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OBJECTIVES: Fibrotic interstitial lung disease (ILD) is a progressive lung disease characterized by loss of lung volume, resulting in a leading cause of death in patients with RA. Crucially, acute exacerbation (AE) of ILD shows higher morbidity and mortality with rapid deterioration of the lungs. However, a quantitative assessment for physiological changes at AE has yet to be performed. This study hypothesized that quantitative assessments of lung volume (LV) accurately indicate disease severity and mortality risk in patients with AE-RA-ILD. METHODS: This multicentre cohorts study quantitatively assessed physiological changes of RA-ILD at diagnosis (n = 54), at AE (discovery-cohorts; n = 20, and validation-cohort; n = 33), and controls (n = 35) using 3D CT (3D-CT) images. LV was quantitatively measured using 3D-CT and standardized by predicted forced vital capacity. RESULTS: Patients with RA-ILD at diagnosis showed decreased LV, predominantly in lower lobes, compared with controls. Further substantial volume loss was found in upper- and lower lobes at AE compared with those at diagnosis. During AE, decreased standardized 3D-CT LV was associated with a worse prognosis in both cohorts. Subsequently, standardized 3D-CT LV was identified as a significant prognostic factor independent of age, sex and the presence of UIP pattern on CT by multivariate analyses. Notably, a composite model of age and standardized 3D-CT LV successfully classified mortality risk in patients with AE-RA-ILD. CONCLUSION: Volume loss at AE in patients with RA-ILD was associated with increased mortality. Assessing physiological change using standardized 3D-CT might help evaluate disease severity and mortality risk in patients with AE-RA-ILD.
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Artritis Reumatoide , Enfermedades Pulmonares Intersticiales , Humanos , Artritis Reumatoide/complicaciones , Artritis Reumatoide/diagnóstico por imagen , Enfermedades Pulmonares Intersticiales/etiología , Enfermedades Pulmonares Intersticiales/complicaciones , Pulmón/diagnóstico por imagen , Pronóstico , Capacidad Vital , Tomografía Computarizada por Rayos X , Estudios RetrospectivosRESUMEN
BACKGROUND: Airway epithelial cells (AECs) play a crucial role in the induction and development of allergic inflammation through the development and activation of immune cells, including Th2 cells and ILC2s. Recent studies have revealed that STAT3 expressed in epithelial cells protects against pathogens and maintains homeostasis in the intestine. However, the roles of STAT3 in airway epithelium are poorly understood. Therefore, we sought to elucidate the roles of airway epithelial STAT3 in allergic airway inflammation. METHODS: Allergic airway inflammation was induced by intratracheal administration of house dust mite (HDM) extract in doxycycline-induced AEC-specific STAT3-deficient (STAT3-cKO) mice and their genetic control (STAT3-WT) mice. Airway inflammation was evaluated by flow cytometric analysis of bronchoalveolar lavage fluid cells and histological analysis of the lung. Purified airway epithelial cells were analyzed by quantitative PCR and RNA-sequencing (RNA-seq). RESULTS: HDM-induced airway inflammation was exacerbated in STAT3-cKO mice compared with STAT3-WT mice. RNA-seq analyses revealed that Scd1, coding stearoyl-CoA desaturase 1, was most significantly upregulated in HDM-treated STAT3-WT mice compared to HDM-treated STAT3-cKO mice. Notably, the administration of an SCD1 inhibitor exacerbated HDM-induced airway inflammation. AECs of HDM-treated STAT3-cKO mice and those of HDM-treated SCD1 inhibitor-injected mice shared 45 differentially expressed genes (DEGs). Gene enrichment analysis of the DEGs revealed that the enriched ontology clusters included fatty acid biosynthetic process and regulation of lipid biosynthetic process, suggesting the involvement of the STAT3-SCD1-lipid metabolism axis in suppressing allergic inflammation. CONCLUSIONS: STAT3 is crucial for suppressing HDM-induced allergic airway inflammation, possibly inducing SCD1 expression in AECs.
