RESUMO
BACKGROUND: Hereditary anemias are a group of genetic diseases prevalent worldwide and pose a significant health burden on patients and societies. The clinical phenotype of hereditary anemias varies from compensated hemolysis to life-threatening anemia. They can be roughly categorized into three broad categories: hemoglobinopathies, membranopathies, and enzymopathies. Traditional therapeutic approaches like blood transfusions, iron chelation, and splenectomy are witnessing a paradigm shift with the advent of targeted treatments. However, access to these treatments remains limited due to lacking or imprecise diagnoses. The primary objective of the study is to establish accurate diagnoses for patients with hereditary anemias, enabling optimal management. As a secondary objective, the study aims to enhance our diagnostic capabilities. RESULTS: The DAHEAN study is a nationwide cohort study that collects advanced phenotypic and genotypic data from patients suspected of having hereditary anemias from all pediatric and hematological departments in Denmark. The study deliberates monthly by a multidisciplinary anemia board involving experts from across Denmark. So far, fifty-seven patients have been thoroughly evaluated, and several have been given diagnoses not before seen in Denmark. CONCLUSIONS: The DAHEAN study and infrastructure harness recent advancements in diagnostic tools to offer precise diagnoses and improved management strategies for patients with hereditary anemias.
Assuntos
Anemia , Humanos , Dinamarca , Estudos de Coortes , Feminino , Masculino , Anemia/diagnóstico , Garantia da Qualidade dos Cuidados de Saúde , CriançaRESUMO
Cardiovascular diseases, especially congestive heart failure (CHF), are known complications of anthracyclines, but the risk for patients undergoing high-dose chemotherapy and autologous stem cell transplant (HDT-ASCT) is not well established. With T-cell therapies emerging as alternatives, studies of long-term complications after HDT-ASCT are warranted. Danish patients treated with HDT-ASCT for aggressive lymphoma between 2001 and 2017 were matched 1:5 on sex, birth year and Charlson comorbidity score to the general population. Events were captured using nationwide registers. A total of 787 patients treated with HDT-ASCT were identified. Median follow-up was 7.6 years. The risk of CHF was significantly increased in the HDT-ASCT population compared to matched comparators with an adjusted hazard ratio (HR) of 5.5 (3.8-8.1). The 10-year cumulative incidence of CHF was 8.0% versus 2.0% (p < 0.001). Male sex, ≥2 lines of therapy, hypertension and cumulative anthracycline dose (≥300 mg/m2 ) were risk factors for CHF. In a separate cohort of 4089 lymphoma patients, HDT-ASCT was also significantly associated with increased risk of CHF (adjusted HR of 2.6 [1.8-3.8]) when analysed as a time-dependent exposure. HDT-ASCT also increased the risk of other cardiac diseases. These findings are applicable for the benefit/risk assessment of HDT-ASCT versus novel therapies.
Assuntos
Doenças Cardiovasculares , Transplante de Células-Tronco Hematopoéticas , Linfoma , Humanos , Masculino , Resultado do Tratamento , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transplante Autólogo , Transplante de Células-Tronco , DinamarcaRESUMO
