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1.
Exp Dermatol ; 31(6): 962-969, 2022 06.
Artículo en Inglés | MEDLINE | ID: mdl-35297512

RESUMEN

Interleukin (IL)-12 and IL-23 are pro-inflammatory cytokines produced by dendritic cells (DCs) and associated with Psoriasis (Pso) and Psoriatic Arthritis (PsA) pathogenesis. Tofacitinib, a Janus kinase inhibitor, effectively suppresses inflammatory cascades downstream the IL-12/IL-23 axis in Pso and PsA patients. Here, we investigated whether Tofacitinib directly regulates IL-12/IL-23 production in DCs, and how this regulation reflects responses to Tofacitinib in Pso patients. We treated monocyte-derived dendritic cells and myeloid dendritic cells with Tofacitinib and stimulated cells with either lipopolysaccharide (LPS) or a combination of LPS and IFN-γ. We assessed gene expression by qPCR, obtained skin microarray and blood Olink data and clinical parameters of Pso patients treated with Tofacitinib from public data sets. Our results indicate that in DCs co-stimulated with LPS and IFN-γ, but not with LPS alone, Tofacitinib leads to the decreased expression of IL-23/IL-12 shared subunit IL12B (p40). In Tofacitinib-treated Pso patients, IL-12 expression and psoriasis area and severity index (PASI) are significantly reduced in patients with higher IFN-γ at baseline. These findings demonstrate for the first time that Tofacitinib suppresses IL-23/IL-12 shared subunit IL12B in DCs upon active IFN-γ signaling, and that Pso patients with higher IFN-γ baseline levels display improved clinical response after Tofacitinib treatment.


Asunto(s)
Interferón gamma , Subunidad p40 de la Interleucina-12 , Inhibidores de las Cinasas Janus , Piperidinas , Psoriasis , Pirimidinas , Piel , Artritis Psoriásica/tratamiento farmacológico , Células Dendríticas/inmunología , Humanos , Interferón gamma/metabolismo , Subunidad p40 de la Interleucina-12/antagonistas & inhibidores , Subunidad p40 de la Interleucina-12/sangre , Subunidad p40 de la Interleucina-12/metabolismo , Inhibidores de las Cinasas Janus/farmacología , Inhibidores de las Cinasas Janus/uso terapéutico , Lipopolisacáridos/inmunología , Piperidinas/farmacología , Piperidinas/uso terapéutico , Psoriasis/tratamiento farmacológico , Pirimidinas/farmacología , Pirimidinas/uso terapéutico , Piel/efectos de los fármacos , Piel/inmunología
2.
Dermatology ; 238(6): 1108-1119, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35551372

RESUMEN

BACKGROUND: Early identification of patients at risk of psoriatic arthritis (PsA) is essential to facilitate early diagnosis and improve clinical outcomes. Severe cutaneous psoriasis has been proposed to be associated with PsA, but a recent assessment of the evidence is lacking. Therefore, in this systematic review, we address the association of psoriasis skin severity with the presence and development of PsA. SUMMARY: We included articles from a review published in 2014 and supplemented these with recent literature by performing an additional systematic search to identify studies published between 1 January 2013 and 11 February 2021. A meta-analysis was performed when sufficient comparable evidence was available. Of 2,000 screened articles, we included 29 in the analysis, of which 16 were identified by our updated search. Nineteen studies reported psoriasis severity as psoriasis area and severity index (PASI), ten studies as body surface area (BSA), and two studies as "number of affected sites." Most studies show that more extensive skin disease is associated with the presence of PsA. The quantitative pooled analyses demonstrate higher PASI (mean difference [Δ] 1.59; 95% confidence interval [CI] 0.29-2.89) and higher BSA (Δ 5.31; 95% CI 1.78-8.83) in patients with PsA as compared to psoriasis patients without PsA. Results from prospective studies - that assess the risk of future development of PsA in psoriasis patients - were inconclusive. KEY MESSAGES: In patients with psoriasis, more severe skin involvement is associated with the presence of PsA, underpinning the importance of optimal dermatology-rheumatology collaboration in clinical care. There are insufficient data to support the use of psoriasis skin severity to predict the future development of PsA in psoriasis patients.


