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Rheumatoid Arthritis (RA) is associated with an increased risk of cardiovascular disease and mortality, however, traditional cardiovascular risk factors do not fully explain this relationship. This high risk of cardiovascular morbidity and mortality in RA has been increasingly acknowledged in past decades, with accumulating evidence that RA is an independent cardiovascular risk factor; RA is also associated with metabolic syndrome, which correlates with disease activity, contributing to the increased prevalence of coronary heart disease in RA patients. Moreover, multimorbidity, including the presence of long-term conditions, impacts adverse clinical outcomes in RA patients, emphasizing the need for holistic management that requires an understanding of shared pathophysiological mechanisms, such as systemic inflammation and immune dysregulation. For all these reasons, the management of RA patients with cardiometabolic comorbidities is a complex endeavor that requires a patient-centered, multidisciplinary approach. In this sense, there is a need to re-evaluate the approach toward a proactive model of care, moving away from a reactive medical paradigm to a multidimensional integrated management model, including aggressive screening, preventive strategies, and tailored therapeutic interventions. The aim of this review was to thoroughly review the literature on cardiometabolic comorbidities and related conditions linked to RA to enable us to identify the necessary actions required to effectively tackle the increasing burden of illness from a fully comprehensive perspective.
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OBJECTIVES: We investigated the effectiveness and safety of filgotinib in a real-life multicentre cohort of rheumatoid arthritis (RA) patients. METHODS: RA patients were evaluated at baseline and after 12 and 24 weeks and were stratified based on previous treatments as biologic disease-modifying anti-rheumatic drug (bDMARD)-naive and bDMARD-insufficient responders (IR). Concomitant usage of methotrexate (MTX) and oral glucocorticoids (GC) was recorded. At each timepoint we recorded disease activity, laboratory parameters and adverse events. RESULTS: 126 patients were enrolled. 15.8% were bDMARD-naive (G0), while 84% were bDMARD-IR (G1). In G0, 45% of patients were in monotherapy (G2) and 55% were taken MTX (G3). In G1, 50% of patients were in monotherapy (G4) and 50% used MTX (G5).A significant reduction in all parameters at 12 weeks was observed; in the extension to 24 weeks the significant reduction was maintained for patient global assessment (PGA), examiner global assessment (EGA), visual analogue scale (VAS) pain, VAS fatigue, disease activity score (DAS)28- C-reactive protein (CRP) and CRP values. Filgotinib in monotherapy showed better outcomes in bDMARD-naive patients, with significant differences for patient reported outcomes (PROs) and DAS28-CRP. At 12 weeks, low disease activity (LDA) and remission were achieved in a percentage of 37.2 % and 10.7 % by simplified disease activity index (SDAI), 42.6 % and 5.7 % by clinical disease activity index (CDAI), 26.8 % and 25.2 % by DAS28-CRP, respectively. A significant decrease in steroid dose was evidenced in all patients. We observed a major adverse cardiovascular event in one patient and an increase in transaminase in another. No infections from Herpes Zoster were reported. CONCLUSIONS: Our real-world data confirm the effectiveness and safety of filgotinib in the management of RA, especially in bDMARD-naive patients.
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Antirreumáticos , Artritis Reumatoide , Metotrexato , Humanos , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/diagnóstico , Masculino , Femenino , Persona de Mediana Edad , Antirreumáticos/efectos adversos , Antirreumáticos/uso terapéutico , Resultado del Tratamiento , Anciano , Metotrexato/uso terapéutico , Metotrexato/efectos adversos , Adulto , Quimioterapia Combinada , Triazoles/uso terapéutico , Triazoles/efectos adversos , Inducción de Remisión , Índice de Severidad de la Enfermedad , Factores de Tiempo , Glucocorticoides/efectos adversos , Glucocorticoides/administración & dosificación , Glucocorticoides/uso terapéutico , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/uso terapéuticoRESUMEN
Introduction: Psoriatic arthritis (PsA) is a heterogeneous, chronic inflammatory disease that negatively impacts patients' quality of life. Patient-reported outcome measures (PROMs) are used to capture patient perspectives in disease assessment, and physicians use the Disease Activity Index for Psoriatic Arthritis (DAPSA) to evaluate disease activity in PsA. The study aimed to assess the relationship between PROMs and the DAPSA score in consecutive outpatients affected by PsA. Materials and methods: A cross-sectional study was conducted from March 2018 to October 2020 at the PsA clinic of the ARNAS Civico in Palermo (Italy), enrolling outpatients with PsA. Patients were assessed for their disease activity according to the DAPSA score, and PROMs, such as PHQ-9, HAQ, FACIT-F, and PsAID, were evaluated. Linear regression analysis evaluated the relationship between the DAPSA Score and the included PROMs. Results: 158 PsA consecutive peripheral subset psoriatic arthritis outpatients were recruited. The median years of illness was 10.6 (9.3-11.9), and the median DAPSA score was 19.02 (9-33.1). The regression analysis highlighted a strong relationship between the DAPSA score and the PsAID (adjR2 26%, p < 0.0001), the FACIT-F (adjR2 25.4%, p < 0.0001), the HAQ (adjR2 23.7%, p < 0.0001), and PHQ-9 (adjR2 15%, p < 0.0001). Conclusion: PROMs are strongly associated with the DAPSA score, but it allows in-depth evaluation of the impact of the disease on different domains of PsA patients' life.
