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Importance: Hematopoietic stem cell transplantation (HSCT) represents a potentially useful approach to slow or prevent progressive disability in relapsing-remitting multiple sclerosis (MS). Objective: To compare the effect of nonmyeloablative HSCT vs disease-modifying therapy (DMT) on disease progression. Design, Setting, and Participants: Between September 20, 2005, and July 7, 2016, a total of 110 patients with relapsing-remitting MS, at least 2 relapses while receiving DMT in the prior year, and an Expanded Disability Status Scale (EDSS; score range, 0-10 [10 = worst neurologic disability]) score of 2.0 to 6.0 were randomized at 4 US, European, and South American centers. Final follow-up occurred in January 2018 and database lock in February 2018. Interventions: Patients were randomized to receive HSCT along with cyclophosphamide (200 mg/kg) and antithymocyte globulin (6 mg/kg) (n = 55) or DMT of higher efficacy or a different class than DMT taken during the previous year (n = 55). Main Outcomes and Measures: The primary end point was disease progression, defined as an EDSS score increase after at least 1 year of 1.0 point or more (minimal clinically important difference, 0.5) on 2 evaluations 6 months apart, with differences in time to progression estimated as hazard ratios. Results: Among 110 randomized patients (73 [66%] women; mean age, 36 [SD, 8.6] years), 103 remained in the trial, with 98 evaluated at 1 year and 23 evaluated yearly for 5 years (median follow-up, 2 years; mean, 2.8 years). Disease progression occurred in 3 patients in the HSCT group and 34 patients in the DMT group. Median time to progression could not be calculated in the HSCT group because of too few events; it was 24 months (interquartile range, 18-48 months) in the DMT group (hazard ratio, 0.07; 95% CI, 0.02-0.24; P < .001). During the first year, mean EDSS scores decreased (improved) from 3.38 to 2.36 in the HSCT group and increased (worsened) from 3.31 to 3.98 in the DMT group (between-group mean difference, -1.7; 95% CI, -2.03 to -1.29; P < .001). There were no deaths and no patients who received HSCT developed nonhematopoietic grade 4 toxicities (such as myocardial infarction, sepsis, or other disabling or potential life-threatening events). Conclusions and Relevance: In this preliminary study of patients with relapsing-remitting MS, nonmyeloablative HSCT, compared with DMT, resulted in prolonged time to disease progression. Further research is needed to replicate these findings and to assess long-term outcomes and safety. Trial Registration: ClinicalTrials.gov Identifier: NCT00273364.
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Trasplante de Células Madre Hematopoyéticas , Inmunosupresores/uso terapéutico , Esclerosis Múltiple Recurrente-Remitente/terapia , Adolescente , Adulto , Suero Antilinfocítico/uso terapéutico , Terapia Combinada , Ciclofosfamida/uso terapéutico , Progresión de la Enfermedad , Femenino , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Factores Inmunológicos/uso terapéutico , Masculino , Persona de Mediana Edad , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Adulto JovenRESUMEN
Leaf mass per area (LMA) is a primary plant functional trait that represents the cost of constructing a leaf. Ultimately, plants modify LMA by altering leaf thickness (LT), leaf dry matter content (LDMC), or both. While LMA can be modified through both of these constituents, studies of LMA have found that there is variation in whether LT or LDMC changes are responsible for LMA-and the relationships change depending on the species or functional groups being compared. In this study, we used a phylogenetic framework to determine that evolutionary shifts in LMA are driven by LT, and not LDMC, among 45 Serengeti grass species. We considered two alternative hypotheses that could result in evolutionary correlation of LMA on LT but not LDMC: either (1) LT is more labile than LDMC-and is therefore a less costly means to change LMA or (2) LDMC is tightly coupled to a different dimension of leaf variation (e.g., leaf hydraulics), leaving LT as the source of variation in LMA. LT was not more labile than LDMC, leading us to conclude that the evolution of LMA has been shaped by LT because LDMC is responding to other demands on leaf physiology. We speculate that leaf hydraulics provide this constraint on LDMC. The decoupling of LDMC from LT may allow plants to better optimize resource allocation in ecosystems where gradients in light competition, herbivory, and aridity place competing demands on leaf economics.