Asunto(s)
Artritis Psoriásica , Psoriasis , Reumatología , Humanos , Artritis Psoriásica/complicaciones , Artritis Psoriásica/diagnóstico , Estudios Prospectivos , Psoriasis/complicaciones , Psoriasis/diagnóstico , Piel , Índice de Severidad de la Enfermedad
3.
Eur J Immunol ; 50(8): 1209-1219, 2020 08.
Artículo en Inglés | MEDLINE | ID: mdl-32198923

RESUMEN

Ankylosing spondylitis (AS) is associated with autoantibody production to class II MHC-associated invariant chain peptide, CD74/CLIP. In this study, we considered that anti-CD74/CLIP autoantibodies present in sera from AS might recognize CD74 degradation products that accumulate upon deficiency of the enzyme signal peptide peptidase-like 2A (SPPL2a). We analyzed monocytes from healthy controls (n = 42), psoriatic arthritis (n = 25), rheumatoid arthritis (n = 16), and AS patients (n = 15) for SPPL2a enzyme activity and complemented the experiments using SPPL2a-sufficient and -deficient THP-1 cells. We found defects in SPPL2a function and CD74 processing in a subset of AS patients, which culminated in CD74 and HLA class II display at the cell surface. These findings were verified in SPPL2a-deficient THP-1 cells, which showed expedited expression of MHC class II, total CD74 and CD74 N-terminal degradation products at the plasma membrane upon receipt of an inflammatory trigger. Furthermore, we observed that IgG anti-CD74/CLIP autoantibodies recognize CD74 N-terminal degradation products that accumulate upon SPPL2a defect. In conclusion, reduced activity of SPPL2a protease in monocytes from AS predisposes to endosomal accumulation of CD74 and CD74 N-terminal fragments, which, upon IFN-γ-exposure, is deposited at the plasma membrane and can be recognized by anti-CD74/CLIP autoantibodies.


Asunto(s)
Antígenos de Diferenciación de Linfocitos B/inmunología , Ácido Aspártico Endopeptidasas/fisiología , Autoanticuerpos/inmunología , Antígenos de Histocompatibilidad Clase II/inmunología , Proteolisis , Espondilitis Anquilosante/inmunología , Adulto , Anciano , Antígenos de Diferenciación de Linfocitos B/metabolismo , Femenino , Antígenos HLA-DR/análisis , Antígenos de Histocompatibilidad Clase II/metabolismo , Humanos , Inmunoglobulina G/inmunología , Interferón gamma/farmacología , Masculino , Persona de Mediana Edad , Células THP-1
4.
Eur J Immunol ; 50(1): 86-96, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-31713839

RESUMEN

Non-Hodgkin orbital lymphoma (NHOL) and idiopathic orbital inflammation (IOI) are common orbital conditions with largely unknown pathophysiology that can be difficult to diagnose. In this study we aim to identify serum miRNAs associated with NHOL and IOI. We performed OpenArray® miRNA profiling in 33 patients and controls. Differentially expressed miRNAs were technically validated across technology platforms and replicated in an additional cohort of 32 patients and controls. We identified and independently validated a serum miRNA profile of NHOL that was remarkably similar to IOI and characterized by an increased expression of a cluster of eight miRNAs. Pathway enrichment analysis indicated that the miRNA-cluster is associated with immune-mediated pathways, which we supported by demonstrating the elevated expression of this cluster in serum of patients with other inflammatory conditions. The cluster contained miR-148a, a key driver of B-cell tolerance, and miR-365 that correlated with serum IgG and IgM concentrations. In addition, miR-29a and miR-223 were associated with blood lymphocyte and neutrophil populations, respectively. NHOL and IOI are characterized by an abnormal serum miRNA-cluster associated with immune pathway activation and linked to B cell and neutrophil dysfunction.


