Efectividad de Rituximab en el tratamiento de citopenias autoinmunes refractarias en adultos / Effectiveness of Rituximab in the treatment of cytopenias refractory autoimmune in adults

The term autoimmune cytopenias is referred to a heterogeneous group of diseases characterized by a reduced peripheral blood cell counts in one or more cellular series, because an immunological disorder. The first line therapy is steroids, followed by splenectomy or immunesupressant therapy in non-responders. Rituximab is an anti CD20 monoclonal antibody used as a third line in refractory patients or as an alternative to splenectomy. We present a retrospective study of nine patients with autoimmune cytopenias treated in a public hospital setting with rituximab. Five patients with the diagnosis of inmune thrombocytopenic purpura received it, all of them achieved hematological response (4 complete and one partial). The median time to the best response was 6 weeks, staying in this category after 6 months of follow up. Four patients with autoimmune hemolytic anemia received rituximab, three of them achieving partial response and one was lost from follow up. No severe adverse effects related to rituximab were registered.

Circulating myeloid-derived suppressor cells predict disease activity and treatment response in patients with immune thrombocytopenia

Immune thrombocytopenia (ITP) is a disease characterized by isolated thrombocytopenia. Abnormal effector T cell activation is an important mechanism in the pathogenesis of ITP. Regulatory T cells (Treg) have a strong immunosuppressive function for T cell activation and their importance in the pathophysiology and clinical treatment of ITP has been confirmed. Myeloid-derived suppressor cells (MDSCs) are other immunosuppressive cells, which can also suppress T cell activation by secreting arginase, iNOS and ROS, and are essential for Treg cells’ differentiation and maturation. Therefore, we speculate that MDSCs might also be involved in the immune-dysregulation mechanism of ITP. In this study, we tested MDSCs and Treg cells in peripheral blood samples of twenty-five ITP patients and ten healthy donors. We found that MDSCs and Treg cells decreased simultaneously in active ITP patients. Relapsed ITP patients showed lower MDSCs levels compared with new patients. All patients received immunosuppressive treatment including dexamethasone alone or in combination with intravenous immune globulin. We found that MDSCs’ level after treatment correlated with platelet recovery. Our study is the first that focused on MDSCs’ role in ITP. Based on our results, we concluded that circulating MDSCs could predict disease activity and treatment response in ITP patients. This preliminary conclusion indicates a substantial significance of MDSCs in the pathophysiology and clinical treatment of ITP, which deserves further investigation.

Idiopathic thrombocytopenic purpura and oral surgery: case report / Púrpura trombocitopênica idiopática e cirurgia bucal: relato de caso

OBJECTIVES: To review the function of platelets in the blood clotting mechanism. To address,conceptualize and classify thrombocytopenic purpura, especially idiopathic thrombocytopenic purpura (ITP),emphasizing the immunological aspects involved in the etiology of the disease. To address the clinicalmanifestations of the disease and the appropriate therapy. To present the case study of a patient with ITPwho requires oral surgical intervention. DISCUSSION: Leukopenia in ITP can be subclinical. The firstmanifestation of the disease can be severe hemorrhaging due to small lacerations or minor medical anddental surgical procedures. The cause of the platelet reduction is idiopathic; an autoimmune reaction in whichthe antibodies destroy the platelets appears to participate in the process. A variety of situations can occur,leading to mild to severe thrombocytopenia. One frequent aspect is the instability of the platelet count,which oscillates inconsistently and may be related to infections and other factors that have not been clearlydetermined, including stress. In the case presented here, the leukopenia in the patient was mild in presentation.However, it was decided that the patient should be referred to a hematologist for preparation and clearance.Oral surgery that compromises the bone, such as exodontia, can present significant difficulties in localizingand clamping intraosseous vessels, which does not only occur in small soft tissue surgeries. CONCLUSIONS:Platelet destruction in ITP occurs from a complex process that is comprised of multiple components of theimmune system. The platelets are prematurely destroyed by antibodies that are aimed at the platelet glycoprotein,which can results in serious, even fatal consequences. It is important to emphasize the significance of themedical history and the appropriate physical examination during the diagnostic process, as well as collaborationwith the patient’s medical...