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Filogenia , Poaceae , Ecosistema , Hojas de la Planta , PlantasRESUMEN
We evaluated the safety and clinical outcome of autologous nonmyeloablative hematopoietic stem cell transplantation (HSCT) in patients with severe Crohn disease (CD) defined as a Crohn Disease Activity Index (CDAI) greater than 250, and/or Crohn Severity Index greater than 16 despite anti-tumor necrosis factor therapy. Stem cells were mobilized from the peripheral blood using cyclophosphamide (2.0 g/m(2)) and G-CSF (10 µg/kg/day), enriched ex vivo by CD34(+) selection, and reinfused after immune suppressive conditioning with cyclophosphamide (200 mg/kg) and either equine antithymocyte globulin (ATG, 90 mg/kg) or rabbit ATG (6 mg/kg). Eighteen of 24 patients are 5 or more years after transplantation. All patients went into remission with a CDAI less than 150. The percentage of clinical relapse-free survival defined as the percent free of restarting CD medical therapy after transplantation is 91% at 1 year, 63% at 2 years, 57% at 3 years, 39% at 4 years, and 19% at 5 years. The percentage of patients in remission (CDAI < 150), steroid-free, or medication-free at any posttransplantation evaluation interval more than 5 years after transplantation has remained at or greater than 70%, 80%, and 60%, respectively. This trial was registered at www.clinicaltrials.gov as NCT0027853.
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Anticuerpos Monoclonales/uso terapéutico , Enfermedad de Crohn/terapia , Resistencia a Medicamentos , Trasplante de Células Madre Hematopoyéticas , Agonistas Mieloablativos/uso terapéutico , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Adalimumab , Adolescente , Adulto , Animales , Anticuerpos Monoclonales Humanizados , Femenino , Estudios de Seguimiento , Movilización de Célula Madre Hematopoyética , Humanos , Masculino , Persona de Mediana Edad , Conejos , Inducción de Remisión , Tasa de Supervivencia , Factores de Tiempo , Acondicionamiento Pretrasplante , Trasplante Autólogo , Resultado del Tratamiento , Adulto JovenRESUMEN
OBJECTIVE: To investigate the results of real-world application of non-myeloablative autologous HSCT for multiple sclerosis (MS). METHODS: Between July 2003 and October 2019 at a single center (Northwestern University), 414 patients with relapsing remitting MS (RRMS) and 93 patients with newly diagnosed secondary progressive MS (SPMS) underwent non-myeloablative HSCT. RESULTS: There was one treatment-related death (0.19%) due to hospital-acquired legionella pneumonia, and one patient developed neutropenic bacteremia (Klebsiella pneumonia) without sepsis. Overall 5-year survival was 98.8%. Post HSCT secondary autoimmune diseases (2nd ADs) were idiopathic thrombocytopenia (ITP) and hypo or hyperthyroidism. ITP was highest with alemtuzumab (14%) and 0 to 2.8% for the non-alemtuzumab regimens. After HSCT, 16 patients developed hypothyroidism (3.5%) and 15 developed hyperthyroidism / Grave's disease (3.3%). Relapse free survival (RFS) at 5 years for RRMS and SPMS was 80.1% and 98.1%, respectively, while progression free survival (PFS) at 4 years for RRMS and SPMS was 95% versus 66%, respectively. For patients with RRMS, the EDSS significantly improved (p < 0.0001) at each follow-up from a pre-HSCT mean of 3.87 to 2.51, 2.50, 2.41, 2.33, and 2.19 at 1, 2, 3, 4, and 5 years, respectively. For SPMS, the EDSS improved significantly only at 1 year but not thereafter. For SPMS, the mean baseline EDSS of 5.09 changed post-HSCT to 4.85 (p = 0.04), 4.88 (p = 0.2), 4.92 (p = .27), 4.72 (p = 0.07), and 4.2 (p = 0.21) at 1, 2, 3, 4, 5 years, respectively. CONCLUSION: In patients with RRMS, autologous non-myeloablative HSCT is an effective one-time therapy, while HSCT appears of less benefit for newly diagnosed SPMS.