Asunto(s)
Inflamación/inmunología , Linfoma no Hodgkin/inmunología , MicroARNs/inmunología , Enfermedades Orbitales/inmunología , Neoplasias Orbitales/inmunología , Adulto , Anciano , Femenino , Humanos , Inflamación/genética , Linfoma no Hodgkin/genética , Masculino , Persona de Mediana Edad , Enfermedades Orbitales/genética , Neoplasias Orbitales/genética
5.
Rheumatology (Oxford) ; 60(2): 780-784, 2021 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-32797218

RESUMEN

OBJECTIVES: Conventional synthetic DMARDs (csDMARDs) are the first-line treatment for PsA, but there is conflicting data regarding their efficacy and scarce reports describing the duration of use (drug retention) of csDMARD in this population. Their position in treatment recommendations is a matter of growing debate due to the availability of alternative treatment options with higher levels of evidence. We aimed to study drug retention and predictors for drug retention among PsA patients receiving first-line csDMARD monotherapy. METHODS: Retrospective cohort study in DMARD-naïve adult PsA patients in whom a first csDMARD was prescribed as monotherapy primarily to treat PsA-related symptoms. The main outcome was time to failure of the csDMARD (i.e. stopping the csDMARD or adding another DMARD). RESULTS: A total of 187 patients were included, who were mainly prescribed MTX (n = 163) or SSZ (n = 21). The pooled median drug retention time was 31.8 months (interquartile range 9.04-110). Drug retention was significantly higher in MTX (median 34.5 months; interquartile range 9.60-123) as compared with SSZ-treated patients (median 12.0 months; interquartile range 4.80- 55.7) (P =0.016, log-rank test). In multivariable Cox regression, the use of MTX and older age were associated with increased retention. The main reasons for treatment failure were inefficacy (52%) and side effects (28%). Upon failure, MTX treated patients were more commonly, subsequently treated with a biologic DMARD compared with SSZ (P < 0.05). CONCLUSION: MTX outperforms SSZ as a first-line csDMARD in DMARD-naïve PsA patients with respect to monotherapy drug retention in daily clinical practice.


Asunto(s)
Artritis Psoriásica/tratamiento farmacológico , Metotrexato/uso terapéutico , Sulfasalazina/uso terapéutico , Antirreumáticos/uso terapéutico , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Insuficiencia del Tratamiento , Resultado del Tratamiento
6.
Eur J Immunol ; 48(3): 522-531, 2018 03.
Artículo en Inglés | MEDLINE | ID: mdl-29193036

RESUMEN

CXCL4 regulates multiple facets of the immune response and is highly upregulated in various Th17-associated rheumatic diseases. However, whether CXCL4 plays a direct role in the induction of IL-17 production by human CD4+ T cells is currently unclear. Here, we demonstrated that CXCL4 induced human CD4+ T cells to secrete IL-17 that co-expressed IFN-γ and IL-22, and differentiated naïve CD4+ T cells to become Th17-cytokine producing cells. In a co-culture system of human CD4+ T cells with monocytes or myeloid dendritic cells, CXCL4 induced IL-17 production upon triggering by superantigen. Moreover, when monocyte-derived dendritic cells were differentiated in the presence of CXCL4, they orchestrated increased levels of IL-17, IFN-γ, and proliferation by CD4+ T cells. Furthermore, the CXCL4 levels in synovial fluid from psoriatic arthritis patients strongly correlated with IL-17 and IL-22 levels. A similar response to CXCL4 of enhanced IL-17 production by CD4+ T cells was also observed in patients with psoriatic arthritis. Altogether, we demonstrate that CXCL4 boosts pro-inflammatory cytokine production especially IL-17 by human CD4+ T cells, either by acting directly or indirectly via myeloid antigen presenting cells, implicating a role for CXCL4 in PsA pathology.


Asunto(s)
Artritis Psoriásica/inmunología , Interleucina-17/biosíntesis , Interleucinas/metabolismo , Factor Plaquetario 4/inmunología , Células Th17/inmunología , Células Presentadoras de Antígenos/inmunología , Estudios de Casos y Controles , Diferenciación Celular/inmunología , Técnicas de Cocultivo , Células Dendríticas/inmunología , Humanos , Activación de Linfocitos , Monocitos/inmunología , Interleucina-22
7.
Rheumatology (Oxford) ; 58(10): 1740-1745, 2019 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-31220315

RESUMEN

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.


