scholarly journals Identification of New, Functionally Relevant Mutations in the Coding Regions of the Human Fos and Jun Proto-Oncogenes in Rheumatoid Arthritis Synovial Tissue

Life ◽  
2020 ◽  
Vol 11 (1) ◽  
pp. 5
Author(s):  
René Huber ◽  
Sandra Augsten ◽  
Holger Kirsten ◽  
Roland Zell ◽  
Axel Stelzner ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Joint Inflammation ◽  
Germline Mutations ◽  
The Novel ◽  
Coding Regions ◽  
Cleavage Assay ◽  
Inflammatory Proteins ◽  
Functional Relevance ◽  
Nih 3T3 ◽  
Synovial Membranes

In rheumatoid arthritis (RA), the expression of many pro-destructive/pro-inflammatory proteins depends on the transcription factor AP-1. Therefore, our aim was to analyze the presence and functional relevance of mutations in the coding regions of the AP-1 subunits of the fos and jun family in peripheral blood (PB) and synovial membranes (SM) of RA and osteoarthritis patients (OA, disease control), as well as normal controls (NC). Using the non-isotopic RNAse cleavage assay, one known polymorphism (T252C: silent; rs1046117; present in RA, OA, and NC) and three novel germline mutations of the cfos gene were detected: (i) C361G/A367G: Gln121Glu/Ile123Val, denoted as “fos121/123”; present only in one OA sample; (ii) G374A: Arg125Lys, “fos125”; and (iii) C217A/G374A: Leu73Met/Arg125Lys, “fos73/125”, the latter two exclusively present in RA. In addition, three novel somatic cjun mutations (604–606ΔCAG: ΔGln202, “jun202”; C706T: Pro236Ser, “jun236”; G750A: silent) were found exclusively in the RA SM. Tansgenic expression of fos125 and fos73/125 mutants in NIH-3T3 cells induced an activation of reporter constructs containing either the MMP-1 (matrix metalloproteinase) promoter (3- and 4-fold, respectively) or a pentameric AP-1 site (approximately 5-fold). Combined expression of these two cfos mutants with cjun wildtype or mutants (jun202, jun236) further enhanced reporter expression of the pentameric AP-1 construct. Finally, genotyping for the novel functionally relevant germline mutations in 298 RA, 288 OA, and 484 NC samples revealed no association with RA. Thus, functional cfos/cjun mutants may contribute to local joint inflammation/destruction in selected patients with RA by altering the transactivation capacity of AP-1 complexes.

HYPERBARIC OXYGENATION IN COMPLEX THERAPY OF RHEUMATOID ARTHRITIS IN PATIENTS WITH CONCOMITANT ANEMIA

2020 ◽  
pp. 42-52
Author(s):  
T.S. Golubtsova ◽  
A.B. Peskov ◽  
S.V. Peskova ◽  
M.P. Markevich ◽  
V.V. Gnoevykh ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Chronic Inflammation ◽  
Hyperbaric Oxygenation ◽  
Joint Inflammation ◽  
Primary Objective ◽  
Hemoglobin Level ◽  
Standard Scheme ◽  
Comparison Results ◽  
Complex Therapy ◽  
Activity Indices

