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INTRODUCTION: Psoriatic arthritis (PsA) is a chronic, inflammatory, musculoskeletal disease that affects up to 30% of patients with psoriasis. Current challenges in clinical care and research include personalised treatment, understanding the divergence of therapy response and unravelling the multifactorial pathophysiology of this complex disease. Moreover, there is an urgent clinical need to predict, assess and understand the cellular and molecular pathways underlying the response to disease-modifying antirheumatic drugs (DMARDs). The TOFA-PREDICT clinical trial addresses this need. Our primary objective is to determine key immunological factors predicting tofacitinib efficacy and drug-free remission in PsA. METHODS AND ANALYSIS: In this investigator-initiated, phase III, multicentre, open-label, four-arm randomised controlled trial, we plan to integrate clinical, molecular and imaging parameters of 160 patients with PsA. DMARD-naïve patients are randomised to methotrexate or tofacitinib. Additionally, patients who are non-responsive to conventional synthetic (cs)DMARDs continue their current csDMARD and are randomised to etanercept or tofacitinib. This results in four arms each with 40 patients. Patients are followed for 1 year. Treatment response is defined as minimal disease activity at week 16. Clinical data, biosamples and images are collected at baseline, 4 weeks and 16 weeks; at treatment failure (treatment switch) and 52 weeks. For the first 80 patients, we will use a systems medicine approach to assess multiomics biomarkers and develop a prediction model for treatment response. Subsequently, data from the second 80 patients will be used for validation. ETHICS AND DISSEMINATION: The study was approved by the Medical Research Ethics Committee in Utrecht, Netherlands, is registered in the European Clinical Trials Database and is carried out in accordance with the Declaration of Helsinki. The study's progress is monitored by Julius Clinical, a science-driven contract research organisation. TRIAL REGISTRATION NUMBER: EudraCT: 2017-003900-28.
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Antirreumáticos , Artrite Psoriásica , Piperidinas , Pirimidinas , Antirreumáticos/uso terapêutico , Artrite Psoriásica/tratamento farmacológico , Biomarcadores , Ensaios Clínicos Fase III como Assunto , Etanercepte/uso terapêutico , Furanos , Humanos , Fatores Imunológicos/uso terapêutico , Metotrexato/uso terapêutico , Estudos Multicêntricos como Assunto , Piperidinas/uso terapêutico , Pirimidinas/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do TratamentoRESUMO
OBJECTIVE: To compare immune cell phenotype and function in psoriatic arthritis (PsA) versus psoriasis in order to better understand the pathogenesis of PsA. METHODS: In-depth immunophenotyping of different T cell and dendritic cell subsets was performed in patients with PsA, psoriasis, or axial spondyloarthritis and healthy controls. Subsequently, we analyzed cells from peripheral blood, synovial fluid (SF), and skin biopsy specimens using flow cytometry, along with high-throughput transcriptome analyses and functional assays on the specific cell populations that appeared to differentiate PsA from psoriasis. RESULTS: Compared to healthy controls, the peripheral blood of patients with PsA was characterized by an increase in regulatory CD4+ T cells and interleukin-17A (IL-17A) and IL-22 coproducing CD8+ T cells. One population specifically differentiated PsA from psoriasis: i.e., CD8+CCR10+ T cells were enriched in PsA. CD8+CCR10+ T cells expressed high levels of DNAX accessory molecule 1 and were effector memory cells that coexpressed skin-homing receptors CCR4 and cutaneous lymphocyte antigen. CD8+CCR10+ T cells were detected under inflammatory and homeostatic conditions in skin, but were not enriched in SF. Gene profiling further revealed that CD8+CCR10+ T cells expressed GATA3, FOXP3, and core transcriptional signature of tissue-resident memory T cells, including CD103. Specific genes, including RORC, IFNAR1, and ERAP1, were up-regulated in PsA compared to psoriasis. CD8+CCR10+ T cells were endowed with a Tc2/22-like cytokine profile, lacked cytotoxic potential, and displayed overall regulatory function. CONCLUSION: Tissue-resident memory CD8+ T cells derived from the skin are enhanced in the circulation of patients with PsA compared to patients with psoriasis alone. This may indicate that aberrances in cutaneous tissue homeostasis contribute to arthritis development.