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BACKGROUND AND AIMS: Patients with systemic sclerosis (SSc) often complain reduced capacity at submaximal exercise; conversely, physical capacity in performing daily duties has never been measured in SSc. The aim of this study is to evaluate this performance and its correlates, in patients with SSc compared with healthy controls, in a free-living setting. METHODS: Twenty-seven outpatients with stable SSc and 11 controls were recruited. Physical activity was assessed by portable multiple sensor device (SenseWear Armband) worn for at least 6 days. Physical activity duration (PAD; in minutes) for non-sedentary activities and physical activity level (PAL = total daily energy/resting energy expenditure) per day were calculated. Nutritional status was estimated by bioelectrical impedance analysis and pulmonary arterial hypertension excluded by echocardiography. RESULTS: Daily physical activities (243 ± 145 min per day vs 397 ± 142 min, respectively; P = 0.005) and PAL were significantly reduced in SSc compared with controls (1.5 ± 0.4 vs 2 ± 0.7, respectively; P = 0.019). Seventy-four per cent of SSc patients showed PAL < 1.70, whereas only 27% of controls were below this threshold for sedentary life style. Both PAD and PAL positively correlated with DLco. Patients and controls did not differ for spirometric parameters, body mass index, phase angle at bioelectrical impedance analysis, fat mass or fat-free mass indexes. In SSc, exercise capacity during daily activity was reduced compared with controls, and was associated with early evidence of functional decay (decreasing DLco) but not with malnutrition (undernutrition). CONCLUSIONS: A reduction of daily physical activity is already present even in early stages of lung involvement in SSc, characterized by unaltered spirometry and well-preserved nutritional status.
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Hipertensión Pulmonar/fisiopatología , Esclerodermia Sistémica/fisiopatología , Actividades Cotidianas , Adulto , Anciano , Ejercicio Físico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Evaluación Nutricional , EspirometríaRESUMEN
BACKGROUND: The aim of the study was to better characterise the immunological origin and the behaviour of interleukin (IL)-23-responsive innate lymphoid cells (ILCs) in the gut, synovial fluid (SF) and bone marrow (BM) of patients with ankylosing spondylitis (AS). METHODS: ILC1, ILC2 and ILC3 cells were determined and characterised by confocal microscopy and flow cytometry in ileal and BM biopsies, in peripheral blood (PB) and SF mononuclear cells obtained from patients with AS and controls. Mucosal vascular addressin cell adhesion molecule 1 (MADCAM-1), IL-7, IL-15 and aggregates of lymphoid tissue inducer cells (LTi) were evaluated by immunohistochemistry. The in vitro ability of epithelial cells in driving the differentiation of ILC3 and the effect of tumour necrosis factor inhibitors (TNFi) on the frequency of ILC3 and the expression of MADCAM1 were also assessed. RESULTS: ILC3 characterised as Lyn(-)RORc(-)Tbet(+) NKp44(+) cells were significantly expanded in the gut, SF and BM of patients with AS compared with controls, produced high levels of IL-17 and IL-22 and expressed α4ß7. MADcAM1 was overexpressed in BM and ileal high endothelial venules. IL-7 was significantly increased in AS gut, especially in the context of Paneth cells, and accompanied by the presence of aggregates of c-kit/IL-7R(+) cells (LTi). In in vitro experiments, epithelial cells from patients with AS actively induced differentiation of ILC3 from LTi. TNFi efficacy was accompanied by a significant decrease in the percentage of intestinal and circulating ILC3 and in the expression of MADCAM1. CONCLUSIONS: Gut-derived IL-17(+) and IL-22(+)ILC3 are expanded in the peripheral blood, SF and inflamed BM of patients with AS, suggesting the presence of an active homing axis between the gut and the inflamed sacroiliac joints.
