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1.
Clin Immunol ; 161(2): 333-8, 2015 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-26387628

RESUMEN

Systemic sclerosis (SSc) is a multi-organ fibrotic disease that affects the skin and various internal organs. Therapeutic strategies for tissue fibrosis have not been established; however, aberrantly activated fibroblasts in affected lesions are key targets for modulating fibrosis. Recently, increased intracellular cyclic GMP (cGMP) levels were demonstrated to improve fibrosis levels in various diseases. The purpose of this study was to assess the anti-fibrotic properties of cGMP in cultured fibroblasts from patients with SSc. The phosphodiesterase (PDE) 5 inhibitor sildenafil increased the intracellular cGMP levels in skin fibroblasts in a dose-dependent manner. Sildenafil treatment also significantly decreased the expression of several pro-fibrotic factors that were upregulated by TGF-ß1 treatment in SSc skin fibroblasts. These inhibitory effects occurred via non-canonical TGF-ß signaling. Our findings revealed that sildenafil might be a novel strategy to treat tissue fibrosis and vasculopathy in SSc.


Asunto(s)
GMP Cíclico/metabolismo , Fibroblastos/efectos de los fármacos , Citrato de Sildenafil/farmacología , Piel/patología , Adulto , Anciano , Western Blotting , Células Cultivadas , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Cadena alfa 1 del Colágeno Tipo I , Factor de Crecimiento del Tejido Conjuntivo/genética , Factor de Crecimiento del Tejido Conjuntivo/metabolismo , Relación Dosis-Respuesta a Droga , Femenino , Fibroblastos/metabolismo , Fibrosis/prevención & control , Humanos , Masculino , Persona de Mediana Edad , Inhibidores de Fosfodiesterasa 5/farmacología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Esclerodermia Sistémica/genética , Esclerodermia Sistémica/metabolismo , Esclerodermia Sistémica/patología , Piel/metabolismo , Factor de Crecimiento Transformador beta1/farmacología
2.
Rheumatology (Oxford) ; 53(12): 2196-203, 2014 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-24970922

RESUMEN

OBJECTIVE: PM and DM are often complicated by interstitial lung disease (ILD). In this study we aimed to evaluate various serum cytokines in patients with PM/DM with ILD so as to clarify the differences in pathophysiology between anti-melanoma differentiation-associated gene 5 antibody-associated ILD (anti-MDA5-ILD) and anti-aminoacyl tRNA synthetase antibody-associated ILD (anti-ARS-ILD). METHODS: We evaluated the serum cytokine profiles of 38 patients with PM/DM and compared the cytokine profiles of the non-ILD and ILD subsets as well as the anti-MDA5-ILD and anti-ARS-ILD subsets. RESULTS: The myositis intention-to-treat activity index score, which indicates whole disease activity, significantly correlated with serum IL-6, IL-8, TNF-α and IP-10. These cytokine levels were significantly higher in the ILD subset than the non-ILD subset and were lower in the ILD subset following treatment. By multivariate analysis, TNF-α was the most significant cytokine [P = 0.0006, odds ratio (OR) 1.4, CI 1.1, 2.2] associated with PM/DM with ILD. IL-8 levels were significantly higher in anti-MDA5-ILD than in anti-ARS-ILD, although IL-6, TNF-α and IP-10 levels were high in both subsets. IL-8 was the most significant cytokine (P = 0.0006, OR 1.5, CI 1.1, 3.0) associated with anti-MDA5-ILD by multivariate analysis. Moreover, the ratio of IL-4 to IFN-γ was lower in anti-MDA5-ILD than in anti-ARS-ILD. CONCLUSION: IL-6, IL-8, TNF-α and IP-10 are associated with global disease activity in PM/DM. These cytokine levels were high, especially in the ILD subset. Serum IL-8 levels and the balance between IL-4 and IFN-γ may contribute to the differences in pathophysiology between anti-ARS-ILD and anti-MDA5-ILD.


Asunto(s)
Citocinas/sangre , Dermatomiositis/inmunología , Enfermedades Pulmonares Intersticiales/inmunología , Polimiositis/inmunología , Adulto , Enfermedad Crónica , Dermatomiositis/complicaciones , Progresión de la Enfermedad , Femenino , Humanos , Interleucina-6/sangre , Interleucina-8/sangre , Enfermedades Pulmonares Intersticiales/etiología , Masculino , Persona de Mediana Edad , Polimiositis/complicaciones , Pronóstico , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Factor de Necrosis Tumoral alfa/sangre
3.
Int J Rheum Dis ; 27(1): e14978, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-37983908