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Trasplante de Células Madre Hematopoyéticas , Hipertiroidismo , Esclerosis Múltiple Crónica Progresiva , Esclerosis Múltiple Recurrente-Remitente , Esclerosis Múltiple , Progresión de la Enfermedad , Trasplante de Células Madre Hematopoyéticas/métodos , Humanos , Esclerosis Múltiple/complicaciones , Esclerosis Múltiple/terapia , Esclerosis Múltiple Crónica Progresiva/diagnóstico , Esclerosis Múltiple Recurrente-Remitente/terapia , Trasplante AutólogoRESUMEN
Background: Intravenous immunoglobulin (IVIG) is effective as standard first line therapy for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), but some patients remain dependent on its long-term use. Recently, we have reported that autologous non-myeloablative hematopoietic stem cell transplantation (HSCT) is an effective second line therapy for CIDP. Objectives: To compare the cost of chronic IVIG vs. autologous HSCT (a one-time therapy), we collected data on patients with CIDP undergoing HSCT between 2017 and 2019. This was compared with published literature on the costs and efficacy defined by the Inflammatory Neuropathy Cause And Treatment (INCAT) disability score, Medical Research Council (MRC) sum score, hand grip strength, and SF-36 quality of life (QOL) for CIDP. Methods: Between 2017 and 2019, nineteen patients with chronic CIDP (mean disease treatment duration prior to HSCT of 6 years) underwent autologous HSCT with mean cost of $108,577 per patient (range $56,327-277,119, standard deviation $53,092). After HSCT, 80% of patients remain IVIG and immune treatment free for up to 5 years. In comparison, published cost of IVIG treatment in the USA for an average CIDP patient exceeds $136,000 per year. Despite remaining treatment free, HSCT demonstrated greater improvement in efficacy compared to immunoglobulins. Recommendations: Given the long-term treatment-free remission and better outcome measurements, autologous HSCT is more cost effective than long-term IVIG treatment in patients with chronic CIDP. However, costs will depend on patient selection, the HSCT regimen, and regional variations. Further analysis of the health economics, i.e., cost/outcome ratio, of HSCT as therapy for chronically IVIG dependent CIDP is warranted.
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Prescribed fire is widely used for ecosystem restoration, yet the mechanisms that determine its effectiveness remain poorly characterized. Because soil hydrology influences ecosystem processes like erosion, runoff, and plant competition, it is important to understand how fire affects soil hydrology. A systematic approach to understanding relationships among vegetation, topography, and fire is needed to advance knowledge of how fire influences soil properties that in turn affect restoration success. Our objective was to characterize relationships among burn severity, vegetation, and soil hydrology in a heterogenous landscape under restoration management. Our study took place in a barrens-forest mosaic with recent prescribed fire history ranging from 0 to 10 burns since 1960, and additional variation in fuel loading, burn severity, vegetation cover, topography, and soils. We measured soil hydraulic conductivity (SHC) during two consecutive years, which represented control, prefire, postfire, and 1-year postfire conditions. Regression tree analysis identified an important threshold effect of antecedent soil moisture on SHC; soils with initial moisture < 13% had lower SHC than soils with initial moisture > 13%. Furthermore, above this threshold, sites with intermediate to high recent burn frequency (4-10 burns) had significantly greater SHC than unburned control sites. High fuel loads associated with brush cutting and piling increased SHC at barrens sites but not brush or pine sites, suggesting an interaction between vegetation cover and fire effects on SHC. At the local hillslope scale, toe-slopes had greater SHC than summits. Our results suggest that repeated prescribed fires of moderate to high frequency may enhance SHC, thereby reducing soil water retention and potentially restoring functional pine barren processes that limit woody plant growth. Prescribed fire may therefore be an important management tool for reversing mesophication and restoring a global array of open canopy ecosystems.