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Médula Ósea/inmunología , Mucosa Intestinal/inmunología , Linfocitos/inmunología , Espondilitis Anquilosante/inmunología , Líquido Sinovial/inmunología , Adolescente , Adulto , Anciano , Estudios de Casos y Controles , Moléculas de Adhesión Celular , Femenino , Humanos , Íleon/inmunología , Íleon/patología , Inmunoglobulinas/metabolismo , Interleucina-15/inmunología , Interleucina-17/inmunología , Interleucina-7/inmunología , Interleucinas/inmunología , Masculino , Microscopía Confocal , Persona de Mediana Edad , Mucoproteínas/metabolismo , Receptor 2 Gatillante de la Citotoxidad Natural , Adulto Joven , Interleucina-22RESUMEN
OBJECTIVE: The aim of this study was to evaluate the role of rituximab (RTX) in modulating the expression of the IL-17/IL-23 pathway in the salivary glands (SGs) of patients with primary SS (pSS). METHODS: Consecutive SG biopsies were obtained from 15 patients with pSS before and after 1 year of RTX therapy. The SG expression of IL-17, IL-23p19 and p-STAT3 was evaluated by immunohistochemistry at baseline and after RTX therapy. The role of mast cells in pSS patients in modulating the Th17 response and the immunologic effect of RTX on mast cells were also studied in in vitro experiments. RESULTS: IL-17 was overexpressed in the SGs of patients with pSS mainly by infiltrating T cells and mast cells. After RTX therapy, the SG expression of IL-17, but not of IL-23p19 and p-STAT3, was significantly reduced and was accompanied by the depletion of tissue mast cells. In in vitro experiments with heterologous peripheral lymphocytes RTX significantly induced the apoptosis of isolated mast cells. Finally, mast cells isolated from peripheral blood mononuclear cells of pSS patients in vitro significantly increased Th17 lymphocytes. CONCLUSION: RTX acts on pSS patients by globally reducing the expression of IL-17 and specifically inducing a pronounced apoptotic depletion of mast cells.
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Anticuerpos Monoclonales de Origen Murino/farmacología , Anticuerpos Monoclonales de Origen Murino/uso terapéutico , Interleucina-17/metabolismo , Glándulas Salivales/efectos de los fármacos , Glándulas Salivales/metabolismo , Síndrome de Sjögren/tratamiento farmacológico , Adulto , Anciano , Antirreumáticos/farmacología , Antirreumáticos/uso terapéutico , Apoptosis/efectos de los fármacos , Apoptosis/fisiología , Femenino , Humanos , Técnicas In Vitro , Interferones , Interleucina-23/metabolismo , Interleucinas/metabolismo , Masculino , Mastocitos/efectos de los fármacos , Mastocitos/patología , Persona de Mediana Edad , Rituximab , Factor de Transcripción STAT3 , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , Síndrome de Sjögren/metabolismo , Células Th17/efectos de los fármacos , Células Th17/patología , Resultado del TratamientoRESUMEN
OBJECTIVE: The aim of this study was to assess the expression of IL-22, IL-22 receptor 1 (IL-22R1), IL-22 binding protein (IL-22BP) and p-STAT3 in muscle tissue from patients with PM and DM. METHODS: Levels of IL-22, IL-22R1, IL-22BP and STAT3 mRNA were quantified by RT-PCR. The expression of IL-22, IL-22R1, IL-22BP and p-STAT3 was also analysed using immunohistochemistry. RESULTS: Significant modulation of the IL-22 pathway was observed in inflammatory myopathic tissues. In particular, a significant overexpression of IL-22 at the protein but not the mRNA level was observed in PM/DM tissues and was correlated with myositis activity. IL-22R1 aberrant expression was also observed among infiltrating mononuclear cells and necrotic muscle cells. IL-22BP, which inhibits IL-22 signalling, was expressed only in some muscle fibres in PM/DM patients. CONCLUSION: Our findings indicate that the IL-22 pathway is activated in inflammatory myopathic tissues and may be involved in the induction of muscle inflammatory processes and muscle necrosis.
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Dermatomiositis/metabolismo , Interleucinas/metabolismo , Músculo Esquelético/metabolismo , Polimiositis/metabolismo , Índice de Severidad de la Enfermedad , Transducción de Señal/fisiología , Biopsia , Estudios de Casos y Controles , Dermatomiositis/patología , Dermatomiositis/fisiopatología , Humanos , Inflamación/metabolismo , Inflamación/patología , Inflamación/fisiopatología , Músculo Esquelético/patología , Músculo Esquelético/fisiopatología , Necrosis/metabolismo , Necrosis/patología , Necrosis/fisiopatología , Polimiositis/patología , Polimiositis/fisiopatología , ARN Mensajero/metabolismo , Receptores de Interleucina/metabolismo , Factor de Transcripción STAT3/metabolismo , Interleucina-22RESUMEN
In primary Sjögren's syndrome (pSS) a complex of interconnections between epithelial barrier, innate and adaptive immunity occurs. IL-22 is a pleiotropic cytokine that in pSS may be placed at the intersection of the adaptive and innate branches of immunity. Some evidence suggests that, in pSS, IL-22 may play a prominent pro-inflammatory role driving the early phase of tissue and systemic inflammation and participating in the self-perpetuation of disease. Despite contradictory data in literature about the role of NK cells in pSS, recent data also suggest an important contribution of this subset of cells of the innate immune system in the development and perpetuation of inflammation. Here, we discuss the role of IL-22 in the pathogenesis of pSS and in epithelial barrier function.