RESUMEN

AIM: To assess the usefulness of carbohydrate antigen 19-9 (CA19-9) as a biomarker for systemic sclerosis-associated interstitial lung disease (SSc-ILD), using serum samples and clinical parameters of patients with SSc. METHODS: Patients with SSc admitted to Tokyo Women's Medical University Hospital between 2010 and 2021 and those who underwent chest computed tomography (CT) were included. Patients were diagnosed with ILD based on chest CT findings, and SSc-ILD was categorized as either a limited or extensive disease based on chest CT and pulmonary function test findings. Serum CA19-9 levels were measured in 56 patients with SSc and in 32 healthy individuals. Additionally, we evaluated the difference in serum CA19-9 levels between the groups, the correlation with ILD area and pulmonary function, and discriminative performance to diagnose extensive ILD. RESULTS: Of the 56 patients with SSc, 40 (71.4%) had ILD, and 17 (30.4%) were classified as having extensive disease. Serum CA19-9 levels were significantly elevated in patients with extensive disease compared to those with limited disease (median [interquartile range]: 25.7 U/mL [10.1-50.8] vs. 8.8 U/mL [4.5-17.6], p = .02) and correlated with ILD area (r = .30, p = .02). There was no significant correlation between serum CA19-9 level and pulmonary function. The cutoff of CA19-9 for the diagnosis of the extensive disease was determined to be 19.8 U/mL, with a sensitivity of 64% and specificity of 82% and an area under the curve of 0.74 (95% confidence interval 0.58-0.90). CONCLUSION: The serum CA19-9 level may be a useful marker for identifying patients with SSc-ILD with extensive disease.


Asunto(s)
Enfermedades Pulmonares Intersticiales , Esclerodermia Sistémica , Humanos , Femenino , Estudios Transversales , Antígeno CA-19-9 , Enfermedades Pulmonares Intersticiales/diagnóstico , Enfermedades Pulmonares Intersticiales/etiología , Pulmón/diagnóstico por imagen , Esclerodermia Sistémica/complicaciones , Esclerodermia Sistémica/diagnóstico , Carbohidratos
4.
Int J Rheum Dis ; 27(7): e15254, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38973340

RESUMEN

AIM: To evaluate whether seasonal changes influence fluctuations in serum Krebs von den Lungen-6 (KL-6) levels in systemic sclerosis-related interstitial lung disease (SSc-ILD). METHODS: Summer was defined as the period between July and September, and winter as between December and February. The study was conducted between 2015 and 2016, with a focus on these two seasons. A diagnosis of ILD and ILD progression overtime were evaluated using chest computed tomography. Among patients with SSc-ILD, those with data on serum KL-6 and lactate dehydrogenase (LDH) levels in the 2015 winter, 2015 summer, and 2016 winter seasons were included. Patients with comorbidities that could affect serum KL-6 levels were excluded. RESULTS: Of 60 patients with SSc-ILD, 52 (86.7%) had stable ILD, 5 (8.3%) had worsened ILD, and 3 (5.0%) had improved ILD. Serum KL-6 levels were significantly higher during the winter than those during the summer (2015 winter vs. 2015 summer: 649 U/mL vs. 585 U/mL, p < .0001; 2016 winter vs. 2015 summer: 690 U/mL vs. 585 U/mL, p < .0001). No significant differences were observed between the winters of 2015 and 2016 (649 U/mL vs. 690 U/mL, p = .78). However, serum LDH levels did not exhibit seasonal fluctuations (2015 winter vs. 2015 summer: 203 U/L vs. 199 U/L, p = .3; 2016 winter vs. 2015 summer: 201 U/L vs. 199 U/L, p = .6; 2015 winter vs. 2016 winter: 203 U/L vs. 201 U/L, p = .24). CONCLUSION: Seasonal fluctuations in serum KL-6 levels were observed in patients with SSc-ILD.


Asunto(s)
Biomarcadores , Enfermedades Pulmonares Intersticiales , Mucina-1 , Esclerodermia Sistémica , Estaciones del Año , Humanos , Enfermedades Pulmonares Intersticiales/sangre , Enfermedades Pulmonares Intersticiales/diagnóstico , Enfermedades Pulmonares Intersticiales/etiología , Mucina-1/sangre , Femenino , Masculino , Persona de Mediana Edad , Biomarcadores/sangre , Esclerodermia Sistémica/sangre , Esclerodermia Sistémica/complicaciones , Esclerodermia Sistémica/diagnóstico , Anciano , Factores de Tiempo , Progresión de la Enfermedad , Adulto , Estudios Retrospectivos , Tomografía Computarizada por Rayos X , Regulación hacia Arriba
5.
Nat Commun ; 15(1): 319, 2024 Jan 31.
Artículo en Inglés | MEDLINE | ID: mdl-38296975

RESUMEN

Here we report the largest Asian genome-wide association study (GWAS) for systemic sclerosis performed to date, based on data from Japanese subjects and comprising of 1428 cases and 112,599 controls. The lead SNP is in the FCGR/FCRL region, which shows a penetrating association in the Asian population, while a complete linkage disequilibrium SNP, rs10917688, is found in a cis-regulatory element for IRF8. IRF8 is also a significant locus in European GWAS for systemic sclerosis, but rs10917688 only shows an association in the presence of the risk allele of IRF8 in the Japanese population. Further analysis shows that rs10917688 is marked with H3K4me1 in primary B cells. A meta-analysis with a European GWAS detects 30 additional significant loci. Polygenic risk scores constructed with the effect sizes of the meta-analysis suggest the potential portability of genetic associations beyond populations. Prioritizing the top 5% of SNPs of IRF8 binding sites in B cells improves the fitting of the polygenic risk scores, underscoring the roles of B cells and IRF8 in the development of systemic sclerosis. The results also suggest that systemic sclerosis shares a common genetic architecture across populations.


