Autoantibodies in systemic vasculitis

Systemic vas culitis is a heterogeneous group of disorders characterized by inflammation and necrosis in the vessel wall. the diagnosis of a systemic vasculitis is challenging, because patients usually present a broad spectrum of manifestations that vary according to the predominant size of vessels affected, organs and systems involved, and the extent of the inflammatory process (I). in systemic vasculitis, disease manifestations usually cluster into clinical phenotypes and definite diagnosis rely on confirmation by tissue biopsy, angiography, or by serologic tests. However, when a systemic vasculitis is under investigation, it is of paramount importance to keep in mind vasculitis mimics (e.g., genetic vascular disorders and atheroembolic diseases) and secondary causes (i.e., infections, malignancy, connective tissue disorders, or drugs) (2).The main serologic tests for the diagnosis of primary systemic vasculitides are antineutrophil cytoplasmic antibodies (ANCA), cryoglobulins, anti-glomerular basement membrane (anti-GBM) antibodies, and anti-Clq antibodies (3). Although, several other autoantibodies have been investigated in systemic vasculitis, the clinical usefulness of these antibodies still needs further investigation (Table 1). Herein, the main autoantibodies and their clinical associations in systemic vasculitis are reviewed.Universidade Federal de São Paulo, Escola Paulista Med, Dept Internal Med, Div Rheumatol, São Paulo, BrazilUniversidade Federal de São Paulo, Escola Paulista Med, Dept Internal Med, Div Rheumatol, São Paulo, BrazilWeb of Scienc

Testicular vasculitis: a rare manifestation of rheumatoid arthritis

Testicular vasculitis is a very rare extra-articular manifestation of rheumatoid arthritis (RA). We describe the case of a 53-year-old man diagnosed with RA for eight years, who was poorly controlled and developed rheumatoid vasculitis, which manifested as leg ulcers and peripheral polyneuropathy. The patient also had acute neutrophilic meningitis and was treated with antibiotics and intravenous pulse therapy with methylprednisolone (500 mg daily) for three days, followed by oral cyclophosphamide (2 mg/kg daily) and prednisone. Overall improvement was observed, and the patient was discharged. But 15 days later, the meningitis recurred, and the patient was readmitted and treated again with antibiotics. Three days later, he developed pain and enlargement of his left testicle with gangrene. Unilateral orchiectomy was performed, revealing lymphocytic vasculitis. The patient died two days later due to aspiration pneumonia. This case illustrates a rare and severe manifestation of rheumatoid vasculitis.A vasculite testicular é uma manifestação extra-articular muito rara da artrite reumatoide (AR). Descrevemos o caso de um homem de 53 anos com diagnóstico de AR por oito anos, sem controle adequado da doença. O paciente desenvolveu vasculite reumatoide, manifestada por úlceras de membros inferiores e neuropatia periférica. Apresentou ainda meningite neutrofílica aguda, tendo sido tratado com antibióticos e posterior pulsoterapia endovenosa com metilprednisolona (500 mg/dia) por três dias, seguida de ciclofosfamida (2 mg/kg/ dia) e prednisona orais. O paciente apresentou melhora do quadro, mas 15 dias após a alta hospitalar, houve reativação da meningite bacteriana. O paciente foi reinternado e tratado novamente com antibióticos. Três dias depois da segunda admissão hospitalar, o paciente apresentou dor, aumento de volume do testículo esquerdo e posteriormente gangrena. Foi realizada orquiectomia unilateral e o exame anatomopatológico revelou vasculite linfocítica. O paciente faleceu dois dias após a cirurgia devido a pneumonia aspirativa. Esse caso ilustra a vasculite testicular como uma manifestação rara e grave da vasculite reumatoide.Universidade Federal de São Paulo (UNIFESP) Escola Paulista de MedicinaUNIFESP, EPMSciEL