OBJETIVOS: Revisar a função das plaquetas no mecanismo de coagulação sanguínea. Conceituare classificar a púrpura trombocitopênica, especialmente a púrpura idiopática, enfatizando osaspectos imunológicos envolvidos na etiologia da doença. Enfocar as manifestações clínicas dadoença e a terapia apropriada. Apresentar um caso de manifestação clínica da doença e a terapiaapropriada. Apresentar o caso de uma paciente com púrpura que necessitava de intervençãocirúrgica bucal. DISCUSSÃO: A leucopenia na púrpura trombocitopênica idiopática pode sersubclínica. A primeira manifestação da doença pode ser uma hemorragia severa por causa depequenas lacerações ou pequenos procedimentos médicos e odontológicos. A causa da reduçãodas plaquetas é idiopática; uma reação autoimune na qual os anticorpos destroem as plaquetasparece participar do processo. Uma variedade de situações pode ocorrer, levando àtrombocitopenia discreta a severa. Um aspecto frequente é a instabilidade da contagem plaquetária,que oscila inconsistentemente e pode relacionar-se com infecções e outros fatores ainda nãoclaramente determinados, incluindo estresse. No presente caso, o paciente apresentava discretaleucopenia. Entretanto, decidiu-se que o paciente deveria ser avaliado por um hematologista,para preparação e liberação para cirurgia, pois a cirurgia bucal que compromete osso, como aexodontia, pode apresentar dificuldades significativas na localização e pinçamento de vasosintraósseos, o que não acontece em pequenas cirurgias de tecidos moles. CONCLUSÕES: Adestruição plaquetária na púrpura trombocitopênica ocorre por meio de um complexo processo,com múltipos componentes do sistema imune. As plaquetas são destruídas prematuramente poranticorpos dirigidos contra as glicoproteínas plaquetárias, o que pode resultar em sérias – emesmo fatais – consequências. É importante enfatizar o significado da história médica e o examefísico adequado no processo diagnóstico...

Treatment of chronic immune thrombocytopenic purpura with rituximab.

Objective. To evaluate the rituximab treatment in children with chronic immune thrombocytopenic purpura Methods. This study included ten children with chronic immune thrombocytopenic purpura, which were nonresponsive to Steroid (S), IVIG and anti-D treatments. Rituximab was given with a dosage of 375 mg/m2 weekly for 4-6 weeks. Initial platelet count was less than 30x109/L and responses were assessed in follow-up. The patients’ groups were categorized as complete remission (CR);a platelet count ≥150x109/L,partial remission (PR);a platelet count ranging from 50x109/L to 150x109/L, minimal remission (MR); a platelet count ranging from 30x109/L to 50x109/L and no response (NR); a platelet count less than 30x109/L. Results. Of our patients, four female and six male, their ages ranged from 39 mth to 13 yr and the mean age was 83.4±44.58 mo. None of the patients was splenectomized. The follow-up period after rituximab treatment ranged between 12 to 42 mo and the mean follow-up period was 25.10±13.03 months. While on this treatment, we had a CR in two patients, a PR in one, a MR in three, but no response in four. The patients in CR/PR are still being followed as in remission and they have 40 mo of mean follow-up period. The three patients in MR had a decrease in values of platelets earliest in one mo and the latest in four mo. Adverse effects of rituximab, such as itching and scraps that were not clinically significant were observed in three patients during rituximab infusion. There were no increase in infections after rituximab in any patient. Conclusion. CR was found in 20% of our patients, PR in 10% and MR in 30% with rituximab. On this treatment, while some series had good outcomes with this treatment (72%-100%, remission ratios), but many series, such as ours, had a poor response rate contrast to many reported case series in the literature. This condition may be associated with the age of our most patients who were young at the time of commenced rituximab. However, we believe that more studies are required to elucidate the reasons for different results in different case series reported in literature.