Asunto(s)
Predisposición Genética a la Enfermedad , Esclerodermia Sistémica , Humanos , Predisposición Genética a la Enfermedad/genética , Estudio de Asociación del Genoma Completo , Receptores de IgG/genética , Puntuación de Riesgo Genético , Esclerodermia Sistémica/genética , Polimorfismo de Nucleótido Simple , Factores Reguladores del Interferón/genética , Sitios Genéticos
6.
Clin Immunol ; 147(2): 71-8, 2013 May.
Artículo en Inglés | MEDLINE | ID: mdl-23571102

RESUMEN

Systemic sclerosis (SSc) is a connective tissue disease characterized by thickening of the skin and tissue fibrosis of the internal organs. Ghrelin is primarily described as a gut hormone, and many studies currently indicate that ghrelin has protective effects in different organs, including the heart, pancreas, lung and liver, resulting from its anti-fibrotic properties. We found decreased levels of ghrelin in the plasma from patients with SSc compared with those from healthy controls. In skin fibroblast cultures, recombinant ghrelin diminished the production of collagen type I. In addition, the mRNA levels of COL1A2 and TGFB genes were significantly decreased by the stimulation of ghrelin. We showed that ghrelin may exert anti-fibrotic effects in the skin fibroblasts from patients with SSc. Because the plasma levels of ghrelin are low in SSc, the administration of ghrelin could be a new strategy for the treatment of SSc.


Asunto(s)
Colágeno Tipo I/metabolismo , Ghrelina/sangre , Esclerodermia Sistémica/sangre , Adolescente , Adulto , Anciano , Autoanticuerpos/inmunología , Estudios de Casos y Controles , Células Cultivadas , Colágeno Tipo I/genética , Femenino , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Ghrelina/farmacología , Humanos , Masculino , Persona de Mediana Edad , ARN Mensajero/metabolismo , Receptores de Ghrelina/metabolismo , Esclerodermia Sistémica/inmunología , Esclerodermia Sistémica/metabolismo , Esclerodermia Sistémica/patología , Factor de Crecimiento Transformador beta1/genética , Adulto Joven
7.
Rheumatology (Oxford) ; 52(12): 2149-57, 2013 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-23463805

RESUMEN

OBJECTIVES: To evaluate the use of urinary free light chains (FLCs) as a biomarker for proliferative LN and the potential association between the intensity of plasma cell infiltration of the kidney and urinary FLC levels in LN. METHODS: Forty-three SLE patients were consecutively enrolled in the study. These patients were divided into an International Society of Nephrology and Renal Pathology Society (ISN/RPS) class III/IV LN subset (n = 18) and an ISN/RPS class I/II/V (class non-III/IV) LN subset (n = 25). The expression of κ-LCs, λ-LCs, CD19 and CD138 in kidney specimens was also evaluated with immunohistochemical staining. To measure FLC levels before and after treatment, an additional six patients with class III/IV LN were consecutively enrolled. RESULTS: Urinary FLCs were significantly higher in the class III/IV LN subset than in the class non-III/IV LN subset. Urinary λ-FLC levels were significantly correlated with the urinary protein-creatinine ratio in the class III/IV LN subset (rs = 0.67, P < 0.01). Moreover, the LC-secreting CD19(-)/CD138(+) cell counts in the kidney specimens were higher in the class III/IV LN subset than in the class non-III/IV LN subset. Total urinary FLC levels were correlated with the numbers of CD138(+) cells in the kidney (r = 0.71, P = 0.03). Following treatment, urinary λ-FLCs could not be detected in any of the patients. CONCLUSION: The intensity of plasma cell infiltration of the kidney is associated with urinary FLC levels. Urinary FLCs are potentially useful biomarkers in ISN/RPS class III/IV LN or proliferative LN.


Asunto(s)
Cadenas Ligeras de Inmunoglobulina/orina , Nefritis Lúpica/diagnóstico , Antígenos CD19/metabolismo , Biomarcadores/sangre , Biomarcadores/orina , Creatinina/orina , Humanos , Cadenas Ligeras de Inmunoglobulina/sangre , Inmunohistoquímica , Inmunosupresores/uso terapéutico , Nefritis Lúpica/clasificación , Nefritis Lúpica/tratamiento farmacológico , Sindecano-1/metabolismo
8.
Arthritis Rheum ; 64(11): 3736-40, 2012 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-22886382