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Inmunidad Adaptativa , Inmunidad Innata , Interleucinas/inmunología , Células Asesinas Naturales/inmunología , Síndrome de Sjögren/inmunología , Humanos , Síndrome de Sjögren/patología , Interleucina-22RESUMEN
OBJECTIVE: To evaluate the safety and efficacy of therapy with etanercept and methotrexate (MTX) in patients with active rheumatoid arthritis (RA) and mild hepatitis C virus (HCV) infection. METHODS: In this prospective open study, 29 patients with active RA were randomly assigned to receive therapy with MTX alone, etanercept alone, or a combination of MTX and etanercept, and monitored up to 54 weeks. The primary endpoint was safety; secondary aims were efficacy as defined by the 44-joint Disease Activity Score (DAS44) and health assessment questionnaire (HAQ). Serum liver enzymes and HCV viral load were serially measured. RESULTS: In the whole cohort, aspartate aminotransferase (AST) serum levels were (mean ± SD) 35 ± 3 at entry, 39 ± 5, 41 ± 7, and 38 ± 4 at 14, 30, and 54 weeks, respectively; alanine aminotransferase (ALT) serum levels were 43 ± 5 at entry, 47 ± 5, 53 ± 9, and 50 ± 6 at 14, 30, and 54 weeks, respectively. HCV viral load was 5.6 ± 0.5 at entry, 5.9 ± 0.6, 5.7 ± 0.3, and 5.6 ± 0.6 at 14, 30, and 54 weeks, respectively. AST and ALT did not significantly change in all 3 arms of treatment, nor did HCV viral load. A significant reduction of DAS44 (p < 0.01) and HAQ (p < 0.04) was detected at 54 weeks compared to baseline. No patient discontinued the therapy because of worsening of liver disease. CONCLUSION: This study showed that patients with RA and chronic HCV and mild hepatitis may be successfully treated with etanercept and MTX without increasing the risk of hepatotoxicity and HCV replication. ClinicalTrials.gov Identifier NCT01543594.
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Antirreumáticos/efectos adversos , Artritis Reumatoide/tratamiento farmacológico , Hepatitis C/complicaciones , Inmunoglobulina G/efectos adversos , Metotrexato/efectos adversos , Adulto , Anciano , Alanina Transaminasa/sangre , Antirreumáticos/uso terapéutico , Artritis Reumatoide/sangre , Artritis Reumatoide/complicaciones , Aspartato Aminotransferasas/sangre , Quimioterapia Combinada , Etanercept , Femenino , Hepacivirus , Hepatitis C/sangre , Humanos , Inmunoglobulina G/uso terapéutico , Pruebas de Función Hepática , Masculino , Metotrexato/uso terapéutico , Persona de Mediana Edad , Estudios Prospectivos , Receptores del Factor de Necrosis Tumoral/uso terapéutico , Índice de Severidad de la Enfermedad , Resultado del Tratamiento , Carga Viral , Replicación ViralRESUMEN
The aim of this study was to evaluate the clinical outcomes of etanercept in rheumatoid arthritis (RA) patients with moderate or severe disease activity. We analyzed data from the Italian biologics register Gruppo Italiano Studio Early Arthritides (GISEA) to investigate the rate of disease remission and functional improvement, based on the 28-Joint Disease Activity Score (DAS28) and the (Health Assessment Questionnaire (HAQ) score in RA patients with moderate or severe disease activity beginning etanercept therapy. Disease was defined as severe (H-RA) with DAS28 ≥5.1 and moderate (M-RA) with DAS28 ≥3.2 to 5.1 at baseline. Patients were considered in remission if DAS28 was ≤2.6, and HAQ ≤0.5 defined normal function. We enrolled 953 RA patients, 320 with M-RA and 633 H-RA. Age and disease duration were similar in the two cohorts, but H-RA patients had significantly more comorbidities (p < 0.01) and took significantly more disease-modifying antirheumatic drugs (p < 0.001) than M-RA patients. After 1 year, the percentage of patients achieving disease remission and normal function (DAS28 ≤2.6 plus HAQ ≤0.5) was higher in M-RA (21.4 %) than in H-RA patients (14.8 %, p = 0.007), regardless of the disease duration. Additionally, female gender (p = 0.006) and H-RA class (p = 0.002) negatively predicted disease remission at 1 year. However, the drug survival rate did not differ between the two subsets. This study confirms that etanercept was effective in the treatment of active RA, but best response, in terms of disease remission and normal function ability, was greater and easier to attain in M-RA patients. These findings may aid clinicians to choose the best strategy to treat RA.