Asunto(s)
Interferones/sangre , Lupus Eritematoso Sistémico/sangre , Linfocitos/metabolismo , Síndrome de Sjögren/sangre , Receptor fas/metabolismo , Estudios de Casos y Controles , Células Dendríticas/metabolismo , Citometría de Flujo , Humanos , Inmunidad Innata , Interferones/inmunología , Lupus Eritematoso Sistémico/inmunología , Síndrome de Sjögren/inmunología
9.
J Pers Med ; 12(11)2022 Oct 25.
Artículo en Inglés | MEDLINE | ID: mdl-36573712

RESUMEN

Enthesitis is a common clinical feature of spondyloarthritis (SpA). For reliable assessment of enthesitis the Heel Enthesitis Magnetic Resonance Imaging Scoring System (HEMRIS) was developed. The aims of this study were to evaluate changes in HEMRIS over time and to evaluate whether these changes correlated with changes in clinical parameters. This single-center observational study followed patients with SpA and psoriasis, regardless of presence of clinical heel enthesitis, for two years. Clinical evaluation and ankle MRIs were performed annually. Changes in HEMRIS were compared at one-year intervals using the Wilcoxon signed-rank test. The association between changes in the HEMRIS with changes in clinical parameters was evaluated using Spearman's correlation coefficient. In total, 38 patients were included. An increase in the inflammatory and structural HEMRIS was identified in, respectively, 12 (17.9%) and 4 (6.0%) patients in one-year intervals. We found non-significant changes in the HEMRIS during longitudinal follow-up. Changes in the HEMRIS did not correlate with changes in local or general disease activity. Our results show that MRI-findings of enthesitis assessed with HEMRIS changed in a small number of patients in a one-year interval in an observational setting. Changes in HEMRIS were not associated with changes in clinical disease activity.

10.
Lupus Sci Med ; 9(1)2022 03.
Artículo en Inglés | MEDLINE | ID: mdl-35296555

RESUMEN

INTRODUCTION: Plasmacytoid dendritic cells (pDCs) are the main producers of type I interferon (IFN) in SLE. pDCs express high secretory carrier membrane protein 5 (SCAMP5). Recent work in transfected HEK cells connects SCAMP5 to the type I IFN secretory pathway. To further study the role of SCAMP5 in IFNα secretion by pDCs, we focused on the subcellular distribution of SCAMP5 in human pDCs freshly isolated from peripheral blood. METHODS: We measured SCAMP5 expression by flow cytometry in peripheral blood mononuclear cells of healthy subjects (n=8). Next, we assessed the colocalisation of SCAMP5 with IFNα in pDCs of healthy subjects (n=4) by evaluating bright detail similarity (BDS) scores using ImageStream technology. RESULTS: We confirm that SCAMP5 is highly expressed by pDCs derived from peripheral blood. In activated pDCs, we show that SCAMP5 colocalises with IFNα (mean BDS 2.0±0.1; BDS >2.0 in 44% of pDCs). CONCLUSION: SCAMP5 colocalises with IFNα in activated human pDCs, in support of a role of this trafficking protein in the secretion of type I IFN by pDCs.


Asunto(s)
Interferón Tipo I , Lupus Eritematoso Sistémico , Células Dendríticas/metabolismo , Humanos , Interferón-alfa/metabolismo , Leucocitos Mononucleares/metabolismo , Proteínas de la Membrana/metabolismo
11.
Sci Rep ; 12(1): 20675, 2022 11 30.
Artículo en Inglés | MEDLINE | ID: mdl-36450783

