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OBJECTIVES: To perform a population-based study in rheumatoid arthritis (RA) patients, in order to evaluate the efficacy and safety of pharmacologic treatments. METHODS: 1087 patients with RA were enrolled; inclusion criteria were: newly diagnosed RA, already diagnosed RA with high disease activity (HDA) (DAS28≥4.2) starting biologic DMARDs (bDMARDs), already diagnosed RA with HDA continuing with conventional DMARDs (cDMARDs). The following data were collected: demographics, clinical and laboratory features, imaging and prescribed drugs. All parameters except immunology and imaging (performed yearly) were repeated at each follow-up evaluations (after 3, 6 and 12 months, and thereafter every 12 months). In order to evaluate clinical response, the EULAR response criteria were used as the gold standard. RESULTS: 414 (38.1%) newly diagnosed patients with RA, 477 (43.9%) RA patients who started bDMARDs and 196 (18.0%) RA patients who continued with cDMARDs were enrolled from April 2012 to March 2015 at 12 Rheumatology Centres in the Emilia Romagna Region. Statistical analyses showed a relative risk ratio (RRR) for moderate response of 1.65 in RA patients who started bDMARDs (p=0.16) and 2.49 for newly diagnosed RA (p=0.01). Sex, age and Health Assessment Questionnaire were not statistically significant. A RRR of 2.00 has been confirmed for RA patients who started bDMARDs (p<0.0005) for a good response as well as 2.20 for newly diagnosed RA (p<0.0005). An increase in adverse events among bDMARDs was found, but when looking at infections or neoplasia, no differences were highlighted between RA which started bDMARDs and RA who continued with cDMARDs. CONCLUSIONS: Our results are in line with already published papers from British and Swedish Registries: a greater likelihood to have a good response is demonstrated for not longstanding RA starting cDMARDs or RA with HDA when a bDMARD is started. Also a good safety profile is demonstrated.
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Antirreumáticos/uso terapéutico , Artritis Reumatoide/diagnóstico , Artritis Reumatoide/tratamiento farmacológico , Productos Biológicos/uso terapéutico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Antirreumáticos/efectos adversos , Artritis Reumatoide/epidemiología , Productos Biológicos/efectos adversos , Distribución de Chi-Cuadrado , Femenino , Humanos , Italia/epidemiología , Modelos Logísticos , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Estudios Prospectivos , Sistema de Registros , Inducción de Remisión , Factores de Riesgo , Índice de Severidad de la Enfermedad , Factores de Tiempo , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND AND AIM: Iloprost is recommend worldwide for the treatment of RP and the healing of DUs. The aim of this study is to report the regimens of Iloprost administered in different rheumatological centers within the same regional Health System Methods: A questionnaire exploring different items related to the use of Iloprost was developed and reviewed by three expert rheumatologists. The questionnaire was distributed as an online survey to all local SSc referral centers in Emilia-Romagna (Italy). Data are reported as percentage or median with interquartile range (IQR), as appropriate. An updated review of world literature on this topic was also carried out. RESULTS: All the invited centers completed the survey. There were both local (8) and university hospitals (4). The majority (58%) had a rheumatologist as head physician. All centers used Iloprost: a single monthly administration was the most common treatment (75%). The cycle lasted 1 [IQR 1-2] days with a 0.5-2.0 ng/Kg/min dose according to the drug tolerance of the patients. There were overall 68 spots (beds, reclining armchair, or simple armchair); 2.0 [1.5-4.0] patients were able to receive Iloprost at the same time. University Hospitals had more physicians at their disposal than local hospitals but less paramedic personnel (respectively: 1.8 vs 1.2 physicians, 1.5 vs 2.1 nurses). CONCLUSIONS: These observations were in line with the majority of previous studies reporting different regimens, comparing similar (but not identical) dose and schedule administration, however, despite differences being at times substantial, no standard infusion method is yet available.