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Antirreumáticos/administración & dosificación , Artritis Reumatoide/tratamiento farmacológico , Productos Biológicos/administración & dosificación , Inmunoglobulina G/administración & dosificación , Receptores del Factor de Necrosis Tumoral/administración & dosificación , Inducción de Remisión , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Quimioterapia Combinada , Etanercept , Femenino , Glucocorticoides/administración & dosificación , Humanos , Italia , Masculino , Metotrexato/administración & dosificación , Persona de Mediana Edad , Estudios Prospectivos , Sistema de Registros , Índice de Severidad de la Enfermedad , Encuestas y Cuestionarios , Resultado del Tratamiento , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Adulto JovenRESUMEN
OBJECTIVES: Interleukin (IL)-23 has been implicated in the pathogenesis of ankylosing spondylitis (AS). The aim of the study was to clarify the mechanisms underlying the increased IL-23 expression in the gut of AS patients. METHODS: Consecutive gut biopsies from 30 HLA-B27(+) AS patients, 15 Crohn's disease (CD) patients and 10 normal subjects were obtained. Evidence for HLA-B27 misfolding was studied. Unfolded protein response (UPR) and autophagy were assessed by RT-PCR and immunohistochemistry. The contribution of UPR and autophagy in the regulation of IL-23 expression was evaluated in in vitro experiments on isolated lamina propria mononuclear cells (LPMCs). RESULTS: Intracellular colocalisation of SYVN1 and FHCs but not a significant overexpression of UPR genes was observed in the gut of AS patients. Conversely, upregulation of the genes involved in the autophagy pathway was observed in the gut of AS and CD patients. Immunohistochemistry showed an increased expression of LC3II, ATG5 and ATG12 but not of SQSTM1 in the ileum of AS and CD patients. LC3II was expressed among infiltrating mononuclear cells and epithelial cells resembling Paneth cells (PC) and colocalised with ATG5 in AS and CD. Autophagy but not UPR was required to modulate the expression of IL-23 in isolated LPMCs of AS patients with chronic gut inflammation, CD patients and controls. CONCLUSIONS: Our data suggest that HLA-B27 misfolding occurs in the gut of AS patients and is accompanied by activation of autophagy rather than a UPR. Autophagy appears to be associated with intestinal modulation of IL-23 in AS.
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Autofagia/inmunología , Antígeno HLA-B27/inmunología , Ileítis/inmunología , Subunidad p19 de la Interleucina-23/inmunología , Intestinos/inmunología , Espondilitis Anquilosante/inmunología , Respuesta de Proteína Desplegada/inmunología , Adulto , Anciano , Biopsia , Enfermedad de Crohn/inmunología , Enfermedad de Crohn/patología , Femenino , Expresión Génica/inmunología , Antígeno HLA-B27/química , Antígeno HLA-B27/genética , Humanos , Ileítis/patología , Subunidad p19 de la Interleucina-23/genética , Intestinos/patología , Masculino , Persona de Mediana Edad , Membrana Mucosa/inmunología , Membrana Mucosa/patología , Pliegue de Proteína , Espondilitis Anquilosante/patología , Adulto JovenRESUMEN
OBJECTIVE: Long-term evolution of subclinical gut inflammation to overt Crohn's disease (CD) has been described in AS patients. The aim of this study was to evaluate macrophage polarization occurring in the inflamed gut of patients with AS. METHODS: Twenty-seven HLA-B27(+) AS patients, 20 CD patients and 17 normal controls were consecutively enrolled. Classic M1 (iNOS(+)IL-10(-)), resolution phase (iNOS(+)IL-10(+)), M2 and CD14(+) macrophages were characterized by immunohistochemistry and flow cytometry. Quantitative gene expression analysis of IFN-γ, IL-4, IL-5, IL-33 and STAT6 was performed by real time PCR. RESULTS: Classic M1 macrophages were expanded in CD and AS, where resolution phase macrophages predominate. A large increase in CD163(+) (M2) macrophages was observed in AS strictly correlated with the expression of IL-33, a Th2 cytokine involved in M2 polarization. Unlike in CD, CD14(+) macrophages were virtually absent in the gut of AS patients and controls. CONCLUSION: The absence of CD14(+) macrophages together with the expansion of resolution phase and M2 macrophages is the immunological signature of subclinical ileal inflammation in AS.
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Citocinas/genética , ADN/genética , Regulación de la Expresión Génica , Ileítis/etiología , Macrófagos/inmunología , Espondilitis Anquilosante/genética , Adulto , Anciano , Biopsia , Citocinas/inmunología , Citocinas/metabolismo , Femenino , Citometría de Flujo , Humanos , Ileítis/genética , Ileítis/metabolismo , Íleon/inmunología , Íleon/metabolismo , Íleon/patología , Inmunohistoquímica , Macrófagos/metabolismo , Masculino , Persona de Mediana Edad , Fenotipo , Reacción en Cadena en Tiempo Real de la Polimerasa , Espondilitis Anquilosante/complicaciones , Espondilitis Anquilosante/inmunología , Adulto JovenRESUMEN
OBJECTIVES: To investigate the expression of IL-34 in labial salivary glands (LSGs) of patients with primary SS (p-SS) and its role in inducing a pro-inflammatory monocyte phenotype. METHODS: LSG biopsies were obtained from 20 patients with p-SS and 10 patients with non-Sjögren's sicca syndrome (n-SS). The expression of IL-34, IL-1ß, TNF-α, IL-17 and IL-23 was assessed by real-time PCR. IL-34 expression was also investigated in LSGs by immunohistochemistry. The frequencies of subpopulations of CD14(+) monocytes were evaluated by flow cytometry among isolated mononuclear cells from peripheral blood and salivary glands from both patients and controls. The role of recombinant IL-34 on isolated peripheral blood mononuclear cells was also evaluated. RESULTS: IL-34 m-RNA was overexpressed in the inflamed salivary glands of p-SS and associated with increased expression of TNF-α, IL-1ß, IL-17 and IL-23p19. The increased expression of IL-34 was confirmed by immunohistochemistry in paraffin-embedded salivary glands from p-SS patients. IL-34 expression was accompanied by the expansion of pro-inflammatory CD14(bright)CD16(+) monocytes in the salivary glands. In vitro stimulation of peripheral blood mononuclear cells with IL-34 induced the expansion of both CD14(+)CD16(-) cells and CD14(bright)CD16(+) cells in p-SS and non-SS subjects. CONCLUSION: IL-34 seems to be involved in the pathogenesis of salivary gland inflammation in p-SS.