BACKGROUND: Second primary malignancies (SPMs) are known complications after chemotherapy, but the risk is not well characterised for patients with lymphoma treated with high-dose chemotherapy and autologous haematopoietic stem-cell transplantation (HSCT). We aimed to investigate the rate of SPMs in this population relative to matched control individuals from the general population. METHODS: In this retrospective, population-based cohort study, patients aged 18 years or older with an aggressive lymphoma who received high-dose chemotherapy and autologous HSCT in Denmark between Jan 1, 2001, and Dec 31, 2017, were included from the Danish Lymphoma Registry and matched (1:5) to control individuals from the general population on birth year and sex via the Danish Civil Registration System. Patients were eligible if they had a registered date of autologous HSCT and patients with primary CNS lymphoma were excluded. Exclusion criteria for both patients and matched control individuals were HIV infection, organ transplantation, or other malignancies before inclusion. The key endpoint was the incidence of SPMs assessed in all study participants. The effect of treatment on SPMs was also investigated in patients who were followed up from first lymphoma diagnosis, with high-dose chemotherapy and autologous HSCT as a time-dependent exposure. FINDINGS: Of 910 patients with lymphoma assessed, 803 were included (537 [67%] were male and 266 [33%] were female); 4015 matched control individuals were included (2685 [67%] were male and 1330 [33%] were female). Ethnicity data were not available. Median follow-up was 7·76 years (IQR 4·77-11·73). The SPM rate was higher among patients receiving high-dose chemotherapy and autologous HSCT than matched control individuals (adjusted hazard ratio [HR] 2·35, 95% CI 1·93-2·87, p<0·0001). Patients receiving high-dose chemotherapy and autologous HSCT had a higher rate of non-melanoma skin cancer (2·94, 2·10-4·11, p<0·0001) and of myelodysplastic syndrome or acute myeloid leukaemia (AML; 41·13, 15·77-107·30, p<0·0001) than matched control individuals, but there was no significant difference in the rate of solid tumours (1·21, 0·89-1·64, p=0·24). The cumulative risk of SPMs at 10 years was 20% (95% CI 17-23) in patients compared with 14% (13-15) in matched control individuals. High-dose chemotherapy and autologous HSCT was associated with an increased risk of SPMs when analysed as a time-dependent exposure from first lymphoma diagnosis (adjusted HR 1·58, 95% CI 1·14-2·17, p=0·0054). INTERPRETATION: High-dose chemotherapy and autologous HSCT was associated with an increased risk of non-melanoma skin cancer and myelodysplastic syndrome or AML but not with increased risk of solid tumours in patients treated for lymphoma. These findings are relevant for future individualised risk-benefit assessments when choosing between high-dose chemotherapy and autologous HSCT and chimeric antigen receptor T-cell therapy in this setting. FUNDING: Danish Cancer Society.
Assuntos
Imunoglobulinas Intravenosas/uso terapêutico , Imunossupressores/uso terapêutico , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Receptores de Trombopoetina/agonistas , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Feminino , Humanos , Imunoglobulinas Intravenosas/farmacologia , Imunossupressores/farmacologia , Lactente , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
The role of excess reactive oxygen species (ROS) with consequent DNA/RNA damage is now recognized as a hallmark of cancer. In JAK2V617F mutated myeloproliferative neoplasms, ROS have been suggested to be important factors in disease initiation and progression. Ruxolitinib is the most widely used drug for myelofibrosis, because it improves symptom-score. However, both the anti-clonal potential and improvement in overall survival are limited. We investigated the impact of ruxolitinib on formation of superoxide radical and hydrogen peroxide by monocytes in sequentially acquired blood samples from patients with myelofibrosis. We also investigated the impact on RNA and DNA damage by measuring urinary excretion of 8-oxo-Guo and 8-oxo-d-Guo. The formation of superoxide by monocytes was reduced significantly during ruxolitinib therapy, but no impact on the formation of hydrogen peroxide by monocytes or the systemic amount of oxidatively damaged RNA or DNA could be demonstrated. We conclude that ruxolitinib holds little anti-oxidative potential.