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OBJECTIVE: To test the hypothesis that autologous nonmyeloablative hematopoietic stem cell transplantation (HSCT) is safe and shows efficacy in the treatment of stiff-person spectrum disorder (SPSD). METHODS: Twenty-three participants were treated in a prospective open-label cohort study of safety and efficacy. After stem cell mobilization with cyclophosphamide (2 g/m2) and filgrastim (5-10 µg/kg/d), participants were treated with cyclophosphamide (200 mg/kg) divided as 50 mg/kg IV on day -5 to day -2; rabbit anti-thymocyte globulin (thymoglobulin) given intravenously at 0.5 mg/kg on day -5, 1 mg/kg on days -4 and -3, and 1.5 mg/kg on days -2, and -1 (total dose 5.5 mg/kg); and rituximab 500 mg IV on days -6 and +1. Unselected peripheral blood stem cells were infused on day 0. Safety was assessed by survival and National Cancer Institute common toxicity criteria for adverse events during HSCT. Outcome was assessed by ≥50% decrease or discontinuation of antispasmodic drugs and by quality of life instruments. RESULTS: There was no treatment-related mortality. One participant died 1 year after transplantation of disease progression. Of the 74% of participants who responded, 47% have stayed in remission for a mean of 3.5 years; 26% did not respond. Compared to nonresponders, responders were more likely to have pretransplantation intermittent muscle spasms (16 of 17 vs 0 of 6), normal reflexes (12 of 17 vs 0 of 6), and positive CSF anti-glutamic acid decarboxylase serology (12 of 14 vs 2 of 6). Compared to responders, nonresponders were more likely to have lead pipe rigidity (4 of 6 vs 0 of 17) and EMG-documented simultaneous contraction of agonist/antagonist limb muscles (4 of 6 vs 1 of 17). Pre-HSCT use of prescription serotonin selective receptor inhibitor (SSRI) or serotonin and norepinephrine reuptake inhibitor (SNRI) was more common in those who relapsed or never responded (9 of 12) compared to those responders who never relapsed (0 of 11). CONCLUSION: In this cohort, HSCT was safe, but the beneficial effect of HSCT was variable and confined predominately to participants with episodic spasms and normal tendon reflexes without simultaneous cocontraction of limb agonist/antagonist muscles who were not taking SSRI or SNRI antidepressants. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that, for a subset of people with SPSD, autologous nonmyeloablative HSCT improves outcomes. CLINICALTRIALSGOV IDENTIFIER: NCT02282514.
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Trasplante de Células Madre Hematopoyéticas , Inmunosupresores/administración & dosificación , Evaluación de Resultado en la Atención de Salud , Síndrome de la Persona Rígida/fisiopatología , Síndrome de la Persona Rígida/terapia , Adulto , Femenino , Estudios de Seguimiento , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Masculino , Persona de Mediana Edad , Síndrome de la Persona Rígida/tratamiento farmacológico , Trasplante AutólogoRESUMEN
Secondary autoimmune diseases (2ndADs), most frequently autoimmune cytopenias (AICs), were first described after allogeneic hematopoietic stem cell transplantation (HSCT) undertaken for malignant and hematological indications, occurred at a prevalence of ~5-6.5%, and were attributed to allogeneic immune imbalances in the context of graft versus host disease, viral infections, and chronic immunosuppression. Subsequently, 2ndADs were reported to complicate roughly 2-14% of autologous HSCTs performed for an autoimmune disease. Alemtuzumab in the conditioning regimen has been identified as a risk for development of 2ndADs after either allogeneic or autologous HSCT and is consistent with the high rates of 2ndADs when using alemtuzumab as monotherapy. Due to the significant consequences but variable incidence, depending on conditioning regimen, of 2ndADs and similarity in known immune reconstitution kinetics after autologous HSCT for autoimmune diseases and after alemtuzumab monotherapy, we propose that an imbalance between B and T lineage regeneration early after HSCT may underlie the pathogenesis of 2ndADs.
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Enfermedades Autoinmunes , Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Esclerosis Múltiple , Enfermedades Autoinmunes/etiología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Esclerosis Múltiple/terapia , Acondicionamiento Pretrasplante/efectos adversos , Trasplante AutólogoRESUMEN
We compared three fludarabine-based regimens for systemic sclerosis patients with a high-risk cardiac phenotype that according to EBMT criteria would be a contraindication for a high-dose cyclophosphamide (200 mg/kg) transplant regimen. All three regimens included fludarabine, ATG, and cyclophosphamide (60 mg/kg), while two regimens also included rituximab with or without IVIG. Treatment related mortality (TRM) was 2.4%. The mean number of days of neutropenia (ANC < 500) was 5.2, the mean number of platelet and red blood cell transfusions was 0.3 and 1.85, respectively. Skin score, forced vital capacity (FVC), and total lung capacity (TLC) improved with all three regimens. For patients whose regimen did not include rituximab versus those that included rituximab, 1-year overall relapse rate was higher 36% (5/14) versus 3.6% (1 of 28) (p = 0.01), secondary autoimmune diseases were higher 21% (3/14) versus 0% (0/28) (p = 0.03), and upper respiratory tract infections were higher 28% (4/14) versus 3.6% (1/28) (p = 0.04). In this safety study, a fludarabine-based regimen was relatively safe with a TRM of 2.4% and a neutropenic interval of only 5.2 days in systemic sclerosis patients with a high-risk cardiac phenotype. The addition of rituximab decreased 1-year relapse rate, risk of late secondary autoimmune diseases, and upper-respiratory tract infections.