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Interleucinas/metabolismo , Receptores de Lipopolisacáridos/metabolismo , Monocitos/metabolismo , Receptores de IgG/metabolismo , Glándulas Salivales/metabolismo , Síndrome de Sjögren/metabolismo , Adulto , Anciano , Femenino , Citometría de Flujo , Humanos , Inflamación/metabolismo , Inflamación/patología , Interleucina-17/metabolismo , Interleucina-1beta/metabolismo , Interleucina-23/metabolismo , Masculino , Persona de Mediana Edad , Monocitos/patología , Glándulas Salivales/patología , Síndrome de Sjögren/patología , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
OBJECTIVE: To study the expression of interleukin (IL)-33 and to evaluate its relationship with macrophage polarisation in artery biopsy specimens from patients with giant cell arteritis (GCA). METHODS: IL-33, ST2, p-STAT-6 and perivascular IL-1 receptor-associated kinase 1 (p-IRAK1) tissue distribution was evaluated by immunohistochemistry. Inducible nitric oxide synthase and CD163 were also used by immunohistochemistry to evaluate the M1 and M2 polarisation, respectively. Quantitative gene expression analysis of IL-33, T-helper (Th)2-related transcription factor STAT6, Th2 cytokines (IL-4, IL-5, IL-25) and interferon (IFN)-γ was performed in artery biopsy samples obtained from 20 patients with GCA and 15 controls. Five additional patients who had received prednisone when the temporal artery biopsy was performed were also enrolled. RESULTS: IFN-γ and IL-33 were significantly overexpressed in the inflamed arteries of GCA patients. IL-33 overexpression was not accompanied by a concomitant increase of Th2 cytokines. Neovessels scattered through the inflammatory infiltrates were the main sites of IL-33 expression. The expression of IL-33 receptor ST2 and of p-IRAK1 was also increased in GCA patients. Arteries from glucocorticoid-treated patients had a lower expression of IL-33. IL-33 was accompanied by the expression of p-STAT6 and a clear M2 macrophages polarisation. CONCLUSIONS: A role for IL-33 in the inflammation of GCA patients is supported by these findings.
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Arteritis de Células Gigantes/inmunología , Arteritis de Células Gigantes/metabolismo , Interleucinas/biosíntesis , Arterias Temporales/inmunología , Arterias Temporales/metabolismo , Anciano , Anciano de 80 o más Años , Femenino , Arteritis de Células Gigantes/patología , Humanos , Inmunohistoquímica , Inflamación/inmunología , Inflamación/metabolismo , Interleucina-33 , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Arterias Temporales/patología , TranscriptomaAsunto(s)
Anticuerpos Monoclonales de Origen Murino/uso terapéutico , Interleucinas/metabolismo , Glándulas Salivales/efectos de los fármacos , Síndrome de Sjögren/tratamiento farmacológico , Adulto , Anciano , Femenino , Humanos , Factores Inmunológicos/uso terapéutico , Interleucinas/inmunología , Masculino , Persona de Mediana Edad , Rituximab , Glándulas Salivales/inmunología , Glándulas Salivales/metabolismo , Síndrome de Sjögren/inmunología , Síndrome de Sjögren/metabolismo , Resultado del Tratamiento , Interleucina-22RESUMEN
OBJECTIVE: To study the mRNA expression and protein tissue distribution of IL-32 in ileal biopsy specimens from patients with AS. METHODS: Quantitative gene expression analysis, by real-time PCR, of IL-32, IL-1ß, IL-10, TNF-α and IFN-γ was performed on ileal biopsies of 15 AS and 15 Crohn's disease (CD) patients and 10 healthy subjects (HSs). IL-32 tissue distribution was evaluated by immunohistochemistry. The effect of IL-32 on the production of IL-10 by intestinal epithelial cell lines was also evaluated. RESULTS: In the ileal specimens of patients with AS and intestinal chronic inflammation, significant up-regulation of IL-32 at both the mRNA and protein levels was found as compared with non-inflamed AS patients and controls. IL-32 over-expression in AS was accompanied by a significant increase of IL-10 but not of cytokines involved in IL-32 induction. IL-32 stimulates intestinal epithelial cell lines in vitro to produce IL-10. CONCLUSION: Our findings suggest IL-32 as an important cytokine probably involved in the innate immune response occurring in early phases of intestinal inflammation, where it seems to play a prevalent protective role.