RESUMEN

OBJECTIVE: The complication of interstitial lung disease (ILD) in polymyositis/dermatomyositis (PM/DM) is associated with anti-aminoacyl-transfer RNA synthetase (anti-aaRS) antibody or anti-melanoma differentiation-associated gene 5 (anti-MDA-5) antibody positivity. Anti-MDA-5 antibody is associated with clinically amyopathic DM and fatal outcome due to rapidly progressive ILD in Asian populations. The association between genetic factors and anti-MDA-5 antibody-positive DM is unclear. This study was undertaken to investigate the HLA-DRB1 genotype in patients with anti-MDA-5 antibody-positive DM. METHODS: We examined genetic differences among 17 patients with anti-MDA-5 antibody-positive DM, 33 patients with anti-aaRS antibody-positive PM/DM, 33 patients with PM/DM without anti-aaRS antibody or ILD, and 265 healthy controls. RESULTS: The frequencies of HLA-DRB1*0101 and DRB1*0405 were 29% and 71%, respectively, in patients with anti-MDA-5 antibody-positive DM, which were higher than the frequencies in healthy controls (10% and 25%, respectively). Among the 17 patients with anti-MDA-5 antibody-positive DM, 16 (94%) harbored either the DRB1*0101 or DRB1*0405 allele. The combined frequency of the DRB1*0101 allele and the DRB1*0405 allele was significantly higher in patients with anti-MDA-5 antibody-positive DM than in patients with PM/DM without anti-aaRS antibody or ILD, with an odds ratio (OR) of 42.7 (95% confidence interval [95% CI] 4.9-370.2) (P = 1.1 × 10(-5)), or in patients with anti-aaRS antibody-positive PM/DM (OR 13.3 [95% CI 1.6-112.6], P = 4.5 × 10(-3)). CONCLUSION: Our findings indicate that HLA-DRB1*0101/*0405 is associated with susceptibility to anti-MDA-5 antibody-positive DM in the Japanese population.


Asunto(s)
Pueblo Asiatico/genética , ARN Helicasas DEAD-box/genética , Dermatomiositis/genética , Cadenas HLA-DRB1/genética , Adolescente , Adulto , Anciano , Pueblo Asiatico/estadística & datos numéricos , Autoanticuerpos/inmunología , ARN Helicasas DEAD-box/inmunología , Dermatomiositis/etnología , Dermatomiositis/inmunología , Femenino , Predisposición Genética a la Enfermedad/etnología , Predisposición Genética a la Enfermedad/genética , Genotipo , Humanos , Helicasa Inducida por Interferón IFIH1 , Masculino , Persona de Mediana Edad
9.
Mod Rheumatol ; 23(2): 210-7, 2013 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-22918594

RESUMEN

Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) is a dominantly inherited autoinflammatory syndrome that is characterized by recurrent episodes of fever attacks associated with rashes, abdominal pain, myalgia, conjunctivitis, chest pain, and arthralgia. Some patients have severe abdominal pain leading to abdominal surgery. Most reported cases of TRAPS involve patients of European ancestry, but there have been nine reports of patients with TRAPS in Japan. Here, we review these nine case reports. Reported TNFRSF1A gene mutations in these nine index patients were C70S, T61I, C70G, C30Y, C30R, N101K, and N25D. Fever (100 %) was seen in all 23 cases. Most patients developed rash (erythema) (84.6 %) and arthralgia (73.3 %), and half suffered from myalgia (54.5 %) and abdominal pain (50.0 %). Although one-half of the patients suffered from abdominal pain, none underwent surgery. In contrast, only a small percentage of patients suffered from chest pain (20.0 %), conjunctivitis (20.0 %), and headache (10.0 %). Almost all cases (95.7 %) concerned patients whose relatives suffered from periodic fever. These findings suggest that the clinical features of Japanese TRAPS patients may be milder than those of patients in Western countries.


Asunto(s)
Enfermedades Autoinflamatorias Hereditarias/diagnóstico , Enfermedades Autoinflamatorias Hereditarias/genética , Femenino , Fiebre , Humanos , Japón , Masculino , Mutación
11.
Sci Rep ; 13(1): 19378, 2023 11 08.
Artículo en Inglés | MEDLINE | ID: mdl-37938601

RESUMEN

Phosphodiesterase (PDE) 4 inhibitors have been reported to suppress the progression of dermal fibrosis in patients with systemic sclerosis (SSc); however, the precise mechanisms remain to be elucidated. Therefore, we conducted experiments focusing on the antifibrotic and anti-inflammatory effects of apremilast using dermal fibroblasts derived from patients with SSc and an SSc mouse model. Dermal fibroblasts derived from healthy controls and patients with SSc were incubated with apremilast in the presence or absence of 10 ng/ml transforming growth factor (TGF)-ß1 for the measurement of intracellular cAMP levels and evaluation of mRNA and protein expression. A bleomycin-induced dermal fibrosis mouse model was used to evaluate the inhibitory effects of apremilast on the progression of dermal fibrosis. Intracellular cAMP levels were significantly reduced in dermal fibroblasts derived from patients with SSc compared with those derived from healthy controls. Apremilast reduced the mRNA expression of profibrotic markers and the protein expression of type I collagen and Cellular Communication Network Factor 2 (CCN2) in dermal fibroblasts. Additionally, apremilast inhibited the progression of dermal fibrosis in mice, partly by acting on T cells. These results suggest that apremilast may be a potential candidate for treating dermal fibrosis in SSc.


