RESUMO
Psoriatic arthritis (PsA) is a complex inflammatory disease that challenges diagnosis and complicates the rational selection of effective therapies. Although T cells are considered active effectors in psoriasis and PsA, the role of CD8+ T cells in pathogenesis is not well understood. We selected the humanized mouse model NSG-SGM3 transgenic strain to examine psoriasis and PsA endotypes. Injection of PBMCs and sera from patients with psoriasis and PsA generated parallel skin and joint phenotypes in the recipient mouse. The transfer of human circulating memory T cells was followed by migration and accumulation in the skin and synovia of these immunodeficient mice. Unexpectedly, immunoglobulins were required for recapitulation of the clinical phenotype of psoriasiform lesions and PsA domains (dactylitis, enthesitis, bone erosion). Human CD8+ T cells expressing T-bet, IL-32 and CXCL14 were detected by spatial transcriptomics in murine synovia and by immunofluorescence in the human PsA synovia. Importantly, depletion of human CD8+ T cells prevented skin and synovial inflammation in mice humanized with PsA peripheral blood cells. The humanized model of psoriasis and PsA represents a valid platform for accelerating the understanding of disease pathogenesis, improving the design of personalized therapies, and revealing psoriatic disease targets.
Assuntos
Artrite Psoriásica , Linfócitos T CD8-Positivos , Modelos Animais de Doenças , Animais , Artrite Psoriásica/imunologia , Artrite Psoriásica/patologia , Humanos , Camundongos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Camundongos Transgênicos , Pele/patologia , Pele/imunologia , Feminino , Masculino , Fenótipo , Psoríase/imunologia , Psoríase/patologiaRESUMO
Psoriatic arthritis (PsA) is part of the psoriatic disease spectrum and is characterized by a chronic inflammatory process that affects entheses, tendons and joints. Cytokines produced by immune and non-immune cells play a central role in the pathogenesis of PsA by orchestrating key aspects of the inflammatory response. Pro-inflammatory cytokines such as TNF, IL-23 and IL-17 have been shown to regulate the initiation and progression of PsA, ultimately leading to the destruction of the architecture of the local tissues such as soft tissue, cartilage and bone. The important role of cytokines in PsA has been underscored by the clinical success of antibodies that neutralize their function. In addition to biologic agents targeting individual pro-inflammatory cytokines, signaling inhibitors that block multiple cytokines simultaneously such as JAK inhibitors have been approved for PsA therapy. In this review, we will focus on our current understanding of the role of cytokines in the disease process of PsA and discuss potential new treatment options based on modulation of cytokine function.
Assuntos
Artrite Psoriásica , Citocinas , Artrite Psoriásica/tratamento farmacológico , Artrite Psoriásica/imunologia , Humanos , Citocinas/imunologia , Animais , Interleucina-17/antagonistas & inibidores , Interleucina-17/imunologia , Interleucina-23/imunologia , Interleucina-23/antagonistas & inibidores , Transdução de Sinais , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/imunologia , Inibidores de Janus Quinases/uso terapêuticoRESUMO
Objectives: Programmed cell death protein-1 (PD-1) maintains peripheral immune tolerance by preventing T cell continuous activation. Aiming to understand the extent of PD-1 expression in inflammatory arthritis beyond its involvement with T cells, we assess its presence on various circulating single cells. Methods: Mass cytometry analysis of patients with active seropositive/seronegative rheumatoid (RA; n=9/8) and psoriatic (PsA; n=9) arthritis versus healthy controls (HC; n=13), re-evaluating patients after 3 months of anti-rheumatic treatment. Results: PD-1 was expressed in all leukocyte subpopulations, with the highest PD-1+ cell frequencies in eosinophils (59-73%) and T cells (50-60%), and the lowest in natural-killer cells (1-3%). PD-1+ cell frequencies and PD-1 median expression were comparable between patient subgroups and HC, in the majority of cell subsets. Exceptions included increases in certain T cell/B cell subsets of seropositive RA and specific monocyte subsets and dendritic cells of PsA; an expanded PD-1+CD4+CD45RA+CD27+CD28+ T subset, denoting exhausted T cells, was common across patient subgroups. Strikingly, significant inverse correlations between individual biomarkers of systemic inflammation (ESR and/or serum CRP) and PD-1+ cell frequencies and/or median expression were evident in several innate and adaptive immunity cell subsets of RA and PsA patients. Furthermore, all inverse correlations noted in individuals with active arthritis were no longer discernible in those who attained remission/low disease activity post-treatment. Conclusion: PD-1 expression may be insufficient, relative to the magnitude of the concomitant systemic inflammatory response on distinct leukocyte subsets, varying between RA and PsA. Our results point to the potential therapeutic benefits of pharmacological PD-1 activation, to rebalance the autoimmune response and reduce inflammation.