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Iloprost , Esclerodermia Sistémica , Humanos , Iloprost/uso terapéutico , Iloprost/efectos adversos , Epoprostenol/uso terapéutico , Prostaglandinas I , Cicatrización de Heridas , Encuestas y Cuestionarios , Esclerodermia Sistémica/tratamiento farmacológico , Esclerodermia Sistémica/inducido químicamenteRESUMEN
The impact of COVID-19 pandemic put the Italian health system into a test. In the period between September 2020 and June 2021, a weekly average of 114 SARS-CoV-2 infections were recorded in Forlì-Cesena province (north of Italy), with a maximum of 330 cases per week in March 2021; in the same months, the Internal Medicine Unit of Cesena M. Bufalini Hospital managed 954 COVID-19 patients. To allow the management of these patients, the ward was divided into areas at different intensity of care, with a maximum of 39-47 beds and 19-24 in ordinary and sub-intensive area, respectively. Patients had an average age of 66 years, and 62% of the total was female; prevalent comorbidities were arterial hypertension (53%), smoking habit (28.7%), obesity (27.9%), uncomplicated (10%), and complicated diabetes (9%). On the total, 339 patients were hospitalized in sub-intensive area, subjected to non-invasive ventilatory support. Hospitalization lasted about 7 days in the ordinary ward and 13 days in the sub-intensive area. One hundred six patients died. In the considered period, the mean percentage of deaths compared to hospitalizations in Italy was equal to 22.21%; in our experience, the overall mortality rate was 11%. Our organizational model, which included different intensity areas in the same ward and various specialist skills, as the ability to manage non-invasive ventilation and bedside ultrasound, allowed flexible management of the "complex" COVID patient. Even the mortality rate may be the result of this model. These features mark what modern Internal Medicine should be like.
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BACKGROUND: Systemic sclerosis (scleroderma) is characterized by immunologic abnormalities, injury of endothelial cells, and tissue fibrosis. Abnormal oxidative stress has been documented in scleroderma and linked to fibroblast activation. Since platelet-derived growth factor (PDGF) stimulates the production of reactive oxygen species (ROS) and since IgG from patients with scleroderma reacts with human fibroblasts, we tested the hypothesis that patients with scleroderma have serum autoantibodies that stimulate the PDGF receptor (PDGFR), activating collagen-gene expression. METHODS: We analyzed serum from 46 patients with scleroderma and 75 controls, including patients with other autoimmune diseases, for stimulatory autoantibodies to PDGFR by measuring the production of ROS produced by the incubation of purified IgG with mouse-embryo fibroblasts carrying inactive copies of PDGFR alpha or beta chains or the same cells expressing PDGFR alpha or beta. Generation of ROS was assayed with and without specific PDGFR inhibitors. Antibodies were characterized by immunoprecipitation, immunoblotting, and absorption experiments. RESULTS: Stimulatory antibodies to the PDGFR were found in all the patients with scleroderma. The antibodies recognized native PDGFR, inducing tyrosine phosphorylation and ROS accumulation. Autoantibody activity was abolished by preincubation with cells expressing the PDGFR alpha chain or with recombinant PDGFR or by PDGFR tyrosine kinase inhibitors. Stimulatory PDGFR antibodies selectively induced the Ha-Ras-ERK1/2 and ROS cascades and stimulated type I collagen-gene expression and myofibroblast phenotype conversion in normal human primary fibroblasts. CONCLUSIONS: Stimulatory autoantibodies against PDGFR appear to be a specific hallmark of scleroderma. Their biologic activity on fibroblasts strongly suggests that they have a causal role in the pathogenesis of the disease.
