Responses to Cytokine Inhibitors Associated with Cellular Composition in Models of Immune‐Mediated Inflammatory Arthritis

Nielsen, Morten Aagaard; Lomholt, Søren; Mellemkjær, Anders; Andersen, Morten Nørgaard; Buckley, Christopher D.; Kragstrup, Tue Wenzel

doi:10.1002/acr2.11094

Cited by 20 publications

(23 citation statements)

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“…R. Ng 1 , K. Sheridan 1 , S. Cowley 1 , E. Dorris 1 , D. Veale 2 , U. Fearon 3 , A. G. Wilson 1 . 1 University College Dublin, Centre for Arthritis Research,Dublin,Ireland;2 University College Dublin,Rheumatology,Dublin,Ireland;3 Trinity College Dublin,TBSI,Dublin,Ireland Background: Rheumatoid Arthritis synovial fibroblasts (RASFs) are key player in tissue destruction via the production of a wide range of chemical reactions in the joint with high growth rate and resistance to mortality [1]. Methotrexate (MTX) is a dihydrofolate reductase inhibitor that attenuates inflammation within joints resulting in reduced cartilage and bone damage and is the anchor therapy for RA.…”

Section: Discussionmentioning

confidence: 99%

“…Methods: In the present study, paired peripheral blood mononuclear cells (PBMC) and SF-FLS from patients with RA were obtained (n=7). FLS were isolated from the synovial fluid by a strict trypsinization protocol 1 and their cellular characteristics and functionality were evaluated at passage 4. Monocultures (SF-FLS) and autologous co-cultures (SF-FLS and PBMC) were established from five patients with RA and subsequently evaluated by flow cytometry, Western blotting and multiplex immunoassays.…”

Section: Discussionmentioning

confidence: 99%

“…The test may be used to reduce the risk of low-energy fractures and to improve the quality of life in RA. References: [1] Background: The paracaspase Malt1 is a cysteine protease, which forms a complex leading to the activation of the in proinflammatory transcription factor NF-κB in lymphocytes with CARMA1 and Bcl10. Previously, we showed that the myeloid equivalent of CARMA1, Card9 is important in neutrophils in Fcγ receptor-mediated cytokine release together with Bcl10 and Malt1.…”

Section: Table 1 Methylation and Expression Between Patients Dividedmentioning

confidence: 99%

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Ab0098 the Effect of Malt1-Deficiency on the Effector Phase of Experimental Autoimmune Arthritis

et al. 2020

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Background:The paracaspase Malt1 is a cysteine protease, which forms a complex leading to the activation of the in proinflammatory transcription factor NF-κB in lymphocytes with CARMA1 and Bcl10. Previously, we showed that the myeloid equivalent of CARMA1, Card9 is important in neutrophils in Fcγ receptor-mediated cytokine release together with Bcl10 and Malt1. In line with these findings, we observed a significant decrease in the severity of autoantibody-triggered arthritis in the absence of Card9 and Bcl10.Objectives:Our aim was to directly investigate whether the genetic deficiency of Malt1, the third component of the complex altered the process of the K/BxN serum transfer arthritis (that resembles to the effector phase of rheumatoid arthritis).Methods:We used wild type and Malt1–/–mice for our experiments. Autoantibody-mediated arthritis was induced by a single intraperitoneal injection of K/BxN serum. Clinical signs of joint inflammation were scored on a scale based on the cardinal inflammatory clues for two weeks. Ankle thickness was measured by a spring-loaded caliper.Results:Similar to the deficiency of the other two components of the complex, Malt1–/–mice showed a partial, but significant decrease in the macroscopic joint inflammation compared to arthritic serum-treated wild type animals during the entire experimental process. In line with this phenomenon, Malt1–/–animals had reduced autoantibody-triggered ankle thickening.Conclusion:Our results show that Malt1 seems to be an important molecule in the development and progression of experimental autoantibody-induced arthritis in mice, highlighting the role of the molecule as a potential therapeutic target in the future.Disclosure of Interests:None declared

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Table 1 Methylation and Expression Between Patients Dividedmentioning

confidence: 99%

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Ab0098 the Effect of Malt1-Deficiency on the Effector Phase of Experimental Autoimmune Arthritis

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“…Таким образом, БАРИ (и ТОФА) обладают потенциальной способностью блокировать патогенетически значимые механизмы активации врожденного и приобретенного (Th1-и Th17-типы иммунного ответа) иммунитета. Выявлена способность ТОФА и БАРИ (а также мАТ к ИЛ6-рецепторам -тоцилизумаба) ингибировать (>50%) синтез моноцитарного хемоаттрактантного белка 1 (МХБ1) в культуре синовиальных и периферических мононуклеарных клеток [106]. В другом исследовании обнаружено, что БАРИ ингибирует синтез ИЛ1β нейтрофилами, стимулированными ИЛ6 и кристаллами мочевой кислоты [107].…”

