Comparative Analysis of TNF-alpha, TNF-R1, and TNF-R2 in Patients with Low-impact Fractures Due to Osteoporosis / Análise comparativa de TNF-alfa, TNF-R1 e TNF-R2 em pacientes com fraturas de baixo impacto decorrentes de osteoporose

Abstract Objective To analyze the serum levels of TNF-alpha and its TNF-R1 and TNF-R2 receptors in the blood of patients with low-impact fractures due to osteoporosis, comparing between genders and with healthy patients. Methods The present study was conducted with a blood sample of 62 patients, divided into patients with osteoporosis and healthy patients. The results were obtained using the ELISA method. Cytokine concentrations were determined based on the absorbance values obtained. Results Serum TNF-alpha levels were undetectable in female patients, while in males they were found only in one patient, with no significant difference. Similar results were found in the analyses of TNF-R1 and TNF-R2 levels, a significant increase in levels of TNF-alpha receptors in the groups of patients with osteoporosis compared with the control groupinbothsexes.There wasnosignificant difference between the sexes in the dosage of both receptors within the group with osteoporosis. There was also a positive and significant correlation in the levels of TNF-R1 and TNF-R2 only in women. Conclusion The significant increase in TNF-R1 and TNF-R2 levels in women with osteoporosis suggest that the release and expression of these receptors may be contributing differently to the development of osteoporosis in men and women.

Resumo Objetivo Analisar os níveis séricos de TNF-alfa e de seus receptores TNF-R1 e TNF-R2 no sangue de pacientes com fraturas de baixo impacto, decorrentes de osteoporose, comparando entre os sexos e com pacientes saudáveis. Métodos Oestudofoi realizadocom amostradesanguede 62 pacientes,divididos em pacientes com osteoporose e pacientes saudáveis. Os resultados foram obtidos através do método de ELISA. As concentrações de citocinas foram determinadas com base nos valores de absorbância obtidos. Resultados Os níveis séricos de TNF-alfa foram indetectáveis nos pacientes do sexo feminino, enquanto no masculino encontrou-se somente em um paciente, não havendo diferença significativa. Encontrou-se resultados semelhantes nas análises dos níveis de TNF-R1 e TNF-R2, aumento significativo nos níveis dos receptores de TNF-alfa nos grupos de pacientes com osteoporose em comparação com o grupo controle, em ambos os sexos. Não houve diferença significativa entre os sexos na dosagem de ambos os receptores dentro do grupo com osteoporose. Houve ainda correlação positiva e significativa nos níveis de TNF-R1 e TNF-R2 apenas nas mulheres. Conclusão O aumento significativo nos níveis de TNF-R1 e TNF-R2 em mulheres com osteoporose sugerem que a liberação e expressão destes receptores pode estar contribuindo de maneira distinta no desenvolvimento da osteoporose em homens e mulheres.

Protective effects of Baicalin injection on severe acute pancreatitis through regulating follistatin-like-1 signaling pathway by down-regulating miR-429 expression in mice

Abstract In China, Scutellaria is used for treating inflammatory-related diseases. Baicalin is the main active component of Scutellaria and has protective effects on acute pancreatitis. However, the mechanism of Baicalin is still unclear. In this study, the protective effects of baicalin on acute pancreatitis induced by taurocholate and its mechanism are investigated. In this study, mice were randomly divided into three groups: sham operation, model, and treatment groups. Acute pancreatitis in mice was induced by intraperitoneal injection of taurocholate (35 mg/kg). The treatment group was given baicalin (100 mg/kg) 2 h before acute pancreatitis induction. The mRNA expression levels of miR-429, nuclear factor kappa B65(NF-kB65), toll-like receptor 4(TLR4), TNF receptor associated factor6 (TRAF6), NF-kappa-B inhibitor(IkB), Follistatin-like 1 (FSTL1), and interleukin-1 receptor-associated kinase (IRAK) in the liver tissues 24 h after intraperitoneal injection were detected by RT-PCR. Then, the expression levels of NF-kB65, p-NF-κB65, TLR4, TRAF6, IkB, FSTL1, IRAK, p- IRAK, and p- IkB-а proteins were detected by Western blot. IL-6, TNF-α and IL-1 ß in plasma were measured by ELISA, and histopathological changes in the pancreases of the mice were observed. The results showed that after baicalin treatment, miR-429 expression in the pancreatic tissues and the expression levels of NF-kB65, TLR4, TRAF6, p-IkB-а, FSTL1, and p-IRAK decreased. Similarly, pancreatic myeloperoxidase (MPO) activity and the plasma levels of IL-6, TNF-а, IL-12, IL-1ß1, endotoxin, serum amylase, and lipase were reduced. Thus, the pancreatic injury induced by taurocholate was alleviated. The present study indicates that pretreatment with Baicalin can alleviate acute pancreatic injury induced by taurocholate in mice. The mechanism may be associated with the decreased miR-429 expression, reduced FSTL1 signaling pathway activity, TLR4 and TLR4/MyD88 signaling pathway inhibition, and reduced pancreatic inflammation. FSTL1 is the regulatory target for miR-429

