Bedside to bench: defining the immunopathogenesis of psoriatic arthritis

Bravo, A. E. Rätz; Kavanaugh, Arthur

doi:10.1038/s41584-019-0285-8

Cited by 42 publications

(28 citation statements)

References 169 publications

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“…Among these, interleukin (IL)-23, IL-12, the IL-17 family and TNF constitute key players in PsA pathogenesis. 1,2 IL-23, consisting of IL23A (IL-23p19) and IL12B (IL-12p40) subunits, is predominantly produced by myeloid dendritic cells (mDCs). While the p19 subunit is unique to IL-23, the p40 subunit is shared with IL-12.…”

Section: Discussionmentioning

confidence: 99%

“…In mice, spontaneous OA can occur in wild-type or genetically modified animals. The first report of spontaneous OA developing in wild-type mice was published in 1956 2 and changes affecting the knee joint were further related to OA by using ultrastructural-histochemical analyses. However, a quantitative assessment of age-related evolution of OA-type cartilage lesions is lacking.…”

Section: Oa Aetiology Pathology and Animal Modelsmentioning

confidence: 99%

“…Background: Cell-free DNA (cfDNA) is a molecule with undisputable immunogenic potential [1] . Its role is well established in etiopathogenesis of systemic lupus erythematosus and many reports suggest it may play an important role in other rheumatic diseases [2] . Patients suffering from rheumatic diseases are at higher risk of osteoporosis [3] , which may be a consequence of increased generation of osteoclasts (OC).…”

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Ab0062 characterization of Il-12 and Il-23 Reduction by Tofacitinib in MDCS

et al. 2020

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Background:Psoriatic arthritis (PsA) is a chronic inflammatory auto-immune disease characterized by an excessive production of pathogenic mediators that cause inflammation of the skin, peripheral joints, entheses and the spine. Among these, interleukin (IL)-23, IL-12, the IL-17 family and TNF constitute key players in PsA pathogenesis.1,2IL-23, consisting of IL23A (IL-23p19) and IL12B (IL-12p40) subunits, is predominantly produced by myeloid dendritic cells (mDCs). While the p19 subunit is unique to IL-23, the p40 subunit is shared with IL-12. Together, IL-12 and IL-23 play a crucial role in promoting the differentiation of naïve T lymphocytes into T helper (Th) interferon (IFN)-γ-producing Th1 or IL17-producing Th17 cells, respectively.3Small-molecule inhibitors, such as the JAK/STAT inhibitor Tofacitinib, have recently shown promising therapeutic potential in PsA clinical trials.4The inhibition of JAKs by Tofacitinib results in the direct suppression of multiple intracellular signaling pathways which constitute key hubs in the cytokine network.5However, whether Tofacitinib is able directly target IL-12/IL-23 production by mDCs has not yet been documented. Suppression of these canonical inflammatory pathways would provide further evidence that Tofacitinib is an effective drug in halting both innate and adaptive immune responses.Objectives:To evaluate the transcriptional and molecular events underlining IL-12 and IL-23 regulation by Tofacitinib in mDCs.Methods:Peripheral blood mononuclear cells from healthy donors were isolated by Ficoll gradient. Monocytes and myeloid dendritic cells (mDCs) were isolated by using magnetic beads on autoMACS. Monocytes were cultured for 6 days in the presence of IL-4 and granulocyte-macrophage colony-stimulating factor (GM-CSF) to generate monocyte-derived dendritic cells (moDCs). MoDCs were harvested, washed and put to rest for 1 day prior to stimulation, while mDCs were stimulated on the same day of isolation. Both moDCs and mDCs were pre-treated with Tofacitinib and then stimulated with either lipopolysaccharide (LPS) or combination of LPS with IFN-γ for 4 hours. Cytokines were measured using enzyme-linked immunosorbent assay (ELISA) and gene expression was assessed using quantitative polymerase chain reaction (qPCR).Results:Treatment of both mDCs and moDCs with Tofacitinib led to a decreased mRNA expression of IL-12 p40 (IL12B) in the presence of TLR4 and IFNγ co-stimulation. The decreasedIL12BmRNA expression also resulted in lower production of IL-12 p40 and IL-23 proteins in mDCs.Conclusion:In this work, we demonstrated for the first time that Tofacitinib can suppress the production of IL-23/IL-12 p40 subunit in mDCs, upon the condition that an active type II IFN signalling is also present in these cells. This observation indicates that specific factors, such as endogenous IFN-γ levels in the serum of PsA patients, can possibly predict differential responses to Tofacitinib treatment.References:[1]Gaffen SL. et al. The IL-23-IL-17 immune axis: from mechanisms to therapeutic testing. Nat Rev Immunol. 2014 Sep;14(9):585-600[2]Bravo A, Kavanaugh A. Bedside to bench: defining the immunopathogenesis of psoriatic arthritis. Nat Rev Rheumatol. 2019 Nov;15(11):645-656[3]Floss DM. et al. Insights into IL-23 biology: From structure to function. Cytokine Growth Factor Rev. 2015 Oct;26(5):569-78[4]Berekmeri A. et al. Tofacitinib for the treatment of psoriasis and psoriatic arthritis. Expert Rev Clin Immunol. 2018 Sep;14(9):719-730[5]T Virtanen A. et al. Selective JAKinibs: Prospects in Inflammatory and Autoimmune Diseases. BioDrugs. 2019 Feb;33(1):15-32Disclosure of Interests:None declared