Asunto(s)
Inhibidores de Fosfodiesterasa 4 , Esclerodermia Sistémica , Humanos , Animales , Ratones , Bleomicina/efectos adversos , Modelos Animales de Enfermedad , Fibroblastos , Inhibidores de Fosfodiesterasa 4/farmacología , Inhibidores de Fosfodiesterasa 4/uso terapéutico , ARN Mensajero/genética , Esclerodermia Sistémica/inducido químicamente , Esclerodermia Sistémica/tratamiento farmacológico , Fibrosis
12.
Respir Med Case Rep ; 46: 101941, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-38025248

RESUMEN

Mycobacterium abscessus subsp. abscessus (MABA) is refractory and sometimes fatal especially in an immunocompromised patient. Also, MABA-associated pneumothorax is an extremely rare complication. We report a case of MABA pulmonary infection complicated pneumothorax treated successfully. A 69-year-old Japanese female with immunosuppressed systemic sclerosis-associated interstitial lung disease experienced left-sided secondary spontaneous pneumothorax. MABA was detected in the pleural effusion and blood culture. Microbial sensitivity test showed the MABA was sensitive to only amikacin, sitafloxacin, and clofazimine. Combination therapy with these antibiotics including azithromycin achieved remission within three weeks. In the treatment of MABA infection, compliance with microbial sensitivity test is crucial.

13.
Rheumatology (Oxford) ; 51(9): 1563-70, 2012 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-22589330

RESUMEN

OBJECTIVE: The aim of this study was to investigate the precise clinical characteristics and to analyse the association between the anti-MDA5 antibody (anti-MDA5ab) titre and disease status in patients with anti-MDA5ab-positive DM. METHODS: Twenty-seven patients who presented with DM and were positive for the anti-MDA5ab were enrolled. The association between the clinical manifestations and the clinical parameters, including the anti-MDA5ab, was analysed. RESULTS: The complication of rapidly progressive interstitial lung disease (RP-ILD) occurred in 20 (74%) patients. The frequencies of fatal outcome, relapse and malignancy were 33, 4 and 4%, respectively. Remarkably, a fatal outcome occurred within the first 6 months. Compared with six non-RP-ILD patients, elderly age at onset, severely involved pulmonary function and high levels of serum ferritin were present in 20 RP-ILD patients with anti-MDA5ab. Alveolar-arterial oxygen difference (AaDO(2)) ≥32 mmHg and ferritin ≥828 ng/ml at admission were poor prognostic factors in RP-ILD patients with anti-MDA5ab-positive DM. The median value of the anti-MDA5ab titre on admission was higher in patients who later died than in those who survived. The efficacy of treatment was indicated by the anti-MDA5ab, ferritin and IL-18 concentrations. The decline index of the anti-MDA5ab titre after treatment was lower in the subset of patients who died than in the subset of patients who lived. Sustained high levels of anti-MDA5ab, ferritin and IL-18 were present in the patients who died. CONCLUSION: Anti-MDA5ab titre and ferritin and IL-18 concentrations are useful for the evaluation of the response to treatment and the status of ILD in patients with anti-MAD5ab-positive DM.


Asunto(s)
Autoanticuerpos/sangre , ARN Helicasas DEAD-box/inmunología , Dermatomiositis/diagnóstico , Ferritinas/sangre , Interleucina-18/sangre , Enfermedades Pulmonares Intersticiales/diagnóstico , Inhibidores de la Calcineurina , Ciclosporina/uso terapéutico , Dermatomiositis/tratamiento farmacológico , Dermatomiositis/mortalidad , Quimioterapia Combinada , Femenino , Glucocorticoides/uso terapéutico , Humanos , Helicasa Inducida por Interferón IFIH1 , Japón/epidemiología , Enfermedades Pulmonares Intersticiales/tratamiento farmacológico , Enfermedades Pulmonares Intersticiales/mortalidad , Masculino , Persona de Mediana Edad , Prednisolona/uso terapéutico , Pronóstico , Estudios Retrospectivos , Tasa de Supervivencia , Resultado del Tratamiento
14.
J Autoimmun ; 36(3-4): 181-8, 2011 May.
Artículo en Inglés | MEDLINE | ID: mdl-21377836