RESUMEN

In psoriatic arthritis (PsA), predisposing class I HLA alleles, the presence of synovial clonally proliferated CD8 + T cells and autoantibodies all point towards the loss of immune tolerance. However, the key mechanisms that lead to immune dysregulation are not fully understood. In other types of inflammatory arthritis, T regulatory cell (Treg) dysfunction and plasticity at sites of inflammation were suggested to negatively affect peripheral tolerance. We here addressed if Treg variances associate with psoriatic disease. We collected clinical data, sera and peripheral blood mononuclear cells from 13 healthy controls, 21 psoriasis and 21 PsA patients. In addition, we obtained synovial fluid mononuclear cells from 6 PsA patients. We studied characteristics of CD4 + CD25 + CD127loFoxp3 + Tregs by flow cytometry and used ELISA to quantify antibodies against ADAMTSL5, a recently discovered autoantigen in psoriatic disease. In comparison with their circulating counterparts, Tregs from inflamed joints express increased levels of ICOS, CTLA-4 and TIGIT. Furthermore, synovial fluid-derived Tregs have a distinct phenotype, characterized by IL-17A production and upregulation of CD161 and RORγt. We identified a subset of Tregs with intermediate Foxp3 expression as the major cytokine producer. Furthermore, ICOS + Tregs associate with PsA disease activity as measured by PASDAS. Lastly, we observed that presence of the Foxp3int Tregs associates with an increased abundance of anti-ADAMTSL5 autoantibodies. Tregs derived from the inflammatory environment of inflamed PsA joints exhibit a distinct phenotype, which associates with loss of peripheral immune tolerance in psoriatic disease.


Asunto(s)
Artritis Psoriásica , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares , Humanos , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/genética , Interleucina-17 , Linfocitos T Reguladores , Autoanticuerpos , Leucocitos Mononucleares , Fenotipo , Factores de Transcripción , Factores de Transcripción Forkhead , Proteína Coestimuladora de Linfocitos T Inducibles , Proteínas ADAMTS
12.
J Invest Dermatol ; 142(2): 402-413, 2022 02.
Artículo en Inglés | MEDLINE | ID: mdl-34333017

RESUMEN

Dermal fibroblasts are strategically positioned underneath the basal epidermis layer to support keratinocyte proliferation and extracellular matrix production. In inflammatory conditions, these fibroblasts produce cytokines and chemokines that promote the chemoattraction of immune cells into the dermis and the hyperplasia of the epidermis, two characteristic hallmarks of psoriasis. However, how dermal fibroblasts specifically contribute to psoriasis development remains largely uncharacterized. In this study, we investigated through which cytokines and signaling pathways dermal fibroblasts contribute to the inflammatory features of psoriatic skin. We show that dermal fibroblasts from lesional psoriatic skin are important producers of inflammatory mediators, including IL-6, CXCL8, and CXCL2. This increased cytokine production was found to be regulated by ZFP36 family members ZFP36, ZFP36L1, and ZFP36L2, RNA-binding proteins with mRNA-degrading properties. In addition, the expression of ZFP36 family proteins was found to be reduced in chronic inflammatory conditions that mimic psoriatic lesional skin. Collectively, these results indicate that dermal fibroblasts are important producers of cytokines in psoriatic skin and that reduced expression of ZFP36 members in psoriasis dermal fibroblasts contributes to their inflammatory phenotype.


Asunto(s)
Factor 1 de Respuesta al Butirato/metabolismo , Fibroblastos/metabolismo , Psoriasis/inmunología , Factores de Transcripción/metabolismo , Tristetraprolina/metabolismo , Biopsia , Factor 1 de Respuesta al Butirato/genética , Estudios de Casos y Controles , Epidermis/inmunología , Epidermis/metabolismo , Epidermis/patología , Técnicas de Silenciamiento del Gen , Voluntarios Sanos , Humanos , Mediadores de Inflamación/metabolismo , Queratinocitos/inmunología , Queratinocitos/metabolismo , Psoriasis/patología , Factores de Transcripción/genética , Tristetraprolina/genética
13.
BMJ Open ; 12(10): e064338, 2022 10 10.
Artículo en Inglés | MEDLINE | ID: mdl-36216430

RESUMEN

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.