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Section: Discussionmentioning

confidence: 99%

Section: Oa Aetiology Pathology and Animal Modelsmentioning

confidence: 99%

mentioning

confidence: 99%

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Ab0062 characterization of Il-12 and Il-23 Reduction by Tofacitinib in MDCS

et al. 2020

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“…Псориатический артрит (ПсА) -ИВРЗ, которое, с одной стороны, рассматривается как наиболее частая коморбидная патология при псориазе в рамках «системной псориатической болезни» [7], а с другой -классифицируется как клиническая форма спондилоартритов (СпА) [8], находится на стыке фундаментальных проблем ревматологии и дерматологии. ПсА -гетерогенное заболевание в отношении как патогенеза, характеризующегося комплексным взаимодействием факторов внешней среды, генетической предрасположенности, аутоим-мунных и аутовоспалительных механизмов [9][10][11][12], так и спектра клинических проявлений, вариантов течения и исходов, и фактически он представляет собой клинико-иммунологический синдром. В настоящее время в лечении ПсА достигнут существенный прогресс, связанный с применением генно-инженерных биологических препаратов (ГИБП) [13][14][15][16][17][18], блокирующих патогенетически значимые цитокины (табл.…”

Section: псориатический артритunclassified

“…Основные механизмы развития ПсА (по [10,11], в собственной модификации) П р о г р е с с в р е в м а т о л о г и и в X X I в е к е…”

Section: таблицаunclassified

Efficacy and Safety of Tofacitinib for Immunemediated Inflammatory Rheumatic Diseases (Part Ii)

Nasonov

Авдеева²,

Лила

2020

Naučno-praktičeskaâ revmatologiâ

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Разработка «таргетных» пероральных противовоспалительных лекарственных препаратов-ингибиторов Янус-киназ (Janus kinase, JAK) [1, 2], первым представителем которых является тофацитиниб (ТОФА), рассматривается как крупное достижение био-П р о г р е с с в р е в м а т о л о г и и в X X I в е к е Насонов Е.Л.научный руководитель ФГБНУ «НИИР им. В.А. Насоновой», академик РАН, профессор, докт. мед. наук 1 ФГБНУ «Научно-исследовательский институт ревматологии им. В.А. Насоновой»,

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Incidence of Psoriatic Arthritis Among Patients Receiving Biologic Treatments for Psoriasis: A Nested Case–Control Study

Rosenthal

Schwartz

Sagy

et al. 2021

Arthritis & Rheumatology

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Objective To investigate the effect of biologic treatments for psoriasis on the incidence of psoriatic arthritis (PsA). Methods This retrospective cohort study was conducted using electronic medical records from a large health maintenance organization. Patients who received biologic treatment for psoriasis and were not diagnosed as having PsA before or at the time of biologic treatment initiation were included. Control psoriasis patients who did not receive biologic treatment were matched by age at time of diagnosis, sex, time from psoriasis diagnosis until treatment initiation, maximum body mass index, and smoking status. The groups were different in most characteristics. Therefore, propensity score matching was implemented. Log rank test and multivariable Cox proportional hazards regression were used to compare the groups. Results Overall, 1,326 patients were included, of whom 663 had received biologic treatment and 663 had not. The Kaplan‐Meier curve for the propensity score–matched groups reflected a statistically significant increased risk for PsA among the control group compared to the biologic treatment group. The results of the multivariable Cox regression showed that the control group had a significantly higher risk for PsA compared to the biologic treatment group within 10 years of follow‐up (adjusted hazard ratio 1.39 [95% confidence interval 1.03–1.87]). Conclusion Our findings show a statistically and clinically significant decreased risk for developing PsA among patients with psoriasis who receive biologic treatments. The results suggest that biologic medications should be considered for patients who present with significant risk factors for PsA at an earlier stage of treatment.

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Bedside to bench: defining the immunopathogenesis of psoriatic arthritis

Cited by 42 publications

References 169 publications

Ab0062 characterization of Il-12 and Il-23 Reduction by Tofacitinib in MDCS

Ab0062 characterization of Il-12 and Il-23 Reduction by Tofacitinib in MDCS

Efficacy and Safety of Tofacitinib for Immunemediated Inflammatory Rheumatic Diseases (Part Ii)

Incidence of Psoriatic Arthritis Among Patients Receiving Biologic Treatments for Psoriasis: A Nested Case–Control Study

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