RESUMEN
OBJECTIVES: To perform, in real conditions of prescription, the medico-economic evaluation of infliximab in severe RA. METHODS: A cost-effectiveness analysis of the annual costs was done with a comparison between the previous and the following year under infliximab. The effectiveness, determined from the HAQ, was expressed in clinically significant units and in quality-adjusted life years (QALYs). The incremental net benefit (INB), defined as willingness to pay (lambda), was used to express the results. RESULTS: A cohort of 635 patients was formed. Before the use of infliximab, after 1 and 2 years, the mean annual cost per patient for the care of RA was 9832, 27,723 and 46,704 euro, respectively. Among the direct costs, infliximab accounts for 21,182 euro for the first year. The distribution of the different costs was similar after 2 years. By using the INB, the difference before and after 1 year under infliximab is significant, on average by 1.86 (S.E.M. = 0.76) when the effectiveness is expressed in clinically significant units. For severe HAQ, lambda is 9841 euro (18,593 for all HAQ). When it is expressed in QALYs, also for severe HAQ, lambda > 100,000 euro. This can be explained by a short follow-up although severe complication of RA appears later. CONCLUSION: An evaluation of the more long-term costs is required in order to determine whether there are any full economic benefits with this treatment.
Asunto(s)
Anticuerpos Monoclonales/economía , Antirreumáticos/economía , Artritis Reumatoide/economía , Adulto , Anciano , Anticuerpos Monoclonales/uso terapéutico , Antirreumáticos/uso terapéutico , Artritis Reumatoide/tratamiento farmacológico , Costo de Enfermedad , Análisis Costo-Beneficio , Costos de los Medicamentos/estadística & datos numéricos , Métodos Epidemiológicos , Femenino , Francia , Costos de la Atención en Salud/estadística & datos numéricos , Humanos , Infliximab , Masculino , Persona de Mediana Edad , Resultado del Tratamiento , Factor de Necrosis Tumoral alfa/antagonistas & inhibidoresRESUMEN
OBJECTIVE: To investigate resource consumption and quality of life (utility) in a sample of patients covering the full spectrum of the disease, modalities of patient management and geographic areas. METHODS: Information on demographics, disease parameters, work capacity and resource consumption (in the past 1, 3 or 12 months depending on the resource) was collected in an anonymous mail survey from all members of a national patient association (ANDAR). Results are presented for the sample and by level of functional capacity, in 2005 euro. RESULTS: 1487 patients were included in the analysis (response rate 49%). Mean age was 62.7 years and 83.5% of respondents were female. Mean disease duration was 18 years; mean HAQ was 1.42; fatigue and pain ranked 5.6 and 4.8 on a scale between 0 and 10, respectively. Of patients below 60 years, 34% had taken early retirement due to RA, and only 15% of patients with a HAQ of 2 or higher were working. Productivity losses were estimated at 5076 euro, of which indemnity payments covered 1944 euro. Direct health care costs were 11,757 euro in the societal perspective and 9216 euro in the perspective of the national health insurance. Direct non-medical costs (including informal care) were 4857 euro and 136 euro respectively. Costs to society increased from 9400 euro in mild disease to 40,700 euro in severe disease, and to public payers from 6000 euro to 19,000 euro. Utility decreased simultaneously from 0.80 to 0.06. CONCLUSION: The study confirms overall findings in other studies in other countries, and provides the first estimate of all costs by disease severity in France.
