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Arthritis and gene therapy

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https://www.readbyqxmd.com/read/27912794/a-genetic-risk-score-composed-of-rheumatoid-arthritis-risk-alleles-hla-drb1-haplotypes-and-response-to-tnfi-therapy-results-from-a-swedish-cohort-study
#1
Xia Jiang, Johan Askling, Saedis Saevarsdottir, Leonid Padyukov, Lars Alfredsson, Sebastien Viatte, Thomas Frisell
BACKGROUND: To prevent debilitating and irreversible joint damage, rheumatoid arthritis (RA) is often treated with tumor necrosis factor inhibitor (TNFi), but many patients do not respond to this costly therapy. Few predictors for response are known, and it has been proposed that genetic factors which influence the development of RA may also influence disease severity and response to therapy. Several previous studies have attempted to confirm this but results remain inconclusive. We expand on previous studies by including more RA risk alleles, and maximize power by combining them into a genetic risk score...
December 3, 2016: Arthritis Research & Therapy
https://www.readbyqxmd.com/read/27910765/gene-therapy-for-rheumatoid-arthritis
#2
Shuang Liu, Kazutaka Maeyama
With the aim of controlling disease relapse and bone deformation of individual joints, the application of gene therapy in rheumatoid arthritis (RA) has slowly progressed on a trial-and-error basis. Several new therapeutic targets have been identified in preclinical studies in animal models, although a limited number of gene-based clinical trials have been conducted. In this article, we summarize the status of gene therapy for RA by addressing issues related to innovating drug development. More disease- and target-specific preclinical tests are required to overcome the insufficient information regarding pharmacokinetics and toxicokinetics, which are related to safety issues in the field of RA gene therapy...
2016: Critical Reviews in Immunology
https://www.readbyqxmd.com/read/27906774/lessons-from-characterization-and-treatment-of-the-autoinflammatory-syndromes
#3
Ivona Aksentijevich, Michael F McDermott
PURPOSE OF REVIEW: The list of genes associated with systemic inflammatory diseases has been steadily growing because of the explosion of new genomic technologies. Significant advances in the past year have deepened our understanding of the molecular mechanisms linked to inflammation and elucidated insights on the efficacy of specific therapies for these and related conditions. We review the molecular pathogenesis of four recently characterized monogenic autoinflammatory diseases: haploinsufficiency of A20, otulipenia, a severe form of pyrin-associated disease, and a monogenic form of systemic juvenile idiopathic arthritis...
November 30, 2016: Current Opinion in Rheumatology
https://www.readbyqxmd.com/read/27885916/atic-missense-variant-affects-response-to-methotrexate-treatment-in-rheumatoid-arthritis-patients
#4
Mateusz Kurzawski, Damian Malinowski, Natalia Szarmach, Anna Nowak, Aleksandra Goryniak, Andrzej Pawlik, Marek Droździk
AIM: The study was aimed at investigation of several gene variants of folate pathway enzymes for their potential association with methotrexate (MTX) treatment response in patients with rheumatoid arthritis. PATIENTS & METHODS: Four hundred and twenty two Caucasian patients were classified as good or poor responders, and subsequently genotyped for common SNPs in DHFR, FPGS and ATIC genes. RESULTS: No significant differences were observed in case of DHFR and FGPS SNPs...
November 25, 2016: Pharmacogenomics
https://www.readbyqxmd.com/read/27870898/functional-tissue-analysis-reveals-successful-cryopreservation-of-human-osteoarthritic-synovium
#5
Mathijs G A Broeren, Marieke de Vries, Miranda B Bennink, Peter L E M van Lent, Peter M van der Kraan, Marije I Koenders, Rogier M Thurlings, Fons A J van de Loo
Osteoarthritis (OA) is a degenerative joint disease affecting cartilage and is the most common form of arthritis worldwide. One third of OA patients have severe synovitis and less than 10% have no evidence of synovitis. Moreover, synovitis is predictive for more severe disease progression. This offers a target for therapy but more research on the pathophysiological processes in the synovial tissue of these patients is needed. Functional studies performed with synovial tissue will be more approachable when this material, that becomes available by joint replacement surgery, can be stored for later use...