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Enfermedad de Crohn/metabolismo , Íleon/metabolismo , Interleucinas/metabolismo , Espondilitis Anquilosante/metabolismo , Adolescente , Adulto , Estudios de Casos y Controles , Enfermedad de Crohn/inmunología , Células Epiteliales/metabolismo , Femenino , Células HCT116 , Humanos , Ileítis/inmunología , Ileítis/metabolismo , Inmunidad Innata , Interferón gamma/metabolismo , Interleucina-10/biosíntesis , Interleucina-10/metabolismo , Interleucina-1beta/metabolismo , Interleucinas/genética , Macrófagos/metabolismo , Masculino , Persona de Mediana Edad , ARN Mensajero/metabolismo , Espondilitis Anquilosante/inmunología , Factor de Necrosis Tumoral alfa/metabolismo , Adulto JovenRESUMEN
OBJECTIVE: To evaluate the risk of serious infections (SIs) in RA patients receiving anti-TNF therapy on the basis of the data included in the GISEA register. METHODS: The study involved 2769 adult patients with long-standing RA (mean age 53.2±13.4 years; mean disease duration 9.0±8.3 years) enrolled in the GISEA register, who had been treated for at least 6 months with TNF inhibitors or had discontinued therapy due to SI: 837 (30%) treated with infliximab (IFN), 802 (29%) with adalimumab (ADA), and 1130 (41%) with etanercept (ETN). RESULTS: 176 patients had experienced at least one of the 226 Sis during the 9 years of treatment with an anti-TNF agent, an overall incidence of 31.8/1000 patient-years (95% CI 25.2-38.3): 23.7/1000 patient-years (95% CI 13.1-34.2) on ADA; 12.8/1000 patient-years (95% CI 6.3-19.4) on ETN and 65.1/1000 patient-years (95% CI 48.4-81.8) on IFN. The risk was higher in the first than in the second year of treatment, but this difference was not statistically significant (p=0.08) (38.9% of the SIs were recorded in the first 12 months of treatment). The risk of SI was significantly different among the three treatment groups (p<0.0001). Multivariate models confirmed that the use of steroids (p<0.046), concomitant DMARD treatment during anti-TNF therapy (p=0.004), advanced age at the start of anti-TNF treatment (p<0.0001), and the use of IFN or ADA rather than ETN (respectively p<0.0001 and p=0.023) were strong and statistically significant predictors of infection. CONCLUSIONS: Anti-TNF therapy is associated with a small but significant risk of SI that is associated with the concomitant use of steroids, advanced age at the start of anti-TNF treatment, and the type of anti-TNF agent.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Antirreumáticos/uso terapéutico , Artritis Reumatoide/complicaciones , Artritis Reumatoide/tratamiento farmacológico , Infecciones/complicaciones , Inhibidores del Factor de Necrosis Tumoral , Adalimumab , Adulto , Anciano , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Antirreumáticos/efectos adversos , Etanercept , Femenino , Humanos , Inmunoglobulina G/efectos adversos , Inmunoglobulina G/uso terapéutico , Incidencia , Infecciones/inducido químicamente , Infecciones/epidemiología , Infliximab , Masculino , Persona de Mediana Edad , Receptores del Factor de Necrosis Tumoral/uso terapéutico , Sistema de RegistrosRESUMEN
OBJECTIVE: To evaluate 4-year retention rates of tumor necrosis factor-α (TNF-α) inhibitors adalimumab, etanercept, and infliximab among patients with longstanding rheumatoid arthritis (RA), as derived from an Italian national registry. METHODS: The clinical records of 853 adult patients with RA in the GISEA (Gruppo Italiano Studio Early Arthritis) registry were prospectively analyzed to compare drug survival rates and the baseline factors that may predict adherence to therapy. RESULTS: In 2003 and 2004, 324 patients started treatment with adalimumab, 311 with etanercept, and 218 with infliximab. After 4 years, the global retention rate of anti-TNF-α therapy was 42%. Etanercept survival (51.4%) was significantly better than that of infliximab (37.6%) or adalimumab (36.4%; p < 0.0001). Accordingly, the mean duration of therapy was significantly longer for etanercept (3.1 ± 2 yrs) than for adalimumab (2.6 ± 2 yrs) or infliximab (2.7 ± 2 yrs; p < 0.05). The use of concomitant disease-modifying antirheumatic drugs, mainly methotrexate, and the presence of comorbidities significantly predicted drug continuation (p < 0.01), whereas a high Disease Activity Score did not. CONCLUSION: The 4-year global drug survival of adalimumab, etanercept, and infliximab was lower than 50%, with etanercept having the best retention rate. The main positive predictor of adherence to anti-TNF-α therapy was the concomitant use of methotrexate. Our study provides further evidence that the real-life treatment of patients with RA may be different from that of randomized clinical trials.