Guidelines for the treatment of antiphospholipid syndrome

The antiphospholipid syndrome (APS) is a systemic autoimmune disease characterized by arterial and venous thrombosis, gestational morbidity and presence of elevated and persistently positive serum titers of antiphospholipid antibodies. The treatment of APS is still controversial, because any therapeutic decision potentially faces the risk of an insufficient or excessive antithrombotic coverage associated with anticoagulation and its major adverse effects. This guideline was elaborated from nine relevant clinical questions related to the treatment of APS by the Committee of Vasculopathies of the Brazilian Society of Rheumatology. Thus, this study aimed at establishing a guideline that included the most relevant and controversial questions in APS treatment, based on the best scientific evidence available. The questions were structured by use of the PICO (patient, intervention or indicator, comparison and outcome) process, enabling the generation of search strategies for evidence in the major primary scientific databases (MEDLINE/PubMed, Embase, Lilacs, Scielo, Cochrane Library, Premedline via OVID). A manual search for evidence and theses was also conducted (BDTD and IBICT). The evidence retrieved was selected based on critical assessment by using discriminatory instruments (scores) according to the category of the therapeutic question (JADAD scale for randomized clinical trials and Newcastle-Ottawa scale for non-randomized studies). After defining the potential studies to support the recommendations, they were selected according to level of evidence and grade of recommendation, according to the Oxford classification.A síndrome do anticorpo antifosfolipídeo (SAF) é uma doença sistêmica autoimune caracterizada por trombose arterial e venosa, morbidade gestacional e presença de níveis séricos de anticorpos antifosfolipídeos elevados e persistentemente positivos. O tratamento da SAF ainda é sujeito a controvérsias, já que qualquer decisão terapêutica potencialmente irá confrontar-se com o risco de uma cobertura antitrombótica insuficiente ou com o risco excessivo associado à anticoagulação e seus principais efeitos adversos. Esta diretriz foi elaborada a partir de nove questões clínicas relevantes e relacionadas ao tratamento da SAF pela Comissão de Vasculopatias da Sociedade Brasileira de Reumatologia. O objetivo deste trabalho foi criar uma diretriz que incluísse as questões mais relevantes e controversas no tratamento da SAF, com base na melhor evidência científica disponível. As questões foram estruturadas por meio do P.I.C.O. (paciente, intervenção ou indicador, comparação e outcome/desfecho), o que possibilitou a geração de estratégias de busca da evidência nas principais bases primárias de informação científica (MEDLINE/Pubmed, Embase, Lilacs/Scielo, Cochrane Library, Premedline via OVID). Também realizou-se busca manual da evidência e de teses (BDTD e IBICT). A evidência recuperada foi selecionada a partir da avaliação crítica, utilizando instrumentos (escores) discriminatórios de acordo com a categoria da questão terapêutica (JADAD para ensaios clínicos randomizados e New Castle Ottawa Scale para estudos não randomizados). Após definir os estudos potenciais para sustento das recomendações, eles foram selecionados pela força da evidência e pelo grau de recomendação, segundo a classificação de Oxford.Hospital Federal dos Servidores do EstadoUniversidade Federal de Goiás Faculdade de MedicinaUniversidade Federal de Minas Gerais Faculdade de Medicina Departamento LocomotorUniversidade Federal do Paraná Hospital de ClínicasCentro Médico AliançaIUniversidade Federal da BahiaUniversidade Federal de São Paulo (UNIFESP) Escola Paulista de MedicinaUniversidade do Estado do Rio de JaneiroUNIFESP, EPMSciEL

Genetic variability of two Nile tilapia strains by microsatellites markers

O objetivo desse trabalho foi avaliar a variabilidade genética de duas variedades de tilápia nilótica (Oreochromis niloticus), Chitralada e Red Stirling, e de suas progênies submetidas a programas de melhoramento genético, em sistemas intensivos de cultivo por meio de marcadores microssatélites. Foram utilizados 30 animais de cada variedade parental, 30 animais híbridos (CH), provenientes do cruzamento entre as variedades Chitralada e Red Stirling, e 30 animais (RR) provenientes do cruzamento entre os parentais da variedade Red Stirling. Utilizaram-se cinco microssatélites: UNH104, UNH108, UNH118, UNH222 e UNH231. Observaram-se baixos índices de endogamia, com valores de FIS negativo para as duas variedades e seus cruzamentos. Verificou-se diferença genética entre as duas variedades, obtida pelo cálculo do índice de fixação de alelos (FST = 0,131 e RST = 0,130). As variedades parentais Chitralada e Red Stirling apresentaram 24,4% de distância genética, o que se refletiu na presença de vigor híbrido com 23,5% de incremento em rendimento no plantel CH.The objective of this work was to evaluate the genetic variability of two Nile tilapia strains (Oreochromis niloticus), Chitralada and Red Stirling, as well as its offsprings submitted to genetic enhancement programs, in intensive systems farming by microsatellites markers. Thirty individuals of each parental strain, 30 crossbred (CH) individuals from Chitralada and Red Stirling strains, and 30 individuals from Red Stirling progeny (RR) were used. Five microsatellites loci were utilized: UNH104, UNH108, UNH118, UNH222 e UNH231. Low values of inbreeding were observed with a negative FIS in both strains and their crossings. Genetic differences between the two strains were detected through FST = 0.131 and RST = 0.130. The parental strains Chitralada and Red Stirling presented 24.4% of genetic distance, which produced 23.5% of hybrid vigor in the CH stock