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Artrite Psoriásica/imunologia , Linfócitos T CD8-Positivos/imunologia , Psoríase/imunologia , Pele/imunologia , Subpopulações de Linfócitos T/imunologia , Linfócitos T Reguladores/imunologia , Adulto , Aminopeptidases/genética , Antígenos CD/genética , Antígenos de Diferenciação de Linfócitos T/imunologia , Artrite Psoriásica/genética , Artrite Psoriásica/patologia , Linfócitos T CD8-Positivos/metabolismo , Estudos de Casos e Controles , Feminino , Fatores de Transcrição Forkhead/genética , Fator de Transcrição GATA3/genética , Perfilação da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Memória Imunológica/imunologia , Imunofenotipagem , Cadeias alfa de Integrinas/genética , Interleucina-17/imunologia , Interleucinas/imunologia , Masculino , Pessoa de Meia-Idade , Antígenos de Histocompatibilidade Menor/genética , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Oligossacarídeos/metabolismo , Psoríase/genética , Psoríase/patologia , Receptor de Interferon alfa e beta/genética , Receptores CCR10/metabolismo , Receptores CCR4/metabolismo , Antígeno Sialil Lewis X/análogos & derivados , Antígeno Sialil Lewis X/metabolismo , Pele/patologia , Espondiloartropatias/genética , Espondiloartropatias/imunologia , Espondiloartropatias/patologia , Líquido Sinovial/citologia , Subpopulações de Linfócitos T/metabolismo , Linfócitos T Citotóxicos/imunologia , Linfócitos T Reguladores/metabolismo , Interleucina 22RESUMO
OBJECTIVE: To examine the role of Tie2 signalling in macrophage activation within the context of the inflammatory synovial microenvironment present in patients with RA and PsA. METHODS: Clinical responses and macrophage function were examined in wild-type and Tie2-overexpressing (Tie2-TG) mice in the K/BxN serum transfer model of arthritis. Macrophages derived from peripheral blood monocytes from healthy donors, RA and PsA patients, and RA and PsA synovial tissue explants were stimulated with TNF (10 ng/ml), angiopoietin (Ang)-1 or Ang-2 (200 ng/ml), or incubated with an anti-Ang2 neutralizing antibody. mRNA and protein expression of inflammatory mediators was analysed by quantitative PCR, ELISA and Luminex. RESULTS: Tie2-TG mice displayed more clinically severe arthritis than wild-type mice, accompanied by enhanced joint expression of IL6, IL12B, NOS2, CCL2 and CXCL10, and activation of bone marrow-derived macrophages in response to Ang-2 stimulation. Ang-1 and Ang-2 significantly enhanced TNF-induced expression of pro-inflammatory cytokines and chemokines in macrophages from healthy donors differentiated with RA and PsA SF and peripheral blood-derived macrophages from RA and PsA patients. Both Ang-1 and Ang-2 induced the production of IL-6, IL-12p40, IL-8 and CCL-3 in synovial tissue explants of RA and PsA patients, and Ang-2 neutralization suppressed the production of IL-6 and IL-8 in the synovial tissue of RA patients. CONCLUSION: Tie2 signalling enhances TNF-dependent activation of macrophages within the context of ongoing synovial inflammation in RA and PsA, and neutralization of Tie2 ligands might be a promising therapeutic target in the treatment of these diseases.