RESUMEN

Systemic sclerosis (SSc) is a chronic disease of unknown etiology that is characterized by multiple tissue fibrosis. Transforming Growth Factor-beta (TGF-ß) is thought to be the most important mediator that induces fibrosis. However, the molecular mechanisms by which fibrosis is induced have not been fully elucidated. In this study, the role of activin, a member of the TGF-ß superfamily, was investigated in the pathogenesis of fibrosis in SSc. Serum activin A levels in patients with SSc were measured by ELISA, and the expression of the activin receptor type IB (ACVRIB/ALK4) and the activity of the signaling pathway via ACVRIB/ALK4 were investigated using western blotting. To evaluate a potential therapeutic strategy for SSc, we also attenuated the ACVRIB/ALK4 pathway using an inhibitor. Serum activin A levels were significantly higher in SSc patients than in normal controls. Activin A and ACVRIB/ALK4 expression were also higher in cultured SSc fibroblasts. Activin A stimulation induced phosphorylation of Smad2/3 and CTGF expression in SSc fibroblasts. Procollagen production and Col1α mRNA also increased upon stimulation by activin A. The basal level of Smad2/3 phosphorylation was higher in cultured SSc fibroblasts than in control cells, and treatment with the ALK4/5 inhibitor SB431542 prevented phosphorylation of Smad2/3 and CTGF expression. Furthermore, production of collagen was also induced by activin A. Activin A-ACVRIB/ALK4-Smad-dependent collagen production was augmented in SSc fibroblasts, suggesting the involvement of this signaling mechanism in SSc. Inhibition of the activin A-ACVRIB/ALK4-Smad pathway would be a new approach for the treatment of SSc.


Asunto(s)
Receptores de Activinas Tipo I/fisiología , Activinas/fisiología , Esclerodermia Sistémica/metabolismo , Transducción de Señal , Proteína Smad2/fisiología , Proteína smad3/fisiología , Receptores de Activinas Tipo I/antagonistas & inhibidores , Células Cultivadas , Colágeno/biosíntesis , Fibroblastos/metabolismo , Humanos , Óxido Nítrico/biosíntesis , Esclerodermia Sistémica/tratamiento farmacológico , Esclerodermia Sistémica/etiología , Factor de Crecimiento Transformador beta/fisiología
15.
Mod Rheumatol ; 21(3): 296-301, 2011 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-21240620

RESUMEN

Interstitial lung disease (ILD) is a noteworthy condition in the treatment of systemic sclerosis (SSc) because of its associated mortality and morbidity; however, the efficacy of various treatments for ILD has been controversial in previous reports. In this study, we examined the efficacy and safety of intravenous cyclophosphamide (IVCY) pulse therapy with prednisolone (PSL) for the treatment of ILD with SSc. A total of 121 patients with SSc were screened and evaluated for ILD, using high-resolution computed tomography of the chest, pulmonary function testing, and bronchoalveolar lavage. Thirteen patients with active ILD were enrolled in this study. The treatment protocol for ILD was 0.4 g/m(2) of body surface area of IVCY monthly plus 0.8 mg/kg of body weight of PSL daily. Two to six doses of IVCY were administered, depending on the remission of ILD. Initial PSL doses were maintained for a month and then gradually tapered to 10 mg daily. An activity index of ILD showed improvements in all patients in the 12 months after the initial intervention; however, four patients experienced recurrence of ILD after 24 months, and one additional patient had recurrence of ILD after 36 months. Seven patients reached the 48-month point with no recurrence of ILD. This long observational study for 48 months showed the efficacy of IVCY with PSL for active alveolitis in the first year. However, because five patients had recurrence of ILD more than 1 year after the treatment, it would be necessary to consider maintenance therapy for ILD beyond 1 year.


Asunto(s)
Ciclofosfamida/administración & dosificación , Inmunosupresores/administración & dosificación , Enfermedades Pulmonares Intersticiales/tratamiento farmacológico , Prednisolona/administración & dosificación , Esclerodermia Sistémica/tratamiento farmacológico , Administración Oral , Adulto , Anciano , Ciclofosfamida/efectos adversos , Quimioterapia Combinada , Femenino , Estudios de Seguimiento , Glucocorticoides/administración & dosificación , Glucocorticoides/efectos adversos , Humanos , Inmunosupresores/efectos adversos , Inyecciones Intravenosas , Enfermedades Pulmonares Intersticiales/etiología , Enfermedades Pulmonares Intersticiales/inmunología , Masculino , Persona de Mediana Edad , Prednisolona/efectos adversos , Estudios Prospectivos , Esclerodermia Sistémica/complicaciones , Esclerodermia Sistémica/inmunología , Resultado del Tratamiento
16.
Int J Rheum Dis ; 24(6): 803-808, 2021 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-33909342

RESUMEN

AIM: Calcinosis is often observed in systemic sclerosis (SSc), but its pathogenesis remains unclear. The aim of the present study was to explore the association of clinical features with calcinosis in patients with SSc. METHODS: A retrospective cohort study was performed analyzing 416 SSc patients from our SSc database. We examined the clinical features with relation to calcinosis and SSc. RESULTS: Calcinosis was observed in 24.0% of patients with SSc. The group with calcinosis comprised more female patients (P < 0.05) and diffuse cutaneous types (P < 0.001) than the group without calcinosis. Complications of Raynaud's phenomenon (P < 0.05), nail fold bleeding (NFB) (P < 0.001), peripheral bone resorption (P < 0.001), myositis (P < 0.001), and pulmonary hypertension (P < 0.05) were more frequently observed in patients with calcinosis compared with those without calcinosis. The group with calcinosis had a higher modified Rodnan total skin-thickness score (mRSS) than the group without calcinosis (P < 0.001). The factors that affected calcinosis in multivariable analysis were peripheral bone resorption (partial correlation coefficient 0.46, 34%), anti-Scl-70 antibody (partial correlation coefficient 0.29, 20%), diffuse type (partial correlation coefficient 0.34, 16%) and NFB (partial correlation coefficient 0.23, 11.2%). CONCLUSIONS: Calcinosis in SSc is associated with Raynaud's phenomenon, NFB, and pulmonary hypertension, so peripheral circulatory insufficiency seems to be one of the causes of calcinosis. Furthermore, as it is related to mRSS and the diffuse cutaneous type, common factors related to skin fibrosis are considered to be involved.