Assuntos
Artrite Psoriásica , Artrite Reumatoide , Receptor de Morte Celular Programada 1 , Proteômica , Análise de Célula Única , Humanos , Receptor de Morte Celular Programada 1/metabolismo , Masculino , Feminino , Pessoa de Meia-Idade , Artrite Reumatoide/imunologia , Artrite Reumatoide/sangue , Artrite Psoriásica/imunologia , Proteômica/métodos , Idoso , Adulto , Autoimunidade , BiomarcadoresRESUMO
We aim to systemically review the genomics, transcriptomics, epigenetics, proteomics, metabonomics and microbiota of psoriatic arthritis and psoriasis, illustrating the differences of these two diseases, broadening our understanding of the pathogenesis of them and providing important clues for valuable biomarkers of earlier diagnosis and treatments. To our knowledge, this is the first study that combine all omics studies from genomics to microbiota and may serve as a reference for future studies to identify the key underlying pathways in psoriatic arthritis.
Assuntos
Artrite Psoriásica , Genômica , Metabolômica , Proteômica , Psoríase , Humanos , Artrite Psoriásica/diagnóstico , Artrite Psoriásica/imunologia , Psoríase/diagnóstico , Psoríase/imunologia , Genômica/métodos , Microbiota/imunologia , Biomarcadores/metabolismo , Epigênese Genética , Transcriptoma , MultiômicaRESUMO
Biologics and Janus kinase (JAK) inhibitors are immunomodulating and immunosuppressing medications utilized to treat atopic dermatitis (AD), psoriasis (PSO), psoriatic arthritis (PsA), and alopecia areata (AA). Special recommendations must be considered when prescribing vaccinations in this population, as the pneumococcal and herpes zoster vaccine are recommended to patients ≥ 19-years-old (rather than ≥ 65-years-old and ≥ 50-years-old as in the general population, respectively), along with a yearly influenza and up to date COVID-19 vaccination. Additionally, TNF-α and JAK-inhibitors may increase the risk of latent Hepatitis B virus (HBV) reactivation among high-risk patients. Prior to prescribing these medications, a quantitative HepB Surface Antibody (HepB SA) test is performed to determine immunity. This study utilized the SlicerDicer function on EPIC Medical Records to search for any patient ≥ 19-years-old prescribed a biologic or JAK inhibitor for AD, PSO, PsA, or AA between 10/2003 and 10/2023 at a large tertiary institution. Vaccination rates among patients on biologics and JAK inhibitors were low, with rates being significantly lower in patients 19-64 years-old, compared to those ≥ 65 years-old for most disease states (p < 0.01). Among AD, PSO/PsA, and AA patients, on average, 9.39% were vaccinated for influenza, 6.76% for herpes zoster, 16.56% for pneumococcal pneumonia, and 63.98% for COVID-19. Only 3.16% of patients were adequately vaccinated for HepB after an abnormal HepB SA test. Here, extremely low rates of vaccination among patients on biologics and JAK inhibitors at our institution were highlighted, emphasizing the imperative need for ensuring vaccination in this group.