Propylthiouracil-induced cutaneous vasculitis

The use of propylthiouracil (PTU) is associated with the development of different auto-antibodies, amongst them are antineutrophil cytoplasmic antibodies (ANCA) that are involved in the pathogenesis of ANCA associated systemic vasculitis. The case of a 46-years old woman who presented cutaneous vasculitis when taking PTU for Graves' disease is reported. Perinuclear ANCA (p-ANCA) was positive with titer > 1/320, but anti-myeloperoxidase antibodies were not detected. Skin biopsy showed leucocytoclastic vasculitis. The patient improved within ten days after withdrawing PTU and the resolution of hyperthyroidism was achieved with radioiodine (131I). The p-ANCA test remained positive > 1/320 eight months and four years after PTU withdrawal.O uso do propiltiouracil (PTU) está associado ao desenvolvimento de diferentes auto-anticorpos, entre eles anticorpos anticitoplasma de neutrófilos (ANCA), que estão envolvidos na patogênese das vasculites sistêmicas ANCA-associadas (VSAA). Será relatado o caso de um paciente do sexo feminino, de 46 anos, que apresentou vasculite cutânea durante o uso de PTU como terapêutica para doença de Graves. O ANCA com padrão perinuclear (p-ANCA) foi positivo em títulos > 1/320, porém anticorpos antimielo-peroxidase (MPO) não foram detectados. A biópsia de pele revelou uma vasculite leucocitoclástica. Houve melhora clínica em dez dias após a retirada do PTU e optou-se pelo iodo radioativo (I131) para o tratamento do hipertireoidismo. O p-ANCA manteve-se positivo em títulos > 1/320 em duas medidas, realizadas oito meses e quatro anos após a suspensão do PTU.Hospital do Servidor Público Estadual Francisco Morato de OliveiraUniversidade Federal de São Paulo (UNIFESP) Escola Paulista de MedicinaUNIFESP, EPMSciEL

Is serum HMGB1 a biomarker in ANCA-associated vasculitis?

Background: Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) are systemic inflammatory disorders that include granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), Churg-Strauss syndrome and renal limited vasculitis (RLV). Extracellular high-mobility group box 1 (HMGB1) acts as an alarmin and has been shown to be a biomarker of disease activity as well as an autoantigen in systemic lupus erythematosus (SLE) and, possibly, in AAV. This study aims to assess antibodies against HMGB1 and HMGB1 levels as biomarkers for AAV disease activity and predictors of relapsing disease.Methods: AAV patients with active disease and healthy controls (HC) were evaluated for anti-HMGB1 antibodies while serum HMGB1 levels were measured longitudinally in AAV patients at presentation, during remission, prior to and at relapses.Results: HMGB1 levels were similar between AAV patients at presentation (n = 52) and HC (n = 35) (2.64 +/- 1.80 ng/ml vs. 2.39 +/- 1.09 ng/ml; P = 0.422) and no difference regarding HMGB1 levels could be found among AAV disease subsets (GPA: 2.66 +/- 1.83 ng/ml vs. MPA: 3.11 +/- 1.91 ng/ml vs. RLV: 1.92 +/- 1.48 ng/ml; P = 0.369). AAV patients with renal involvement had lower HMGB1 levels than patients without renal involvement at presentation (2.35 +/- 1.48 ng/ml vs. 3.52 +/- 2.41 ng/ml; P = 0.042). A negative correlation was observed between HMGB1 levels and 24-hour proteinuria (rho = -0.361, P = 0.028). Forty-nine AAV patients were evaluated for HMGB1 levels during follow-up and no differences were observed between relapsing and nonrelapsing patients (P = 0.350). No significant increase in HMGB1 levels was observed prior to a relapse compared with the remission period and changes in HMGB1 levels were not associated with an increased risk for relapse in AAV. Positivity for anti-HMGB1 antibodies was low in patients with active AAV (three out of 24 patients).Conclusions: Serum HMGB1 levels at presentation are not increased and are lower in patients with renal involvement. Relapses are not preceded or accompanied by significant rises in HMGB1 levels and changes in HMGB1 levels are not related to ensuing relapses. Anti-HMGB1 antibodies are present in only a few patients in AAV. in contrast to SLE, HMGB1 is not a useful biomarker in AAV.Univ Groningen, Univ Med Ctr Groningen, Dept Rheumatol & Clin Immunol, NL-9713 GZ Groningen, NetherlandsUniversidade Federal de São Paulo, Escola Paulista Med Unifesp EPM, Div Rheumatol, BR-04023900 São Paulo, BrazilUniv Groningen, Univ Med Ctr Groningen, Dept Lab Med, NL-9713 GZ Groningen, NetherlandsUniv Groningen, Univ Med Ctr Groningen, Div Nephrol, Dept Internal Med, NL-9713 GZ Groningen, NetherlandsMartini Hosp, Dept Rheumatol & Internal Med, NL-9728 NT Groningen, NetherlandsUniversidade Federal de São Paulo, Escola Paulista Med Unifesp EPM, Div Rheumatol, BR-04023900 São Paulo, BrazilWeb of Scienc