Asunto(s)
Antirreumáticos , Artritis Psoriásica , Piperidinas , Pirimidinas , Antirreumáticos/uso terapéutico , Artritis Psoriásica/tratamiento farmacológico , Biomarcadores , Ensayos Clínicos Fase III como Asunto , Etanercept/uso terapéutico , Furanos , Humanos , Factores Inmunológicos/uso terapéutico , Metotrexato/uso terapéutico , Estudios Multicéntricos como Asunto , Piperidinas/uso terapéutico , Pirimidinas/uso terapéutico , Ensayos Clínicos Controlados Aleatorios como Asunto , Resultado del Tratamiento
14.
Immunother Adv ; 1(1): ltaa004, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-36284900

RESUMEN

Objectives: Signals at the contact site of antigen-presenting cells (APCs) and T cells help orchestrate the adaptive immune response. CD155 on APCs can interact with the stimulatory receptor DNAM1 or inhibitory receptor TIGIT on T cells. The CD155/DNAM1/TIGIT axis is under extensive investigation as immunotherapy target in inflammatory diseases including cancer, chronic infection and autoimmune diseases. We investigated a possible role for CD155/DNAM1/TIGIT signaling in psoriatic disease. Methods: By flow cytometry, we analyzed peripheral blood mononuclear cells of patients with psoriasis (n = 20) or psoriatic arthritis (n = 21), and healthy individuals (n = 7). We measured CD155, TIGIT, and DNAM1 expression on leukocyte subsets and compared activation-induced cytokine production between CD155-positive and CD155-negative APCs. We assessed the effects of TIGIT and DNAM1 blockade on T cell activation, and related the expression of CD155/DNAM1/TIGIT axis molecules to measures of disease activity. Results: High CD155 expression associates with tumor necrosis factor (TNF) production in myeloid and plasmacytoid dendritic cells (DC). In CD1c+ myeloid DC, activation-induced CD155 expression associates with increased HLA-DR expression. CD8 T cells - but not CD4 T cells - express high levels of TIGIT. DNAM1 blockade decreases T cell pro-inflammatory cytokine production, while TIGIT blockade increased T cell proliferation. Finally, T cell TIGIT expression shows an inverse correlation with inflammation biomarkers in psoriatic disease. Conclusion: CD155 is increased on pro-inflammatory APCs, while the receptors DNAM1 and TIGIT expressed on T cells balance the inflammatory response by T cells. In psoriatic disease, low TIGIT expression on T cells is associated with systemic inflammation.

15.
RMD Open ; 6(3)2020 11.
Artículo en Inglés | MEDLINE | ID: mdl-33277402

RESUMEN

OBJECTIVE: To compare the Heel Enthesitis MRI Scoring model (HEMRIS) with clinical and PET/CT outcomes in patients with cutaneous psoriasis (Pso), psoriatic arthritis (PsA) or ankylosing spondylitis (AS). METHODS: This prospective, observational study included 38 patients with Pso, PsA and AS. Patients were included regardless of presence or absence of clinical heel enthesitis. MRI-scans of both ankles and a whole-body 18F-FDG PET/CT were acquired. MRIs were assessed for enthesitis by two independent and blinded observers according to the HEMRIS. A physician, blinded for imaging results, performed clinical evaluations of enthesitis at the Achilles tendon and plantar fascia. RESULTS: In total, 146 entheses were scored according to the HEMRIS and clinically assessed for enthesitis (6 entheses were clinically affected). In Achilles tendons with clinical enthesitis, the HEMRIS structural damage score was significantly higher, compared to Achilles tendons without clinical enthesitis (respective median scores 1.0 and 0.5; p=0.04). In clinically unaffected entheses, HEMRIS abnormalities occurred in 44/70 (63%) of Achilles tendons and in 23/70 (33%) of plantar fascia. At the Achilles tendon, local metabolic activity measured on PET/CT was weakly associated with the structural (rs=0.25, p=0.03) and total HEMRIS (rs=0.26, p=0.03). CONCLUSION: This study revealed a high prevalence of subclinical HEMRIS abnormalities and discrepancy between HEMRIS and clinical and PET/CT findings. This may suggest that the HEMRIS is a sensitive method for detection of inflammatory and structural disease of enthesitis at the Achilles tendon and plantar fascia, although the clinical significance of these MRI findings remains to be determined in longitudinal studies.


