PCR studies were performed to demonstrate the pluripotency of iPSCs. Chromosomal abnormalities were determined based on the karyotype. SCID-beige mice were injected with iPSCs and sacrificed to test for teratoma formation. RESULTS: After 14 days of transduction using the 4-in-1 lentiviral vector, RA FLSs and OA FLSs were transformed into spherical shapes that resembled embryonic stem cell colonies. Colonies were picked and cultivated on matrigel plates to produce iPSC lines. Real-time PCR of RA and OA iPSCs detected positive markers of pluripotency. Immunohistochemical staining tests with Nanog, Oct4, Sox2, Tra-1-80, Tra-1-60, and SSEA-4 were also positive. Teratomas that comprised three compartments of ectoderm, mesoderm, and endoderm were formed at the injection sites of iPSCs. Established iPSCs were shown to be compatible by karyotyping. Finally, we confirmed that the patient-derived iPSCs were able to differentiate into osteoblast, which was shown by an osteoimage mineralization assay. CONCLUSION: FLSs derived from RA and OA could be cell resources for iPSC reprogramming. Disease- and patient-specific iPSCs have the potential to be applied in clinical settings as source materials for molecular diagnosis and regenerative therapy.
24255545 Inhibition of notch signalling ameliorates experimental inflammatory arthritis. 2015 Jan OBJECTIVE: To test the hypothesis that Notch signalling plays a role in the pathogenesis of rheumatoid arthritis (RA) and to determine whether pharmacological inhibition of Notch signalling with γ-secretase inhibitors can ameliorate the RA disease process in an animal model. METHODS: Collagen-induced arthritis was induced in C57BL/6 or Notch antisense transgenic mice by immunisation with chicken type II collagen (CII). C57BL/6 mice were administered with different doses of inhibitors of γ-secretase, an enzyme required for Notch activation, at disease onset or after onset of symptoms. Severity of arthritis was monitored by clinical and histological scores, and in vivo non-invasive near-infrared fluorescence (NIRF) images. Micro-CT was used to confirm joint destruction. The levels of CII antibodies and cytokines in serum were determined by ELISA and bead-based cytokine assay. The expression levels of cytokines were studied by quantitative PCR in rheumatoid synovial fibroblasts. RESULTS: The data show that Notch signalling stimulates synoviocytes and accelerates their production of proinflammatory cytokines and immune responses involving the upregulation of IgG1 and IgG2a. Pharmacological inhibition of γ-secretase and antisense-mediated knockdown of Notch attenuates the severity of inflammatory arthritis, including arthritis indices, paw thickness, tissue damage and neutrophil infiltration, and reduces the levels of active NF-κB, ICAM-1, proinflammatory cytokines and matrix metalloproteinase-3 activity in the mouse model of RA. CONCLUSIONS: These results suggest that Notch is involved in the pathogenesis of RA and that inhibition of Notch signalling is a novel approach for treating RA.
23632129 Largazole, a class I histone deacetylase inhibitor, enhances TNF-α-induced ICAM-1 and VCA 2013 Jul 15 In the present study, we evaluated the effect of largazole (LAR), a marine-derived class I HDAC inhibitor, on tumor necrosis factor-α (TNF-α)-induced expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), and matrix metalloproteinase-2 (MMP-2) activity. LAR (1-5 μM) had no adverse effect on the viability of RA synovial fibroblasts. Among the different class I HDACs screened, LAR (0.5-5 μM) inhibited the constitutive expression of HDAC1 (0-30%). Surprisingly, LAR increased class II HDAC [HDAC6] by ~220% with a concomitant decrease in HDAC5 [30-58%] expression in RA synovial fibroblasts. SAHA (5 μM), a pan-HDAC inhibitor, also induced HDAC6 expression in RA synovial fibroblasts. Pretreatment of RA synovial fibroblasts with LAR further enhanced TNF-α-induced ICAM-1 and VCAM-1 expression. However, LAR inhibited TNF-α-induced MMP-2 activity in RA synovial fibroblasts by 35% when compared to the TNF-α-treated group. Further, the addition of HDAC6 specific inhibitor Tubastatin A with LAR suppressed TNF-α+LAR-induced ICAM-1 and VCAM-1 expression and completely blocked MMP-2 activity, suggesting a role of HDAC6 in LAR-induced ICAM-1 and VCAM-1 expression. LAR also enhanced TNF-α-induced phospho-p38 and phospho-AKT expression, but inhibited the expression of phospho-JNK and nuclear translocation of NF-κBp65 in RA synovial fibroblasts. These results suggest that LAR activates p38 and Akt pathways and influences class II HDACs, in particular HDAC6, to enhance some of the detrimental effects of TNF-α in RA synovial fibroblasts. Understanding the exact role of different HDAC isoenzymes in RA pathogenesis is extremely important in order to develop highly effective HDAC inhibitors for the treatment of RA.