Asunto(s)
Artritis Reumatoide/economía , Costo de Enfermedad , Costos de la Atención en Salud/estadística & datos numéricos , Calidad de Vida , Anciano , Eficiencia , Empleo , Femenino , Francia , Servicios de Salud/estadística & datos numéricos , Humanos , Masculino , Persona de Mediana Edad , Índice de Severidad de la EnfermedadRESUMEN
The progress of immunopathology allowed the development of targeted drugs or biotherapies. Among them, monoclonal antibodies against T or B lymphocytes or against a cytokine are reported. Monoclonal anti-TNF antibodies are a major therapeutic advance because they can stop the clinical, biological and radiographic evolution of rheumatoid arthritis (RA). Monoclonal anti-CD20 lymphocytes give promising results; they are able to induce prolonged remissions. Monoclonal anti-IL6 receptors are currently being evaluated. They are efficacious in adult RA and in Still's disease. Because of the infectious risk linked to these drugs, the ratio benefit/risk must be carefully evaluated before the prescription of a biotherapy.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/inmunología , Adalimumab , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales Humanizados , Humanos , Interleucina-6/inmunología , Factor de Necrosis Tumoral alfa/inmunologíaRESUMEN
Anti-tumor necrosis factor-a (anti-TNF-a) therapy strategies result in significant clinical benefits in patients with rheumatoid arthritis, but with an increased rate of serious infectious diseases. We describe a patient receiving infliximab who developed a primary cutaneous Nocardia otitidiscaviarum infection after a skin injury.
Asunto(s)
Anticuerpos Monoclonales/efectos adversos , Antirreumáticos/efectos adversos , Artritis Reumatoide/tratamiento farmacológico , Nocardiosis/inducido químicamente , Enfermedades Cutáneas Bacterianas/inducido químicamente , Anciano , Anticuerpos Monoclonales/uso terapéutico , Antirreumáticos/uso terapéutico , Artritis Reumatoide/complicaciones , Diabetes Mellitus Tipo 1/complicaciones , Humanos , Infliximab , Masculino , Nocardiosis/patología , Piel/lesiones , Enfermedades Cutáneas Bacterianas/patología , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Heridas y Lesiones/microbiologíaRESUMEN
Previous studies have reported that mesenchymal stem cells (MSC) may be isolated from the synovial membrane by the same protocol as that used for synovial fibroblast cultivation, suggesting that MSC correspond to a subset of the adherent cell population, as MSC from the stromal compartment of the bone marrow (BM). The aims of the present study were, first, to better characterize the MSC derived from the synovial membrane and, second, to compare systematically, in parallel, the MSC-containing cell populations isolated from BM and those derived from the synovium, using quantitative assays. Fluorescent-activated cell sorting analysis revealed that both populations were negative for CD14, CD34 and CD45 expression and that both displayed equal levels of CD44, CD73, CD90 and CD105, a phenotype currently known to be characteristic of BM-MSC. Comparable with BM-MSC, such MSC-like cells isolated from the synovial membrane were shown for the first time to suppress the T-cell response in a mixed lymphocyte reaction, and to express the enzyme indoleamine 2,3-dioxygenase activity to the same extent as BM-MSC, which is a possible mediator of this suppressive activity. Using quantitative RT-PCR these data show that MSC-like cells from the synovium and BM may be induced to chondrogenic differentiation and, to a lesser extent, to osteogenic differentiation, but the osteogenic capacities of the synovium-derived MSC were significantly reduced based on the expression of the markers tested (collagen type II and aggrecan or alkaline phosphatase and osteocalcin, respectively). Transcription profiles, determined with the Atlas Human Cytokine/Receptor Array, revealed discrimination between the MSC-like cells from the synovial membrane and the BM-MSC by 46 of 268 genes. In particular, activin A was shown to be one major upregulated factor, highly secreted by BM-MSC. Whether this reflects a different cellular phenotype, a different amount of MSC in the synovium-derived population compared with BM-MSC adherent cell populations or the impact of a different microenvironment remains to be determined. In conclusion, although the BM-derived and synovium-derived MSC shared similar phenotypic and functional properties, both their differentiation capacities and transcriptional profiles permit one to discriminate the cell populations according to their tissue origin.