Immune system - part II: basis of the immunological response mediated by T and B lymphocytes

The immune system consists of an intricate network of organs, cells, and molecules responsible for maintaining the body's homeostasis and responding to aggression in general. Innate immunity operates in conjunction with adaptive immunity and is characterized by rapid response to aggression, regardless of previous stimulus, being the organism first line of defense. Its mechanisms include physical, chemical and biological barriers, cellular components, as well as soluble molecules. The organism first line of defense against tissue damage involves several steps closely integrated and constituted by different components of this system. The aim of this review is to restore the foundations of this response, which has high complexity and consists of several components that converge to articulate the development of adaptive immune response. We selected some of the following steps to review: perception and molecular recognition of aggressive agents; activation of intracellular pathways, which result in vascular and tissue changes; production of a myriad of mediators with local and systemic effects on cell activation and proliferation, synthesis of new products involved in the chemoattraction and migration of cells specialized in destruction and removal of offending agent; and finally, tissue recovery with restoration of functional tissue or organ.O sistema imunológico é constituído por uma intrincada rede de órgãos, células e moléculas, e tem por finalidade manter a homeostase do organismo, combatendo as agressões em geral. A imunidade inata atua em conjunto com a imunidade adaptativa e caracteriza-se pela rápida resposta à agressão, independentemente de estímulo prévio, sendo a primeira linha de defesa do organismo. Seus mecanismos compreendem barreiras físicas, químicas e biológicas, componentes celulares e moléculas solúveis. A primeira defesa do organismo frente a um dano tecidual envolve diversas etapas intimamente integradas e constituídas pelos diferentes componentes desse sistema. A presente revisão tem como objetivo resgatar os fundamentos dessa resposta, que apresenta elevada complexidade e é constituída por diversos componentes articulados que convergem para a elaboração da resposta imune adaptativa. Destacamos algumas etapas: reconhecimento molecular dos agentes agressores; ativação de vias bioquímicas intracelulares que resultam em modificações vasculares e teciduais; produção de uma miríade de mediadores com efeitos locais e sistêmicos no âmbito da ativação e proliferação celulares, síntese de novos produtos envolvidos na quimioatração e migração de células especializadas na destruição e remoção do agente agressor, e finalmente a recuperação tecidual com o restabelecimento funcional do tecido ou órgão.Universidade Federal de São Paulo (UNIFESP)UNIFESPSciEL

Immune system: part III. The delicate balance of the immune system between tolerance and autoimmunity

The immune system consists of an intricate network of organs, cells, and molecules responsible for maintaining the body's homeostasis and responding to aggression in general. Innate immunity operates in conjunction with adaptive immunity and is characterized by rapid response to aggression, regardless of previous stimulus, being the organism first line of defense. Its mechanisms include physical, chemical and biological barriers, cellular components, as well as soluble molecules. The organism first line of defense against tissue damage involves several steps closely integrated and constituted by different components of this system. The aim of this review is to restore the foundations of this response, which has high complexity and consists of several components that converge to articulate the development of adaptive immune response. We selected some of the following steps to review: perception and molecular recognition of aggressive agents; activation of intracellular pathways, which result in vascular and tissue changes; production of a myriad of mediators with local and systemic effects on cell activation and proliferation, synthesis of new products involved in the chemoattraction and migration of cells specialized in destruction and removal of offending agent; and finally, tissue recovery with restoration of functional tissue or organO sistema imunológico é constituído por uma intrincada rede de órgãos, células e moléculas e tem por finalidade manter a homeostase do organismo, combatendo as agressões em geral. A imunidade inata atua em conjunto com a imunidade adaptativa e caracteriza-se pela rápida resposta à agressão, independentemente de estímulo prévio, sendo a primeira linha de defesa do organismo. Seus mecanismos compreendem barreiras físicas, químicas e biológicas, componentes celulares e moléculas solúveis. A primeira defesa do organismo frente a um dano tecidual envolve diversas etapas intimamente integradas e constituídas pelos diferentes componentes desse sistema. A presente revisão tem como objetivo resgatar os fundamentos dessa resposta, que apresenta elevada complexidade e é constituída por diversos componentes articulados que convergem para a elaboração da resposta imune adaptativa. Destacamos algumas etapas: reconhecimento molecular dos agentes agressores; ativação de vias bioquímicas intracelulares que resultam em modificações vasculares e teciduais; produção de uma miríade de mediadores com efeitos locais e sistêmicos no âmbito da ativação e proliferação celulares; síntese de novos produtos envolvidos na quimioatração e migração de células especializadas na destruição e remoção do agente agressor; e finalmente a recuperação tecidual com o restabelecimento funcional do tecido ou órgãoUNIFESPPontifícia Universidade Católica de Goiás cursos de Medicina e BiomedicinaUNIFESPSciEL

