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ID PMID Title PublicationDate abstract
25959608 TNF signals are dispensable for the generation of CD23+ CD21/35-high CD1d-high B cells in 2015 Aug Tumor necrosis factor (TNF) is a key cytokine in rheumatoid arthritis (RA) pathogenesis, as underscored by the clinical effectiveness of TNF antagonists. While several of TNF's key targets in RA are well understood, its many pleiotropic effects remain to be elucidated. TNF-transgenic mice develop inflammatory-erosive arthritis associated with disruption of draining lymph node histology and function, and accumulation of B cells with unique phenotypic and functional features consistent with contribution to pathogenesis (B cells in inflamed nodes, Bin). Bin cell induction depends on the inflamed microenvironment, but the specific signals are unknown. Using anti-TNF treatment and TNF-receptor-deficient mice, here we show that Bin cells are induced and maintained independently of B cell-intrinsic TNF signals.
26617214 Certolizumab treatment during late pregnancy in patients with rheumatic diseases: Low drug 2016 May OBJECTIVE: Due to reduction of immune-suppressive drugs, patients with rheumatic diseases can experience an increase in disease activity during pregnancy. In such cases, TNF-inhibitors may be prescribed. However, monoclonal antibodies with the Fc moiety are actively transported across the placenta, resulting in therapeutic drug levels in the newborn. As certolizumab (CZP) lacks the Fc moiety, it may bear a lower risk for the child. METHOD: We report a case series of thirteen patients (5 with rheumatoid arthritis and 8 with spondyloarthritis) treated with CZP during late pregnancy to control disease activity. RESULT: CZP measured in cord blood of eleven infants ranged between undetectable levels and 1μg/mL whereas the median CZP level of maternal plasma was 32.97μg/mL. Three women developed an infection during the third trimester, of whom one had a severe infection and one had an infection that resulted in a pre-term delivery. During the postpartum period, 6 patients remained on CZP while breastfeeding. CZP levels in the breast milk of two breastfeeding patients were undetectable. CONCLUSION: The lack of the active transplacental transfer of CZP gives the possibility to treat inflammatory arthritis during late gestation without potential harm to the newborn. However, in pregnant women treated with TNF-inhibitors and prednisone, attention should be given to the increased susceptibility to infections, which might cause prematurity. CZP treatment can be continued while breastfeeding.
26768725 Nanostructured lipid carrier mediates effective delivery of methotrexate to induce apoptos 2016 Feb 29 Present study was designed to develop novel nano-structured lipid carriers (NLCs) formulated by lipid mixture and chemical permeation enhancer-based hydrogel for an effective transdermal delivery of methotrexate (MTX). The prepared NLCs were optimized with different preparative variables such as particle size <200 nm, poly-dispersity index (PDI) <0.2, and entrapment efficiency ∼85%. The drug incorporated into NLCs-gel base showed excellent spread ability without any grittiness during rheological behavior and texture profile analysis. The in vitro release showed biphasic release pattern with initial fast release of drug (>50%) in 8h followed by sustained release (up to 85%) by the end of 48thh. NLCs showed greater uptake in human hyper-proliferative keratinocyte cell line (HaCaT). NLCs showed increased expression of inflammatory mediators as well asapoptosis in U937 monocytic cells. The greater expression of pro-apoptotic gene Bim regulated by NF-κB-IkB and FOXO1 is supported by fold regulations calculated for various apoptotic and pro-inflammatory biomarkers carried out by RT-PCR. The immunocytochemistry to detect IL-6 expression and immunofluorescence assay suggested that induced apoptosis occurs in experimentally induced in vitro arthritis model treated with NLCs-MTX. We saw reduced inflammation and triggered apoptosis through NF-κB & FOXO1 pathways induced by MTX loaded NLCs in rheumatoid arthritic cells. In addition, formulated NLCs exhibit better skin permeation with higher permeation flux & enhancement ratio as shown by confocal laser scanning microscopy (CLSM). Moreover, histopathological examinations of skin are suggestive of safety potential of NLCs.