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Autoanticuerpos/sangre , Enfermedades Autoinmunes/inmunología , Inmunoglobulina G/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Receptores del Factor de Crecimiento Derivado de Plaquetas/inmunología , Esclerodermia Sistémica/inmunología , Adulto , Anciano , Animales , Bioensayo , Estudios de Casos y Controles , Células Cultivadas , Colágeno/genética , Colágeno/metabolismo , Femenino , Fibroblastos/citología , Fibroblastos/metabolismo , Expresión Génica , Genes ras/fisiología , Humanos , Masculino , Ratones , Ratones Noqueados , Persona de Mediana Edad , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Receptores del Factor de Crecimiento Derivado de Plaquetas/antagonistas & inhibidores , Transducción de Señal , Tirfostinos/farmacologíaRESUMEN
Acid-suppressive therapy (AST) is largely prescribed in both hospital and general practice setting but few data are available on appropriateness of AST use in hospitalized patients and its fallout on prescribing in general practice. We assessed AST in patients consecutively admitted to an internal medicine department to determine the type and timing of prescription and indication for use according to widely accepted guidelines. Prescriptions were rated as indicated, acceptable, or not indicated. Overall, 58.7% of 834 admitted patients received AST, mainly proton pump inhibitors. The prescriptions were indicated in 50.1% of patients, not indicated in 41.5%, and acceptable in 6.5%. The main reason for inappropriate use was prophylaxis in low-risk patients (64.8%). On admission, 35.7% of 112 patients already on AST were judged to receive inappropriate prescription; of 348 patients discharged on AST, overuse was identified in 38.5%. No significant difference was observed for inappropriate use at admission, during hospitalization, and at discharge. In 64 inpatients (7.7%) AST, although indicated, mainly for ulcer prophylaxis in high-risk patients, was not prescribed. In conclusion, AST is substantially over-used in both hospital and general practice settings, mainly for ulcer prophylaxis in low-risk patients. On the other hand, AST is underused in a small, but not negligible proportion of high-risk patients.
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Antiácidos/administración & dosificación , Antiulcerosos/administración & dosificación , Inhibidores de la Bomba de Protones , Factores de Edad , Anciano , Anciano de 80 o más Años , Actitud del Personal de Salud , Utilización de Medicamentos , Medicina Familiar y Comunitaria/normas , Medicina Familiar y Comunitaria/tendencias , Femenino , Encuestas de Atención de la Salud , Hospitales Comunitarios/normas , Hospitales Comunitarios/tendencias , Humanos , Italia/epidemiología , Masculino , Persona de Mediana Edad , Pautas de la Práctica en Medicina , Medición de Riesgo , Factores SexualesRESUMEN
The levels of Ras proteins in human primary fibroblasts are regulated by PDGF (platelet-derived growth factor). PDGF induced post-transcriptionally Ha-Ras by stimulating reactive oxygen species (ROS) and ERK1/2. Activation of ERK1/2 and high ROS levels stabilize Ha-Ras protein, by inhibiting proteasomal degradation. We found a remarkable example in vivo of amplification of this circuitry in fibroblasts derived from systemic sclerosis (scleroderma) lesions, producing vast excess of ROS and undergoing rapid senescence. High ROS, Ha-Ras, and active ERK1/2 stimulated collagen synthesis, DNA damage, and accelerated senescence. Conversely ROS or Ras inhibition interrupted the signaling cascade and restored the normal phenotype. We conclude that in primary fibroblasts stabilization of Ras protein by ROS and ERK1/2 amplifies the response of the cells to growth factors and in systemic sclerosis represents a critical factor in the onset and progression of the disease.
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Fibroblastos/metabolismo , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Factor de Crecimiento Derivado de Plaquetas/fisiología , Especies Reactivas de Oxígeno , Esclerodermia Sistémica/patología , Proteínas ras/metabolismo , Apoptosis , Northern Blotting , Células Cultivadas , Daño del ADN , Citometría de Flujo , Humanos , Immunoblotting , MAP Quinasa Quinasa 1/metabolismo , Microscopía Fluorescente , Modelos Biológicos , Oxidación-Reducción , Fenotipo , Factor de Crecimiento Derivado de Plaquetas/metabolismo , ARN Mensajero/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factores de Tiempo , TransfecciónRESUMEN
We have characterized the role of c-Myb and B-Myb in the regulation of human type I collagen alpha2 chain gene expression in fibroblastic cells. We have identified four Myb-binding sites (MBSs) in the promoter. Transactivation assays on wild type and mutant promoter-reporter constructs demonstrated that c-Myb, but not B-Myb, can transactivate the human type I collagen alpha 2 chain gene promoter via the MBS-containing region. Electrophoretic mobility shift assay experiments showed that c-Myb specifically binds to each of the four MBS; however, the mutagenesis of site MBS-4 completely inhibited transactivation by c-Myb, at least in the full-length promoter. In agreement with these results, c-myb(-/-) mouse embryo fibroblasts (MEFs) showed a selective lack of expression of type I collagen alpha 2 chain gene but maintained the expression of fibronectin and type III collagen. Furthermore, transforming growth factor-beta induced type I collagen alpha 2 chain gene expression in c-myb(-/-) MEFs, implying that the transforming growth factor-beta signaling pathway is maintained and that the absence of COL1A2 gene expression in c-myb(-/-) MEFs is a direct consequence of the lack of c-Myb. The demonstration of the importance of c-Myb in the regulation of the type I collagen alpha 2 chain gene suggests that uncontrolled expression of c-Myb could be an underlying mechanism in the pathogenesis of several fibrotic disorders.