Asunto(s)
Artritis Reumatoide , Células de la Médula Ósea/metabolismo , Células Madre Mesenquimatosas/metabolismo , Osteoartritis , Membrana Sinovial/metabolismo , Activinas/metabolismo , Agrecanos , Fosfatasa Alcalina/genética , Fosfatasa Alcalina/metabolismo , Antígenos CD/metabolismo , Artritis Reumatoide/inmunología , Artritis Reumatoide/patología , Biomarcadores/metabolismo , Células de la Médula Ósea/inmunología , Células de la Médula Ósea/patología , Diferenciación Celular , Linaje de la Célula , Células Cultivadas , Colágeno Tipo II/genética , Colágeno Tipo II/metabolismo , Proteínas de la Matriz Extracelular/genética , Proteínas de la Matriz Extracelular/metabolismo , Humanos , Inmunofenotipificación/métodos , Subunidades beta de Inhibinas/metabolismo , Lectinas Tipo C/genética , Lectinas Tipo C/metabolismo , Células Madre Mesenquimatosas/inmunología , Células Madre Mesenquimatosas/patología , Análisis de Secuencia por Matrices de Oligonucleótidos , Osteoartritis/inmunología , Osteoartritis/patología , Osteocalcina/genética , Osteocalcina/metabolismo , Proteoglicanos/genética , Proteoglicanos/metabolismo , ARN Mensajero/metabolismo , Membrana Sinovial/inmunología , Membrana Sinovial/patología , Transcripción GenéticaRESUMEN
OBJECTIVE: To determine whether patient's sex influences the severity of rheumatoid arthritis (RA) in terms of clinical severity or need for treatments. METHODS: This was a retrospective, single-center study. We compared 133 male patients with 133 female patients presenting with RA and matched for disease duration. Data collection included demographic characteristics, pattern of joint involvement, extraarticular manifestations, medical treatment, and joint surgery. Biological measures, HLA genotypes, Larsen radiological scores on radiographs of hands and feet, and Health Assessment Questionnaire (HAQ) results were obtained. RESULTS: Mean disease duration was 7.4 +/- 6.9 years. Concerning clinical pattern of involvement, sicca syndrome was more frequent in women than in men (p = 0.0003). There were no significant differences concerning absence or presence of at least one disease associated gene (HLA-DRB1*01 or *04) in our patients; however, women more often carried 2 disease associated genes (21% vs 11%). No other difference in clinical, biological, or radiological indicators was noted between the 2 populations. Concerning treatment, there was no difference for large joint arthroplasties; female patients underwent significantly more distal joint arthrodesis, 6.7% vs 1.5% (p = 0.03); they were prescribed slightly more disease modifying drugs, 3.33 vs 2.83 (p = 0.04); and showed a trend toward more large joint arthrodesis, 15% vs 7.5% (p = 0.05), and metacarpophalangeal joint arthroplasties, 5.2% vs 0.7% (p = 0.08). CONCLUSION: When patients are matched for RA duration, sex has little effect on the disease pattern and severity, yet women undergo more distal joint surgery.
Asunto(s)
Artritis Reumatoide/epidemiología , Índice de Severidad de la Enfermedad , Adulto , Antirreumáticos/uso terapéutico , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/genética , Artritis Reumatoide/cirugía , Artroplastia/estadística & datos numéricos , Estudios de Cohortes , Femenino , Genotipo , Antígenos HLA-DR/genética , Cadenas HLA-DRB1 , Indicadores de Salud , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Distribución por Sexo , Síndrome de Sjögren/epidemiología , Encuestas y CuestionariosRESUMEN
OBJECTIVE: Adult mesenchymal stem cells (MSCs) represent promising tools for therapeutic applications such as tissue engineering and cellular therapy. Recent data suggest that, due to their immunosuppressive nature, MSCs may be of interest to enhance allogeneic hematopoietic engraftment and prevent graft-versus-host disease. Using a murine model of rheumatoid arthritis (RA), this study investigated whether the immunosuppressive properties of MSCs could be of therapeutic value to inhibit reactive T cells in autoimmune diseases such as RA. METHODS: In mice with collagen-induced arthritis (CIA), we injected various doses of C3 MSCs at the time of immunization or booster injection, and subsequently evaluated the clinical and immunologic parameters. The immunosuppressive properties of MSCs were determined in vitro in mixed lymphocyte reactions with or without the addition of tumor necrosis factor alpha (TNFalpha). RESULTS: In the CIA model of arthritis, MSCs did not confer any benefit. Both the clinical and the immunologic findings suggested that MSCs were associated with accentuation of the Th1 response. Using luciferase-expressing MSCs, we were unable to detect labeled cells in the articular environment of the knee, suggesting that worsening of the symptoms was unlikely due to the homing of MSCs in the joints. Experiments in vitro showed that the addition of TNFalpha was sufficient to reverse the immunosuppressive effect of MSCs on T cell proliferation, and this observation was associated with an increase in interleukin-6 secretion. CONCLUSION: Our data suggest that environmental parameters, in particular those related to inflammation, may influence the immunosuppressive properties of MSCs.