Asunto(s)
Calcinosis/complicaciones , Esclerodermia Sistémica/complicaciones , Adulto , Anciano , Calcinosis/epidemiología , Femenino , Humanos , Hipertensión Pulmonar/epidemiología , Japón/epidemiología , Masculino , Persona de Mediana Edad , Enfermedad de Raynaud/epidemiología , Estudios Retrospectivos , Esclerodermia Sistémica/epidemiología , Piel/patología
17.
Rheumatology (Oxford) ; 49(10): 1878-81, 2010 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-20601655

RESUMEN

OBJECTIVE: To determine whether IL-18 is involved in the inflammation of DM and PM. METHODS: Thirty-three patients with DM were enrolled in this study, including 25 with interstitial lung disease (ILD). In addition, 16 patients with PM were enrolled, including 6 with ILD. All patients were admitted to our hospital as a result of their condition requiring treatment, and clinical laboratory data including serum IL-18 were recorded on admission. RESULTS: Serum IL-18 was significantly (P < 0.0001) higher in both DM and PM patients than in healthy controls (n = 30). Serum ferritin and IL-18 were significantly (P = 0.003 and 0.0044, respectively) higher in DM than in PM patients. Additionally, ferritin and IL-18 were significantly (P = 0.023 and 0.034, respectively) higher in DM patients with ILD than in DM patients without ILD. Significant positive correlations were found between creatine kinase (CK) and ferritin (r(s) = 0.39, P = 0.024); CK and IL-18 (r(s) = 0.48, P = 0.005); and IL-18 and ferritin (r(s) = 0.54, P = 0.0012) in the DM group as a whole. These findings were different for the DM plus ILD subgroup: significant positive correlations were found between CK and ferritin (r(s) = 0.40, P = 0.047); CK and IL-18 (r(s) = 0.63, P = 0.0008); and IL-18 and ferritin (r(s) = 0.41, P = 0.042). CONCLUSION: Serum IL-18 was strikingly elevated in patients with DM and was associated particularly with disease activity and ILD complication in DM.


Asunto(s)
Dermatomiositis/complicaciones , Ferritinas/inmunología , Interleucina-18/inmunología , Enfermedades Pulmonares Intersticiales/etiología , Polimiositis/complicaciones , Adulto , Anciano , Estudios de Casos y Controles , Dermatomiositis/tratamiento farmacológico , Humanos , Enfermedades Pulmonares Intersticiales/tratamiento farmacológico , Macrófagos/inmunología , Persona de Mediana Edad , Polimiositis/tratamiento farmacológico , Estudios Retrospectivos , Estadística como Asunto
18.
Rheumatology (Oxford) ; 49(9): 1713-9, 2010 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-20498012

RESUMEN

OBJECTIVE: The aim of this study is to evaluate the clinical manifestation and prognostic factors of anti-melanoma differentiation-associated gene 5 (MDA5) antibody-associated interstitial lung disease (ILD) with DM. METHODS: Fourteen patients who presented with anti-MDA5 antibody and 10 patients with anti-aminoacyl-tRNA synthetase (ARS) antibody were enrolled. All patients were diagnosed as having DM with ILD. Clinical manifestations in the patients with anti-MDA5 antibody were compared with those in the patients with anti-ARS antibody. RESULTS: The frequencies of acute/subacute interstitial pneumonia (A/SIP) and fatal outcome were significantly higher in the subset with anti-MDA5 antibody. The creatine kinase (CK) value was significantly lower and the gamma-glutamyl transpeptidase and ferritin values were significantly higher in the subset with anti-MDA5 antibody. Significant correlations were found between PaO(2)/F(i)O(2) and ferritin (r(s) = -0.59, P = 0.035), alveolar-arterial oxygen difference (A-aDO(2)) and KL-6 (r(s) = 0.73, P = 0.016) and A-aDO(2) and ferritin (r(s) = 0.66, P = 0.013) in the subset with anti-MDA5 antibody. The most significant prognostic factor was ferritin. The cumulative survival rate was significantly lower (P < 0.0001) in the subset with ferritin >or=1600 ng/ml than that in the subset with ferritin <1600 ng/ml in anti-MDA5 antibody-associated ILD. CONCLUSION: Both serum ferritin and anti-MDA5 antibody are powerful indicators for the early diagnosis of A/SIP with DM. Ferritin also predicts disease severity and prognosis for patients with anti-MDA5 antibody. Intensive treatment should be administered to cases that have anti-MDA5 antibody-associated ILD with DM showing hyperferritinaemia, especially if the ferritin level is >or=1600 ng/ml.