Assuntos
Alopecia em Áreas , Artrite Psoriásica , Produtos Biológicos , Dermatite Atópica , Vacinação , Humanos , Pessoa de Meia-Idade , Dermatite Atópica/tratamento farmacológico , Dermatite Atópica/imunologia , Dermatite Atópica/epidemiologia , Masculino , Adulto , Feminino , Alopecia em Áreas/imunologia , Alopecia em Áreas/tratamento farmacológico , Alopecia em Áreas/epidemiologia , Produtos Biológicos/uso terapêutico , Produtos Biológicos/efeitos adversos , Idoso , Adulto Jovem , Artrite Psoriásica/tratamento farmacológico , Artrite Psoriásica/imunologia , Vacinação/estatística & dados numéricos , Inibidores de Janus Quinases/uso terapêutico , Psoríase/tratamento farmacológico , Psoríase/imunologia , COVID-19/prevenção & controle , COVID-19/epidemiologia , COVID-19/imunologia , Estudos Retrospectivos , SARS-CoV-2/imunologiaRESUMO
In recent years, research has intensified in exploring the genetic basis of psoriasis (PsO) and psoriatic arthritis (PsA). Genome-wide association studies (GWASs), including tools like ImmunoChip, have significantly deepened our understanding of disease mechanisms by pinpointing risk-associated genetic loci. These efforts have elucidated biological pathways involved in PsO pathogenesis, particularly those related to the innate immune system, antigen presentation, and adaptive immune responses. Specific genetic loci, such as TRAF3IP2, REL, and FBXL19, have been identified as having a significant impact on disease development. Interestingly, different genetic variants at the same locus can predispose individuals to either PsO or PsA (e.g., IL23R and deletion of LCE3B and LCE3C), with some variants being uniquely linked to PsA (like HLA B27 on chromosome 6). This article aims to summarize known and new data on the genetics of PsO and PsA, their associated genes, and the involvement of the HLA system and cytokines.
Assuntos
Artrite Psoriásica , Citocinas , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Antígenos HLA , Psoríase , Humanos , Artrite Psoriásica/genética , Artrite Psoriásica/imunologia , Psoríase/genética , Psoríase/imunologia , Antígenos HLA/genéticaRESUMO
Objectives: IL26 levels are elevated in the blood and synovial fluid of patients with inflammatory arthritis. IL26 can be produced by Th17 cells and locally within joints by tissue-resident cells. IL26 induces osteoblast mineralization in vitro. As osteoproliferation and Th17 cells are important factors in the pathogenesis of axial spondyloarthritis (axSpA), we aimed to clarify the cellular sources of IL26 in spondyloarthritis. Methods: Serum, peripheral blood mononuclear cells (n = 15-35) and synovial tissue (n = 3-9) of adult patients with axSpA, psoriatic arthritis (PsA) and rheumatoid arthritis (RA) and healthy controls (HCs, n = 5) were evaluated by ELISA, flow cytometry including PrimeFlow assay, immunohistochemistry and immunofluorescence and quantitative PCR. Results: Synovial tissue of axSpA patients shows significantly more IL26-positive cells than that of HCs (p < 0.01), but numbers are also elevated in PsA and RA patients. Immunofluorescence shows co-localization of IL26 with CD68, but not with CD3, SMA, CD163, cadherin-11, or CD90. IL26 is elevated in the serum of RA and PsA (but not axSpA) patients compared with HCs (p < 0.001 and p < 0.01). However, peripheral blood CD4+ T cells from axSpA and PsA patients show higher positivity for IL26 in the PrimeFlow assay compared with HCs. CD4+ memory T cells from axSpA patients produce more IL26 under Th17-favoring conditions (IL-1ß and IL-23) than cells from PsA and RA patients or HCs. Conclusion: IL26 production is increased in the synovial tissue of SpA and can be localized to CD68+ macrophage-like synoviocytes, whereas circulating IL26+ Th17 cells are only modestly enriched. Considering the osteoproliferative properties of IL26, this offers new therapeutic options independent of Th17 pathways.