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Trasplante de Células Madre Hematopoyéticas , Esclerodermia Sistémica , Ciclofosfamida , Humanos , Recurrencia Local de Neoplasia , Acondicionamiento Pretrasplante , VidarabinaRESUMEN
Grasses accumulate high concentrations of silicon (Si) in their tissues, with potential benefits including herbivore defense, improved water balance, and reduced leaf construction costs. Although Si is one of the most widely varying leaf constituents among individuals, species, and ecosystems, the environmental forces driving this variation remain elusive and understudied. To understand relationships between environmental factors and grass Si accumulation better, we analyzed foliar chemistry of grasses from 17 globally distributed sites where nutrient inputs and grazing were manipulated. These sites span natural gradients in temperature, precipitation, and underlying soil properties, which allowed us to assess the relative importance of soil moisture and nutrients across variation in climate. Foliar Si concentration did not respond to large mammalian grazer exclusion, but significant variation in herbivore abundance among sites may have precluded the observation of defoliation effects at these sites. However, nutrient addition consistently reduced leaf Si, especially at sites with low soil nitrogen prior to nutrient addition. Additionally, a leaf-level trade-off between Si and carbon (C) existed that was stronger at arid sites than mesic sites. Our results suggest soil nutrient limitation favors investment in Si over C-based leaf construction, and that fixing C is especially costly relative to assimilating Si when water is limiting. Our results demonstrate the importance of soil nutrients and precipitation as key drivers of global grass silicification patterns.
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Poaceae , Suelo , Animales , Ecosistema , Humanos , Nutrientes , Hojas de la PlantaRESUMEN
OBJECTIVE: To estimate differences in treatment costs and health outcomes between non-myeloablative hematopoietic stem cell transplantation (HSCT) and disease-modifying therapies (DMTs) for the treatment of relapsing-remitting multiple sclerosis (RRMS). METHODS: We collected data on costs and reimbursements for patients who underwent HSCT for RRMS at Northwestern Memorial Hospital in Chicago (USA) between January 2017 and January 2019. The costs of HSCT were compared against those for DMTs in the United States, obtained from the literature. We also conducted a literature review to interpret the cost comparisons in terms of disease control and patients' wellbeing defined as no evidence of disease activity (NEDA), neurologic disability by the Expanded Disability Status Scale (EDSS), and quality of life by the short form SF-36, respectively. RESULTS: Outside of the data, herein, no other studies on cost of HSCT for RRMS were found in the literature. HSCT mean total costs, based on our own hospital, were $85,184 (range $70,635 to $120,260). Mean revenue collected was $95,268 (range $16,544 to $173,204). In comparison, according to the literature, 2019 DMT costs in the USA ranged from $80,000 to $100,000 per year per patient. Compared to DMTs, studies of HSCT reported greater improvement in no evidence of disease activity, disability, and quality of life. LIMITATIONS: Costs of HSCT would be expected to vary by conditioning regimen utilized, patient selection, center experience, and regional variation. No cost data on other HSCT regimens or on the three most recently licensed DMTs, alemtuzumab, ocrelizumab, and cladribine, are available. Randomized trials for cost comparisons are missing and variations in HSCT designs, populations, and methodology preclude more precise cost estimates. CONCLUSION: Costs of non-myeloablative HSCT after which DMTs are indefinitely discontinued, are approximately the same cost as those for one year of prescription DMTs. Since DMTs assessed in this analysis are given on an ongoing basis, whilst HSCT is not, HSCT is expected to produce long-term cost-savings. When considered alongside the available clinical evidence, which suggests that HSCT may generate more health gains than DMTs, HSCT is likely to represent a cost-effective use of resources. Model-based health economic analyses are required to substantiate this conclusion.