2016: PloS One
https://www.readbyqxmd.com/read/27849614/epipolymorphisms-associated-with-the-clinical-outcome-of-autoimmune-arthritis-affect-cd4-t-cell-activation-pathways
#6
Roberto Spreafico, Maura Rossetti, John W Whitaker, Wei Wang, Daniel J Lovell, Salvatore Albani
Multifactorial diseases, including autoimmune juvenile idiopathic arthritis (JIA), result from a complex interplay between genetics and environment. Epigenetic mechanisms are believed to integrate such gene-environment interactions, fine-tuning gene expression, and possibly contributing to immune system dysregulation. Although anti-TNF therapy has strongly increased JIA remission rates, it is not curative and up to 80% of patients flare upon treatment withdrawal. Thus, a crucial unmet medical and scientific need is to understand the immunological mechanisms associated with remission or flare to inform clinical decisions...
November 29, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27826300/treatment-with-dexamethasone-and-monophosphoryl-lipid-a-removes-disease-associated-transcriptional-signatures-in-monocyte-derived-dendritic-cells-from-rheumatoid-arthritis-patients-and-confers-tolerogenic-features
#7
Paulina A García-González, Katina Schinnerling, Alejandro Sepúlveda-Gutiérrez, Jaxaira Maggi, Lorena Hoyos, Rodrigo A Morales, Ahmed M Mehdi, Hendrik J Nel, Lilian Soto, Bárbara Pesce, María Carmen Molina, Miguel Cuchacovich, Milton L Larrondo, Óscar Neira, Diego Francisco Catalán, Catharien M Hilkens, Ranjeny Thomas, Ricardo A Verdugo, Juan C Aguillón
Tolerogenic dendritic cells (TolDCs) are promising tools for therapy of autoimmune diseases, such as rheumatoid arthritis (RA). Here, we characterize monocyte-derived TolDCs from RA patients modulated with dexamethasone and activated with monophosphoryl lipid A (MPLA), referred to as MPLA-tDCs, in terms of gene expression, phenotype, cytokine profile, migratory properties, and T cell-stimulatory capacity in order to explore their suitability for cellular therapy. MPLA-tDCs derived from RA patients displayed an anti-inflammatory profile with reduced expression of co-stimulatory molecules and high IL-10/IL-12 ratio, but were capable of migrating toward the lymphoid chemokines CXCL12 and CCL19...
2016: Frontiers in Immunology
https://www.readbyqxmd.com/read/27823620/immunomodulatory-proteins-fip-gts-and-chloroquine-induce-caspase-independent-cell-death-via-autophagy-for-resensitizing-cisplatin-resistant-urothelial-cancer-cells
#8
I-Lun Hsin, Shao-Chuan Wang, Jian-Ri Li, Tsai-Chun Ciou, Chih-Hsien Wu, Hung-Ming Wu, Jiunn-Liang Ko
BACKGROUND: Chloroquine, a lysosomal inhibitor, is used for malaria, rheumatoid arthritis, and lupus erythematosus therapy. In our previous study, FIP-gts, an immunomodulatory protein from Ganoderma tsugae, inhibited cell viability in lung cancer cells and urothelial cancer cells. Urothelial carcinoma is the most common type of bladder cancer. Cisplatin resistance is an important issue in urothelial carcinoma therapy. PURPOSE: The aim of this study is to investigate the effect of combination treatment with FIP-gts and chloroquine on cytotoxicity to resensitize the cisplatin-resistant cells...