Assuntos
Dano ao DNA , Peróxido de Hidrogênio/metabolismo , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Estresse Oxidativo , Mielofibrose Primária/metabolismo , Pirazóis/farmacologia , Superóxidos/metabolismo , Biologia Computacional/métodos , Citometria de Fluxo , Humanos , Janus Quinases/genética , Janus Quinases/metabolismo , Nitrilas , Mielofibrose Primária/tratamento farmacológico , Mielofibrose Primária/etiologia , Mielofibrose Primária/patologia , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas , Espécies Reativas de Oxigênio/metabolismoRESUMO
Bone marrow (BM) fibrosis is a potential side effect of thrombopoietin receptor agonist (TPO-RA) treatment. We aimed to investigate stromal seromarker profiles and growth factors in order to elucidate pathogenic and dynamic aspects of immune thrombocytopenia (ITP)-related BM fibrosis before and during TPO-RA treatment. Connective tissue metabolites [procollagen I and III peptides (PINP/PIIINP); hyaluronan (HYA), C-terminal-telopeptide (ICTP), and fibrosis-related growth factors (transforming growth factor-beta (TGF-beta), HGF, basic fibroblast growth factor)] were measured in blood samples acquired before initiation of TPO-RA and subsequently at 6-month intervals for up to 2 years. BM fibrosis was graded MF-0 in 8 (18%), MF-1 30 (65%), and MF-2 8 (18%) in the last available BM biopsy. In the 21 patients having more than one biopsy, the grade of fibrosis from the first to the last available biopsy decreased in 2 (10%), remained unchanged in 15 (71%), and increased in 4 (19%). Pretreatment levels of PIIINP, PINP, ICTP, and HYA were significantly increased in ITP versus controls. PINP, PIIINP, and HYA decreased on TPO-RA; ICTP remained unchanged. PINP:ICTP was lower before and during treatment compared to controls. Pretreatment, TGF-beta was lower than in controls; HGF exhibited the opposite pattern. HYA, ICTP, and TGF-beta tended to increase while PINP and platelet-derived growth factor tended to decrease with increasing fibrosis grade. In conclusion, ITP is associated with deranged patterns of extracellular matrix seromarkers and growth factors, indicating that BM stromal remodeling is enhanced. During TPO-RA treatment for up to 2 years, this profile was partially reversed while mild BM reticulin fibrosis was still present in the majority of patients. These observations likely reflect a BM injury by autoimmunity that is modified by TPO-RA.
Assuntos
Mielofibrose Primária/diagnóstico , Receptores de Trombopoetina/metabolismo , Trombocitopenia/metabolismo , Adulto , Idoso , Medula Óssea , Feminino , Fibrose , Humanos , Masculino , Pessoa de Meia-Idade , Mielofibrose Primária/patologia , Adulto JovemRESUMO
OBJECTIVE: To investigate the cytokine production and surface marker composition of B cells in adult patients with newly diagnosed primary immune thrombocytopenia (ITP) before and 12 months after treatment with rituximab + dexamethasone (RTX+DXM) or dexamethasone (DXM). METHODS: Peripheral blood mononuclear cells were isolated from nine patients treated with RTX+DXM, seven patients treated with DXM, and seven healthy donors. Expression of the cell-surface markers CD5, CD27, CD25, and CD19, and intracellular content of IL-6 and IL-10 were measured by flow cytometry. RESULTS: PBMCs from ITP patients at baseline contained a lower proportion of IL-10+ B cells (P < .01) and IL-6+ B cells (P < .01) than healthy controls. All patients responded to therapy and levels were normalized at 12 months. The proportion of CD5+ B cells increased (P < .01) and CD27+ memory B cells decreased (P < .05) 12 months after treatment with RTX+DXM compared to baseline, with an inverse correlation between platelet numbers and the proportion of CD27+ B cells (R = -0.71; P < .05). CONCLUSION: Both treatment regimens normalized the frequencies of cytokine-producing B cells. The additional increase in CD5+ B cells after RTX+DXM is compatible with induction of Bregs.