Anemia occurs in approximately 30–70 % of patients with rheumatoid arthritis (RA). The most common cause of low hemoglobin level is chronic inflammation. Hyperbaric oxygenation (HBO) reduces the chronic inflammatory process, hypoxia severity and stimulates erythropoiesis. Therefore, HBO can be considered as one of the promising methods for treating anemia of chronic inflammation. The primary objective of the study is to carry out the efficacy analysis of rheumatoid arthritis (RA) complex therapy using hyperbaric oxygenation (HBO) for comparison results in patients with anemia and with a normal hemoglobin level. Materials and Methods. To assess the advisability of HBO in patients with RA and concomitant anemia, we analyzed indicators of RA activity and local joint inflammation in 120 patients. 30 patients were treated according to the standard scheme, 30 patients underwent one and 60 patients – five additional HBO sessions (1.3 atm during 40 min). Patients who underwent HBO were divided into two subgroups with normal and low hemoglobin levels. Results. On the 14th day of inpatient hospitalization, we fixed decrease in RA activity indices in all groups. The decrease in the activity of RA and local joint inflammation in patients who underwent HBO was faster than in patients who were treated according to the standard scheme, and in patients who underwent only one HBO session. Better results were observed in patients with concomitant anemia compared with patients with normal hemoglobin level. It was confirmed by a significant decrease in acute-phase blood values (ESR and CRP) and RA activity indices (assessment of disease activity (by a doctor and by a patient), CDIA, SDIA and DAS28). Conclusion. Additional HBO in complex RA therapy contributes to the efficacy of inpatient treatment. The most pronounced effect is observed in patients with both RA and anemia. Keywords: hyperbaric oxygenation, rheumatoid arthritis, anemia. Анемия встречается у 30–70 % больных, страдающих ревматоидным артритом (РА). Наиболее частой причиной снижения уровня гемоглобина крови является хроническое воспаление. Гипербарическая оксигенация (ГБО) способствует уменьшению активности хронического воспалительного процесса, выраженности гипоксии и стимулирует эритропоэз, следовательно, применение ГБО можно рассматривать как один из перспективных методов лечения анемии хронического воспаления. Цель работы – провести сравнительный анализ эффективности комплексной терапии пациентов, страдающих ревматоидным артритом, с включением курса гипербарической оксигенации на фоне анемии и при нормальном значении уровня гемоглобина крови. Материалы и методы. Для оценки целесообразности проведения курса ГБО у больных, страдающих РА с сопутствующей анемией, проведен динамический анализ показателей активности РА и локального воспаления в суставе у 120 пациентов (30 пациентов получили лечение по стандартной схеме, 30 больных дополнительно прошли 1 сеанс ГБО и 60 пациентов прошли 5 сеансов ГБО при 1,3 атм в течение 40 мин). Пациенты, прошедшие курс ГБО, были разделены на две подгруппы: с нормальным и сниженным уровнем гемоглобина. Результаты. На 14-й день госпитализации у всех пациентов отмечали регресс клинических проявлений артрита. Снижение показателей активности РА и локального воспаления в суставе у пациентов, прошедших курс ГБО, происходило быстрее, чем у больных, получивших лечение по стандартной схеме, и пациентов, прошедших один сеанс ГБО. Более высокие результаты лечения получены у больных с сопутствующей анемией по сравнению с пациентами с нормальными значениями гемоглобина, что подтверждено значимым снижением острофазовых показателей крови (СОЭ и СРБ) и индексов активности РА (ООАВ, ООАБ, CDIA, SDIA и DAS28). Выводы. Включение курса ГБО в стандартную схему терапии РА повышает эффективность стационарного лечения. Наиболее выраженный эффект наблюдается у больных с РА и анемией. Ключевые слова: гипербарическая оксигенация, ревматоидный артрит, анемия.

Evaluating the efficacy of intra-articular injections of platelet rich plasma (PRP) in rheumatoid arthritis patients and its impact on inflammatory cytokines, disease activity and quality of life.

2020 ◽  
Vol 16 ◽  
Author(s):  
Dalia S. Saif ◽  
Nagwa N. Hegazy ◽  
Enas S. Zahran
Keyword(s):  
Quality Of Life ◽  
Rheumatoid Arthritis ◽  
Disease Activity ◽  
Inflammatory Cytokines ◽  
Platelet Rich Plasma ◽  
Joint Inflammation ◽  
Monthly Interval ◽  
Post Injection ◽  
Tnf Α