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Artrite Experimental/metabolismo , Artrite Psoriásica/metabolismo , Artrite Reumatoide/metabolismo , Ativação de Macrófagos/fisiologia , Receptor TIE-2/metabolismo , Membrana Sinovial/metabolismo , Animais , Artrite Experimental/patologia , Artrite Psoriásica/patologia , Artrite Reumatoide/patologia , Citocinas/metabolismo , Humanos , Inflamação/metabolismo , Inflamação/patologia , Macrófagos/metabolismo , Camundongos , Camundongos Transgênicos , Transdução de Sinais/fisiologia , Líquido Sinovial/metabolismo , Membrana Sinovial/patologiaRESUMO
OBJECTIVE: The role of innate lymphoid cells (ILCs) in the pathophysiology of rheumatic diseases is emerging. Evidence from animal studies implicate type I IFN, produced by plasmacytoid dendritic cells, to be involved in regulating the survival of group 2 and group 3 ILCs (ILC2s and ILC3s) via the upregulation of Fas (CD95) expression. For the first time, we explored the frequency and phenotype of circulating ILCs in SLE and primary Sjögren's syndrome (pSS) in relationship to the IFN signature. METHODS: Frequencies and phenotypes of ILC subsets and plasmacytoid dendritic cells were assessed by flow cytometry in peripheral blood of patients with SLE (n = 20), pSS (n = 20) and healthy controls (n = 17). Patients were stratified by the presence or absence of an IFN signature as assessed by RT-qPCR on circulating mononuclear cells. RESULTS: ILC1 frequencies were increased in peripheral blood of patients with SLE as compared with healthy controls and correlate with disease activity in pSS patients. Overall, the frequencies of ILC2s or ILC3s did not differ between patients with SLE, pSS and healthy controls. However, patients with a high type I IFN signature expressed elevated levels of Fas on ILC2s and ILC3s, which coincided with decreased frequencies of these cells in blood. CONCLUSION: The presence of a type I IFN signature is related to Fas expression and frequencies of circulating ILC2s and ILC3s in patients with SLE and pSS, potentially altering the homeostatic balance of ILCs.
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Interferons/sangue , Lúpus Eritematoso Sistêmico/sangue , Linfócitos/metabolismo , Síndrome de Sjogren/sangue , Receptor fas/metabolismo , Estudos de Casos e Controles , Células Dendríticas/metabolismo , Citometria de Fluxo , Humanos , Imunidade Inata , Interferons/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Síndrome de Sjogren/imunologiaRESUMO
OBJECTIVE: Innate lymphoid cells (ILCs) are a recently discovered group of cells that are essential to epithelial homeostasis and are implicated in psoriasis pathogenesis, yet they have never been reported in psoriatic arthritis (PsA). METHODS: ILC classes and subsets were characterized in the peripheral blood (PB) of healthy controls, patients with psoriasis, and patients with PsA and in the synovial fluid (SF) of patients with PsA and patients with rheumatoid arthritis (RA). Cell surface marker expression and intracellular cytokine production following stimulation were analyzed using flow cytometry. RESULTS: ILCs were identified in the SF and were 4-fold more abundant in PsA SF than in PsA PB. Fewer CCR6+ ILCs were found in PsA PB than in healthy control PB, while PsA SF was enriched for CCR6+ ILCs compared to PsA PB and RA SF. Natural cytotoxicity receptor NKp44+ group 3 ILCs were rare in PB and RA SF, but abundant in PsA SF. Increased numbers of interleukin-17A (IL-17A)-producing ILCs were present in PsA SF compared to RA SF. CCR6, NKp44, and melanoma cell adhesion molecule (MCAM) were expressed on the cell surface of SF ILCs that produced IL-17A. The number of circulating NKp44+, CCR6+, and MCAM+ ILCs in blood was inversely correlated with PsA disease activity. CONCLUSION: Our findings indicate that PsA SF is enriched for group 3 ILCs that express CCR6 and NKp44, which distinguishes the synovial compartment from RA. The increased IL-17A production by SF ILCs indicates a novel role for ILCs in PsA.