Assuntos
Subpopulações de Linfócitos B/efeitos dos fármacos , Subpopulações de Linfócitos B/imunologia , Linfócitos B Reguladores/efeitos dos fármacos , Linfócitos B Reguladores/imunologia , Dexametasona/farmacologia , Fatores Imunológicos/farmacologia , Púrpura Trombocitopênica Idiopática/imunologia , Rituximab/farmacologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Autoanticorpos/sangue , Autoanticorpos/imunologia , Subpopulações de Linfócitos B/metabolismo , Linfócitos B Reguladores/metabolismo , Biomarcadores , Estudos de Casos e Controles , Citocinas/metabolismo , Dexametasona/uso terapêutico , Feminino , Humanos , Fatores Imunológicos/uso terapêutico , Imunofenotipagem , Depleção Linfocítica , Masculino , Pessoa de Meia-Idade , Fenótipo , Contagem de Plaquetas , Púrpura Trombocitopênica Idiopática/diagnóstico , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Rituximab/uso terapêutico , Adulto JovemRESUMO
BACKGROUND: Thrombopoietin-receptor-agonists (TPO-RAs) increase platelet production in Immune Thrombocytopenia (ITP) by stimulating Mpl. The effect of TPO-RAs on inflammatory cytokine production in ITP patients has not been well investigated. METHODS: Plasma samples from 48 ITP patients treated with TPO-RAs (median age 50 years (inter-quartile range; IQR 20-69), median platelet counts 24 × 109/L (IQR 15-47 × 109/L), 28 females) and 16 healthy controls (nine females, median age 37 years, IQR 22-51 years) were collected before and during treatment, and analyzed for a panel of cytokines and chemokines by enzyme-linked immunosorbent assay and immuno-bead-based multiplex assay. RESULTS: Elevated levels of C-X-C motif chemokine 10 (CXCL10; p < 0.001) and osteoprotegerin (OPG; p < 0.05) were observed in pretreatment samples compared to controls; these levels decreased during 6 months of treatment. Pretreatment levels of transforming growth factor (TGF)-ß were lower than in healthy controls and increased after 6 months of treatment (p < 0.05). Levels of sCD40L increased after 6 months of treatment (p < 0.05), but decreased thereafter to pretreatment values. The increase in TGF-ß and sCD40L may reflect increased platelet turnover. Levels of tumor necrosis factor (TNF)-α, interferon (IFN)-γ and interleukin (IL)-10 did not change during treatment. CONCLUSION: These findings suggest that treatment with TPO-RA creates a more balanced steady-state of immune activation.
Assuntos
Plaquetas/metabolismo , Ligante de CD40/sangue , Citocinas/sangue , Púrpura Trombocitopênica Idiopática/sangue , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Receptores de Trombopoetina , Adolescente , Adulto , Idoso , Pré-Escolar , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de TempoRESUMO
Canine immune thrombocytopenia (ITP) is analogous to human ITP, with similar platelet counts and heterogeneity in bleeding phenotype among affected individuals. With a goal of ultimately investigating this bleeding heterogeneity, a canine model of antibody-mediated ITP was developed. Infusion of healthy dogs with 2F9, a murine IgG2a monoclonal antibody to the canine platelet glycoprotein GPIIb (a common target of autoantibodies in ITP) resulted in profound, dose-dependent thrombocytopenia. Model dogs developed variable bleeding phenotypes, e.g. petechiae and haematuria, despite similar degrees of thrombocytopenia. 2F9 infusion was not associated with systemic inflammation, consumptive coagulopathy, or impairment of platelet function. Unexpectedly however, evaluation of cytokine profiles led to the identification of platelets as a potential source of serum interleukin-8 (IL8) in dogs. This finding was confirmed in humans with ITP, suggesting that platelet IL8 may be a previously unrecognized modulator of platelet-neutrophil crosstalk. The utility of this model will allow future study of bleeding phenotypic heterogeneity including the role of neutrophils and endothelial cells in ITP.