December 1, 2016: Phytomedicine: International Journal of Phytotherapy and Phytopharmacology
https://www.readbyqxmd.com/read/27807194/therapeutic-targeting-of-the-g-csf-receptor-reduces-neutrophil-trafficking-and-joint-inflammation-in-antibody-mediated-inflammatory-arthritis
#9
Ian K Campbell, David Leong, Kirsten M Edwards, Veronika Rayzman, Milica Ng, Gabrielle L Goldberg, Nicholas J Wilson, Karen Scalzo-Inguanti, Charley Mackenzie-Kludas, Kate E Lawlor, Ian P Wicks, Lorena E Brown, Adriana Baz Morelli, Con Panousis, Michael J Wilson, Andrew D Nash, Brent S McKenzie, Arna E Andrews
G-CSF is a hemopoietic growth factor that has a role in steady state granulopoiesis, as well as in mature neutrophil activation and function. G-CSF- and G-CSF receptor-deficient mice are profoundly protected in several models of rheumatoid arthritis, and Ab blockade of G-CSF also protects against disease. To further investigate the actions of blocking G-CSF/G-CSF receptor signaling in inflammatory disease, and as a prelude to human studies of the same approach, we developed a neutralizing mAb to the murine G-CSF receptor, which potently antagonizes binding of murine G-CSF and thereby inhibits STAT3 phosphorylation and G-CSF receptor signaling...
November 2, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/27799070/capture-hi-c-identifies-a-novel-causal-gene-il20ra-in-the-pan-autoimmune-genetic-susceptibility-region-6q23
#10
Amanda McGovern, Stefan Schoenfelder, Paul Martin, Jonathan Massey, Kate Duffus, Darren Plant, Annie Yarwood, Arthur G Pratt, Amy E Anderson, John D Isaacs, Julie Diboll, Nishanthi Thalayasingam, Caroline Ospelt, Anne Barton, Jane Worthington, Peter Fraser, Stephen Eyre, Gisela Orozco
BACKGROUND: The identification of causal genes from genome-wide association studies (GWAS) is the next important step for the translation of genetic findings into biologically meaningful mechanisms of disease and potential therapeutic targets. Using novel chromatin interaction detection techniques and allele specific assays in T and B cell lines, we provide compelling evidence that redefines causal genes at the 6q23 locus, one of the most important loci that confers autoimmunity risk...
November 1, 2016: Genome Biology
https://www.readbyqxmd.com/read/27788309/the-role-of-rare-protein-coding-variants-to-anti-tnf-treatment-response-in-rheumatoid-arthritis
#11
Jing Cui, Dorothee Diogo, Eli A Stahl, Helena Canhao, Xavier Mariette, Jeffrey D Greenberg, Yukinori Okada, Dimitrios A Pappas, Robert S Fulton, Paul P Tak, Michael T Nurmohamed, Annette Lee, David E Larson, Fina Kurreeman, Tracie L Deluca, Michelle O'Laughlin, Catrina C Fronick, Lucinda L Fulton, Elaine R Mardis, Irene E van der Horst-Bruinsma, Gert-Jan Wolbink, Peter K Gregersen, Joel M Kremer, J Bart A Crusius, Niek de Vries, Tom W J Huizinga, João Eurico Fonseca, Corinne Miceli-Richard, Elizabeth W Karlson, Marieke Jh Coenen, Anne Barton, Robert M Plenge, Soumya Raychaudhuri
Objective Many rheumatoid arthritis (RA) patients have their disease controlled with anti-tumor necrosis factor alpha (anti-TNF) biologic therapies. However, a significant number of RA patients fail to respond to anti-TNF therapy. Here, we hypothesized that rare and low-frequency variants might influence anti-TNF treatment response. Methods We sequenced the coding region of 750 genes in 1,094 RA patients of European ancestry treated with anti-TNF medications. After quality control, we included 690 genes in the analysis...