Patogenia de las citopenias autoinmunes primarias / Primary autoimmune cytopenias

Las enfermedades autoinmunes son trastornos secundarios a una des regulación del sistema inmune; éste pierde la capacidad de autotolerancia, y produce un daño crónico, continuo y progresivo. Son patologías muy diversas y pueden llegar a afectar hasta el 5 por ciento de la población. Pueden ser clasificadas en sistémicas u órgano-especificas, dependiendo si el antígeno reconocido es exclusivo del tejido target. A este grupo de enfermedades corresponden las citopenias autoinmunes, condiciones que se caracterizan por disminución del recuento de glóbulos rojos, plaquetas, leucocitos o la mezcla de ellos. Si bien los mecanismos patogénicos que participan en producción de cada una de ellas son similares, cada la tiene características que la hacen particularmente interesante. De esta manera tenemos que la anemia hemolítica autoinmune (AHAI) en un síndrome clínico que se produce debido a la disminución de glóbulos rojos secundaria a una destrucción exagerada de ellos, mediada por la alteración de la respuesta inmune, en la que los antígenos de la membrana de estas células son reconocidos como extraños por nuestro sistema inmune. La clasificación de la AHA/ está dada por la temperatura óptima de unión entre el anticuerpo y la membrana del glóbulo rojo; de esta forma, tenemos tres grandes grupos: por Anticuerpos calientes (WAHA), por Anticuerpos fríos (CAHA) y Mixtas (mediadas por anticuerpos calientes y frios). El diagnóstico de AHAl se confirma con la demostración de anticuerpos y/o proteínas del complemento en la superficie de los eritrocitos; entre ellos encontramos: Coombs directo y Coombs indirecto, test de Coombs recto anti-lgM , búsqueda de C3b en la membrana del glóbulo rojo y finalmente la prueba cualitativa de Donath-Landsteine Las trombopenias autoinmunes corresponden a un grupo de desórdenes que se caracterizan por tener un recuento plaquetario bajo 150.000, mediado por una alteración del sistema inmune. (3.14) La trombocitopenia autoinmune puede ser...

Autoimmune diseases are disorders secondary to a deregulation of the immune system, which loses the capacity for self-tolerance, resulting in chronic, continuous and progressive damage. These pathologies are very diverse and affect up to 5 percent of the population. They can be classified into systemic or organ-specific, depending on whether the recognized antigen is unique to the target tissue. Autoimmune cytopenias belong to this group of diseases and are characterized by a decreased count of red blood cells, platelets, leukocytes, or a mix of these. While the pathogenic mechanisms involved in the production of each are similar, each has features that make it particularly interesting. We have autoimmune hemolytic anemia (AlHA), which is a clinical syndrome that occurs due to a decreased number of red blood cells secondary to an exaggerated destruction of the same, mediated by an alteration of the immune response, in which the membrane antigens of these cells are recognized as foreign by our immune system. The classification of AIHA is given by the optimum bond temperature between the antibody and red blood cell membrane. There are 3 main groups: warm antibodies(WAHA), Cold antibodies (CAHA) and mixed (mediated by hot and cold antibodies). AIHA diagnosis is confirmed with the demonstration of antibodies and/or complement proteins on the surface of red blood cells, among these are the direct and indirect Coombs test, direct anti-IgM Coombs test, the search for C3b in the membrane of the red cell and, finally, the qualitative Donath-Landsteiner test. Autoimmune thrombocytopenia isassociated with a group of disorders characterized by a platelet count under 150,000, mediated by an alteration of the immune system.(3-14) Autoimmune thrombocytopenia can be classified as primary or secondary, and these, in turn, into acute and chronic, depending on whether they last 6 months or more, respectively. Antibodies that react against the glycoproteins of the plate...

autoimmune diseases manifested by production of autoantibodies: the autoantigens identified by random peptide library

