Inflammasome and Its Therapeutic Targeting in Rheumatoid Arthritis

Inflammasome is a cytoplasmic multiprotein complex that facilitates the clearance of exogenous microorganisms or the recognition of endogenous danger signals, which is critically involved in innate inflammatory response. Excessive or abnormal activation of inflammasomes has been shown to contribute to the development of various diseases including autoimmune diseases, neurodegenerative changes, and cancers. Rheumatoid arthritis (RA) is a chronic and complex autoimmune disease, in which inflammasome activation plays a pivotal role in immune dysregulation and joint inflammation. This review summarizes recent findings on inflammasome activation and its effector mechanisms in the pathogenesis of RA and potential development of therapeutic targeting of inflammasome for the immunotherapy of RA.

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Antibody modified gold nanoparticles for fast colorimetric screening of rheumatoid arthritis

The Analyst ◽

10.1039/c9an00319c ◽

2019 ◽

Vol 144 (11) ◽

pp. 3613-3619 ◽

Cited By ~ 5

Author(s):

Bruno Veigas ◽

Ana Matias ◽

Tomás Calmeiro ◽

Elvira Fortunato ◽

Alexandra R. Fernandes ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Gold Nanoparticles ◽

Autoimmune Disease ◽

Joint Inflammation ◽

Systemic Autoimmune Disease ◽

Ageing Population ◽

Chronic Disability ◽

High Prevalence

Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic joint inflammation and one of the main causes of chronic disability worldwide with high prevalence in the ageing population.

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RelA/MicroRNA-30a/NLRP3 signal axis is involved in rheumatoid arthritis via regulating NLRP3 inflammasome in macrophages

Cell Death and Disease ◽

10.1038/s41419-021-04349-5 ◽

2021 ◽

Vol 12 (11) ◽

Author(s):

Qiudong Yang ◽

Wenhua Zhao ◽

Yuyi Chen ◽

Yue Chen ◽

Jiali Shi ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Transcriptional Regulation ◽

Nlrp3 Inflammasome ◽

Joint Inflammation ◽

Inflammasome Activation ◽

Nlrp3 Inflammasome Activation ◽

Bone Damage ◽

Post Transcriptional Regulation ◽

Deficient Mice ◽

Nlrp3 Expression

AbstractNLRP3 inflammasome plays an important role in the pathogenesis of rheumatoid arthritis (RA). However, the post-transcriptional regulation of NLRP3 expression by miRNA in synovial macrophages is still not well understood. The aim of the study is to elucidate the mechanisms of RA with the focus on miRNAs mediated post-transcriptional regulation of the NLRP3 inflammasome. Here, we used NLRP3-deficient mice (NLRP3KO) to cross with TNFα-transgenic mice (TNFTG) to generate NLRP3KO/TNFTG mice, and compared their joint phenotypes with those of their TNFTG and wild-type (WT) littermates at 5 months of age. In comparison to WT mice, articular bone volume and cartilage area are decreased, whereas inflammed area, eroded surface, ALP+ osteoblast number, TRAP+ osteoclast number, and the areas of RelA+F4/80+, Caspase-1+F4/80+, IL-1β+F4/80+ synoviocytes are increased in the TNFTG mice. Knockout of NLRP3 ameliorates joint inflammation and bone damage in TNFTG mice. Further, in TNFα-primed BMDMs, RelA positively regulates NLRP3 expression, but negatively regulates miR-30a. Additionally, miR-30a negatively mediates NLRP3 expression by directly binding to its 3ʹ UTR, suggesting a miR-30a-mediated feedforward loop acting on NLRP3. Finally, intra-articular injection of AAV-miR-30a inhibits NLRP3 inflammasome activation, reduces joint inflammation, and attenuates bone damage in TNFTG mice. Thus, RelA/miR-30a/NLRP3 signal axis is involved in RA through regulating NLRP3 Inflammasome in macrophages.

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Inflammasomes take the acid test

Inflammasome ◽

10.2478/infl-2014-0007 ◽

2014 ◽

Vol 1 (1) ◽

Author(s):

David Brough

Keyword(s):

Extracellular Atp ◽

Inflammasome Activation ◽

Danger Signals ◽

Acid Test

Editorial highlight on Takenouchi et al., ‘Inflammasome activation by danger signals: extracellular ATP and pH.’

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

Ulyanovsk Medico-biological Journal ◽

10.34014/2227-1848-2020-1-42-52 ◽

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.

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Novel Nano Carriers for the Treatment of Progressive Auto Immune Disease Rheumatoid Arthritis

Current Pharmaceutical Design ◽

10.2174/1381612826666201021130146 ◽

2020 ◽

Vol 26 ◽

Author(s):

Ritu Mishra ◽

Swati Gupta

Keyword(s):

Rheumatoid Arthritis ◽

Drug Delivery ◽

Autoimmune Disease ◽

Drug Delivery Systems ◽

Clinical Manifestations ◽

Adaptive Immune Response ◽

Delivery Systems ◽

Current Therapy ◽

Genetic And Environmental Factors ◽

Novel Drug

Background: Rheumatoid arthritis (RA) is the most common occurring progressive, autoimmune disease, affecting 1% of the population and the ratio of affected women is three times as compared to men in most developing countries. Clinical manifestations of RA are the presence of anti-citrullinated protein antibody (ACPA) and rheumatoid factor (RF) in blood, tendered joints and soreness of the muscles. Some other factors which may lead to chronic inflammation are genetic and environmental factors as well as adaptive immune response. Several conventional drugs are available for the treatment of RA but have their own drawbacks which can be overcome by the use of novel drug delivery systems. : The objective of the present review is to focus on the molecular pathogenesis of the disease and its current conventional treatment with special reference to the role of novel drug delivery systems encapsulating anti rheumatic drugs and herbal drugs in passive and receptor mediated active targeting against RA. On reviewing the conventional and current therapeutics agains RA, we conclude that, although the current therapy for the treatment of RA is capable enough, yet more advances in the field of targeted drug delivery will sanguinely result in effective and appropriate treatment of this autoimmune disease.

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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.

Current Rheumatology Reviews ◽

10.2174/1573397116666201113090629 ◽

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.

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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

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.5583 ◽

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

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

International Journal of Molecular Sciences ◽

10.3390/ijms22031022 ◽

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.

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Solar Radiation and Vitamin D: Mitigating Environmental Factors in Autoimmune Disease

Journal of Environmental and Public Health ◽

10.1155/2012/619381 ◽

2012 ◽

Vol 2012 ◽

pp. 1-9 ◽

Cited By ~ 18

Author(s):

Gerry K. Schwalfenberg

Keyword(s):

Rheumatoid Arthritis ◽

Multiple Sclerosis ◽

Inflammatory Bowel Disease ◽

Vitamin D ◽

Type 1 Diabetes ◽

Autoimmune Disease ◽

Solar Radiation ◽

Inflammatory Bowel

This paper looks at the environmental role of vitamin D and solar radiation as risk reduction factors in autoimmune disease. Five diseases are considered: multiple sclerosis, type 1 diabetes, rheumatoid arthritis, autoimmune disease of the thyroid, and inflammatory bowel disease. Clinical relevant studies and factors that may indicate evidence that autoimmune disease is a vitamin D-sensitive disease are presented. Studies that have resulted in prevention or amelioration of some autoimmune disease are discussed. An example of the utility of supplementing vitamin D in an unusual autoimmune disease, idiopathic thrombocytic purpura, is presented.

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