Asunto(s)
Artritis/terapia , Factor de Necrosis Tumoral alfa/fisiología , Animales , Artritis/inducido químicamente , Artritis/inmunología , Colágeno/administración & dosificación , Tolerancia Inmunológica , Interleucina-10/biosíntesis , Células Madre Mesenquimatosas/inmunología , Ratones , Ratones Endogámicos C3HRESUMEN
OBJECTIVES: To develop recommendations for the physical and laboratory-test follow-up of patients with rheumatoid arthritis (RA) seen in everyday practice, using evidence from the literature, supplemented with expert opinion when needed. METHODS: A scientific committee selected 7-10 questions using the Delphi consensus procedure. Evidence-based responses to each question were sought in the literature and were then used by a panel to develop recommendations. To fill in gaps in knowledge from the literature, the panelists relied on their personal opinion. RESULTS: The seven questions dealt with the physical and laboratory-test follow-up of RA and the factors predicting disease severity. The literature review identified 799 articles whose title and abstract suggested relevance to the study. Elimination of articles that provided no data on the study topic left 128 original articles. The panel developed seven recommendations, one for each question, which were accepted by consensus. CONCLUSION: Recommendations about the physical and laboratory-test follow-up of patients with RA seen in everyday practice were developed. Because they constitute an objective foundation built by consensus among experts, should improve the uniformity and quality of care provided to RA patients in everyday practice.
Asunto(s)
Artritis Reumatoide , Pruebas de Química Clínica , Directrices para la Planificación en Salud , MEDLINE , Examen Físico/métodos , Reumatología/métodos , Artritis Reumatoide/diagnóstico , Artritis Reumatoide/terapia , Consenso , Humanos , Examen Físico/normas , Reumatología/normasRESUMEN
OBJECTIVES: To develop French evidence-based recommendations for the structural evaluation of rheumatoid arthritis (RA) in everyday practice. METHODS: A scientific committee selected 10 questions using the Delphi consensus procedure. Evidence-based responses to each question were sought by searching the PubMed and Ovid databases and the abstract databases for the 2002, 2003, and 2004 annual meetings of the French Society for Rheumatology, the EULAR, and the American College of Rheumatology. The following indexing terms were used: rheumatoid arthritis, arthritis, patient, diagnostic imaging, radiography, joint, erosion, and joint space width. All articles published in French or English prior to May 2004 were identified. The evidence from these articles was reported to a panel of 77 rheumatologists working in hospital or office practice. The panel developed detailed recommendations, filling gaps in evidence with their expert opinion. The strength of each recommendation was determined. RESULTS: The 10 questions probed the structural evaluation of RA by plain radiography, magnetic resonance imaging (MRI), and ultrasonography, both for diagnostic and monitoring purposes. The literature search retrieved 673 publications, of which 166 were selected and reviewed. The panel developed 10 recommendations, one for each question, which were accepted by consensus. CONCLUSION: Recommendations relative to the diagnosis or monitoring of structural involvement in patients with RA in everyday practice were developed. They should help to improve practice uniformity and, ultimately, to improve the management of RA.