Phage-displayed random peptide libraries [RPL] provide a powerful technique for identification, structural and functional analysis of ligands for many different target molecules, including, antibodies, receptors or other proteins. This strategy has been verified to be an effective tool for research in immunology and successfully has been used to determine the target sequence for monoclonal and polyclonal antibodies. The peptide library approach provides great promise for characterization of ligands with no prior information concerning antibody specificity. This would allow the recognition of candidate antigens involved in initiation or perpetuation of autoimmune diseases. This technology also offers the potential for new therapeutic opportunities, production of diagnostic reagents, or even development of effective new vaccines. This review focuses on studies regarding the identification of autoantigens recognized by antibodies in autoimmune diseases using phage-display peptide libraries

Púrpura trombocitopênica imune: diagnóstico e tratamento / Immune thrombocytopenic purpura: diagnosis and treatment

Objetivo: revisar os critérios vigentes para o diagnóstico e o tratamento da púrpura trombocitopênica imune da criança. Fonte dos dados: foram selecionados os artigos da literatura da base MedLine mais relevantes dos últimos 20 anos relativos ao termo púrpura trombocitopênica...

Objective: to assess the current criteria for immune thrombocytopenic purpura (PTI) diagnosis and tretament. Data source: MedLine database articles published in the last twenty years selecte upon the therm thrombocytopenic purpura...

Eficacia de la asociación rituximab-vindesina en el tratamiento de un caso de púrpura trombótico-trombopénico (PTT) adquirido idiopático refractario / Successful treatment of idiopathic acquired refractory thrombotic thrombocytopenic purpura with an association of rituximab - vindesine. Report of one case

We report a 23 years old female who presented a second episode of thrombotic thrombocytopenic purpura (TTP). She was treated with fresh frozen plasma infusions and 14 plasma exchange (PE) sessions without response. Therefore a second-line therapy was started, associating a weekly cycle administration of vindesine (Vds) 2 mg/m2 and rituximab (R) 375 mg/m2. Five cycles of this association plus one cycle of R exclusively, were administered. After the third course, biological signs of improvement were observed and complete normalization of blood cell counts and other specific parameters was seen after 8 weeks. From the beginning of her second relapse we detected a severe deficit (<5%) in von Willebrand-cleaving factor (ADAMTS13) associated to the presence of ADAMTS13 inhibitors. The combined treatment induced an improvement in ADAMTS13 values without detectable inhibitors. After 21 months of follow-up the patient was well, without signs of relapse but ADAMTS13 values were still under normal, which may be an unfavorable prognostic factor. PE is the treatment of choice for acquired idiopathic TTP, but for refractory cases or TTP cases with severe ADAMTS13 values/high inhibitor titers, PE associated to an immunosuppressive treatment should be considered.

Purpura trombocitopenica imunologica associada a hepatite A: relato de caso / Immune thrombocytopenic purpura associated to hepatitis A: a case report

Relatar um caso grave de purpura trombocitopenica imunologica apos infeccoes pelo virus da hepatite A...

Determinación de anticuerpos antinucleares en la anemia hemolítica autoinmune y la púrpura trombocitopénica autoinmune / Determination of antinuclear antibodies in autoimmune hemolytic anemia and autoimmune thrombocytopenic purpura

Se detectó la presencia de anticuerpos antinucleares mediante un método de inmunofluorescencia indirecta en uno de los 18 pacientes estudiados con anemia hemolítica autoinmune y en 3 de los 16 pacientes con púrpura trombocitopénica autoinmune. Los resultados establecen la importancia de la detección de los anticuerpos antinucleares como elemento indicador de la existencia o desarrollo de otra enfermedad autoinmune asociada

El sistema del complemento sérico, parte II: patología del complemento / Serum complement system, part II: pathology of the complement