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Artrite Psoriásica/patologia , Imunidade Inata/fisiologia , Linfócitos/patologia , Líquido Sinovial/citologia , Adulto , Artrite Psoriásica/metabolismo , Artrite Reumatoide/metabolismo , Artrite Reumatoide/patologia , Antígeno CD146/metabolismo , Estudos de Casos e Controles , Humanos , Interleucina-17/metabolismo , Linfócitos/metabolismo , Pessoa de Meia-Idade , Receptor 2 Desencadeador da Citotoxicidade Natural/metabolismo , Receptores CCR6/metabolismo , Líquido Sinovial/metabolismoRESUMO
OBJECTIVE: To study the effects of interleukin-7 receptor α-chain (IL-7Rα) blockade on collagen-induced arthritis (CIA) and to investigate the effects on T cell numbers, T cell activity, and levels of proinflammatory mediators. METHODS: We studied the effect of anti-IL-7Rα antibody treatment on inflammation and joint destruction in CIA in mice. Numbers of thymocytes, splenocytes, T cell subsets, B cells, macrophages, and dendritic cells were assessed. Cytokines indicative of Th1, Th2, and Th17 activity and several proinflammatory mediators were assessed by multianalyte profiling in paw lysates. In addition, T cell-associated cytokines were measured in supernatants of lymph node cell cultures. RESULTS: Anti-IL-7Rα treatment significantly reduced clinical arthritis severity in association with reduced radiographic joint damage. Both thymic and splenic cellularity were reduced after treatment with anti-IL-7Rα. IL-7Rα blockade specifically reduced the total number of cells as well as numbers of naive, memory, CD4+, and CD8+ T cells from the spleen and significantly reduced T cell-associated cytokines (interferon-γ, IL-5, and IL-17). IL-7Rα blockade also decreased local levels of proinflammatory cytokines and factors associated with tissue destruction, including tumor necrosis factor α, IL-1ß, IL-6, matrix metalloproteinase 9, and RANKL. IL-7Rα blockade did not significantly affect B cells, macrophages, and dendritic cells. B cell activity, indicated by serum anticollagen IgG antibodies, was not significantly altered. CONCLUSION: Blockade of IL-7Rα potently inhibited joint inflammation and destruction in association with specific reductions of T cell numbers, T cell-associated cytokines, and numerous mediators that induce inflammation and tissue destruction. This study demonstrates an important role of IL-7R-driven immunity in experimental arthritis and indicates the therapeutic potential of IL-7Rα blockade in human arthritic conditions.
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Anticorpos Bloqueadores/farmacologia , Artrite Experimental/terapia , Subunidade alfa de Receptor de Interleucina-7/antagonistas & inibidores , Linfócitos T/efeitos dos fármacos , Animais , Artrite Experimental/imunologia , Artrite Experimental/metabolismo , Linfócitos B/citologia , Linfócitos B/efeitos dos fármacos , Contagem de Células , Citocinas/metabolismo , Células Dendríticas/citologia , Células Dendríticas/efeitos dos fármacos , Membro Posterior , Subunidade alfa de Receptor de Interleucina-7/imunologia , Articulações/efeitos dos fármacos , Articulações/metabolismo , Articulações/patologia , Linfonodos/efeitos dos fármacos , Linfonodos/metabolismo , Linfonodos/patologia , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos DBA , Baço/citologia , Baço/efeitos dos fármacos , Subpopulações de Linfócitos T/citologia , Subpopulações de Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Timo/citologia , Timo/efeitos dos fármacosRESUMO