Assuntos
Modelos Animais de Doenças , Púrpura Trombocitopênica Idiopática/diagnóstico , Púrpura Trombocitopênica Idiopática/imunologia , Animais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/imunologia , Plaquetas/imunologia , Plaquetas/metabolismo , Citocinas/sangue , Citocinas/metabolismo , Cães , Hemorragia/imunologia , Fenótipo , Contagem de Plaquetas , Púrpura Trombocitopênica Idiopática/sangueRESUMO
Activated platelets are known to modulate immune responses by secreting or shedding a range of immunomodulatory substances. We examined the influence of activated platelets on cytokine production by normal human mononuclear cells, induced by tetanus toxoid (TT), human thyroglobulin (TG), Escherichia coli LPS, or intact Porphyromonas gingivalis. Addition of platelets activated by thrombin-receptor-activating peptide enhanced IL-10 production induced by LPS (p < 0.001), TG (p < 0.05), and P. gingivalis (p < 0.01), and reduced the production of TNF-α induced by LPS (p < 0.001), TG (p < 0.05), and P. gingivalis (p < 0.001), and of IL-6 in LPS- and P. gingivalis-stimulated cultures (p < 0.001). Similar effects on IL-10 and TNF-α production were observed on addition of platelet supernatant to mononuclear cells, whereas addition of recombinant soluble CD40L mimicked the effects on IL-10 production. Moreover, Ab-mediated blockade of CD40L counteracted the effect of platelets and platelet supernatants on TNF-α production. Monocytes separated into two populations with respect to IL-10 production induced by TG; the high-secreting fraction increased from 0.8 to 2.1% (p < 0.001) on addition of activated platelets. Adherence of platelets increased TG- and TT-induced IL-10 secretion by monocytes (p < 0.05). In addition, activated platelets inhibited CD4(+) T cell proliferation elicited by TT (p < 0.001) and P. gingivalis (p < 0.001). Our findings suggest that activated platelets have anti-inflammatory properties related to the interaction between CD40L and CD40, and exert a hitherto undescribed immunoregulatory action by enhancing IL-10 production and inhibiting TNF-α production by monocytes.
Assuntos
Plaquetas/imunologia , Interleucina-10/metabolismo , Monócitos/metabolismo , Ativação Plaquetária/imunologia , Fator de Necrose Tumoral alfa/metabolismo , Plaquetas/metabolismo , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Antígenos CD40/metabolismo , Ligante de CD40/imunologia , Proliferação de Células , Células Cultivadas , Humanos , Inflamação/imunologia , Interleucina-10/biossíntese , Interleucina-10/imunologia , Lipopolissacarídeos/imunologia , Monócitos/imunologia , Porphyromonas gingivalis/imunologia , Toxina Tetânica/imunologia , Tireoglobulina/imunologia , Fator de Necrose Tumoral alfa/biossíntese , Fator de Necrose Tumoral alfa/imunologiaRESUMO
In this study, we report the results from the largest cohort to date of newly diagnosed adult immune thrombocytopenia patients randomized to treatment with dexamethasone alone or in combination with rituximab. Eligible were patients with platelet counts ≤25×10(9)/L or ≤50×10(9)/L with bleeding symptoms. A total of 133 patients were randomly assigned to either dexamethasone 40 mg/day for 4 days (n = 71) or in combination with rituximab 375 mg/m(2) weekly for 4 weeks (n = 62). Patients were allowed supplemental dexamethasone every 1 to 4 weeks for up to 6 cycles. Our primary end point, sustained response (ie, platelets ≥50×10(9)/L) at 6 months follow-up, was reached in 58% of patients in the rituximab + dexamethasone group vs 37% in the dexamethasone group (P = .02). The median follow-up time was 922 days. We found longer time to relapse (P = .03) and longer time to rescue treatment (P = .007) in the rituximab + dexamethasone group. There was an increased incidence of grade 3 to 4 adverse events in the rituximab + dexamethasone group (P = .04). In conclusion, rituximab + dexamethasone induced higher response rates and longer time to relapse than dexamethasone alone. This study is registered at http://clinicaltrials.gov as NCT00909077.
Assuntos
Anticorpos Monoclonais Murinos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Dexametasona/administração & dosagem , Dexametasona/uso terapêutico , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Adulto , Idade de Início , Idoso , Algoritmos , Anticorpos Monoclonais Murinos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Dexametasona/efeitos adversos , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Púrpura Trombocitopênica Idiopática/diagnóstico , Púrpura Trombocitopênica Idiopática/epidemiologia , Recidiva , Rituximab , Resultado do TratamentoRESUMO
The objective of this study was to investigate the use of thrombopoietin-receptor agonists (TPO-ra) in patients with refractory primary immune thrombocytopenia (ITP) as well as off-label use of TPO-ra in Danish haematology departments. Hospital medical records from 32 of the 39 patients having received TPO-ra from 2009 to 1 May 2011 were available for data collection and included in the study. Of these patients, 15 received TPO-ra for refractory primary ITP, 7 for secondary ITP (chronic lymphatic leukaemia, systemic lupus erythematosus, Evans syndrome, human immunodeficiency virus and celiac disease) and 10 were treated for non-ITP (chemotherapy-induced, acute myeloid leukaemia, myelodysplastic syndrome, hereditary spherocytosis and suspected chemically induced thrombocytopenia). Initial response to TPO-ra defined as platelet counts >30 × 10(9)/l after 4 weeks of treatment was found in 59% of primary ITP patients, 57% of patients with secondary ITP and 40% of patients with non-ITP. There were four deaths in the cohort, three of which were related to pre-existing medical conditions. Otherwise adverse effects were in general mild. This Danish retrospective registration study has demonstrated that in the off-protocol setting, the use of TPO-ra is associated with response rates largely similar to those seen in previous protocol-monitored studies and no new adverse events were reported.