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Trasplante de Células Madre Hematopoyéticas , Esclerosis Múltiple Recurrente-Remitente , Esclerosis Múltiple , Análisis Costo-Beneficio , Humanos , Inmunosupresores , Esclerosis Múltiple Recurrente-Remitente/terapia , Calidad de Vida , Estados UnidosRESUMEN
OBJECTIVE: Determine toxicity and efficacy of autologous hematopoietic stem cell transplantation (HSCT) for patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) who are dependent on intravenous immunoglobulins or plasmapheresis. METHODS: Unselected peripheral blood stem cells were re-infused on day 0 after conditioning with cyclophosphamide 200 mg/kg/intravenously (IV), rATG (thymoglobulin) 5.5 mg/kg/IV, and rituximab 1000 mg/IV. RESULTS: Sixty-six patients underwent HSCT for CIDP. Data on sixty patients with a mean follow-up of 4.5 years (range 2-5 years) were available for analysis. There were no treatment-related deaths, and overall survival was 97%. Post-transplant immune medication-free remission was 80%, 78%, 76% 78%, and 83% at 1, 2, 3, 4, and 5 years. Ambulation without assistance improved from 33% pre-HSCT to 82% 82%, 81%, 86%, and 83% at 1, 2, 3, 4, and 5 years, respectively. Mean right/left hand grip strength (kg) improved significantly (all p values < 0.01) from 18.1/16.5 pre-HSCT to 26.3/25.4, 29.2/28.2, 28.8/28.6, 30.3/25.5, and 30.8/29.1 at 1, 2, 3, 4, and 5 years, respectively. Average nerve conduction velocity (NCV) (m/s) improved significantly (all p values ≤ 0.001) from a mean of 27.2 pre-HSCT to 33.5, 33.8, 37.7, 38.2, and 38.3 at 1, 2, 3, 4, and 5 years, respectively. Average compound motor action potential (CMAP) (mv) improved significantly (p values ≤ 0.001) from a mean of 3.6 pre-HSCT to 4.6, 4.6, 5.0, 5.1, and 4.1 at 1, 2, 3, 4, and 5 years, respectively. CONCLUSION: A randomized trial is indicated to verify these results and confirm that HSCT reverses disability and offers long-term immune therapy independence.
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Trasplante de Células Madre Hematopoyéticas , Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante , Fuerza de la Mano , Humanos , Inmunoglobulinas Intravenosas/uso terapéutico , Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante/terapia , Trasplante AutólogoRESUMEN
CONTEXT: Manifestations of systemic lupus erythematosus (SLE) may in most patients be ameliorated with medications that suppress the immune system. Nevertheless, there remains a subset of SLE patients for whom current strategies are insufficient to control disease. OBJECTIVE: To assess the safety of intense immunosuppression and autologous hematopoietic stem cell support in patients with severe and treatment-refractory SLE. DESIGN, SETTING, AND PARTICIPANTS: A single-arm trial of 50 patients with SLE refractory to standard immunosuppressive therapies and either organ- or life-threatening visceral involvement. Patients were enrolled from April 1997 through January 2005 in an autologous nonmyeloablative hematopoietic stem cell transplantation (HSCT) study at a single US medical center. INTERVENTIONS: Peripheral blood stem cells were mobilized with cyclophosphamide (2.0 g/m2) and granulocyte colony-stimulating factor (5 microg/kg per day), enriched ex vivo by CD34+ immunoselection, cryopreserved, and reinfused after treatment with cyclophosphamide (200 mg/kg) and equine antithymocyte globulin (90 mg/kg). MAIN OUTCOME MEASURES: The primary end point was survival, both overall and disease-free. Secondary end points included SLE Disease Activity Index (SLEDAI), serology (antinuclear antibody [ANA] and anti-double-stranded (ds) DNA), complement C3 and C4, and changes in renal and pulmonary organ function assessed before treatment and at 6 months, 12 months, and then yearly for 5 years. RESULTS: Fifty patients were enrolled and underwent stem cell mobilization. Two patients died after mobilization, one from disseminated mucormycosis and another from active lupus after postponing the transplantation for 4 months. Forty-eight patients underwent nonmyeloablative HSCT. Treatment-related mortality was 2% (1/50). By intention to treat, treatment-related mortality was 4% (2/50). With a mean follow-up of 29 months (range, 6 months to 7.5 years) for patients undergoing HSCT, overall 5-year survival was 84%, and probability of disease-free survival at 5 years following HSCT was 50%. Secondary analysis demonstrated stabilization of renal function and significant improvement in SLEDAI score, ANA, anti-ds DNA, complement, and carbon monoxide diffusion lung capacity adjusted for hemoglobin. CONCLUSIONS: In treatment-refractory SLE, autologous nonmyeloablative HSCT results in amelioration of disease activity, improvement in serologic markers, and either stabilization or reversal of organ dysfunction. These data are nonrandomized and thus preliminary, providing the foundation and justification for a definitive randomized trial. Clinical Trial Registration ClinicalTrials.gov Identifier: NCT00271934.