Asunto(s)
Entesopatía , Talón , Tomografía Computarizada por Tomografía de Emisión de Positrones , Adulto , Femenino , Talón/diagnóstico por imagen , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Estudios Prospectivos
16.
Ned Tijdschr Geneeskd ; 1632019 07 29.
Artículo en Holandés | MEDLINE | ID: mdl-31361418

RESUMEN

Psoriasis is a common immune-mediated inflammatory condition that primarily affects skin and nails. 6-41% of psoriasis patients develop psoriatic arthritis (PsA). The ways in which PsA can manifest itself include peripheral arthritis, axial spondyloarthritis, dactylitis and enthesitis. This heterogeneous clinical picture makes it sometimes difficult to recognise PsA,potentially resulting in permanent joint damage and functional impairments. Some people see psoriasis and PsA as 2 manifestations of a single disease because the multifactorial origins of psoriasis and PsA are largely overlapping. Psoriatic conditions are associated with a high burden of disease, reduced quality of life and comorbidities, including psychiatric and cardiovascular conditions. In recent years, several immunological pathways, immune cells and cytokines have been identified as important factors in pathophysiology and as new therapeutic targets. For many PsA patients treatment with disease modifying anti-rheumatic drugs leads to significant improvement of symptoms and quality of life.


Asunto(s)
Artritis Psoriásica/fisiopatología , Artritis Psoriásica/psicología , Calidad de Vida , Antirreumáticos/uso terapéutico , Artritis Psoriásica/terapia , Comorbilidad , Humanos , Uñas Malformadas/etiología , Uñas Malformadas/psicología , Psoriasis/fisiopatología , Psoriasis/psicología
18.
Nat Rev Rheumatol ; 11(8): 483-92, 2015 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-25963881

RESUMEN

Rheumatic diseases can be divided in two groups, autoinflammatory and autoimmune disorders. The clinical presentation of both types of diseases overlap, but the pathological pathways underlying rheumatic autoinflammation and autoimmunity are distinct and are the subject of ongoing research. There are a number of ways in which these groups of diseases differ in terms of disease mechanisms and therapeutic responses. First, autoinflammatory diseases are driven by endogenous danger signals, metabolic mediators and cytokines, whereas autoimmunity involves the activation of T and B cells, the latter requiring V-(D)-J recombination of receptor-chain gene segments for maturation. Second, the efficacy of biologic agents directed against proinflammatory cytokines (for example IL-1ß and TNF) also highlights differences between autoinflammatory and autoimmune processes. Finally, whereas autoinflammatory diseases are mostly driven by inflammasome-induced IL-1ß and IL-18 production, autoimmune diseases are associated with type I interferon (IFN) signatures in blood. In this Review, we provide an overview of the monocyte intracellular pathways that drive autoinflammation and autoimmunity. We convey recent findings on how the type I IFN pathway can modulate IL-1ß signalling (and vice versa), and discuss why IL-1ß-mediated autoinflammatory diseases do not perpetuate into autoimmunity. The origins of intracellular autoantigens in autoimmune disorders are also discussed. Finally, we suggest how new mechanistic knowledge of autoinflammatory and autoimmune diseases might help improve treatment strategies to benefit patient care.


Asunto(s)
Autoinmunidad , Inflamación/inmunología , Enfermedades Reumáticas/inmunología , Autoantígenos/inmunología , Humanos , Interferón Tipo I/inmunología , Interleucina-1beta/inmunología , Péptidos/inmunología
19.
Arthritis Rheumatol ; 67(10): 2673-8, 2015 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-26137857

RESUMEN

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.


Asunto(s)
Artritis Psoriásica/patología , Inmunidad Innata/fisiología , Linfocitos/patología , Líquido Sinovial/citología , Adulto , Artritis Psoriásica/metabolismo , Artritis Reumatoide/metabolismo , Artritis Reumatoide/patología , Antígeno CD146/metabolismo , Estudios de Casos y Controles , Humanos , Interleucina-17/metabolismo , Linfocitos/metabolismo , Persona de Mediana Edad , Receptor 2 Gatillante de la Citotoxidad Natural/metabolismo , Receptores CCR6/metabolismo , Líquido Sinovial/metabolismo
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