26567045 Anti-inflammatory effects of N-acylethanolamines in rheumatoid arthritis synovial cells ar 2015 Nov 14 INTRODUCTION: The endocannabinoid system modulates function of immune cells and mesenchymal cells such as fibroblasts, which contribute to cartilage destruction in rheumatoid arthritis (RA). The aim of the study was to determine the influence of N-acylethanolamines anandamide (AEA), palmitoylethanolamine (PEA) and oleylethanolamine (OEA) on several features of arthritic inflammation in vitro (human material) and in vivo (a mouse model). METHODS: Immunofluorescence and western blotting were used to detect cannabinoid receptors and related enzymes. Cytokines and MMP-3 were measured by ELISA. Intracellular signaling proteins were detected by proteome profiling. Proliferation was quantified by CTB reagent. Adhesion was assessed by the xCELLigence system. After onset of collagen type II arthritis, mice were treated daily with the FAAH inhibitor JNJ1661010 (20 mg/kg) or vehicle. RESULTS: IL-6, IL-8 and MMP-3 (determined only in synovial fibroblasts (SFs)) were downregulated in primary synoviocytes and SFs of RA and OA after AEA, PEA and OEA treatment. In SFs, this was due to activation of TRPV1 and TRPA1 in a COX-2-dependent fashion. FAAH inhibition increased the efficacy of AEA in primary synoviocytes but not in SFs. The effects of OEA and PEA on SFs were diminished by FAAH inhibition. Adhesion to fibronectin was increased in a CB1-dependent manner by AEA in OASFs. Furthermore, elevation of endocannabinoids ameliorated collagen-induced arthritis in mice. CONCLUSIONS: N-acylethanolamines exert anti-inflammatory effects in SFs. A dual FAAH/COX-2 inhibitor, increasing N-acylethanolamine levels with concomitant TRP channel desensitization, might be a good candidate to inhibit the production of proinflammatory mediators of synovial cells and to reduce erosions.
25636536 Increased frequency of delayed type hypersensitivity to metals in patients with connective 2015 BACKGROUND: Connective tissue disease (CTD) is a group of inflammatory disorders of unknown aetiology. Patients with CTD often report hypersensitivity to nickel. We examined the frequency of delayed type hypersensitivity (DTH) (Type IV allergy) to metals in patients with CTD. METHODS: Thirty-eight patients; 9 with systemic lupus erythematosus (SLE), 16 with rheumatoid arthritis (RA), and 13 with Sjögren's syndrome (SS) and a control group of 43 healthy age- and sex-matched subjects were included in the study. A detailed metal exposure history was collected by questionnaire. Metal hypersensitivity was evaluated using the optimised lymphocyte transformation test LTT-MELISA(®) (Memory Lymphocyte Immuno Stimulation Assay). RESULTS: In all subjects, the main source of metal exposure was dental metal restorations. The majority of patients (87%) had a positive lymphocyte reaction to at least one metal and 63% reacted to two or more metals tested. Within the control group, 43% of healthy subjects reacted to one metal and only 18% reacted to two or more metals. The increased metal reactivity in the patient group compared with the control group was statistically significant (P<0.0001). The most frequent allergens were nickel, mercury, gold and palladium. CONCLUSIONS: Patients with SLE, RA and SS have an increased frequency of metal DTH. Metals such as nickel, mercury and gold are present in dental restorative materials, and many adults are therefore continually exposed to metal ions through corrosion of dental alloys. Metal-related DTH will cause inflammation. Since inflammation is a key process in CTDs, it is possible that metal-specific T cell reactivity is an etiological factor in their development. The role of metal-specific lymphocytes in autoimmunity remains an exciting challenge for future studies.