Section: механизмы действия и перспек тивыunclassified

Baricitinib: New Pharmacotherapy Options for Rheumatoid Arthritis and Other Immune-Mediated Inflammatory Rheumatic Diseases

Nasonov

Лила

2020

Naučno-praktičeskaâ revmatologiâ

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Deciphering the mechanisms of the pathogenesis of immune-mediated inflammatory rheumatic diseases (IMIRDs) in conjunction with designing a wide range of biological agents is one of the major medical advances in the 21st century. A new promising area of pharmacotherapy for IMIRDs is associated with the design of the so-called targeted oral medications that primarily include Janus kinase (JAK) inhibitors. The review presents new data on the efficacy and safety of the new JAK inhibitor baricitinib in treating rheumatoid arthritis and other IMIRDs.

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“…The in vitro administration of an anti-IL-17A agent to FLS cultures was effective in reducing IL-17A-induced IL-6 production, with no differences between PsA and RA FLS ( Frommer et al, 2019 ). SEC was also tested in vitro in SF mononuclear cell (SFMC) cultures and cocultures of FLS and peripheral blood mononuclear cells (PBMCs), producing a reduction in the release of monocyte chemoattractant protein 1 (MCP-1) after 48 hours ( Nielsen et al, 2020 ). Finally, the adoption of a blocker of IL-17-receptor A (IL-17RA) was tested in PsA FLS cultures, highlighting reductions in IL-6 and IL-8 release into supernatants after stimulation with IL-17A ( Raychaudhuri et al, 2012 ).…”

Section: Introductionmentioning

confidence: 99%

From Bed to Bench and Back: TNF-α, IL-23/IL-17A, and JAK-Dependent Inflammation in the Pathogenesis of Psoriatic Synovitis

et al. 2021

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Psoriatic arthritis (PsA) is a chronic inflammatory immune-mediated disease with a burdensome impact on quality of life and substantial healthcare costs. To date, pharmacological interventions with different mechanisms of action, including conventional synthetic (cs), biological (b), and targeted synthetic (ts) disease-modifying antirheumatic drugs (DMARDs), have been proven efficacious, despite a relevant proportion of failures. The current approach in clinical practice and research is typically “predictive”: the expected response is based on stratification according to clinical, imaging, and laboratory data, with a “heuristic” approach based on “trial and error”. Several available therapeutic options target the TNF-α pathway, while others are directed against the IL-23/IL-17A axis. Janus kinase inhibitors (JAKis), instead, simultaneously block different pathways, endowing these drugs with a potentially “broad-spectrum” mechanism of action. It is not clear, however, whether targeting a specific pathway (e.g., TNF-α or the IL-23/IL-17 axis) could result in discordant effects over other approaches. In particular, in the case of “refractory to a treatment” patients, other pathways might be hyperactivated, with opposing, synergistic, or redundant biological significance. On the contrary, refractory states could be purely resistant to treatment as a whole. Since chronic synovitis is one of the primary targets of inflammation in PsA, synovial biomarkers could be useful in depicting specific biological characteristics of the inflammatory burden at the single-patient level, and despite not yet being implemented in clinical practice, these biomarkers might help in selecting the proper treatment. In this narrative review, we will provide an up-to-date overview of the knowledge in the field of psoriatic synovitis regarding studies investigating the relationships among different activated proinflammatory processes suitable for targeting by different available drugs. The final objective is to clarify the state of the art in the field of personalized medicine for psoriatic disease, aiming at moving beyond the current treatment schedules toward a patient-centered approach.

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Responses to Cytokine Inhibitors Associated with Cellular Composition in Models of Immune‐Mediated Inflammatory Arthritis

Cited by 20 publications

References 46 publications

Ab0098 the Effect of Malt1-Deficiency on the Effector Phase of Experimental Autoimmune Arthritis

Ab0098 the Effect of Malt1-Deficiency on the Effector Phase of Experimental Autoimmune Arthritis

Baricitinib: New Pharmacotherapy Options for Rheumatoid Arthritis and Other Immune-Mediated Inflammatory Rheumatic Diseases

From Bed to Bench and Back: TNF-α, IL-23/IL-17A, and JAK-Dependent Inflammation in the Pathogenesis of Psoriatic Synovitis

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