Background: Among rheumatoid arthritis patients (RA), general disease activity is well regulated by diseasemodifying anti-rheumatic medications (DMARDS), but sometimes local inflammation still persists among a few joints. Adjuvant modern molecular interventions as Platelet Rich Plasma (PRP) with a suggested down regulating effect on inflammatory mediators has a proven effect in management of RA. We aim to evaluate the therapeutic effect of intra-articular PRP versus steroid in RA patients and their impact on inflammatory cytokines IL1B , TNF α, local joint inflammation, disease activity and quality of life (QL). Methods: Open labeled parallel randomized control clinical trial was carried out on 60 RA patients randomly divided into 2 groups, Group 1: included 30 patients received 3 intra-articular injections of PRP at monthly interval, Group 2: included 30 patients received single intra-articular injection of steroid. They were subjected to clinical, laboratory, serum IL1B and TNF α assessment at baseline and at 3, 6 months post injection. Results: Patients of both groups showed improvements in their scores of evaluating tools at 3months post injection and this improvement was persistent in the PRP group up to 6 months post injection while it was continued only for 3 months in the steroid group. Conclusions: PRP is a safe, effective and useful therapy in treating RA patients who had insufficient response and persistent pain and inflammation in just one or two joints through its down regulating effect on inflammatory cytokines IL1B, TNF α with subsequent improvement of local joint inflammation, disease activity and QL.

scholarly journals OP0326 ACPA-INDUCED PAIN-BEHAVIOR, BONE LOSS AND TENDON INFLAMMATION IN MICE: A NOVEL MODEL FOR THE PRE-DISEASE PHASES OF ACPA-POSITIVE RHEUMATOID ARTHRITIS

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 200.2-200
Author(s):  
A. Krishnamurthy ◽  
Y. Kisten ◽  
A. Circiumaru ◽  
K. Sakurabas ◽  
P. Jarvolli ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Bone Loss ◽  
Joint Inflammation ◽  
Tendon Sheath ◽  
Joint Involvement ◽  
Subclinical Inflammation ◽  
Core Motif ◽  
Dixon Method ◽  
Hind Limbs ◽  
Predicting Factor

Background:In rheumatoid arthritis (RA), anti-citrullinated protein antibodies (ACPAs) are associated with bone loss and pain. Recently, tenosynovitis has been suggested as a predicting factor for arthritis progression in individuals at-risk for RA.Objectives:We aimed to investigate if transfer of human ACPAs into mice could induce tenosynovitis and/or subclinical inflammation.Methods:Monoclonal ACPA (1325:04C03 and 1325:01B09) and control (1362:01E02) antibodies (mAbs) were generated from synovial plasma or memory B cells of RA patients. 2mg of combination of monoclonal ACPAs or control antibody were injected in BALB/c female mice (age 12-16 weeks) (n= 9). Pain-like behavior was monitored by measuring mechanical hypersensitivity using von Frey filaments every 3 days and estimation by up-down Dixon method. Bone morphometrics was analyzed by micro-CT. Using specially designed mobilization casts, dedicated mouse MRI coils, and gadolinium enhanced contrast medium, the hind limbs of these mice were scanned in a 9.4 T scanner and resulting T1-weighted images were evaluated for signs of soft tissue joint inflammation. The MRI images were scored for the presence of joint involvement and tendon inflammatory changes by 3 readers in a blinded manner.Figure 1.NAPA performed on healthy donor mo-DCs incubated with native, PAD2-citrullinated, and PAD4-citrullinated fibrinogen. Alpha, beta, and gamma chains of fibrinogen are shown separately. Each colored line represents a unique peptide. Nested peptides with a common core motif are shown in the same color. Grey bar denotes peptides with identical core motif between samples.Results:ACPAs (1325:04C03 and 1325:01B09) induced pain-like behavior (lasting for at least 4 weeks) and reduction of the trabecular and cortical bone thickness in the hind limbs as compared to control monoclonal antibodies (p<0.05). While no macroscopic or MRI signs of synovial inflammation were detected, MRI subclinical inflammation of the tendon sheaths was present in mice injected with ACPAs, but not in those injected with control mAb. Semi-quantitative scoring of the inflammatory tendon changes showed significant higher values in mice injected with ACPA (median of 1, range 0 to 2) than those injected with control mAb (median of 0, range 0 to 1).Conclusion:We show that ACPA induces pain-like behavior, bone loss and tendon sheath inflammation in mice, a model that mimics the preclinical state of ACPA positive RA.References:[1]Harre, U. et al. J Clin Invest (2012)[2]Krishnamurthy, A. et al. Ann Rheum Dis (2016, 2019), JI 2019[3]Wigerblad, G. et al. Ann Rheum Dis (2016, 2019)[4]KleyerA, Seminars in Arthritis and Rheumatism (2016)Disclosure of Interests:Akilan Krishnamurthy: None declared, Yogan Kisten: None declared, Alexandra Circiumaru: None declared, Koji Sakurabas: None declared, Patrik Jarvolli: None declared, Juan Jimenez Jimenez Andrade: None declared, Peter Damberg: None declared, Heidi Wähämaa: None declared, Vivianne Malmström Grant/research support from: VM has had research grants from Janssen Pharmaceutica, Lars Klareskog: None declared, Camilla Svensson: None declared, Bence Réthi: None declared, Anca Catrina: None declared