27587881 Evidence of epistatic interaction between DPP4 and CCR6 in patients with rheumatoid arthri 2016 Dec OBJECTIVE: A recent genome-wide association study identified that genetic variants in DPP4 and CCR6 are connected with a risk of RA in the Han Chinese population. The aim of this study was to estimate the epistatic interaction between DPP4 and CCR6 in RA. METHODS: Two single-nucleotide polymorphisms identified in a Han Chinese genome-wide association study (rs12617656 in DPP4, rs1854853 in CCR6) were genotyped. Logistic regression was used to estimate the multiplicative interaction and the additive interaction was analysed by 2 × 2 factorial design. RESULTS: A total of 1224 subjects (377 RA patients, 847 healthy controls) were included in the initial analysis. Additionally, 600 patients with lupus arthritis were included for comparison. Significant multiplicative interaction between DPP4 and CCR6 was observed in RA [codominant model: odds ratio (OR) = 1.49, P = 0.003]. The epistatic effect seems to be stronger in ACPA-positive RA (codominant model: OR = 1.66, P = 0.001). However, no significant multiplicative interactions were observed in ACPA-negative RA or lupus arthritis. Additive interaction analysis showed a significant epistatic effect, but only in ACPA-positive RA [attributable proportion due to interaction = 0.48 (95% CI 0.10, 0.85)]. A further replication study of an independent cohort (476 subjects) found similar results. Pooled results confirmed that there was significant interaction between DPP4 and CCR6 on both the multiplicative and additive scales. CONCLUSION: The study suggests that a genetic interaction between DPP4 and CCR6 is involved in RA susceptibility. Furthermore, these findings highlight Th17 cell response as an important contributor in the pathogenesis of RA.
27908288 Granulocyte macrophage colony-stimulating factor receptor α expression and its targeting 2016 Dec 1 BACKGROUND: Blockade of granulocyte macrophage colony-stimulating factor (GM-CSF) and its receptor (GM-CSFRα) is being successfully tested in trials in rheumatoid arthritis (RA) with clinical results equivalent to those found with neutralization of the current therapeutic targets, TNF and IL-6. To explore further the role of GM-CSF as a pro-inflammatory cytokine, we examined the effect of anti-GM-CSFRα neutralization on myeloid cell populations in antigen-driven arthritis and inflammation models and also compared its effect with that of anti-TNF and anti-IL-6. METHODS: Cell population changes upon neutralization by monoclonal antibodies (mAbs) in the antigen-induced arthritis (AIA) and antigen-induced peritonitis (AIP) models were monitored by flow cytometry and microarray. Adoptive transfer of monocytes into the AIP cavity was used to assess the GM-CSF dependence of the development of macrophages and monocyte-derived dendritic cells (Mo-DCs) at a site of inflammation. RESULTS: Therapeutic administration of a neutralizing anti-GM-CSF mAb, but not of an anti-colony-stimulating factor (anti-CSF)-1 or an anti-CSF-1R mAb, ameliorated AIA disease. Using the anti-GM-CSFRα mAb, the relative surface expression of different inflammatory myeloid populations was found to be similar in the inflamed tissues in both the AIA and AIP models; however, the GM-CSFRα mAb, but not neutralizing anti-TNF and anti-IL-6 mAbs, preferentially depleted Mo-DCs from these sites. In addition, we were able to show that locally acting GM-CSF upregulated macrophage/Mo-DC numbers via GM-CSFR signalling in donor monocytes. CONCLUSIONS: Our findings suggest that GM-CSF blockade modulates inflammatory responses differently to TNF and IL-6 blockade and may provide additional insight into how targeting the GM-CSF/GM-CSFRα system is providing efficacy in RA.
26050632 10-Hydroxy-2-decenoic acid inhibiting the proliferation of fibroblast-like synoviocytes by 2015 Sep To reveal the mechanism of 10H2DA inhibiting the proliferation of fibroblast-like synoviocytes (FLSs) of RA patients. Cell proliferation, HDAC activity and histone acetylation level of FLS cells treated with 10H2DA were detected by MTT assay, Colorimetric HDAC Activity Assay and Western-blot. Different genes in FLS cells from RA patients were primary cultured and treated with 10H2DA. They were then screened by Human Transcriptome 1.0 ST microarrays and verified by real-time PCR. The results showed dose-dependent and time-dependent decreases in cell viability and HDAC activity in FLSs treated with 10H2DA, and time-dependent induction in the acetylation of H3 and H4 at the same time. 697 different genes were identified by HTA 1.0. The expressions of 7 target genes of the PI3K-AKT pathway were decreased and 4 target genes of cytokine-cytokine receptor interaction were increased verified by real-time PCR. These results imply that 10H2DA is a potential HDACI which inhibits the proliferation of FLS cells by PI3K-AKT pathway.