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Inmunidad Innata , Factor de Transcripción STAT3/metabolismo , Estearoil-CoA Desaturasa/metabolismo , Alérgenos , Animales , Modelos Animales de Enfermedad , Doxiciclina/metabolismo , Ácidos Grasos/metabolismo , Inflamación , Lípidos , Pulmón/patología , Linfocitos , Ratones , Pyroglyphidae , Factor de Transcripción STAT3/genética , Regulación hacia ArribaRESUMEN
BACKGROUND: One of the pathognomonic features of asthma is epithelial hyperproduction of mucus, which is composed of a series of glycoproteins; however, it remains unclear how glycosylation is induced in lung epithelial cells from asthmatic patients and how glycan residues play a role in the pathogenesis of asthma. OBJECTIVE: The objective of this study was to explore comprehensive epithelial glycosylation status induced by allergic inflammation and reveal its possible role in the pathogenesis of asthma. METHODS: We evaluated the glycosylation status of lung epithelium using a lectin microarray. We next searched for molecular mechanisms underlying epithelial glycosylation. We also examined whether epithelial glycosylation is involved in induction of allergic inflammation. RESULTS: On allergen inhalation, lung epithelial cells were heavily α(1,2)fucosylated by fucosyltransferase 2 (Fut2), which was induced by the IL-13-signal transducer and activator of transcription 6 pathway. Importantly, Fut2-deficient (Fut2-/-) mice, which lacked lung epithelial fucosylation, showed significantly attenuated eosinophilic inflammation and airway hyperresponsiveness in house dust mite (HDM)-induced asthma models. Proteome analyses and immunostaining of the HDM-challenged lung identified that complement C3 was accumulated in fucosylated areas. Indeed, Fut2-/- mice showed significantly reduced levels of C3a and impaired accumulation of C3a receptor-expressing monocyte-derived dendritic cells in the lung on HDM challenge. CONCLUSION: Fut2 induces epithelial fucosylation and exacerbates airway inflammation in asthmatic patients in part through C3a production and monocyte-derived dendritic cell accumulation in the lung.
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Asma/inmunología , Células Epiteliales/inmunología , Fucosiltransferasas/inmunología , Pulmón/inmunología , Mucosa Respiratoria/inmunología , Alérgenos/inmunología , Animales , Complemento C3/inmunología , Modelos Animales de Enfermedad , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Eosinofilia Pulmonar/inmunología , Pyroglyphidae/inmunología , Células Th17/inmunología , Células Th2/inmunología , Galactósido 2-alfa-L-FucosiltransferasaRESUMEN
It is well known that sensitization against fungi is closely associated with severity of asthma. Dectin-1 (gene symbol Clec7a), a C-type lectin receptor, recognizes the fungal cell wall component ß-glucan, as well as some component(s) in house dust mite (HDM) extract. However, the roles of Dectin-1 in HDM-induced allergic airway inflammation remain unclear. In this study, we used Dectin-1-deficient (Clec7a-/-) mice to examine whether Dectin-1 is involved in HDM-induced allergic airway inflammation. We found that HDM-induced eosinophil and neutrophil recruitment into the airways was significantly attenuated in Clec7a-/- mice compared with that in wild-type mice. In addition, HDM-induced IL-5, IL-13, and IL-17 production from mediastinum lymph node cells was reduced in HDM-sensitized Clec7a-/- mice. Dectin-1 was expressed on CD11b+ dendritic cells (DCs), an essential DC subset for the development of allergic inflammation, but not on CD103+ DCs, plasmacytoid DCs, or lung epithelial cells. Transcriptome analysis revealed that the expression of chemokine/chemokine receptors, including CCR7, which is indispensable for DC migration to draining lymph nodes, was decreased in Clec7a-/- DCs. In accordance with these results, the number of HDM-labeled CD11b+ DCs in mediastinum lymph nodes was significantly reduced in Clec7a-/- mice compared with wild-type mice. Taken together, these results suggest that Dectin-1 expressed on CD11b+ DCs senses some molecule(s) in HDM extract and plays a critical role in the induction of HDM-induced allergic airway inflammation by inducing the expression of chemokine/chemokine receptors in DCs.