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Colágeno Tipo I/genética , Regulación de la Expresión Génica/fisiología , Proteínas Proto-Oncogénicas c-myb/fisiología , Animales , Secuencia de Bases , Sitios de Unión , Clonación Molecular , Colágeno Tipo I/química , Colágeno Tipo I/metabolismo , Cartilla de ADN , Ensayo de Cambio de Movilidad Electroforética , Ratones , Mutagénesis Sitio-Dirigida , Regiones Promotoras Genéticas , Proteínas Proto-Oncogénicas c-myb/metabolismo , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/metabolismo , Piel/metabolismoRESUMEN
OBJECTIVE: To evaluate, in a pilot study, the efficacy of a short term cyclophosphamide (CYC) pulse regimen on alveolitis in a cohort of patients with systemic sclerosis (SSc). METHODS: Twenty-three patients with SSc (17 diffuse SSc and 6 limited SSc) were selected in 5 centers in Italy, based on the findings of an abnormal bronchoalveolar lavage (BAL) cell analysis in association with altered pulmonary function tests (PFT) or recent deterioration in flow volume curve (FVC). Patients were also evaluated by skin score (Rodnan), esophageal manometry and barium swallow radiography, and electrocardiography and 2-mode echocardiography. The pre-enrolment pulmonary evaluation and after 6 months of therapy included evaluation of the clinical status, PFT (FVC, FEV1, DLCO), BAL. standard chest radiograph, and chest high resolution computed tomography. All patients received i.v. CYC (1000 mg/m2 of body surface monthly for 6 mo) and oral prednisone (25 mg daily for the first month and subsequently 5 mg daily of maintenance dosage for the remaining 5 mo). A complete blood count and urinalysis were obtained at monthly intervals. RESULTS: After 6 months of therapy the values for FVC did not change significantly. Individually, 8 of 23 patients showed an improvement (> 15% increase) in FVC after 6 months, while FVC in 13 cases remained stable. Only 2 patients had an important decline in FVC after 6 months of therapy (17 and 24% decrease). Improvement in DLCO was noted in 15 of 23 patients after 6 months of therapy. Four patients were stable and 4 patients had a worsened DLCO at the end of the study. After therapy the mean value of BAL fluid recovery did not change. There was a reduction in total cell number although this value did not reach statistical significance. The levels of neutrophils, eosinophils, lymphocytes, and macrophages did not change significantly. Scans for patients with grades 1, 2, and 3 did not differ significantly after 6 months of therapy, and 14 patients were stable. Changes in appearance, in relation to changes in extent of disease, were seen in 8 patients and consisted of an extension of reticular pattern and transformation from grade 1 to 2 (6/8 patients). All patients showed a ground-glass appearance indicating an acute alveolitis. Improvement in ground-glass was noted in 10 of 23 patients after 6 mo therapy. At the end of the study, 8 patients were stable and 5 patients had a diffusion of the ground-glass to other segments. No side effects were experienced during the treatment except for mild nausea in 4 patients; no patients discontinued therapy during the study. CONCLUSION: CYC pulse regimen seems to stabilize alveolitis in the majority of cases. The association of CYC pulsed modality with prednisone may be useful in SSc patients to control disease evolution in the lung.