Assuntos
Antígenos CD , Artrite Psoriásica , Interleucinas , Sinoviócitos , Humanos , Artrite Psoriásica/imunologia , Artrite Psoriásica/metabolismo , Sinoviócitos/metabolismo , Sinoviócitos/imunologia , Sinoviócitos/patologia , Masculino , Adulto , Feminino , Antígenos CD/metabolismo , Interleucinas/metabolismo , Interleucinas/sangue , Pessoa de Meia-Idade , Antígenos de Diferenciação Mielomonocítica/metabolismo , Espondiloartrite Axial/imunologia , Células Th17/imunologia , Células Th17/metabolismo , Membrana Sinovial/imunologia , Membrana Sinovial/metabolismo , Membrana Sinovial/patologia , Articulações/patologia , Articulações/imunologia , Articulações/metabolismo , Artrite Reumatoide/imunologia , Artrite Reumatoide/metabolismo , Artrite Reumatoide/sangue , Artrite Reumatoide/patologiaRESUMO
PsoP27 is an antigen expressed in psoriatic lesions. It plays an inflammatory role in psoriasis. This study objective was to characterize antibodies (Abs) against PsoP27 in patients with psoriatic arthritis (PsA) and rheumatoid arthritis (RA). Levels of Abs against native and citrullinated PsoP27 in PsA and RA patients' synovial fluid (SF) and sera were determined by ELISA. SF of osteoarthritis (OA) patients and sera of healthy donors were used as controls. Levels of Abs against PsoP27 were correlated with disease activity scores. Abs against native and citrullinated PsoP27 levels in SF of PsA (n = 48; 0.38 ± 0.03 and 0.44 ± 0.04, respectively) and RA (n = 22; 0.57 ± 0.1 and 0.62 ± 0.09, respectively) were significantly higher than in OA patients (n = 23; 0.14 ± 0.01 and 0.15 ± 0.01, respectively) (p < .0001). For both Abs, there were no significant differences between their level in PsA and RA patients. There was no difference in the level of Abs against citrullinated PsoP27 in SF of seronegative versus seropositive RA patients. Levels of Abs against both native and citrullinated PsoP27 in the SF and level of systemic C-reactive protein in PsA correlated positively, while in RA there were no significant correlations with disease activity scores. No differences in level of Abs against PsoP27 were found in the sera of all three study groups. Abs against native and citrullinated PsoP27 are present in PsA and RA SF but not in those of OA patients, suggesting a potential role of those Abs in inflammatory joint diseases.
Assuntos
Artrite Psoriásica , Artrite Reumatoide , Autoanticorpos , Líquido Sinovial , Humanos , Artrite Psoriásica/imunologia , Artrite Psoriásica/sangue , Artrite Psoriásica/metabolismo , Artrite Reumatoide/imunologia , Artrite Reumatoide/sangue , Líquido Sinovial/imunologia , Líquido Sinovial/metabolismo , Autoanticorpos/sangue , Autoanticorpos/imunologia , Masculino , Pessoa de Meia-Idade , Feminino , Adulto , Idoso , Estudos de Casos e Controles , Osteoartrite/imunologia , Osteoartrite/sangue , Ensaio de Imunoadsorção EnzimáticaRESUMO
AIM: This study aimed to construct prognostic mathematical models utilizing multifactorial regression analysis to assess the risk of developing drug-induced neutralizing antibodies in patients with rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis treated with tumor necrosis factor alpha blockers.
Assuntos
Anticorpos Neutralizantes , Artrite Psoriásica , Artrite Reumatoide , Espondilite Anquilosante , Fator de Necrose Tumoral alfa , Humanos , Espondilite Anquilosante/tratamento farmacológico , Espondilite Anquilosante/imunologia , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/imunologia , Artrite Psoriásica/tratamento farmacológico , Artrite Psoriásica/imunologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/imunologia , Prognóstico , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , Antirreumáticos/uso terapêutico , Modelos TeóricosRESUMO
Interleukin (IL)-23, an IL-12 cytokine family member, is a hierarchically dominant regulatory cytokine in a cluster of immune-mediated inflammatory diseases (IMIDs), including psoriasis, psoriatic arthritis, and inflammatory bowel disease. We review IL-23 biology, IL-23 signaling in IMIDs, and the effect of IL-23 inhibition in treating these diseases. We propose studies to advance IL-23 biology and unravel differences in response to anti-IL-23 therapy. Experimental evidence generated from these investigations could establish a novel molecular ontology centered around IL-23-driven diseases, improve upon current approaches to treating IMIDs with IL-23 inhibition, and ultimately facilitate optimal identification of patients and, thereby, outcomes.