scholarly journals Anti-Rheumatic Effect of Antisense Oligonucleotide Cytos-11 Targeting TNF-α Expression

2021 ◽  
Vol 22 (3) ◽  
pp. 1022
Author(s):  
Tatyana P. Makalish ◽  
Ilya O. Golovkin ◽  
Volodymyr V. Oberemok ◽  
Kateryna V. Laikova ◽  
Zenure Z. Temirova ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Gene Expression ◽  
Rat Model ◽  
Peripheral Blood ◽  
Antisense Oligonucleotide ◽  
Joint Inflammation ◽  
Blood Concentrations ◽  
Tnf Α ◽  
Effective Drugs ◽  
First Time

The urgency of the search for inexpensive and effective drugs with localized action for the treatment of rheumatoid arthritis continues unabated. In this study, for the first time we investigated the Cytos-11 antisense oligonucleotide suppression of TNF-α gene expression in a rat model of rheumatoid arthritis induced by complete Freund’s adjuvant. Cytos-11 has been shown to effectively reduce peripheral blood concentrations of TNF-α, reduce joint inflammation, and reduce pannus development. The results achieved following treatment with the antisense oligonucleotide Cytos-11 were similar to those of adalimumab (Humira®); they also compared favorably with those results, which provides evidence of the promise of drugs based on antisense technologies in the treatment of this disease.

scholarly journals Illuminating the Plant Rhabdovirus Landscape through Metatranscriptomics Data

Viruses ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1304
Author(s):  
Nicolás Bejerman ◽  
Ralf G. Dietzgen ◽  
Humberto Debat
Keyword(s):  
Plant Species ◽  
High Throughput Sequencing ◽  
Plant Viruses ◽  
The Novel ◽  
Coding Regions ◽  
Public Data ◽  
Invaluable Tool ◽  
Sequencing Platforms ◽  
Viral Sequences ◽  
Plant Rhabdovirus

Rhabdoviruses infect a large number of plant species and cause significant crop diseases. They have a negative-sense, single-stranded unsegmented or bisegmented RNA genome. The number of plant-associated rhabdovirid sequences has grown in the last few years in concert with the extensive use of high-throughput sequencing platforms. Here, we report the discovery of 27 novel rhabdovirus genomes associated with 25 different host plant species and one insect, which were hidden in public databases. These viral sequences were identified through homology searches in more than 3000 plant and insect transcriptomes from the National Center for Biotechnology Information (NCBI) Sequence Read Archive (SRA) using known plant rhabdovirus sequences as the query. The identification, assembly and curation of raw SRA reads resulted in sixteen viral genome sequences with full-length coding regions and ten partial genomes. Highlights of the obtained sequences include viruses with unique and novel genome organizations among known plant rhabdoviruses. Phylogenetic analysis showed that thirteen of the novel viruses were related to cytorhabdoviruses, one to alphanucleorhabdoviruses, five to betanucleorhabdoviruses, one to dichorhaviruses and seven to varicosaviruses. These findings resulted in the most complete phylogeny of plant rhabdoviruses to date and shed new light on the phylogenetic relationships and evolutionary landscape of this group of plant viruses. Furthermore, this study provided additional evidence for the complexity and diversity of plant rhabdovirus genomes and demonstrated that analyzing SRA public data provides an invaluable tool to accelerate virus discovery, gain evolutionary insights and refine virus taxonomy.

scholarly journals Fluorescence optical imaging: ready for prime time?