25579091 Evaluation of drug-drug interaction between the novel cPLA2 inhibitor AK106-001616 and met 2015 1. Drug interaction potential between AK106-001616, a novel cytosolic phospholipase A2 inhibitor, and methotrexate (MTX) in rheumatoid arthritis patients was investigated. This trial is registered with ClinicalTrials.gov, number NCT00902369. 2. In the clinical study, the 90% confidence intervals (CIs) for the geometric mean ratio (GMR) of AUC0-t of MTX administered after AK106-001616 200 mg compared to the MTX without AK106-001616 were within 80-125%. However, administration of AK106-001616 at doses of 400 and 600 mg exceeded the 125% threshold. As small but statistically significant increases in AUC0-t were observed, we investigated the mechanism for this drug-drug interaction between MTX and AK106-001616. 3. In vitro, AK106-001616 inhibited OAT1 (IC50 = 18.4 μM, Ki = 33.6 μM) in a non-competitive manner and OAT3 (IC50 = 1.80 μM, Ki = 1.49 μM) in a competitive manner. Both transporters are involved in MTX transport in renal proximal tubules. 4. AK106-001616 has a weak drug interaction with MTX. In vitro studies provide a mechanistic understanding of the in vivo inhibition of transporters by AK106-001616.
25245953 Changes in regulatory B cells and their relationship with rheumatoid arthritis disease act 2015 Aug Regulatory subsets of B cells (Bregs) modulate immune responses in autoimmunity, cancer, and other inflammation diseases. In the present study, we investigated the numbers of circulating Breg cells in patients with rheumatoid arthritis (RA). We evaluated 59 RA patients and 25 healthy controls. CD19(+)CD5(+)CD1d(hi) B cells and granzyme B-secreting B cells (CD19(+)CD5(+)GzmB(+)) were analyzed by flow cytometry in peripheral blood mononuclear cells. We detected serum interleukin 10 (IL-10), interleukin 21 (IL-21), granzyme B (GzmB) using enzyme-linked immunosorbent assay (ELISA). Compared to control subjects, we found a decreased proportion of CD19(+)CD5(+)CD1d(hi) B cells in RA patients. The number of CD19(+)CD5(+)CD1d(hi) B cells negatively correlated with DAS28 (P < 0.05). Moreover, serum IL-10 and IL-21 concentrations were significantly lower in RA patients compared to healthy controls (P < 0.05). Conversely, the number of CD19(+)CD5(+)GzmB(+) B cells was significantly higher in RA patients (P < 0.05), and the number of CD19(+)CD5(+)GzmB(+) B cells did not correlate with DAS28, IL-21, or GzmB (P > 0.05, all). Interestingly, IL-21 and GzmB levels positively correlated in RA patients (P < 0.05). Our data indicate that CD19(+)CD5(+)CD1d(hi) B cells influence RA disease activity. CD19(+)CD5(+)GzmB(+) B cells may be involved in RA development and progression. Our data strongly suggest a role for Bregs in RA, and Bregs may be a viable therapeutic strategy for RA disease.