Assuntos
Interleucina-23 , Animais , Humanos , Artrite Psoriásica/imunologia , Artrite Psoriásica/tratamento farmacológico , Doenças Inflamatórias Intestinais/imunologia , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/terapia , Interleucina-23/antagonistas & inibidores , Interleucina-23/imunologia , Interleucina-23/metabolismo , Psoríase/imunologia , Psoríase/tratamento farmacológico , Transdução de SinaisRESUMO
Restoring peripheral immune tolerance is crucial for addressing autoimmune diseases. An ancient mechanism in maintaining the balance between inflammation and tolerance is the ratio of extracellular ATP (exATP) and adenosine. Our previous research demonstrated the effectiveness of small spleen peptides (SSPs) in inhibiting psoriatic arthritis progression, even in the presence of the pro-inflammatory cytokine TNFα, by transforming dendritic cells (DCs) into tolerogenic cells and fostering regulatory Foxp3+ Treg cells. Here, we identified thymosins as the primary constituents of SSPs, but recombinant thymosin peptides were less efficient in inhibiting arthritis than SSPs. Since Tß4 is an ecto-ATPase-binding protein, we hypothesized that SSPs regulate exATP profiles. Real-time investigation of exATP levels in DCs revealed that tolerogenic stimulation led to robust de novo exATP synthesis followed by significant degradation, while immunogenic stimulation resulted in a less pronounced increase in exATP and less effective degradation. These contrasting exATP profiles were crucial in determining whether DCs entered an inflammatory or tolerogenic state, highlighting the significance of SSPs as natural regulators of peripheral immunological tolerance, with potential therapeutic benefits for autoimmune diseases. Finally, we demonstrated that the tolerogenic phenotype of SSPs is mainly influenced by adenosine receptors, and in vivo administration of SSPs inhibits psoriatic skin inflammation.
Assuntos
Trifosfato de Adenosina , Diferenciação Celular , Células Dendríticas , Baço , Células Dendríticas/metabolismo , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Trifosfato de Adenosina/metabolismo , Trifosfato de Adenosina/farmacologia , Animais , Diferenciação Celular/efeitos dos fármacos , Baço/citologia , Baço/metabolismo , Baço/efeitos dos fármacos , Baço/imunologia , Camundongos , Timosina/farmacologia , Timosina/metabolismo , Peptídeos/farmacologia , Artrite Psoriásica/tratamento farmacológico , Artrite Psoriásica/metabolismo , Artrite Psoriásica/imunologia , Humanos , Camundongos Endogâmicos C57BL , Tolerância Imunológica/efeitos dos fármacosRESUMO
Objectives: 1) To characterize the inflammatory proteome of synovial fluid (SF) from patients with Psoriatic Arthritis (PsA) using a high-quality throughput proteomic platform, and 2) to evaluate its potential to stratify patients according to clinical features. Methods: Inflammatory proteome profile of SF from thirteen PsA patients with active knee arthritis were analyzed using proximity extension assay (PEA) technology (Olink Target 96 Inflammation panel). Four patients with OA were included as control group. Results: Seventy-nine inflammation-related proteins were detected in SF from PsA patients (SF-PsA). Unsupervised analyzes of the molecular proteome profile in SF-PsA identified two specific phenotypes characterized by higher or lower levels of inflammation-related proteins. Clinically, SF-PsA with higher levels of inflammatory proteins also showed increased systemic inflammation and altered glucose and lipid metabolisms. Besides, SF from PsA patients showed 39 out of 79 proteins significantly altered compared to SF-OA specifically related to cell migration and inflammatory response. Among these, molecules such as TNFα, IL-17A, IL-6, IL-10, IL-8, ENRAGE, CCL20, TNFSF-14, OSM, IFNγ, MCP-3, CXCL-11, MCP4, CASP-8, CXCL-6, CD-6, ADA, CXCL-10, TNFß and IL-7 showed the most significantly change. Conclusion: This is the first study that characterizes the inflammatory landscape of synovial fluid of PsA patients by analyzing a panel of 92 inflammatory proteins using PEA technology. Novel SF proteins have been described as potential pathogenic molecules involved in the pathogenesis of PsA. Despite the flare, inflammatory proteome could distinguish two different phenotypes related to systemic inflammation and lipid and glucose alterations.