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Asma/inmunología , Células Dendríticas/inmunología , Hipersensibilidad/inmunología , Lectinas Tipo C/inmunología , Animales , Antígenos Dermatofagoides/inmunología , Antígeno CD11b/inmunología , Quimiotaxis de Leucocito , Modelos Animales de Enfermedad , Ensayo de Inmunoadsorción Enzimática , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Pyroglyphidae/inmunología , Reacción en Cadena en Tiempo Real de la PolimerasaRESUMEN
Clinical manifestations of systemic lupus erythematosus (SLE) in female patients with polysomy X have been less characterized as compared to those in male patients. Here, we describe a 28-year-old woman with trisomy X (47,XXX) who developed SLE. She had polyarthritis, hemolytic anemia, and was positive for anti-nuclear and anti-dsDNA antibodies. We discuss the common SLE manifestations with female polysomy X and the possible link between the development of SLE and the presence of extra X-chromosomes.
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Lupus Eritematoso Sistémico/patología , Trastornos de los Cromosomas Sexuales del Desarrollo Sexual/complicaciones , Adulto , Cromosomas Humanos X/genética , Femenino , Humanos , Lupus Eritematoso Sistémico/complicaciones , Lupus Eritematoso Sistémico/genética , Lupus Eritematoso Sistémico/inmunología , Aberraciones Cromosómicas Sexuales , TrisomíaAsunto(s)
Hipersensibilidad a los Alimentos/inmunología , Interleucinas/inmunología , Intestinos/inmunología , Mastocitos/inmunología , Animales , Hipersensibilidad a los Alimentos/genética , Hipersensibilidad a los Alimentos/patología , Interleucinas/genética , Intestinos/patología , Mastocitos/patología , Ratones , Ratones NoqueadosRESUMEN
Histoplasmosis, a fungal infection caused by Histoplasma capsulatum, is endemic in many parts of the world. However, this is not common in Japan. We herein present a unique case of military histoplasmosis in a 45-year-old female with mixed connective tissue disease (MCTD) who was receiving immunosuppressive therapy. The histological findings coupled with molecular confirmation led to final a diagnosis. This case emphasizes the diagnostic challenges associated with histoplasmosis in immunocompromised patients and underscores the importance of considering it in the differential diagnosis of any atypical presentation in rheumatic patients.
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OBJECTIVE: We aimed to determine the prevalence and risk factors for osteonecrosis of the femoral head (ONFH) in a multicentre cohort of patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAV). METHODS: One hundred and eighty-six AAV patients who underwent radiographs and MRI screening of bilateral hip joints at more than 6 months after initial remission induction therapy (RIT) were retrospectively assessed for the presence of ONFH. RESULTS: Among 186 AAV patients, 33 (18%) were diagnosed with ONFH. Among the patients with ONFH, 55% were asymptomatic and 64% had bilateral ONFH. Seventy-six per cent of ONFH joints were in precollapse stages (stage ≤2), whereas 24% of ONFH joints were in collapse stages (stage ≥3). Moreover, 56% of the precollapse stage joints were already at risk of future collapse (type ≥C-1). Even in asymptomatic ONFH patients, 39% of the precollapse stage joints were type ≥C-1. Prednisolone dose of ≥20 mg/day on day 90 of RIT was an independent risk factor for ONFH in AAV patients (OR 1.072, 95% CI 1.017 to 1.130, p=0.009). Rituximab use was a significant beneficial factor against ONFH (p=0.019), but the multivariate analysis rejected its significance (p=0.257). CONCLUSION: Eighteen per cent of AAV patients developed ONFH, and two-thirds of the ONFH joints were already in collapse stages or at risk of future collapse. Prednisolone dose of ≥20 mg/day on day 90 of RIT was an independent risk factor for ONFH. A rapid reduction of glucocorticoids in RIT and early detection of precollapse ONFH by MRI may decrease and intervene ONFH development in AAV patients.