26669919 Safety and Efficacy of Open-label Subcutaneous Ixekizumab Treatment for 48 Weeks in a Phas 2016 Feb OBJECTIVE: To evaluate ixekizumab, an anti-interleukin 17A monoclonal antibody, for safety and effectiveness through 64 weeks in biologic-naive and tumor necrosis factor-inadequate responder (TNF-IR) patients with rheumatoid arthritis. METHODS: Patients completing the 16-week double-blind period of a phase II study were eligible to enter the open-label extension (OLE) for an additional 48 weeks of ixekizumab treatment. After a treatment hiatus between weeks 10 to 16, 232 biologic-naive and 158 TNF-IR patients entered the OLE with all patients receiving 160 mg ixekizumab at weeks 16, 18, and 20, and then every 4 weeks through Week 64. RESULTS: A total of 201 (87%) biologic-naive and 99 (62%) TNF-IR patients completed the OLE. Treatment-emergent adverse events (AE) occurred in 168 (72%) biologic-naive and 115 (73%) TNF-IR patients during the OLE. Most AE were mild to moderate in severity and did not lead to study discontinuation. Serious AE (SAE) occurred in 17 (7%) biologic-naive patients, including 5 (2%) serious infections and 2 (1%) deaths. SAE occurred in 18 (11%) TNF-IR patients, including 4 (3%) serious infections and 1 (1%) death. No mycobacterial or invasive fungal infections were reported. Clinical responses [American College of Rheumatology (ACR) 20, ACR50, ACR70, and 28-joint Disease Activity Score with C-reactive protein] observed at Week 16 were maintained or improved through Week 64. CONCLUSION: Ixekizumab was well tolerated, and safety findings in the OLE were consistent overall with those in the double-blind period of this study. Clinical improvements observed with ixekizumab through Week 16 were maintained or improved in patients participating in the OLE through Week 64. TRIAL REGISTRATION NUMBER: NCT00966875.
25221852 Relationship between SNPs and expression level for candidate genes in rheumatoid arthritis 2015 OBJECTIVES: The study of polymorphisms of genes differentially expressed may lead to the identification of putative causal genetic variants in multifactorial diseases such as rheumatoid arthritis (RA). Based on preceding transcriptomic results, we genotyped 10 single nucleotide polymorphisms (SNPs) belonging to six genes (S100A8, RNASE2, PGLYRP1, RUNX3, IL2RB, and LY96) showing the highest fold change (> 1.9) when level of expression was compared between RA patients and controls. These SNPs were then analysed to evaluate their role in RA. METHOD: The relationship between gene expression and genotypes of SNPs was first investigated by Kruskal-Wallis and Mann-Whitney tests in RA patients and controls. The genetic association of these SNPs with RA were then analysed using family-based association tests in trio families. RESULTS: We found that RNASE2 gene expression was related to rs2013109 genotypes in 14 RA patients (p = 0.030). The association study in a discovery sample of 200 French trio families revealed a significant association with RA for one SNP, PGLYRP1-rs2041992 (p = 0.019); this association was stronger in trios where RA patients carried the HLA-DRB1 shared epitope (SE) (p = 0.003). However, this association was not found in a replication sample of 240 European trio families (p = 0.6). CONCLUSIONS: Family-based association tests did not reveal an association between RA and any SNP of the candidate genes tested. However, RNASE2 gene expression was differentially expressed in RA patients considering a sequence polymorphism. This result led us to highlight the potential disease-specific regulation for this candidate gene in RA.
26359667 Bioinformatics-Based Identification of MicroRNA-Regulated and Rheumatoid Arthritis-Associa 2015 MicroRNAs (miRNAs) act as epigenetic markers and regulate the expression of their target genes, including those characterized as regulators in autoimmune diseases. Rheumatoid arthritis (RA) is one of the most common autoimmune diseases. The potential roles of miRNA-regulated genes in RA pathogenesis have greatly aroused the interest of clinicians and researchers in recent years. In the current study, RA-related miRNAs records were obtained from PubMed through conditional literature retrieval. After analyzing the selected records, miRNA targeted genes were predicted. We identified 14 RA-associated miRNAs, and their sub-analysis in 5 microarray or RNA sequencing (RNA-seq) datasets was performed. The microarray and RNA-seq data of RA were also downloaded from NCBI Gene Expression Omnibus (GEO) and Sequence Read Archive (SRA), analyzed, and annotated. Using a bioinformatics approach, we identified a series of differentially expressed genes (DEGs) by comparing studies on RA and the controls. The RA-related gene expression profile was thus obtained and the expression of miRNA-regulated genes was analyzed. After functional annotation analysis, we found GO molecular function (MF) terms significantly enriched in calcium ion binding (GO: 0005509). Moreover, some novel dysregulated target genes were identified in RA through integrated analysis of miRNA/mRNA expression. The result revealed that the expression of a number of genes, including ROR2, ABI3BP, SMOC2, etc., was not only affected by dysregulated miRNAs, but also altered in RA. Our findings indicate that there is a close association between negatively correlated mRNA/miRNA pairs and RA. These findings may be applied to identify genetic markers for RA diagnosis and treatment in the future.