October 27, 2016: Arthritis & Rheumatology
https://www.readbyqxmd.com/read/27787607/cytokine-neutralization-at-specific-cellular-source-a%C3%A2-new-therapeutic-paradigm
#12
A A Kruglov, S A Nedospasov
BACKGROUND: Currently, treatment of autoimmune diseases is based on manipulation of general control mechanisms, including those mediated by immunoregulatory cytokines. This approach is non-curative and may cause unwanted side effects due to numerous beneficial and non-redundant functions of a particular cytokine. METHODS: Techniques of reverse genetics, such as conditional gene targeting, were employed to uncover the contributions of two proinflammatory and immunomodulatory cytokines, tumour necrosis factor (TNF) and interleukin 6 (IL-6), in various disease states...
October 27, 2016: Zeitschrift Für Rheumatologie
https://www.readbyqxmd.com/read/27752357/tofacitinib-versus-methotrexate-in-rheumatoid-arthritis-patient-reported-outcomes-from-the-randomised-phase-iii-oral-start-trial
#13
Vibeke Strand, Eun Bong Lee, Roy Fleischmann, Rieke E Alten, Tamas Koncz, Samuel H Zwillich, David Gruben, Bethanie Wilkinson, Sriram Krishnaswami, Gene Wallenstein
OBJECTIVES: To compare patient-reported outcomes (PROs) in methotrexate (MTX)-naive patients (defined as no prior treatment or ≤3 doses) receiving tofacitinib versus MTX. METHODS: In the 24-month, phase III, randomised, controlled, ORAL Start trial (NCT01039688), patients were randomised 2:2:1 to receive tofacitinib 5 mg two times per day (n=373), tofacitinib 10 mg two times per day (n=397) or MTX (n=186). PROs assessed included Patient Global Assessment of disease (PtGA), pain, Health Assessment Questionnaire-Disability Index (HAQ-DI), Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) and health-related quality of life (Short Form-36 [SF-36])...
2016: RMD Open
https://www.readbyqxmd.com/read/27733572/neutrophil-biomarkers-predict-response-to-therapy-with-tumor-necrosis-factor-inhibitors-in-rheumatoid-arthritis
#14
Helen L Wright, Trevor Cox, Robert J Moots, Steven W Edwards
Neutrophils are implicated in the pathology of rheumatoid arthritis (RA), but the mechanisms regulating their activation are largely unknown. RA is a heterogeneous disease, and whereas many patients show clincal improvement during TNF inhibitor (TNFi) therapy, a significant proportion fails to respond. In vitro activation of neutrophils with agents, including TNF, results in rapid and selective changes in gene expression, but how neutrophils contribute to TNF signaling in RA and whether TNFi sensitivity involves differential neutrophil responses are unknown...
October 12, 2016: Journal of Leukocyte Biology
https://www.readbyqxmd.com/read/27726799/polyomaviruses
#15
Linda Cook
Over the last 10 years, the number of identified polyomaviruses has grown to more than 35 subtypes, including 13 in humans. The polyomaviruses have similar genetic makeup, including genes that encode viral capsid proteins VP1, 2, and 3 and large and small T region proteins. The T proteins play a role in viral replication and have been implicated in viral chromosomal integration and possible dysregulation of growth factor genes. In humans, the Merkel cell polyomavirus has been shown to be highly associated with integration and the development of Merkel cell cancers...
August 2016: Microbiology Spectrum
https://www.readbyqxmd.com/read/27695991/the-functional-variants-of-endothelial-nitric-oxide-synthase-gene-associated-with-rheumatoid-arthritis-in-turkish-adults
#16
S Pehlivan, A Aydeniz, T Sever, O Altindag, M Pehlivan, S Gursoy, S Oguzkan-Balci
This study aimed to investigate whether functional variants of endothelial nitric oxide synthase (eNOS) gene play any role in rheumatoid arthritis (RA) ethiopathogenesis and treatment in the Turkish population. Because, eNOS variants are responsible for alteration of the NO level in plasma, by reducing/increasing the endothelial NO synthesis. In the study, two eNOS gene variants (G894T and intron 4 VNTR A/B) were examined at extracted DNAs from 65 peripheral blood cell of RA patients. For the control, blood samples obtained from 70 healthy persons were studied...