Asunto(s)
Artritis Reumatoide , Medicina Basada en la Evidencia , Directrices para la Planificación en Salud , MEDLINE , Reumatología/métodos , Artritis Reumatoide/diagnóstico , Artritis Reumatoide/fisiopatología , Artritis Reumatoide/terapia , Consenso , Reumatología/normasRESUMEN
OBJECTIVES: To develop recommendations for the information and education of patients with rheumatoid arthritis (RA) seen in everyday practice, using evidence from the literature, supplemented with expert opinion when needed. METHODS: A scientific committee developed eight questions using the Delphi consensus procedure. A task force reviewed the literature for answers to these questions, using the PubMed Medline database (1980-2004) and the 2002-2004 databases of the annual meetings held by the French Society for Rheumatology (SFR), the European League Against Rheumatism (EULAR), and the American College of Rheumatology (ACR); the indexing terms for the search were rheumatoid, arthritis, patient, education, information, knowledge, general practitioner, family doctor, and continuing medical education. Only articles in French or English were included. A panel of rheumatologists used the evidence thus compiled to develop recommendations for each question; gaps in evidence were filled by calling on the panelists' expert opinion. For each recommendation, the level of evidence and extent of agreement among panelists were specified. RESULTS: There were four general questions about the objectives, supports, and mode of delivery (group or one-on-one) of patient information and education, as well as on evaluating knowledge, and four specific questions on program content. The search identified 1235 articles; 144 were selected on the title and 118 of those on the abstract. Three abstracts presented at meetings were also kept. The evidence from the literature was presented to the panelists during interactive workshops. The panelists then developed eight recommendations, all of which were grade D because no published studies specifically addressed everyday clinical practice. Agreement among panelists ranged across recommendations from 85.7% to 100%. CONCLUSION: Recommendations about educating and informing patients with RA in everyday practice were developed. They should increase practice uniformity and ultimately optimize the management of patients with RA.
Asunto(s)
Artritis Reumatoide/terapia , Difusión de la Información , Educación del Paciente como Asunto , Guías de Práctica Clínica como Asunto , Edición , Técnica Delphi , HumanosRESUMEN
OBJECTIVE: The economic impact of rheumatoid arthritis (RA) is substantial, but most studies provide cost estimates specific to a US population. We performed a cost-of-illness analysis of patients with RA for French society. METHODS: A cross-sectional study among rheumatologists in 148 hospitals in France was conducted between November and December 2000. Data were collected on health resource consumption associated with RA (treatments, medical devices, physician visits, examinations, hospitalization, other health professional care) during the previous 12 months. Direct costs and social costs were evaluated for 1109 RA patients. The relation of costs to disease activity and severity was analyzed. RESULTS: The annual direct cost of RA per patient was over euro4000. The costs due to hospitalizations represented around 60% of the costs. The major reason for hospitalization was acute care for RA in a rheumatic disease ward. Patients visited a physician an average of 13 times during the 12 months, 7.7 +/- 8.6 visits to an office-based physician and 5.1 +/- 4.4 visits to a hospital-based physician. Among them, 37% of patients were receiving at least one disability pension (16.7%) or sick-leave allowance (11.9%), with an estimated cost of euro7328 per patient. The mean annual budget per patient was euro2742. Medical and social costs increased in patients with severe disease (2 times), longer disease duration since diagnosis (more than double for patients with a history longer than 10 yrs vs patients with less than 2 yrs), active disease (1.4 times), and functional status (4 times more for American College of Rheumatology class IV than for class I). CONCLUSION: Direct costs represented 59% of the total costs for patients with active RA and 57% for patients with severe RA. Social costs represented 41% of the total costs on average.
Asunto(s)
Artritis Reumatoide/economía , Costo de Enfermedad , Costos de la Atención en Salud , Anciano , Estudios Transversales , Economía Hospitalaria , Femenino , Francia , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Reumatología/economíaRESUMEN
Drug-induced aseptic meningitis is uncommon and occurs primarily in patients with autoimmune disease. We report the first known case of leflunomide-induced aseptic meningitis, in a patient with rheumatoid arthritis.