Assuntos
Artrite Psoriásica , Líquido Sinovial , Líquido Sinovial/química , Artrite Psoriásica/imunologia , Artrite Psoriásica/metabolismo , Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Sinoviócitos/metabolismo , Citocinas/análise , Joelho/patologiaRESUMO
OBJECTIVES: To compare the magnitude of cognitive impairment against age-expected levels across the immune mediated inflammatory diseases (IMIDs: systemic lupus erythematosus [SLE], rheumatoid arthritis [RA], axial spondyloarthritis [axSpA], psoriatic arthritis [PsA], psoriasis [PsO]). METHODS: A pre-defined search strategy was implemented in Medline, Embase and Psychinfo on 29/05/2021. Inclusion criteria were: (i) observational studies of an IMID, (ii) healthy control comparison, (iii) measuring cognitive ability (overall, memory, complex attention/executive function, language/verbal fluency), and (iv) sufficient data for meta-analysis. Standardised mean differences (SMD) in cognitive assessments between IMIDs and controls were pooled using random-effects meta-analysis. IMIDs were compared using meta-regression. RESULTS: In total, 65 IMID groups were included (SLE: 39, RA: 19, axSpA: 1, PsA: 2 PsO: 4), comprising 3141 people with IMIDs and 9333 controls. People with IMIDs had impairments in overall cognition (SMD: -0.57 [95% CI -0.70, -0.43]), complex attention/executive function (SMD -0.57 [95% CI -0.69, -0.44]), memory (SMD -0.55 [95% CI -0.68, -0.43]) and language/verbal fluency (SMD -0.51 [95% CI -0.68, -0.34]). People with RA and people with SLE had similar magnitudes of cognitive impairment in relation to age-expected levels. People with neuropsychiatric SLE had larger impairment in overall cognition compared with RA. CONCLUSIONS: People with IMIDs have moderate impairments across a range of cognitive domains. People with RA and SLE have similar magnitudes of impairment against their respective age-expected levels, calling for greater recognition of cognitive impairment in both conditions. To further understand cognition in the IMIDs, more large-scale, longitudinal studies are needed.
Assuntos
Artrite , Disfunção Cognitiva , Lúpus Eritematoso Sistêmico , Psoríase , Humanos , Artrite Psoriásica/complicações , Artrite Psoriásica/imunologia , Artrite Reumatoide/complicações , Artrite Reumatoide/imunologia , Cognição , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/imunologia , Lúpus Eritematoso Sistêmico/complicações , Espondiloartrite Axial/complicações , Espondiloartrite Axial/imunologia , Artrite/complicações , Artrite/imunologia , Inflamação/complicações , Inflamação/imunologiaRESUMO
OBJECTIVE: To assess long-term efficacy and safety of guselkumab, an interleukin-23 p19 subunit (IL-23p19) inhibitor, in patients with active psoriatic arthritis (PsA) from the phase III DISCOVER-2 trial. METHODS: In the DISCOVER-2 trial, patients with active PsA (≥5 swollen joints and ≥5 tender joints; C-reactive protein level ≥0.6 mg/dl) despite prior nonbiologic therapy were randomized to receive the following: guselkumab 100 mg every 4 weeks; guselkumab 100 mg at weeks 0 and 4 and then every 8 weeks; or placebo with crossover to guselkumab 100 mg every 4 weeks, beginning at week 24. Efficacy assessments included American College of Rheumatology ≥20%/50%/70% improvement criteria (ACR20/50/70), Investigator's Global Assessment (IGA) of psoriasis score of 0 (indicating complete skin clearance), resolution of enthesitis (Leeds Enthesitis Index) and dactylitis (Dactylitis Severity Score), and changes in the Sharp/van der Heijde modified