OBJECTIVE: To evaluate the expression and functional ability of the high-affinity interleukin-7 receptor (IL-7Ralpha) in patients with rheumatoid arthritis (RA). METHODS: Expression of IL-7Ralpha and IL-7 was determined in synovial tissue from RA patients and was compared with that in synovial tissue from patients with undifferentiated arthritis (UA) and osteoarthritis (OA). IL-7Ralpha expression on CD4 T cells, CD19 B cells, and CD14 monocyte/macrophages from RA synovial tissue, synovial fluid, and peripheral blood was also assessed. The proliferative capacity of IL-7Ralpha(bright) and IL-7Ralpha(dim/-) T cells was measured. In addition, we examined IL-7R blockade with soluble human IL-7Ralpha (hIL-7Ralpha) in the prevention of immune activation of peripheral blood mononuclear cells. RESULTS: We found significantly higher IL-7Ralpha expression in RA and UA synovial tissue than in OA synovial tissue, and the level of IL-7Ralpha expression correlated significantly with the levels of CD3 and IL-7 expression. CD4 T cells from RA synovial fluid and synovial tissue strongly expressed IL-7Ralpha. A substantial percentage of B cells and macrophages from RA synovial fluid and synovial tissue also expressed IL-7Ralpha, although less prominently than T cells. We found that peripheral blood IL-7Ralpha(bright) T cells that did not express FoxP3 were highly proliferative as compared with IL-7Ralpha(dim/-) T cells that did express high levels of FoxP3. Soluble hIL-7Ralpha inhibited IL-7-induced proliferation and interferon-gamma production by mononuclear cells from RA patients. CONCLUSION: Our data suggest that enhanced expression of IL-7Ralpha and IL-7 in RA patients contributes significantly to the joint inflammation by activating T cells, B cells, and macrophages. The inhibition of IL-7R-mediated immune activation by soluble hIL-7Ralpha further indicates an important role of IL-7Ralpha in inflammatory responses in RA, suggesting IL-7Ralpha as a therapeutic target for immunotherapy in RA.
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Artrite Reumatoide/imunologia , Artrite Reumatoide/metabolismo , Interleucina-7/metabolismo , Articulações/metabolismo , Receptores de Interleucina-7/metabolismo , Membrana Sinovial/metabolismo , Adulto , Idoso , Antígenos CD19/metabolismo , Artrite/imunologia , Artrite/metabolismo , Artrite/patologia , Artrite Reumatoide/patologia , Linfócitos B/imunologia , Linfócitos B/metabolismo , Linfócitos B/patologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/patologia , Feminino , Fatores de Transcrição Forkhead/metabolismo , Humanos , Articulações/imunologia , Articulações/patologia , Receptores de Lipopolissacarídeos/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Pessoa de Meia-Idade , Osteoartrite/imunologia , Osteoartrite/metabolismo , Osteoartrite/patologia , Membrana Sinovial/imunologia , Membrana Sinovial/patologiaRESUMO
OBJECTIVES: To identify the mechanism of interleukin (IL)7-stimulated tumour necrosis factor alpha (TNFalpha) production and to determine the relationship between intra-articular IL7 and TNFalpha expression levels in patients with rheumatoid arthritis (RA). In addition, the effect of TNFalpha blockade on IL7 activity and on IL7 levels was studied. METHODS: The effect of IL7 on isolated CD4 T cells and CD14 monocytes/macrophages was studied. IL7 and TNFalpha levels were measured in the synovial fluid of patients with RA. In RA synovial tissue, IL7 and TNFalpha expression was assessed in addition to IL1beta, numbers of inflammatory cells and adhesion molecule expression. The extent to which TNFalpha blockade could prevent IL7-induced lymphocyte responses was studied in vitro. In addition, regulation of serum IL7 levels on anti-TNFalpha therapy (adalimumab) was studied. RESULTS: IL7 induced cell contact-dependent TNFalpha production by cocultures of T cells and monocytes, but not by T cells and monocytes cultured separately. IL7 and TNFalpha levels in RA synovial fluid and synovial tissue significantly correlated. IL7-stimulated lymphocyte responses were not inhibited by TNFalpha blockade. Circulating IL7 levels were significantly reduced in patients who successfully responded to anti-TNFalpha treatment. However, IL7 levels persisted in non-responders. CONCLUSION: The present data suggest that IL7 is an important inducer of T cell-dependent TNFalpha production in RA joints. This may contribute to the correlation of intra-articular IL7 and TNFalpha in these joints. Furthermore, the persistence of IL7-induced inflammatory activity on TNFalpha blockade in vitro and persistence of IL7 levels and disease activity in anti-TNFalpha non-responders suggest that IL7 might additionally promote TNFalpha-independent inflammation.