Asunto(s)
Antiinflamatorios no Esteroideos/efectos adversos , Isoxazoles/efectos adversos , Meningitis Aséptica/inducido químicamente , Antiinflamatorios no Esteroideos/uso terapéutico , Artritis Reumatoide/tratamiento farmacológico , Humanos , Isoxazoles/uso terapéutico , Leflunamida , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: Etanercept and methotrexate are effective in the treatment of rheumatoid arthritis but no data exist on concurrent initiation or use of the combination compared with either drug alone. We aimed to assess combination treatment with etanercept and methotrexate versus the monotherapies in patients with rheumatoid arthritis. METHODS: In a double-blind, randomised, clinical efficacy, safety, and radiographic study, 686 patients with active rheumatoid arthritis were randomly allocated to treatment with etanercept 25 mg (subcutaneously twice a week), oral methotrexate (up to 20 mg every week), or the combination. Clinical response was assessed by criteria of the American College of Rheumatology (ACR). The primary efficacy endpoint was the numeric index of the ACR response (ACR-N) area under the curve (AUC) over the first 24 weeks. The primary radiographic endpoint was change from baseline to week 52 in total joint damage and was assessed with the modified Sharp score. Analysis was by intention to treat. FINDINGS: Four patients did not receive any drug; thus 682 were studied. ACR-N AUC at 24 weeks was greater for the combination group compared with etanercept alone and methotrexate alone (18.3%-years [95% CI 17.1-19.6] vs 14.7%-years [13.5-16.0], p<0.0001, and 12.2%-years [11.0-13.4], p<0.0001; respectively). The mean difference in ACR-N AUC between combination and methotrexate alone was 6.1 (95% CI 4.5-7.8, p<0.0001) and between etanercept and methotrexate was 2.5 (0.8-4.2, p=0.0034). The combination was more efficacious than methotrexate or etanercept alone in retardation of joint damage (mean total Sharp score -0.54 [95% CI -1.00 to -0.07] vs 2.80 [1.08 to 4.51], p<0.0001, and 0.52 [-0.10 to 1.15], p=0.0006; respectively). The mean difference in total Sharp score between combination and methotrexate alone was -3.34 (95% CI -4.86 to -1.81, p<0.0001) and between etanercept and methotrexate was -27 (-3.81 to -0.74, p=0.0469). The number of patients reporting infections or adverse events was similar in all groups. INTERPRETATION: The combination of etanercept and methotrexate was significantly better in reduction of disease activity, improvement of functional disability, and retardation of radiographic progression compared with methotrexate or etanercept alone. These findings bring us closer to achievement of remission and repair of structural damage in rheumatoid arthritis.
Asunto(s)
Antirreumáticos/uso terapéutico , Artritis Reumatoide/tratamiento farmacológico , Inmunoglobulina G/uso terapéutico , Metotrexato/uso terapéutico , Receptores del Factor de Necrosis Tumoral/uso terapéutico , Proteínas Recombinantes de Fusión/uso terapéutico , Artritis Reumatoide/diagnóstico por imagen , Artrografía/estadística & datos numéricos , Método Doble Ciego , Esquema de Medicación , Quimioterapia Combinada , Etanercept , Femenino , Humanos , Masculino , Persona de Mediana Edad , Resultado del TratamientoRESUMEN
OBJECTIVE: To evaluate agreement between a rheumatologist visit and a telephone interview by a patient organization member, regarding the diagnosis of rheumatoid arthritis (RA) or spondyloarthropathy (SpA) and the classification criteria for these two conditions. METHOD: Patients underwent a standardized interview and physical examination by hospital-based rheumatologists, who diagnosed RA in 230 cases, SpA in 175, and other conditions (controls) in 195. Members of patient organizations then used a standardized questionnaire to interview the patients by telephone about their diagnosis and about 1987 ACR classification criteria for RA and the ESSG criteria for SpA. RESULTS: Agreement between the two sources of data was poor for the classification criteria but satisfactory for the diagnosis (kappa, 0.84 (0.81-0.87) for RA and 0.78 (0.75-0.81) for SpA). CONCLUSION: Standardized telephone interviews conducted by patient organization members accurately identify the diagnosis made by rheumatologists based on a physical examination and medical record review, whereas agreement is poor regarding classification criteria for RA and SpA.