Assuntos
Benzoatos/uso terapêutico , Plaquetas/efeitos dos fármacos , Hidrazinas/uso terapêutico , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Pirazóis/uso terapêutico , Receptores Fc/uso terapêutico , Receptores de Trombopoetina/agonistas , Proteínas Recombinantes de Fusão/uso terapêutico , Trombopoetina/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anemia Hemolítica Autoimune/tratamento farmacológico , Benzoatos/efeitos adversos , Doença Celíaca/tratamento farmacológico , Dinamarca , Feminino , Infecções por HIV/tratamento farmacológico , Humanos , Hidrazinas/efeitos adversos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Uso Off-Label , Contagem de Plaquetas , Pirazóis/efeitos adversos , Proteínas Recombinantes de Fusão/efeitos adversos , Recidiva , Estudos Retrospectivos , Trombocitopenia/tratamento farmacológico , Trombopoetina/efeitos adversosRESUMO
This study assessed the grade of bone marrow (BM) fibrosis and its association with a seromarker for collagen-III formation and fibrosis-related cytokines in 25 immune thrombocytopenia (ITP) patients treated with thrombopoietin receptor agonists (Tpo-RA) who had at least one BM biopsy. Assessment of 8 pre- and on-treatment BM biopsies revealed statistically significant increases in reticulin. Reticulin in biopsies performed after a median of 1·4 years of treatment was graded: MF-0 in 3 (12%), MF-1 in 19 (76%), MF-2 in 2 (8%) and MF-3 in 1 (4%). No cytogenetic or flow-cytometric abnormalities were detected. Median pretreatment Procollagen III N-propeptide (PIIINP) (6·6 µg/l) was significantly higher than on-treatment levels (5·6 µg/l); both were higher than controls (3·4 µg/l; P < 0·001). PIIINP was negatively correlated with treatment duration (r = -0·49) suggesting a decelerated reticulin production over time. There was a trend towards an association between grade of reticulin and PIIINP. Transforming growth factor (GF)-beta and basic-Fibroblast GF were not different between patients and controls but Hepatocyte GF (HGF), an anti-fibrotic cytokine, was significantly elevated in patients. In conclusion, low-grade BM reticulin fibrosis is seen in most ITP patients on Tpo-RA. The novel findings of decreasing PIIINP and elevated HGF need further investigation to explore their significance in BM fibrogenesis.