25557658 The effect of tocilizumab on bone mineral density, serum levels of Dickkopf-1 and bone rem 2015 Mar Previous studies showed that the control of inflammation by biological therapies has a positive effect on bone in inflammatory diseases. The objective of this study was to assess the effects on bone mineral density (BMD) and bone remodeling of an anti-IL-6 monoclonal antibody (tocilizumab (TCZ)) in patients with rheumatoid arthritis (RA). METHODS: One hundred and three patients (75% women, 52±12years) with active RA were treated with TCZ 8mg/kg + methotrexate (MTX) every 4 weeks during 48 weeks. Hip and lumbar spine BMDs were measured at baseline and after 48 weeks by dual energy X-ray absorptiometry (DXA). Pro-collagen serum type I N-terminal propeptide (PINP), serum C-terminal cross-linked telopeptide of type I collagen (CTX-I), and serum levels of total Dickkopf-1 (Dkk-1) and sclerostin were assessed at baseline, 12 and 48 weeks. RESULTS: BMD was available for 76 patients at baseline and at the end of the study. There was no change in lumbar spine and hip BMD over 48 weeks. Serum PINP increased from baseline by 22% (P≤0.001) and 19% (P≤0.001) at week 12 and week 48, whereas serum CTX-I remained stable. Serum DKK-1 significantly decreased from baseline by -31% (P≤0.001) and -25% (P=0.025) at week 12 and 48. Similar results were observed in the patients receiving low doses of oral corticosteroids. CONCLUSION: In this 1-year prospective open study, patients with active RA receiving TCZ and MTX had no change in BMD, a decrease in serum DKK-1 and an increase in bone formation marker.
25160017 Listeria rhomboencephalitis in a patient on a tumor necrosis factor α inhibitor (etanerce 2014 Sep We describe a case of an 87-year-old woman with rheumatoid arthritis on etanercept who developed subacute encephalopathy. Magnetic resonance imaging and blood cultures led to the diagnosis of Listeria monocytogenes rhomboencephalitis, which proved to be fatal. Postmortem examination of the brain revealed abscesses with extensive necrosis. Gram stain showed small gram-positive rods in the necrotic tissue and the wall lining the abscesses. While rhomboencephalitis is a rare entity, and clinical recognition may be hampered by immunosuppression such as in this case, early blood cultures, lumbar puncture, and empiric treatment with ampicillin should be initiated in all patients with suspected rhomboencephalitis if suggested by imaging and by a clinical concern for infection.
24346918 Systemic sarcoidosis induced by etanercept: first Brazilian case report. 2013 Nov The antagonists of tumor necrosis factor alpha (TNF-α) are increasingly being used in the treatment of inflammatory and autoimmune diseases. Several adverse effects of these drugs have been reported, including the paradoxical development of sarcoidosis, especially with the use of etanercept. We present the first Brazilian case report of systemic sarcoidosis induced by etanercept and a literature review.