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Ciclofosfamida/uso terapéutico , Trasplante de Células Madre Hematopoyéticas , Lupus Eritematoso Sistémico/terapia , Agonistas Mieloablativos/uso terapéutico , Adulto , Profilaxis Antibiótica , Femenino , Movilización de Célula Madre Hematopoyética , Trasplante de Células Madre Hematopoyéticas/métodos , Humanos , Lupus Eritematoso Sistémico/inmunología , Masculino , Inducción de Remisión , Terapia Recuperativa , Análisis de Supervivencia , Acondicionamiento Pretrasplante , Trasplante AutólogoRESUMEN
Hematopoietic stem cell transplantation is an increasingly used therapy for treatment of autoimmune diseases and severe immune-mediated disorders. We address some general concepts and principles in the development of hematopoietic stem cell transplantation in order to understand the principles and design of safe autologous and allogeneic transplant regimens for these unique diseases.
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Enfermedades Autoinmunes/cirugía , Trasplante de Células Madre Hematopoyéticas , Alemtuzumab , Animales , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales Humanizados , Anticuerpos Antineoplásicos/uso terapéutico , Enfermedades Autoinmunes/inmunología , Ensayos Clínicos como Asunto , Contraindicaciones , Modelos Animales de Enfermedad , Epítopos , Predicción , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Trasplante de Células Madre Hematopoyéticas/tendencias , Humanos , Sistema Inmunológico/inmunología , Ratones , Acondicionamiento Pretrasplante/efectos adversos , Acondicionamiento Pretrasplante/métodos , Trasplante Autólogo , Trasplante Homólogo , Resultado del TratamientoRESUMEN
Grasses (Poaceae) lack the complex biochemical pathways and structural defenses employed by other plant families; instead they deposit microscopic silica (SiO2) granules in their leaf blades (i.e., phytoliths) as a putative defense strategy. Silica accumulation in grasses has generally been considered an inducible defense; other research suggests silica accumulation occurs by passive diffusion and should therefore be closely coupled with whole plant transpiration. We tested the hypothesis that grasses increase leaf silica concentration in response to artificial defoliation in a common garden study in the Serengeti ecosystem of East Africa. Additionally, a watering treatment tested the alternative hypothesis that leaf silica was largely driven by plant water status. Leaf silica content of two dominant C4 Serengeti grass species, Themeda triandra and Digitaria macroblephara, was quantified after a 10-month clipping × water experiment in which defoliation occurred approximately every 2 months and supplementary water was added every 2 weeks. Themeda had greater silica content than Digitaria, and Themeda also varied in foliar silica content according to collection site. Clipping had no significant effect on leaf silica in either species and watering significantly increased silica content of the dominant tall grass species, Themeda, but not the lawn species, Digitaria. Our data, and those collected as part of a supplementary literature review, suggest that silicon induction responses are contingent upon a combination of plant identity (i.e., species, genotype, life history limitations) and environmental factors (i.e., precipitation, soil nutrients, grazing intensity). Specifically, we propose that an interaction between plant functional type and water balance plays an especially important role in determining silica uptake and accumulation.