Assuntos
Benzoatos/efeitos adversos , Medula Óssea/patologia , Fator de Crescimento de Hepatócito/sangue , Hidrazinas/efeitos adversos , Fragmentos de Peptídeos/sangue , Mielofibrose Primária/induzido quimicamente , Pró-Colágeno/sangue , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Pirazóis/efeitos adversos , Receptores de Trombopoetina/agonistas , Proteínas Recombinantes de Fusão/efeitos adversos , Reticulina/análise , Trombopoetina/efeitos adversos , Adulto , Benzoatos/administração & dosagem , Benzoatos/uso terapêutico , Medula Óssea/metabolismo , Terapia Combinada , Citocinas/sangue , Feminino , Humanos , Hidrazinas/administração & dosagem , Hidrazinas/uso terapêutico , Peptídeos e Proteínas de Sinalização Intercelular/sangue , Masculino , Pessoa de Meia-Idade , Mielofibrose Primária/sangue , Púrpura Trombocitopênica Idiopática/sangue , Púrpura Trombocitopênica Idiopática/patologia , Púrpura Trombocitopênica Idiopática/cirurgia , Pirazóis/administração & dosagem , Pirazóis/uso terapêutico , Receptores Fc/administração & dosagem , Receptores Fc/uso terapêutico , Proteínas Recombinantes de Fusão/administração & dosagem , Proteínas Recombinantes de Fusão/uso terapêutico , Esplenectomia , Trombopoetina/administração & dosagem , Trombopoetina/uso terapêuticoRESUMO
Primary immune thrombocytopenia (ITP)--formerly known as idiopathic thrombocytopenic purpura--is an autoimmune disorder characterized by immune mediated thrombocytopenia. The aetiology of ITP remains unknown, but studies have shown that multiple immunological mechanisms are involved in the pathogenesis of ITP. This article aims to provide an overview of current treatment options, with particular emphasis on new biological therapies: rituximab, a monoclonal anti-CD20 antibody, and the thrombopoietin receptor agonists romiplostim and eltrombopag.
Assuntos
Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Anticorpos Monoclonais Murinos/uso terapêutico , Benzoatos/uso terapêutico , Dexametasona/uso terapêutico , Glucocorticoides/uso terapêutico , Humanos , Hidrazinas/uso terapêutico , Imunoglobulinas Intravenosas/uso terapêutico , Imunossupressores/uso terapêutico , Prednisolona/uso terapêutico , Pirazóis/uso terapêutico , Receptores Fc/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , Rituximab , Esplenectomia , Trombopoetina/uso terapêuticoRESUMO
Primary immune thrombocytopenia (ITP)--formerly known as idiopathic thrombocytopenic purpura--is an autoimmune disorder characterized by immune-mediated thrombocytopenia. The aetiology of ITP remains unknown, but studies have shown that multiple immunological mechanisms are involved in the pathogenesis of ITP.This article aims to provide an overview of our knowledge of the pathogenesis of ITP.
Assuntos
Púrpura Trombocitopênica Idiopática/etiologia , Autoanticorpos/biossíntese , Linfócitos B/imunologia , Humanos , Púrpura Trombocitopênica Idiopática/imunologia , Púrpura Trombocitopênica Idiopática/fisiopatologia , Linfócitos T/imunologia , Trombopoese/fisiologiaRESUMO
INTRODUCTION: Tumour necrosis factor (TNF)-alpha and TNF-beta, also called lymphotoxin (LT), are bound by soluble truncated TNF receptors (sTNFRI and II) that are released from cell surfaces and act as natural inhibitors of TNF-induced inflammation. We investigated the plasma levels of sTNFRI and II in parallel with LT binding capacity (LTBC) in 44 patients with juvenile chronic arthritis (JIA). METHODS: LTBC was determined by spiking diluted plasma samples with 1000 pg/ml of human recombinant LT. Detectable LT was measured by an in-house ELISA and LTBC was expressed in arbitrary units (AU) as the percentage value of bound LT to added LT. The levels of sTNFRI and-II were measured by ELISA (R&D). RESULTS: We found slightly reduced sTNFRI and II levels in JIA patients (n=44) compared with healthy controls sTNFRI: 1118 pg/ml (656-2074) [mean (range)] vs. 1262 pg/ml (819-2280) p=0.015; sTNFRII: 1953 pg/ml (889-4476) vs. 2311 pg/ml (1309-4186) p=0.008. The sTNFRI levels correlated positively with morning stiffness (r=0.30, p=0.044), physician's global assessment (r=0.39; p=0.009) and CRP (r=0.43; p=0.0048). sTNFRII did not correlate with measures of disease activity. In contrast, patient LTBC values were elevated compared to controls: 44 AU (36-52) vs. 31 AU (13-41) [mean (range)], p<0.0001, but did not correlate with disease activity. CONCLUSION: Despite overall slightly reduced plasma levels of sTNFRI and II, the capacity to bind TNF appeared to be increased in plasma samples from JIA patients.