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Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos , Osteonecrosis , Humanos , Cabeza Femoral , Prevalencia , Estudios Retrospectivos , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/complicaciones , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/tratamiento farmacológico , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/epidemiología , Prednisolona , Factores de RiesgoRESUMEN
OBJECTIVES: Interstitial lung disease (ILD) is a common pulmonary manifestation of rheumatoid arthritis (RA) associated with clinical heterogeneity and high mortality. This study aimed to determine whether non-invasive biomarkers, especially monocyte count in peripheral blood, would be useful for predicting outcomes in patients with RA-associated ILD (RA-ILD). METHODS: We retrospectively reviewed the medical records of 72 patients with RA-ILD. We assessed clinical characteristics, laboratory findings at the time of diagnosis. We used Cox proportional hazard analyses to determine significant variables associated with outcomes. Cumulative survival rates were calculated using the Kaplan-Meier method. RESULTS: The median age was 68.6 years (58% male). The 5-year survival rate was 78.4%. Cox proportional hazard analyses adjusted by age and sex showed that increased monocyte count and neutrophil count were significantly associated with poor prognosis in patients with RA-ILD. According to optimal cutoff levels, patients with high monocyte counts (≥458/µl) had significantly lower survival rates than those with low monocyte counts (<458/µl). Similarly, patients with high neutrophil counts (≥9394/µl) had significantly lower survival rates than those with low neutrophil counts (<9394/µl). Combinatorial assessments with peripheral monocyte and neutrophil counts revealed that the patients with both high monocyte and neutrophil counts had the lowest survival. CONCLUSIONS: Increased monocyte and neutrophil counts might be potential cellular biomarkers to predict poor outcomes in patients with RA-ILD.
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Artritis Reumatoide/complicaciones , Artritis Reumatoide/diagnóstico , Recuento de Células Sanguíneas , Enfermedades Pulmonares Intersticiales/diagnóstico , Enfermedades Pulmonares Intersticiales/etiología , Monocitos , Neutrófilos , Anciano , Artritis Reumatoide/mortalidad , Biomarcadores/sangre , Femenino , Humanos , Enfermedades Pulmonares Intersticiales/mortalidad , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Pronóstico , Tasa de SupervivenciaRESUMEN
OBJECTIVE: Musculoskeletal ultrasound (US) is more sensitive than physical examination in detecting synovitis and helps physicians to understand its pathophysiology. In this study, we aimed to determine if the experience in musculoskeletal US scanning is independently associated with improved physical examination skills to detect synovitis. METHOD: Seventy patients with rheumatoid arthritis and twenty-three physicians were enrolled. Patients were first assessed by multiple physicians with a range of clinical/sonographic experience for the swelling of the wrist, metacarpophalangeal and proximal interphalangeal (PIP) joints and next underwent US assessment performed by another physician experienced in musculoskeletal US. We then calculated the positive/negative predictive values (PPV/NPV) of joint swelling to identify US-detected synovial hypertrophy. Finally, the factors independently associated with the accuracy of clinical assessment were identified by using multivariate analyses. RESULTS: One thousand five hundred forty joints were assessed 6116 times in total for swelling. Overall, PPV and NPV of joint swelling were 51.7% and 88.3%, respectively. Multivariate analyses identified wrist joint, tenderness, male and greater patients' age as the factors significantly associated with higher PPV. In addition, there was a trend that longer experience in rheumatology clinical practice was associated with higher PPV (p = 0.058). On the other hand, longer experience in musculoskeletal US, PIP joint and positive rheumatoid factor were identified as the significant factors for higher NPV, while wrist joint, tenderness, presence of osteophyte and obesity as those for lower NPV. CONCLUSION: Our data suggest that the experience in musculoskeletal US improves physical examination skills particularly to avoid overestimation.Key Points⢠Physicians with longer US experience are less likely to overestimate synovitis by physical examination.⢠Musculoskeletal US is a useful tool for rheumatologists to improve their physical examination skill.⢠Presence of osteophytes, joint tenderness and obesity influence the accuracy of physical examination of joints.