radiographic scores for PsA. Clinical data (imputed as no response/no change from baseline if missing) and observed radiographic data were summarized through week 100; safety assessments continued through week 112. RESULTS: Of the 739 randomized and treated patients, 652 (88%) completed treatment through week 100. Across groups of guselkumab-treated patients (including those in the placebo-guselkumab crossover group), the following findings at week 100 indicated that amelioration of arthritis signs/symptoms and extraarticular manifestations was durable through 2 years: ACR20 response (68-76%), ACR50 response (48-56%), ACR70 response (30-36%), IGA score of 0 (55-67%), enthesitis resolution (62-70%), and dactylitis resolution (72-83%). Mean changes in the Sharp/van der Heijde modified score for PsA from weeks 52 to week 100 (range 0.13-0.75) indicated that the low rates of radiographic progression observed among guselkumab-treated patients at earlier time points extended through week 100. Through week 112, 8% (5.8 per 100 patient-years) and 3% (1.9 per 100 patient-years) of the 731 guselkumab-treated patients had a serious adverse event or serious infection, respectively; 1 death occurred (road traffic accident). CONCLUSION: In biologic-naive PsA patients, guselkumab provided durable improvements in multiple disease domains with no unexpected safety findings through 2 years.
Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antirreumáticos/uso terapêutico , Artrite Psoriásica/tratamento farmacológico , Subunidade p19 da Interleucina-23/imunologia , Adulto , Anticorpos Monoclonais Humanizados/efeitos adversos , Antirreumáticos/efeitos adversos , Artrite Psoriásica/diagnóstico , Artrite Psoriásica/imunologia , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
Objective: To examine the role of synovial CD1c+DCs in patients with Inflammatory Arthritis (IA) with a specific focus on the transcriptional and maturation signatures that govern their function. Methods: RNA sequencing was performed on healthy control (HC) peripheral blood (PB), IA PB, and IA synovial fluid (SF) CD1c+DCs. Multiparametric flow-cytometry and SPICE analysis were used to examine site [SF and Synovial Tissue (ST) CD1c+DCs] and disease specific characteristics of CD1c+DCs, while functional assays such as antigen processing, activation, and MMP production were also performed. Results: Increased frequency of CD1c+DCs (p<0.01) with a concomitant increase in CD80, CCR7 (p<0.01), and CXCR3 (p<0.05) expression was identified in IA PB compared to HC PB. Enrichment of CD1c+DCs was identified in IA synovial tissue (ST) (p<0.01) and IA SF (p<0.0001) compared to IA PB, while RNAseq revealed distinct transcriptional variation between PB and SF CD1c+DCs. Flow cytometry revealed increased expression of CD83, CD80, PD-L1, and BTLA (all p<0.05) in IA SF CD1c+DCs compared to PB, while SPICE identified synovial cells with unique co-expression patterns, expressing multiple DC maturation markers simultaneously. Functionally, synovial CD1c+DCs are hyper-responsive to TLR7/8 ligation (p<0.05), have decreased antigen processing capacity (p=0.07), and display dysregulated production of MMPs. Finally, examination of both synovial CD1c+DCs and synovial CD141+DCs revealed distinct maturation and transcriptomic profiles. Conclusion: Synovial CD1c+DCs accumulate in the inflamed IA synovium in a variety of distinct poly-maturational states, distinguishing them transcriptionally and functionally from CD1c+DCs in the periphery and synovial CD141+DCs.