RMD Open ◽  
2021 ◽  
Vol 7 (2) ◽  
pp. e001497
Author(s):  
Sarah Ohrndorf ◽  
Anne-Marie Glimm ◽  
Mads Ammitzbøll-Danielsen ◽  
Mikkel Ostergaard ◽  
Gerd R Burmester
Keyword(s):  
Optical Imaging ◽  
Power Doppler ◽  
Joint Inflammation ◽  
Diagnostic Process ◽  
The Novel ◽  
The European Union ◽  
Fluorescence Optical Imaging ◽  
Disturbed Microcirculation ◽  
The Usa ◽  
Magnetic Resonance Imaging Mri

The novel technique of fluorescence optical imaging (FOI, Xiralite), which is approved in the European Union and the USA for clinical use, has been the object of studies since 2009. Indocyanine green-based FOI can demonstrate an impaired microcirculation caused by inflammation in both hands in one examination. Several studies have investigated FOI for detection of joint inflammation by comparing FOI to magnetic resonance imaging (MRI) and/or musculoskeletal ultrasound (MSUS). The results have shown a generally good agreement (>80%) between FOI and clinical examination, MRI and MSUS by power Doppler in inflammatory joint diseases. Moreover, characteristic enhancements in skin and nails are seen in PsA, which potentially can be useful in the diagnostic process of early undifferentiated arthritis. Furthermore, FOI has been investigated for the visualisation of a disturbed microcirculation in the hands and fingers of patients with systemic sclerosis (SSc), highlighting the potential of monitoring vascular changes in SSc and other vasculopathies. The available data indicate that it is time to consider FOI as a useful part of the imaging repertoire in rheumatology clinical practice, particularly where MSUS and MRI are not easily available.

scholarly journals Osteoblastic PLEKHO1 contributes to joint inflammation in rheumatoid arthritis

EBioMedicine ◽  
2019 ◽  
Vol 41 ◽  
pp. 538-555 ◽  
Author(s):  
Xiaojuan He ◽  
Jin Liu ◽  
Chao Liang ◽  
Shaikh Atik Badshah ◽  
Kang Zheng ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Joint Inflammation

scholarly journals AB0043 EFFECT OF ANTI-INFLAMMATORY MEDICATION ON INTERACTION OF SYNOVIAL FIBROBLASTS WITH MACROPHAGES IN RHEUMATOID ARTHRITIS

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 1054.1-1054
Author(s):  
M. Schmeller ◽  
M. Diller ◽  
R. Hasseli ◽  
A. Knothe ◽  
S. Rehart ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Mononuclear Cells ◽  
Joint Inflammation ◽  
Synovial Fibroblasts ◽  
Therapeutic Effects ◽  
Synergistic Activity ◽  
M1 Macrophages ◽  
Healthy Donors ◽  
Proinflammatory Activity ◽  
Anti Inflammatory