26199453 Final 10-year effectiveness and safety results from study DE020: adalimumab treatment in p 2015 Dec OBJECTIVE: To evaluate the long-term effectiveness and safety of 10 years of adalimumab (ADA) treatment in DMARD-refractory RA patients and to analyse efficacy based on RF status and baseline disease duration. METHODS: DE020 was a multicentre, phase 3, open-label continuation study. Adult RA patients who received s.c. ADA (40 mg every other week or monthly) in one of four early assessment studies could receive ADA for ≤10 years in DE020. Assessments included the 28-joint DAS with CRP (DAS28-CRP), Simplified Disease Activity Index (SDAI), HAQ Disability Index (HAQ-DI) and safety as events per 100 patient-years. RESULTS: Of 846 enrolled patients, mean age at baseline was 55.6 years, 78.1% were women, mean disease duration was 11.7 years and 27.0% were RF(-). Among 286 (33.8%) patients who completed 10 years of ADA, 168/236 (71.2%) achieved DAS28-CRP ≤3.2, 101/238 (42.4%) achieved HAQ-DI <0.5 and 90/241 (37.3%) achieved DAS28-CRP ≤3.2 plus HAQ-DI <0.5. DAS28-CRP- or SDAI-based remission was observed in 135/236 (57.2%) and 70/236 (29.7%) patients, respectively. Effectiveness outcomes were similar regardless of RF status. Higher proportions of patients with shorter vs longer baseline disease duration (≤2 vs >2 years) achieved HAQ-DI <0.5 (60.6% vs 39.5%; P = 0.023) and DAS28-CRP ≤3.2 plus HAQ-DI <0.5 (58.1% vs 32.5%; P = 0.006). Adverse events (317.2 events per 100 patient-years) during ADA exposure were consistent with the expected safety profile for TNF inhibitors. CONCLUSION: ADA led to sustained clinical and functional responses in the 33.8% of treatment-refractory RA patients who completed 10 years of treatment. Patients with shorter disease duration achieved better outcomes, highlighting the need for early treatment. No unexpected safety findings were observed. TRIAL REGISTRATION: ClinicalTrials.gov, http://www.clinicaltrials.gov, NCT00195650.
26382317 Health-related quality of life in midlife women in Qatar: relation to arthritis and sympto 2016 Mar OBJECTIVE: The prevalence of osteoarthritis (OA) and rheumatoid arthritis (RA) has been poorly documented in the Middle East and North African region, including the State of Qatar. Given that musculoskeletal pain is commonly reported among midlife women, we evaluated the association between self-report of either OA or RA and health-related quality of life (HRQoL) among midlife women in Qatar. In addition, HRQoL among women in Qatar was compared with that of women in the Study of Women's Health Across the Nation (SWAN). METHODS: A cross-sectional study was conducted among 841 women 40 to 60 years recruited from primary care centers in Qatar. Face-to-face interviews were conducted and included measures of self-reported OA and RA, health-related symptom experience, and HRQoL using the SF-36 health survey. RESULTS: Most women were obese (75.5%) and reported being bothered by aches and stiffness in joints (71.6%). Prevalence of self-reported OA and RA was 4.8% and 4.3%, respectively. OA was significantly associated with reduced physical function (adjusted odds ratio [OR], 2.97; P=0.003). RA was also significantly related to reduced physical function (adjusted OR, 2.94; P = 0.01) and role physical (adjusted OR, 2.67; P = 0.01). When compared with women from the SWAN, women from the current study had significantly lower mean scores for bodily pain (53.0 vs. 68.9, P = 0.0001) and for vitality (49.9 vs. 54.8, P = 0.0001). CONCLUSIONS: Self-report of OA or RA was associated with significant disability in our sample. Because symptoms of aches and stiff joints were so frequently reported, arthritis may be under-diagnosed, especially given the high rates of obesity observed.