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Patients undergoing autologous hematopoietic stem cell transplantation (auto-HSCT) for autoimmune disease may have an added propensity to develop a second autoimmune disorder, given the genetic predisposition to autoimmunity. Therefore, we undertook a retrospective analysis of all patients who have undergone auto-HSCT for an autoimmune disease in our institution to determine the occurrence of a second autoimmune disorder and possible risk factors. In all, 155 patients underwent auto-HSCT for various autoimmune diseases; of those patients, 6 manifested a distinct secondary autoimmune disease at a median of 8.5 months (range, 2-30 months) after auto-HSCT. There were 2 patients with systemic lupus erythematosus, conditioned with a regimen containing antithymocyte globulin (ATG), who developed factor VIII inhibitors with severe bleeding. There were 4 patients (2 with multiple sclerosis, one each with lupus and systemic sclerosis) who received an alemtuzumab-containing conditioning regimen who developed autoimmune cytopenias. Among the 155 patients, the frequency of secondary autoimmune complications was 16.0% with alemtuzumab (4/25), 1.9% for ATG (2/102), and 0% for conditioning regimens without lympho-depleting antibodies (0/28)-a difference that was found to be significantly higher with alemtuzumab exposure (P = .011). In contrast, sex, type of ATG used, and CD34-selection of peripheral blood stem cells were not found to be significantly associated with development of a secondary autoimmune disorder.
Asunto(s)
Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/patología , Trasplante de Células Madre Hematopoyéticas , Acondicionamiento Pretrasplante/métodos , Adulto , Enfermedades Autoinmunes/metabolismo , Factor VIII/antagonistas & inhibidores , Factor VIII/metabolismo , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND & AIMS: Crohn's disease (CD) is an immunologically mediated inflammatory disease of the gastrointestinal tract. Due to a high morbidity and/or an increase in mortality in refractory cases, a new treatment approach is needed. In theory, maximum immune ablation by autologous hematopoietic stem cell transplantation (HSCT) can induce a remission. METHODS: We conducted a phase 1 HSCT study in 12 patients with refractory CD. Candidates were younger than 60 years of age with a Crohn's Disease Activity Index (CDAI) of 250-400 despite conventional therapies including infliximab. Peripheral blood stem cells were mobilized with cyclophosphamide and granulocyte colony-stimulating factor and CD34 + enriched. The immune ablative (conditioning) regimen consisted of 200 mg/kg cyclophosphamide and 90 mg/kg equine antithymocyte globulin. RESULTS: The procedure was well tolerated with anticipated cytopenias, neutropenic fever, and disease-related fever, diarrhea, anorexia, nausea, and vomiting. The median days for neutrophil and platelet engraftment were 9.5 (range, 8-11) and 9 (range, 9-18), respectively. The initial median CDAI was 291 (range, 250-358). Symptoms and CDAI improved before hospital discharge, whereas radiographic and colonoscopy findings improved gradually over months to years following HSCT. Eleven of 12 patients entered a sustained remission defined by a CDAI < or =150. After a median follow-up of 18.5 months (range, 7-37 months), only one patient has developed a recurrence of active CD, which occurred 15 months after HSCT. CONCLUSIONS: Autologous HSCT may be performed safely and has a marked salutary effect on CD activity. A randomized study will be needed to confirm the efficacy of this therapy.
Asunto(s)
Enfermedad de Crohn/terapia , Trasplante de Células Madre Hematopoyéticas , Adolescente , Adulto , Enfermedad de Crohn/fisiopatología , Femenino , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Masculino , Proyectos Piloto , Recurrencia , Inducción de Remisión , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
This report describes the first allogeneic hematopoietic stem cell transplantation (HSCT) performed for the indication of rheumatoid arthritis (RA). We used nonmyeloablative allogeneic HSCT to treat a 52-year-old woman who had treatment-refractory RA and a poor prognosis (24 swollen and 38 involved joints). She was treated with fludarabine, cyclophosphamide, CAMPATH-1H, and CD34-selected HSCT (8 million CD34+ donor cells/kg); the donor was the patient's HLA-matched, rheumatoid factor-negative sister. One year post-HSCT, the patient has had no infection except dermatomal varicella-zoster virus infection and no acute or chronic graft-versus-host disease (GVHD). Her RA has remained in remission with no immunosuppressive or immunomodulatory medications. The patient is a mixed chimera, with 55% donor T (CD3+) cells and 70% donor myeloid (CD33+) cells. This is the first published report of allogeneic HSCT performed for the indication of RA. Mixed chimerism has resulted in marked amelioration of RA, without GVHD.