September 30, 2016: Clinical Rheumatology
https://www.readbyqxmd.com/read/27638722/genetic-markers-as-therapeutic-target-in-rheumatoid-arthritis-a-game-changer-in-clinical-therapy
#17
A M Mohamed Thoufic Ali, S Vino
Rheumatoid arthritis (RA) is a chronic, inflammatory, multi-systemic autoimmune disease unremitted by genetic and environmental factors. The factors are crucial but inadequate in the development of disease; however, these factors can be representative of potential therapeutic targets and response to clinical therapy. Insights into the contribution of genetic risk factors are currently in progress with studies querying the genetic variation, their role in gene expression of coding and non-coding genes and other mechanisms of disease...
November 2016: Rheumatology International
https://www.readbyqxmd.com/read/27636122/association-of-63-91-length-polymorphism-in-the-dhfr-gene-major-promoter-with-toxicity-of-methotrexate-in-patients-with-rheumatoid-arthritis
#18
Biljana Jekic, Dubravka Vejnovic, Vera Milic, Nela Maksimovic, Tatjana Damnjanovic, Vera Bunjevacki, Ivana Novakovic, Ljiljana Lukovic, Nemanja Damjanov, Maja Krajinovic
AIM: Our aim was to explore the influence of 9-bp insertion/deletion and variable number of 9 bp elements (63/91) length polymorphism in noncoding interfering RNA and major promoter of DHFR gene on methotrexate (MTX) efficacy and toxicity in patients with rheumatoid arthritis (RA). PATIENTS & METHODS: Response to the MTX therapy and adverse effects were estimated in 243 RA patients genotyped for the selected polymorphism. RESULTS: The presence of allele 1 of analyzed polymorphism had significant protective effect against MTX toxicity (odds ratio: 0...
October 2016: Pharmacogenomics
https://www.readbyqxmd.com/read/27633793/nlrp12-autoinflammatory-disease-a-chinese-case-series-and-literature-review
#19
Min Shen, Lin Tang, Xiaochun Shi, Xiaofeng Zeng, Qingping Yao
As one of the systemic autoinflammatory diseases (SAIDs), the nucleotide-binding oligomerization domain-like receptor protein (NLRP)12 autoinflammatory disease (NLRP12-AD) is an autosomal dominant disorder associated with NLRP12 mutation. SAIDs have been hardly reported in the Chinese population, and NLRP12-AD has been reported only in Caucasians. We report the first case series of NLRP12-AD in the Chinese population coupled with literature review. Three Han Chinese adult patients with clinical phenotype suggestive of NLRP12-AD carrying NLRP12 variants were treated by the authors in 2015...
September 16, 2016: Clinical Rheumatology
https://www.readbyqxmd.com/read/27601627/low-density-granulocytes-functionally-distinct-immature-neutrophils-in-rheumatoid-arthritis-with-altered-properties-and-defective-tnf-signalling
#20
Helen L Wright, Fatima A Makki, Robert J Moots, Steven W Edwards
Our aim was to determine whether rheumatoid arthritis (RA) low-density granulocytes (LDGs) are functionally different from RA neutrophils. LDGs from 32 RA patients were characterized using flow cytometry and quantitative PCR (qPCR). RNA sequencing (RNA-Seq) was carried out on paired RA LDGs and neutrophils (n = 4) and validated using qPCR. Functional assays included chemotaxis, phagocytosis, reactive oxygen species (ROS) production, cell-cycle analysis, apoptosis, neutrophil extracellular trap (NET)osis, and measurement of cytokine production (n ≥ 5 paired RA LDGs/neutrophils)...
September 6, 2016: Journal of Leukocyte Biology
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