Al hablar de los aspectos relacionados a la patología del complemento, se hace relación a las deficiencias congénitas, descritas para todos los componentes aislados, pero destacando la mayor frecuencia de la deficiencia congénita de C2. También se menciona la asociación de enfermedades por autoinmunidad con el déficit de los componentes de la vía clásica (C1, C4 y C2), la infección severa y recurrente con el déficit de C3, el angioedema hereditario y deficiencia de C1INH, según sea el sector bloqueado o afectado. Entre los defectos adquiridos se mencionan la relación con diversos grupos de enfermedades como las colageno-vasculares (enfermedad del suero, lupus eritematoso sistémico y artritis reumatoide). En la patología renal se revisa su responsabilidad en las glomerulonefritis agudas, lupus, glomerulonefritis membranoproliferativa y síndrome nefrótico. Finalmente, se menciona la participación del complemento en ciertas hemopatías: anemias y trombocitopenias inmunes y la hemoglobinuria paroxística nocturna

Pathogenetic and prognostic significance of circulating immuno complexes, immunoglobulins and complement-4 in childhood itp

In order to evaluate the role of circulating immune complexes [CIC], immunoglobulins and complement-4 [C4] in the pathogenesis and the prognosis of childhood idiopathic thrombocytopenic purpura [ITP]; 45 children with ITP [35 acute ITP, and 10 chronic ITP] aged 2-13 years as well as 15 healthy children as controls were studied. It was concluded that circulating immune complexes, immunoglobulins G and M and C4 had a role in the pathogenesis of ITP. Factors which might predict chronicity of ITP were older age at onset >7 years, preceding illness >4 weeks, lymphocyte count <20%, polymorphs count >60%, megakaryocyte count 2-6% and CIC level >60% I

Púrpura trombocitopénica autoinmune y embarazo / Autoinmune thrombocytopenic purpura and pregnancy

La púrpura trombocitopénica a utoinmune (PTA) es común en mujeres en edad reproductiva. Como consecuencia, el médico frecuentemente tiene que tratar a pacientes con PTA y embarazo. El tratamiento en la madre es simple, por que la medición de la cuenta plaquetaria materna es fácil de obtener. Sin embarago el manejo del feto es más difícil porque ningún tratamiento materno, ha podido prevenir la trombocitopenia fetal en forma exitosa. La realización de cordocentesis o bien el recuento de plaquetas en cuero cabelludo del neonato, permite la determinación de el número de plaquetas antes de finalizar el embarazo, Si se detecta trombocitopenia fetal de menos de 50,000 plaquetas por mm3, esta indicada la cesárea para evitar hemorragia intracraneana en el feto

La inmunoperoxidasa en el estudio de las trombocitopenias inmunológicas / Immunoperoxidase in the studies of immune thrombocytopenias

The usefulness of different techniques to measure platelet bound IgG has been reviewed by George(16). We present here the results obtained with a technique designed to measure membrane bound IgG employing an anti-human IgG labeled with peroxidase and using O-dianisidine-H2O2 to reveal the enzymatic activity(17). We studied 152 patients with chronic autoimmune thrombocytopenic (ATP) including 120 adults and 32 children (age below 15 years old), diagnosed by exclusion of diseases that may be associated with thrombocytopenic purpura of either immune or non-immune mechanisms. Besides, 79 patients with thrombocytopenia related to other diseases were also evaluated. The normal values in 215 controls were 188 +/- 4 IgG molec/platelet (mean +/- SE), while in the whole population of chronic ATP the results were 4714 +/- 344, p < 0.001. In pediatric cases the results had a tendency to values higher than in adults. A negative correlation was found between the number of platelets and the amount of bound IgG, r = 0.41 p < 0.001. IgG bound platelets were also increased in treated patients at relapse. The percent of normal IgG bound platelet was 4,5 percent in patients with a platelet count below 50.000/microliter and 39 percent in those with normal platelet number. Patients with secondary thrombocytopenia had elevated IgG/platelet while the values were normal in patients with thrombocytopenia of unknown etiology. We conclude that the immunoperoxidase technique is useful to establish the immunologic nature of thrombocytopenia.