Asunto(s)
Artritis Reumatoide/diagnóstico , Entrevistas como Asunto , Tamizaje Masivo , Visita a Consultorio Médico , Espondiloartropatías/diagnóstico , Artritis Reumatoide/epidemiología , Artritis Reumatoide/fisiopatología , Femenino , Francia/epidemiología , Humanos , Masculino , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Espondiloartropatías/epidemiología , Espondiloartropatías/fisiopatología , Encuestas y CuestionariosRESUMEN
Currently available murine models to evaluate mesenchymal stem cell (MSC) differentiation are based on cell injection at ectopic sites such as muscle or skin. Due to the importance of environmental factors on the differentiation capacities of stem cells in vivo, we investigated whether the peculiar synovial/cartilaginous environment may influence the lineage specificity of bone morphogenetic protein (BMP)-2-engineered MSCs. To this aim, we used the C3H10T1/2-derived C9 MSCs that express BMP-2 under control of the doxycycline (Dox)-repressible promoter, Tet-Off, and showed in vitro, using the micropellet culture system that C9 MSCs kept their potential to differentiate toward chondrocytes. Implantation of C9 cells, either into the tibialis anterior muscles or into the joints of CB17-severe combined immunodeficient bg mice led to the formation of cartilage and bone filled with bone marrow as soon as day 10. However, no differentiation was observed after injection of naïve MSCs or C9 cells that were repressed to secrete BMP-2 by Dox addition. The BMP-2-induced differentiation of adult MSCs is thus independent of soluble factors present in the local environment of the synovial/cartilaginous tissues. Importantly, we demonstrated that a short-term expression of the BMP-2 growth factor is necessary and sufficient to irreversibly induce bone formation, suggesting that a stable genetic modification of MSCs is not required for stem cell-based bone/cartilage engineering.
Asunto(s)
Proteínas Morfogenéticas Óseas/biosíntesis , Cartílago/citología , Diferenciación Celular/fisiología , Células Madre Mesenquimatosas/citología , Células Madre Mesenquimatosas/metabolismo , Osteogénesis/fisiología , Factor de Crecimiento Transformador beta , Animales , Proteína Morfogenética Ósea 2 , Proteínas Morfogenéticas Óseas/genética , Huesos/citología , Huesos/embriología , Huesos/metabolismo , Cartílago/embriología , Cartílago/metabolismo , Comunicación Celular/fisiología , Diferenciación Celular/genética , Linaje de la Célula/genética , Condrocitos/citología , Condrocitos/metabolismo , Líquido Extracelular/metabolismo , Regulación del Desarrollo de la Expresión Génica/genética , Sustancias de Crecimiento/metabolismo , Articulaciones/citología , Articulaciones/crecimiento & desarrollo , Articulaciones/cirugía , Ratones , Ratones Endogámicos C3H , Músculo Esquelético/citología , Músculo Esquelético/crecimiento & desarrollo , Músculo Esquelético/cirugía , Células 3T3 NIH , Osteogénesis/genética , Regiones Promotoras Genéticas/efectos de los fármacos , Regiones Promotoras Genéticas/genética , Trasplante de Células MadreRESUMEN
OBJECTIVE: To determine prognostic factors of disability in early rheumatoid arthritis (RA) and to investigate the radiological and functional course of the disease. METHODS: A total of 191 patients with early RA (diagnosed for less than one year) according to American College of Rheumatology criteria were followed prospectively for 5 years. At baseline and at endpoint, Stanford Health Assessment Questionnaire (HAQ) scores and radiological scores (Sharp's score modified by van der Heijde) were performed. Correlations between numerous baseline data and HAQ score at endpoint were analyzed, using nonparametric tests. A multilinear regression model was performed to select independent prognostic factors of HAQ disability. RESULTS: During the 5-year followup, mean HAQ decreased from 1.3 (+/- 0.7) to 0.6 (+/- 0.6). There were 98 (65.3%) patients with a score > 1 point at baseline, but only 46 (27.4%) after 3 years and 34 (21.8%) after 5 years. Moreover, 90% of the patients had an improvement of the disability score. Final HAQ disability was associated with baseline values of HAQ score, Pain, Ritchie index, tender joint count, Disease Activity Score, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and erosion. Multivariate analysis selected baseline HAQ score, Ritchie index, ESR, CRP, and presence of erosion as independent prognostic factors of HAQ disability. The probability cutoff in the logistic model was selected to minimize the sum of false positive and false negative values: negative predictive value = 92.71%, positive predictive value = 46.15%, p = 0.408. Sex, age, IgM and IgA rheumatoid factors, other tested autoantibodies, and HLA class II genes did not contribute significantly to prediction of the disability after 5 years. At baseline, mean scores were 3.6 units (+/- 7.7) for total radiological score, 1.7 (+/- 4.5) for erosion score, and 1.9 (+/- 3.7) for joint space narrowing score. After 5 years, they were 17.9 +/- 22.3, 6.9 +/- 9.5, and 11.0 +/- 15.4, respectively. No erosion was present at the start in 58.0% of patients, compared to 24.2% and 22.4% at 3 and 5 years. Global radiographic progression concerned 87 patients (55.8%) during the 5 years. CONCLUSION: During the first 5 years of RA, radiological damage increased progressively in half of the patients, whereas HAQ disability improved in most of them during the same period of time and could be predicted by baseline values of HAQ score, Ritchie index, ESR, CRP, and presence (or absence) of erosion.