27731365 Intraarticular overexpression of Smad7 ameliorates experimental arthritis. 2016 Oct 12 Rheumatoid arthritis (RA) and Crohn's disease (CD) are autoimmune disorders with a crosstalk between their pathogenesis such as increased expression of TNF in the target organs. Despite a successful clinical trial with an oral Smad7 antisense oligonucleotide in CD, intraarticular (i.a.) modulation of Smad7 expression has not been performed in rheumatoid joint yet. In this study, contradictory to the findings in CD mucosa, higher levels of pSmad2/3 were found in RA synovium. In vitro experiments with synovial fibroblasts revealed that higher acetylated Smad7 expression was associated with lower activation status. Abundant expression of synovial pSmad2/3 with increased levels during the progression of arthritis was detected in collagen-induced arthritis (CIA) mice. To prove the concept that overexpressing Smad7 as a therapeutic strategy in rheumatoid joint, the i.a. injection of lentiviral vectors carrying Smad7 (LVSmad7) was carried out in CIA mice. In LVSmad7-injected joints, there were lower arthritis and histological scores with less synovitis, synovial hyperplasia and erosion on cartilage and bone as well as reduced IL-17 and TNF expression levels in comparison with other control groups. In conclusion, we demonstrate that lentiviral vector-mediated i.a. overexpression of Smad7 can ameliorate rheumatoid joint, implicating a pharmacological development of Smad7-based molecular strategy in RA.
26631094 Design, Synthesis and In Vitro Release Studies of Co-Drugs for Rheumatoid Arthritis. 2015 BACKGROUND: Rheumatoid arthritis (RA) is an autoimmune disease that results in a chronic, systemic inflammation that may affect many tissues and organs, but principally the synovial joints. The tendency for joint destruction is greatest in the early stages of disease hence current trend is to introduce a disease-modifying anti-rheumatic drug (DMARD) immediately after the diagnosis of RA in a step- up approach which is generally followed by its combination with a corticosteroid or NSAID. OBJECTIVE: Hydroxychloroquine (HCQ) is a slow acting DMARD used in the early stage of RA. NSAIDs if given in combination with HCQ would provide immediate symptomatic relief from pain and inflammation even before HCQ starts showing its disease modifying effects. Long half life of HCQ results in its accumulation in the body while frequent intake of NSAIDs results in severe GI side effects. Present project aims at minimizing these shortcomings by designing co-drugs of HCQ and NSAIDs as a potential combination RA therapy. METHOD: Synthesis of two co-drugs was achieved by CDI coupling, followed by their spectral characterization. In vitro release kinetics was studied by HPTLC in aqueous buffers and tissue homogenates of upper GIT. RESULTS: Prodrugs were resistant to hydrolysis in buffers (pH 1.2 and 7.4) and stomach homogenates of Wistar rat but 32- 65% hydrolysis was observed in small intestinal homogenates. CONCLUSION: We propose that the mutual prodrug strategy of a DMARD with NSAID could be useful in initial management of RA wherein NSAIDs would produce their anti-inflammatory effect and simultaneously the process of joint reconstruction by hydroxychloroquine could be initiated.