Background:One of the key mechanisms in the pathogenesis of rheumatoid arthritis (RA) is the interaction of macrophages and synovial fibroblasts during joint inflammation. Increased synergistic proinflammatory activity of both cell types leads to the release of high levels of proinflammatory cytokines, especially of interleukin-6 (IL-6), and of matrix degrading enzymes. If this mechanism is uncontrolled, progressive destruction of articular cartilage and bone will take place.In active disease, immediate anti-inflammatory treatment with glucocorticoids is usually replaced by disease-modifying anti-rheumatic drugs (DMARDS), especially by methotrexate (MTX) and biologics such as TNF-α- or IL-6-inhibitors. This led to great improvements in prognosis and outcome for RA patients. However, about 40% of patients experience no remission or suffer from side effects of medication. To optimize established substances and to develop new treatment strategies, it is necessary to understand the mechanisms underlying the limited therapeutic effects.Objectives:Evaluation of the effect of prednisolone, MTX, adalimumab, tocilizumab on IL-6 secretion by RA synovial fibroblasts (RASF) and macrophages.Methods:RA synovium was used for RASF isolation. Peripheral blood mononuclear cells (PBMCs) were isolated from blood of healthy donors and RA patients by using Ficoll© medium followed by density gradient centrifugation. Mononuclear cells were seeded on six well plates (6x10^6/well) and incubated for one week. Then they were stimulated with Interferon-у (20 ng/ml) and LPS (50 ng/ml) for 48h to initiate differentiation into proinflammatory M1 macrophages. The M1 macrophages were co-cultured with RASF (100.000/well) and different treatments added (prednisolone: 10, 25, 50, 75, 100 nM, 1 µM; adalimumab: 100, 500 µg/ml; tocilizumab: 1, 5 µg/ml; MTX: 0,5, 1, 5, 10, 100 nM, 1µM). After 24h culture supernatants were collected and IL-6- and TNFα-ELISAs were performed.Results:IL-6 concentrations of untreated controls were comparable, regardless whether M1 macrophages from healthy donors or RA-patients were used for co-culture. Prednisolone reduced co-culture-induced IL-6 up to 56% (p<0.001) in co-culture of RASF and M1 macrophages of healthy donors and up to 60% (p<0.001) in co-culture of RASF and RA M1 macrophages. Adalimumab reduced IL-6 up to 28% (p<0.05) in M1 of healthy donors and up to 45% (p<0.01) in RA M1 macrophage co-cultures. A minor reduction by 10-20% of IL-6 was observed with tocilizumab and no significant effect could be achieved after treatment with MTX.Conclusion:Prednisolone and adalimumab clearly decrease but do not eliminate proinflammatory synergistic activity of RASF and M1 macrophages. These results confirm the clinical observation, that there is a large number of RA-patients that independent of anti-inflammatory treatment still suffer from low-level joint inflammation.The synergistic proinflammatory activity of M1 macrophages and RASF seems to be a complex and multifactorial mechanism that is difficult to eliminate by a single treatment substance. Since it is one of the key mechanisms in RA pathogenesis, there is a critical need to investigate how therapy effects could be optimized. This study confirmed RASFs as one of the leading effector cells of increased synergistic proinflammatory activity, thus underlining their promising role as a treatment target in rheumatoid arthritis.Disclosure of Interests:None declared

Patients with Rheumatoid Arthritis in Clinical Remission Manifest Persistent Joint Inflammation on Histology and Imaging Studies

2014 ◽  
Vol 41 (11) ◽  
pp. 2153-2160 ◽  
Author(s):  
Allen Anandarajah ◽  
Ralf Thiele ◽  
Ellen Giampoli ◽  
Johnny Monu ◽  
Gwy-Suk Seo ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Disease Activity ◽  
Clinical Remission ◽  
Severe Disease ◽  
Joint Inflammation ◽  
Imaging Studies ◽  
American College Of Rheumatology ◽  
Remission Criteria ◽  
Magnetic Resonance Imaging Mri ◽  
Active Inflammation

Objective.The purpose of our study was to test the hypothesis that synovitis on magnetic resonance imaging (MRI) and ultrasound (US) observed in patients with rheumatoid arthritis (RA) who meet remission criteria reflects active inflammation on histopathology.Methods.We analyzed 15 synovial specimens obtained during surgical procedures from 14 patients with RA in clinical remission as defined by the American College of Rheumatology criteria. Histological specimens were scored for hyperplasia of synovial lining and synovial stroma, inflammation, lymphoid follicles, and vascularity. The histology scores were classified as minimal, mild, moderate, or severe disease activity. US and MRI performed within a 4-month period of surgery were scored for disease activity. The correlation between histology and imaging scores was examined.Results.Four of 14 patients were receiving anti-tumor necrosis factor (TNF) therapy, 4 were receiving methotrexate (MTX) alone, 4 were taking MTX and hydroxychloroquine (HCQ), and 1 was taking HCQ and sulfasalazine. Four specimens had severe, 6 moderate, 3 mild, and 2 minimal disease activity on histology. Three of 4 specimens with minimal and mild histology were observed in subjects receiving anti-TNF therapy. Synovitis was noted on greyscale in 80% of joints and Doppler signal in 60%. MRI demonstrated synovitis and bone marrow edema in 86% of images. Positive but not significant correlations were noted between histology and synovitis scores on US.Conclusion.Despite clinical remission, histology and imaging studies documented a persistently active disease state that may explain the mechanism for radiographic progression.

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