Asunto(s)
Artritis Reumatoide/fisiopatología , Evaluación de la Discapacidad , Encuestas y Cuestionarios , Adulto , Antirreumáticos/uso terapéutico , Artritis Reumatoide/diagnóstico por imagen , Artritis Reumatoide/tratamiento farmacológico , Estudios de Cohortes , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Pronóstico , Radiografía , Resultado del TratamientoRESUMEN
OBJECTIVE: To evaluate the contribution of HLA-DM alleles to susceptibility to systemic lupus erythematosus (SLE) in a Caucasian population. METHODS: HLA-DMA and DMB alleles were studied in 73 patients with SLE, 147 randomly selected controls, and 86 HLA-DRB1 genotype matched controls by oligotyping of polymerase chain reaction amplified genomic DNA with sequence-specific oligonucleotide probes. RESULTS: There was a significant presence of HLA-DMA*0103, DMA*0104, and DMB*0102 in the SLE patients compared with the randomly selected controls. After stratification of patients and matched controls according to DRB1 genotypes, only HLA-DMA*0104 was increased in SLE patients negative for the SLE susceptibility HLA-DR alleles. For the patients and controls positive for HLA-DR allele-susceptibility for SLE, HLA-DMA*0103, DMA*0104, DMB*0102, and DMB*0103 alleles tended to be more frequent, but without reaching statistical significance. No correlation was found between HLA-DM phenotype frequencies and any clinical or biological manifestations of SLE. CONCLUSION: This is the first study evaluating the influence of HLA-DM in a Caucasian SLE population. Our results suggest that HLA-DMA*0104 may represent a novel allele of susceptibility to SLE.
Asunto(s)
Predisposición Genética a la Enfermedad , Antígenos HLA-D/genética , Lupus Eritematoso Sistémico/genética , Polimorfismo Genético , Adolescente , Adulto , Anciano , Niño , ADN/sangre , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Reacción en Cadena de la PolimerasaRESUMEN
Mesenchymal stem cells (MSCs) are largely studied for their potential clinical use. Recently, they have gained further interest after demonstration of an immunosuppressive role. In this study, we investigated whether in vivo injection of MSCs could display side effects related to systemic immunosuppression favoring tumor growth. We first showed in vitro that the murine C3H10T1/2 (C3) MSC line and primary MSCs exhibit immunosuppressive properties in mixed lymphocyte reaction. We demonstrated that this effect is mediated by soluble factors, secreted only on "activation" of MSCs in the presence of splenocytes. Moreover, the immunosuppression is mediated by CD8+ regulatory cells responsible for the inhibition of allogeneic lymphocyte proliferation. We then demonstrated that the C3 MSCs expressing the human bone morphogenetic protein 2 (hBMP-2) differentiation factor were not rejected when implanted in various allogeneic immunocompetent mice and were still able to differentiate into bone. Importantly, using a murine melanoma tumor model, we showed that the subcutaneous injection of B16 melanoma cells led to tumor growth in allogeneic recipients only when MSCs were coinjected. Although the potential side effects of immunosuppression induced by MSCs have to be considered in further clinical studies, the usefulness of MSCs for various therapeutic applications still remains of great interest.