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Artritis Reumatoide/diagnóstico , Edema/diagnóstico , Sinovitis/diagnóstico , Ultrasonografía , Articulación de la Muñeca/patología , Anciano , Artritis Reumatoide/complicaciones , Artritis Reumatoide/diagnóstico por imagen , Competencia Clínica , Edema/diagnóstico por imagen , Edema/etiología , Femenino , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Examen Físico , Valor Predictivo de las Pruebas , Reumatólogos/normas , Sinovitis/diagnóstico por imagen , Sinovitis/etiología , Articulación de la Muñeca/diagnóstico por imagenAsunto(s)
Infarto Cerebral , Poliarteritis Nudosa , Rotura del Bazo , Humanos , Poliarteritis Nudosa/complicaciones , Poliarteritis Nudosa/diagnóstico , Poliarteritis Nudosa/patología , Infarto Cerebral/etiología , Infarto Cerebral/diagnóstico por imagen , Infarto Cerebral/diagnóstico , Rotura del Bazo/etiología , Rotura del Bazo/diagnóstico , Masculino , Femenino , Tomografía Computarizada por Rayos X , Persona de Mediana EdadRESUMEN
OBJECTIVE: Patients with eosinophilic granulomatosis with polyangiitis (EGPA) frequently experience relapses, which lead to cumulative organ damage. In this retrospective observational study, we aimed to reveal the risk factors for relapse in EGPA. METHODS: A total of 188 Japanese patients with EGPA diagnosed between 1996 and 2015 were identified from medical records in 10 hospitals. The diagnosis was based on the American College of Rheumatology 1990 criteria or Lanham's criteria. Baseline characteristics, treatments, asthma exacerbation, and relapses were evaluated by retrospective chart review. RESULTS: The median followup period was 56 months. The median age at disease onset was 59.7 years. At the disease onset, 95.2% of the patients had a history of bronchial asthma and 44.7% were positive for antineutrophil cytoplasmic antibodies. The cumulative survival and relapse-free survival rates at 5 years were 89.6% and 64.0%, respectively. Multivariate analysis with 2 models, proportional hazards, and competing risk models, was performed to identify the factors associated with relapse. The proportional hazards model identified azathioprine (AZA) maintenance therapy and high eosinophil counts at onset as independent factors with lower relapse risks, and high immunoglobulin E (IgE) levels at onset as a risk factor for relapse. The competing risk model identified no statistically significant factors. CONCLUSION: Although potential benefit of AZA maintenance therapy in preventing relapse of EGPA was suggested by the proportional hazards model, there was a discrepancy in the results between the models. Eosinophil counts and IgE levels at onset were also identified as candidates of factors associated with relapse in EGPA.
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Azatioprina/uso terapéutico , Síndrome de Churg-Strauss/tratamiento farmacológico , Inmunosupresores/uso terapéutico , Anciano , Síndrome de Churg-Strauss/diagnóstico , Eosinófilos , Femenino , Humanos , Japón , Masculino , Persona de Mediana Edad , Recurrencia , Estudios Retrospectivos , Factores de Riesgo , Resultado del TratamientoRESUMEN
Previous studies have shown that IL-22, one of the Th17 cell-related cytokines, plays multiple roles in regulating allergic airway inflammation caused by antigen-specific Th2 cells; however, the underlying mechanism remains unclear. Here, we show that allergic airway inflammation and Th2 and Th17 cytokine production upon intratracheal administration of house dust mite (HDM) extract, a representative allergen, were exacerbated in IL-22-deficient mice. We also found that IL-22 induces Reg3γ production from lung epithelial cells through STAT3 activation and that neutralization of Reg3γ significantly exacerbates HDM-induced eosinophilic airway inflammation and Th2 cytokine induction. Moreover, exostatin-like 3 (EXTL3), a functional Reg3γ binding protein, is expressed in lung epithelial cells, and intratracheal administration of recombinant Reg3γ suppresses HDM-induced thymic stromal lymphopoietin and IL-33 expression and accumulation of type 2 innate lymphoid cells in the lung. Collectively, these results suggest that IL-22 induces Reg3γ production from lung epithelial cells and inhibits the development of HDM-induced allergic airway inflammation, possibly by inhibiting cytokine production from lung epithelial cells.