Assuntos
Artrite Psoriásica/imunologia , Artrite Reumatoide/imunologia , Células Dendríticas/imunologia , Membrana Sinovial/imunologia , Adulto , Antígenos CD1/imunologia , Feminino , Glicoproteínas/imunologia , Humanos , Inflamação/imunologia , Masculino , Pessoa de Meia-IdadeRESUMO
Objectives: To find out the genetic association between IL6 and autoimmune arthritis. Methods: We performed a two-sample Mendelian randomization (MR) study using multiple genome-wide association studies (GWAS) datasets. Furthermore, a sex-stratified MR study was performed to identify sexual dimorphism in the association between IL6 and autoimmune arthritis. Then, LocusZoom plots were displayed based on the IL6R gene region to present evidence of genetic colocalization between diseases. Results: The MR result denoted a genetic association between the increased level of IL-6 signaling and risk of RA (ß=0.325, 95%CI 0.088, 0.561, p=7.08E-03) and AS (ß=1.240, 95%CI 0.495, 1.980, p=1.1E-03). Accordingly, sIL6R was found to have negatively correlation with the onset of RA (ß=-0.020, 95%CI -0.0320, -0.008, p=1.18E-03) and AS (ß=-0.125, 95%CI -0.177, -0.073, p=2.29E-06). However, no genetic association between IL6/sIL6R and PsA was detected. The gender-stratified MR analysis showed that IL6 was associated with AS in the male population, with RA in the female population, and with PsA in the male population. Additionally, ADAR, a gene identified by a sensitive test, could be the reason for the nonsignificant association between IL6 and PsA in a pooled population. Conclusion: Our findings showed that the overactive IL6 signal pathway led to autoimmune arthritis, especially in RA and AS. Sexual difference was also observed in IL6-intermediate susceptibility to autoimmune arthritis.
Assuntos
Artrite Psoriásica/genética , Artrite Reumatoide/genética , Espondiloartrite Axial/genética , Predisposição Genética para Doença , Interleucina-6/genética , Caracteres Sexuais , Artrite Psoriásica/imunologia , Artrite Reumatoide/imunologia , Espondiloartrite Axial/imunologia , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Análise da Randomização MendelianaRESUMO
BACKGROUND: CD146 (MCAM-melanoma cell adhesion molecule) is a cell surface adhesion molecule for Laminin 411. T cells expressing MCAM are mainly responsible for IL-17 production. IL-17 secreting T helper cells (Th17 cells) are critical for the pathogenesis of psoriatic arthritis (PsA). Here we hypothesized enrichment of CD146+IL-17+ memory T cells in PsA synovium and studied the association of CD146 expression and CD4+IL-17+ activated memory (CD11a+CD45RO+) T cells in synovial fluid and blood of PSA, rheumatoid arthritis (RA, a positive control) and osteoarthritis (OA) patients. METHODS: Hi-D FACS studies were done to identify IL-17 in CD4+CD146+CD45RO+ and CD8+CD146+CD45RO+ T cells. RESULTS: We observed that effector CD146+(MCAM+) T cells are enriched at the synovial inflammation site in PsA. CONCLUSION: As CD146+ T cells are a key resource for IL-17 it is likely that the enrichment of these MCAM+ pathologic cells are critical for the disease process of PsA.
Assuntos
Artrite Psoriásica/imunologia , Artrite Psoriásica/patologia , Antígeno CD146/metabolismo , Subpopulações de Linfócitos/imunologia , Linfócitos T/imunologia , Artrite Reumatoide/imunologia , Artrite Reumatoide/patologia , Feminino , Humanos , Memória Imunológica , Inflamação/imunologia , Interleucina-17/metabolismo , Masculino , Pessoa de Meia-Idade , Fenótipo , Membrana Sinovial/patologiaRESUMO
Patients with psoriasis are frequently obese and experience anxiety or suffer from depressive disorders. The immunopathogenesis of psoriasis and indeed psoriatic arthritis is largely based on the pivotal role of IL-17/IL-23 axis, to an extent that currently monoclonal antibodies selectively inhibiting IL-17 or IL-23 are routinely used for the treatment of psoriatic diseases. Emerging data, demonstrating a decisive role for IL-17 and IL-17 producing cell subsets, such as Th17 in the induction and progression of obesity and depression has led authors to suggest that psoriatic disease, obesity and anxiety/depression may indeed be interconnected manifestation of a state of immunedysregulation, the linked being IL-17 and its related cells. We discuss this hypothetical link in depth taking into account the beneficial effects anti-IL17 and anti-IL-17 receptor inhibitors in treating psoriatic disease and the on-going debate as to whether these biologics may exert a direct or indirect effect in ameliorating concomitant obesity and depressive disorders, which are frequently noted in the same patient.