26660188 Quantitation of Teriflunomide in Human Serum/Plasma Across a 40,000-Fold Concentration Ran 2016 Leflunomide is a prodrug used primarily for treatment of rheumatoid arthritis. The active metabolite, teriflunomide (A77 1726), inhibits the enzyme dihydroorotate dehydrogenase and thereby reduces the synthesis of pyrimidine ribonucleotides. Teriflunomide is also administered directly and finds use in treating multiple sclerosis. Therapeutic concentrations are generally in the tens of μg/mL serum or plasma and, due to adverse effects and the time required to reach steady state, therapeutic drug monitoring is beneficial. The drug is also a potential teratogen. A method was developed and validated to quantify the drug teriflunomide over a 40,000-fold concentration range of 5 ng/mL to 200 μg/mL in serum or plasma. This is accomplished by dividing the quantitative range into two separate but overlapping regions; a high curve and a low curve range. Samples are evaluated first against the high curve after a 100-fold dilution of the sample extract. Samples falling below the upper curve region are evaluated again without dilution and quantified, if possible, against the low curve calibration standards. Appropriate choice of a concentration for the deuterated internal standard (D4-teriflunomide) allows for a single, identical, extraction procedure to be performed for both curve regions but with the dilution performed for high curve samples. The method is rugged and reliable with good accuracy and precision statistics.
26292631 Prevalence of dyslipidemia in Japanese patients with rheumatoid arthritis and effects of a 2015 Nov Few studies have examined dyslipidemia in patients with rheumatoid arthritis (RA), especially in Japanese cohorts. The aims of this study were to investigate the lipid profiles of RA patients, to assess the relationships between lipid profiles and RA activity and treatment, and to elucidate the effects of HMG-CoA reductase inhibitors (statins) in Japanese patients with RA. A multicenter observational study was conducted in 488 patients with RA. Serum total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) levels, and RA activity as assessed by disease activity score 28 (DAS28), and treatment for RA were analyzed retrospectively. In statin-treated patients, drug efficacy was also analyzed. The prevalence of hyper LDL-C, hyper TG, and hypo HDL-C were 29.3, 24.2, and 10.2%, respectively, and the overall prevalence of dyslipidemia was 56.5%. The level of HDL-C was inversely correlated with DAS28. Patients treated with low-dose glucocorticoids showed significantly higher levels of HDL-C and lower TC/HDL-C ratios compared with patients not receiving glucocorticoid treatment. Conversely, patients treated with biologic agents showed significantly higher levels of LDL-C, lower levels of HDL-C, and higher TC/HDL-C ratios. Atorvastatin significantly improved lipid profiles after a few months of treatment. The prevalence of dyslipidemia in Japanese patients with RA is higher than that in the non-RA population. Our result suggests that controlling RA disease activity might improve lipid profiles and eventually lower cardiovascular risk. Low-dose atorvastatin was effective for treatment of dyslipidemia in RA patients but had no apparent effect on RA disease activity.
25736355 Evaluation of the pharmacokinetic equivalence and 54-week efficacy and safety of CT-P13 an 2015 OBJECTIVES: To demonstrate the pharmacokinetic equivalence of CT-P13 and its innovator infliximab (IFX) in Japanese patients with rheumatoid arthritis (RA), and to compare the efficacy and safety of these drugs, administered for 54 weeks. METHODS: In a randomized, double-blind, parallel-group, multicenter study, 3 mg/kg of CT-P13 or IFX, in combination with methotrexate (MTX) (6-16 mg/week), was administered for 54 weeks to Japanese active RA patients with an inadequate response to MTX, to demonstrate the pharmacokinetic equivalence, based on the area under the curve (AUC(Ï„)) (weeks 6-14) and C(max) (week 6) of these drugs, and to compare their efficacy and safety. RESULTS: The CT-P13-to-IFX ratios (90% confidence intervals) of the geometric mean AUC(Ï„) and C(max) values in patients negative for antibodies to infliximab at week 14 were 111.62% (100.24-124.29%) and 104.09% (92.12-117.61%), respectively, demonstrating the pharmacokinetic equivalence of these drugs. In the full analysis set, CT-P13 and IFX showed comparable therapeutic effectiveness, as measured by the American College of Rheumatology, Disease Activity Score in 28 joints, the European League Against Rheumatism, and other efficacy criteria, at weeks 14 and 30. The incidence of adverse events was similar for these drugs. CONCLUSION: CT-P13 and IFX, administered at a dose of 3 mg/kg in combination with MTX to active RA patients, were pharmacokinetically equivalent and comparable in efficacy and safety.