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Antirreumáticos/toxicidad , Artritis Reumatoide/tratamiento farmacológico , Sistema de Registros , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Adalimumab , Anticuerpos Monoclonales Humanizados/uso terapéutico , Artralgia/tratamiento farmacológico , Artralgia/etiología , Artralgia/fisiopatología , Artritis Reumatoide/complicaciones , Artritis Reumatoide/fisiopatología , Biomarcadores/sangre , Sustitución de Medicamentos/estadística & datos numéricos , Etanercept , Femenino , Estado de Salud , Humanos , Inmunoglobulina G/uso terapéutico , Infliximab , Italia , Articulaciones/patología , Articulaciones/fisiopatología , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Dimensión del Dolor , Estudios Prospectivos , Receptores del Factor de Necrosis Tumoral/uso terapéutico , Tasa de Supervivencia , Factores de TiempoRESUMEN
OBJECTIVE: The intestinal inflammation observed in patients with ankylosing spondylitis (AS) is characterized by an overexpression of interleukin-23 (IL-23). IL-23 is known to regulate IL-22 production through lamina propria NKp44+ natural killer (NK) cells, which are thought to be involved in protective mucosal mechanisms. This study was undertaken to evaluate the frequency of NKp44+ NK cells and the expression of IL-22 in the ileum of AS patients. METHODS: Tissue NKp44+ NK cells, NKp46+ NK cells, and IL-22-producing cells were analyzed by flow cytometry. Quantitative gene expression analysis of IL-22, IL-23, IL-17, STAT-3, and mucin 1 (MUC-1) was performed by reverse transcriptase-polymerase chain reaction on ileal samples from 15 patients with AS, 15 patients with Crohn's disease (CD), and 15 healthy controls. NKp44, pSTAT-3, and IL-22 expression was analyzed by immunohistochemistry. RESULTS: The frequency of NKp44+ but not NKp46+ NK cells was increased in the inflamed ileum of AS patients compared to CD patients and controls. The frequency of NKp46+ NK cells was significantly increased only in CD patients. Among CD4+ lymphocytes and NKp44+ NK cell subsets, the latter were the major source of IL-22 on lamina propria mononuclear cells from AS patients. Significant up-regulation of IL-22, IL-23p19, MUC-1, and STAT-3 transcripts in the terminal ileum of patients with AS was observed. Immunohistochemical analysis confirmed the increased IL-22 and pSTAT-3 expression in inflamed mucosa from AS and CD patients. CONCLUSION: Our findings indicate that overexpression of IL-22, together with an increased number of IL-22-producing NKp44+ NK cells, occurs in the gut of AS patients, where it appears to play a tissue-protective role.
Asunto(s)
Íleon/inmunología , Interleucinas/metabolismo , Mucosa Intestinal/inmunología , Células Asesinas Naturales/inmunología , Receptor 2 Gatillante de la Citotoxidad Natural/análisis , Espondilitis Anquilosante/inmunología , Adulto , Femenino , Humanos , Íleon/metabolismo , Inflamación/inmunología , Inflamación/metabolismo , Interleucina-23/genética , Interleucina-23/metabolismo , Interleucinas/genética , Mucosa Intestinal/metabolismo , Células Asesinas Naturales/metabolismo , Masculino , Persona de Mediana Edad , Mucina-1/genética , Mucina-1/metabolismo , Factor de Transcripción STAT3/genética , Factor de Transcripción STAT3/metabolismo , Espondilitis Anquilosante/metabolismo , Interleucina-22RESUMEN
OBJECTIVES: In chronic inflammatory disorders, interleukin (IL)-22 may act either as a protective or as a pro-inflammatory cytokine. At mucosal sites, IL-22 is mainly produced by CD4(+) T cells and by a subset of mucosal natural killer (NK) cells expressing the receptor NKp44 (NKp44(+) NK cells). The aim of this study was to investigate the IL-22 expression in the salivary glands of patients with primary Sjögren's syndrome (pSS). METHODS: Minor salivary gland biopsies were obtained from 19 patients with pSS and 16 with non-specific chronic sialoadenitis. Quantitative gene expression analysis by TaqMan real-time PCR and immunohistochemistry for IL-17, IL-22, IL-23 and STAT3 (signal transducer and activator of transcription) was performed on salivary glands from patients and controls. The cellular sources of IL-22 among infiltrating inflammatory cells were also determined by fluorescence-activated cell sorting analysis and immunohistochemistry. RESULTS: IL-22, IL-23 and IL-17 were significantly increased at both protein and mRNA levels in the inflamed salivary glands of patients with pSS. STAT3 mRNA and the tyrosine phosphorylated corresponding protein were also significantly increased in pSS. Th17 and NKp44(+) NK cells were the major cellular sources of IL-22 in patients with pSS. CONCLUSIONS: Our results suggest that, together with IL-17 and IL-23, IL-22 may play a pro-inflammatory role in the pathogenesis of pSS.