Anticuerpos antifosfatidilserina en pacientes con síndrome antifosfolipido primario y en individuos sanos

Objective: To investigate the prevalence of IgM, IgG and IgA anti-phosphatidylserine (aPS) antibodies in patients with primary antiphospholipid syndrome (PAPS) and in healthy controls; to analyze sensitivity, and specificity of aPS antibodies for the diagnosis of APS and finally to assess associations between aPS antibodies with specific APS manifestations. Methods: A cross-sectional study was performed in 36 female PAPS patients and in 200 blood donors. IgM, IgG, and IgA antiphosphatidylserine (aPS) antibodies were tested in PAPS patients and controls using an in house technique and a commercial kit. PAPS patients were also tested for lupus anticoagulant (LAC), IgM and IgG anticardiolipin (aCL) antibodies, and for anti-β2 glycoprotein I (anti-β2GPI) antibodies. Results: The prevalence of IgM, IgG, and IgA aPS antibodies in PAPS patients was as follows: 10.8-16.7%, 32.4-35.7%, and 16.1%, respectively. Although a relatively low sensitivity was found for aPS antibodies in PAPS, the specificity of IgM, IgG, and IgA aPS antibodies for PAPS was 94.7-98.9%, 95.3-96.3%, and 97.9%, respectively. All aPS isotypes were significantly associated with obstetric manifestations of APS. IgM aPS antibodies were associated with an increased risk of venous and arterial thrombosis. IgA aPS antibodies were associated with arterial thrombosis whereas IgG aPS antibodies were associated with an increased risk of venous thrombotic events. IgM and IgG aPS antibodies were frequently found in association with anti-β2GPI antibodies. Conclusions: The prevalence of aPS antibodies is low in PAPS but these antibodies are highly specific for PAPS and are associated with specific PAPS manifestations.Objetivo: Investigar la prevalencia de anticuerpos anti-fosfatidilserina (aFS) de tipo IgM, IgG e IgA en pacientes con síndrome antifosfolípido primario (SAFP) y en controles sanos; analizar la sensibilidad y la especificidad de los anticuerpos aFS para el diagnóstico de aFS y finalmente, evaluar las asociaciones entre los anticuerpos específicos aFS y las manifestaciones clínicas del SAF. Métodos: Estudio transversal de 36 pacientes mujeres con SAFP y 200 donantes de sangre. Se determinaron anticuerpos antifosfatidilserina de tipo IgM, IgG e IgA en pacientes y controles con SAFP utilizando una técnica propia y un kit comercial. A los pacientes com SAFP también se les determinó el anticoagulante lúpico (ACL), los anticuerpos anticardiolipina IgM e IgG (aCL), y los anticuerpos anti-β2 glucoproteína I (anti-β2GPI). Resultados: La prevalencia de los anticuerpos AFS IgM, IgG, IgA en pacientes con SAFP fue la siguiente: 10,8-16,7%, 32,4-35,7%, y 16,1%, respectivamente. Aunque se encontro una sensibilidad relativamente baja para los anticuerpos AFS en el SAFP, la especificidad de los anticuerpos AFS IgM, IgG, IgA para el SAFP fue 94,7-98,9%, 95,3-96,3% y 97,9%, respectivamente. Todos los isotipos de AFS se asociaron significativamente con las manifestaciones obstétricas. Los anticuerpos AFS IgM se asociaron con un riesgo aumentado de trombosis venosa y arterial. Los anticuerpos AFS IgA se asociaron con la trombosis arterial mientras que los anticuerpos AFS IgG se asociaron con un mayor riesgo de eventos trombóticos venosos. Los anticuerpos AFS IgM e IgG se encuentran con frecuencia em asociación con anticuerpos anti-β2GPI. Conclusiones: La prevalencia de anticuerpos AFS es baja en SAFS pero estos anticuerpos son altamente específicos para SAFP y se asocian con manifestaciones SAFP específicos