Asunto(s)
Autoanticuerpos/inmunología , ARN Helicasas DEAD-box/inmunología , Dermatomiositis/complicaciones , Ferritinas/inmunología , Enfermedades Pulmonares Intersticiales/inmunología , Activación de Macrófagos/inmunología , Adulto , Autoanticuerpos/genética , Biomarcadores , ARN Helicasas DEAD-box/genética , Dermatomiositis/inmunología , Dermatomiositis/fisiopatología , Progresión de la Enfermedad , Femenino , Humanos , Helicasa Inducida por Interferón IFIH1 , Enfermedades Pulmonares Intersticiales/genética , Enfermedades Pulmonares Intersticiales/fisiopatología , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Estadística como Asunto
19.
Mod Rheumatol ; 20(5): 427-31, 2010 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-20437071

RESUMEN

The objective of this study was to explore the association of single nucleotide polymorphisms (SNPs) of the CD244 gene with several clinical features of systemic lupus erythematosus (SLE). Two hundred and forty-three patients with SLE and 369 healthy controls were enrolled. Two SNPs (rs6682654 and rs3766379) in the CD244 gene were determined by allelic discrimination using a specific TaqMan probe. Only SNP rs3766379 was significantly associated with susceptibility to SLE [P = 0.009; odds ratio (OR) 1.28; 95% confidence interval (CI) 1.04-1.57]. The association was preferentially observed in subsets of SLE patients with nephritis and neuropsychiatric lupus. The frequency of the rs6682654 C allele was strongly associated with nephritis and neuropsychiatric lupus (P = 0.00065; OR 1.99; 95% CI 1.34-2.95, and P = 1.6 × 10(-7); OR 3.47; 95% CI 2.12-5.70, respectively), as was the frequency of the rs3766379 T allele (P = 0.0014; OR 1.86; 95% CI 1.27-2.71, and P = 2.6 × 10(-7); OR 3.15; 95% CI 2.00-4.96, respectively). In this study, an SNP of the CD244 gene was associated with susceptibility to SLE. There was a strikingly strong association in SLE patients with nephritis and neuropsychiatric lupus, suggesting that this genetic marker could predict involvement of those severe complications.


Asunto(s)
Antígenos CD/genética , Predisposición Genética a la Enfermedad , Nefritis Lúpica/genética , Vasculitis por Lupus del Sistema Nervioso Central/genética , Polimorfismo de Nucleótido Simple , Receptores Inmunológicos/genética , Adolescente , Adulto , Anciano , Femenino , Marcadores Genéticos/genética , Humanos , Nefritis Lúpica/patología , Vasculitis por Lupus del Sistema Nervioso Central/patología , Vasculitis por Lupus del Sistema Nervioso Central/psicología , Masculino , Persona de Mediana Edad , Familia de Moléculas Señalizadoras de la Activación Linfocitaria , Adulto Joven
20.
Int J Rheum Dis ; 23(5): 674-680, 2020 May.
Artículo en Inglés | MEDLINE | ID: mdl-32144871

RESUMEN

AIM: Hypoxia-inducible factor (HIF)1α is induced by endothelial cells under hypoxic conditions, suggesting that HIF1α may be involved in vascular impairment in patients with systemic sclerosis (SSc). The purpose of this study was to evaluate whether single nucleotide polymorphisms (SNPs) of the HIF1A gene are associated with susceptibility to SSc and its complications, including pulmonary arterial hypertension (PAH). METHOD: This study involved 182 Japanese SSc patients (discovery cohort) and 178 healthy controls. Four SNPs (rs11549465, rs11549467, rs1957757, and rs12434438) of the HIF1A gene were genotyped using specific TaqMan probes. We also employed another SSc cohort (N = 135) to validate the significant results of SNPs found in the discovery SSc cohort. RESULTS: The frequencies of the four SNPs did not show any significant differences between the SSc and healthy control groups. The AA genotype at rs12434438 was significantly higher in SSc patients with PAH than in those without PAH (P = .012). These results were validated using another SSc cohort (N = 135, P = .006). Moreover, the AA genotype was significantly associated with the severity of PAH. CONCLUSION: Although HIF1A gene polymorphisms were not associated with susceptibility to SSc, the AA genotype at rs12434438 was associated with a subset of SSc patients with severe PAH, suggesting that the rs12434438 SNP may contribute to the development of PAH with SSc.


Asunto(s)
Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Polimorfismo de Nucleótido Simple , Hipertensión Arterial Pulmonar/genética , Esclerodermia Sistémica/genética , Adulto , Anciano , Estudios de Casos y Controles , Femenino , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Humanos , Masculino , Persona de Mediana Edad , Fenotipo , Valor Predictivo de las Pruebas , Hipertensión Arterial Pulmonar/diagnóstico , Reproducibilidad de los Resultados , Medición de Riesgo , Factores de Riesgo , Esclerodermia Sistémica/complicaciones , Esclerodermia Sistémica/diagnóstico
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