TRAPS, síndrome periódico asociado al receptor de necrosis tumoral: inmunopatogénesis y enfoque clínico / Understanding the immunopathogenic bases and the clinical approach of the periodic syndrome associated with the tumor necrosis receptor, TRAPS

RESUMEN El síndrome periódico asociado al receptor del factor de necrosis tumoral (TRAPS), se caracteriza por episodios de fiebre de más de 10 días de duración, mialgias migratorias, pseudocelulitis, dolor abdominal y edema bipalpebral. Su principal complicación es la amiloidosis y la falla renal producida por el estado inflamatorio crónico. Es una enfermedad autosómica dominante por mutación en el gen TNFRSF1A que codifica el receptor 1 del factor de necrosis tumoral (TNF). En las hipótesis elaboradas para explicar la enfermedad se describen la alteración en la liberación del receptor de TNF mutado, la activación del factor nuclear potenciador de las cadenas ligeras kappa de las células B activadas (NFkB) de forma independiente, las proteínas mal plegadas y alteraciones en el tráfico del receptor mutado, llevando a la acumulación de especies reactivas del oxígeno y defectos en la muerte celular por autofagia y apoptosis. Se han dirigido muchos esfuerzos en descubrir las bases inmunopatogénicas del TRAPS, dificultado por el elevado número de mutaciones encontradas, que se traducen en diferentes mecanismos y formas de presentación de la enfermedad. El tratamiento se basa en el bloqueo del TNF y de la interleuquina-1 (IL-1), la mejor comprensión de la inmunopatogénesis podría permitir un mejor seguimiento de los pacientes y el empleo de otras terapias.

SUMMARY Tumor necrosis factor receptor periodic syndrome (TRAPS) is characterized by episodes of fever of more than 10 days of duration, migratory myalgias, pseudocellulitis, abdominal pain and bipalpebral edema. It´s main complication is amyloidosis and renal failure caused by the chronic inflammatory state. It is an autosomal dominant disease, by mutation in the TNFRSF1A gene encoding tumor necrosis factor (TNF) receptor 1. Among the hypotheses to explain the disease have been proposed the alteration in the release of the mutated TNF receptor; the activation of nuclear factor enhancer of the kappa light chains of independently activated B cells (NFkB); poorly folded proteins, and alterations in the traffic of the mutated receptor. All of them, leading to the accumulation of reactive oxygen species and defects in cell death by autophagy and apoptosis. Many efforts have been directed to discover the immunopathogenic bases of TRAPS, which has been hampered by the high number of mutations found, which translate different mechanisms and forms of presentation of the disease. The treatment is based on the blockade of TNF and interleukin-1 (IL-1). The better understanding of immunopathogenesis could allow better monitoring of patients and the use of other therapies.

Inflammatory biomarkers responses after acute whole body vibration in fibromyalgia

The aims of this study were 1) to characterize the intensity of the vibration stimulation in women diagnosed with fibromyalgia (FM) compared to a control group of healthy women (HW) matched by age and anthropometric parameters, and 2) to investigate the effect of a single session of whole body vibration (WBV) on inflammatory responses. Levels of adipokines, soluble tumor necrosis factor receptors (sTNFr1, sTNFr2), and brain-derived neurotrophic factor (BDNF) were determined by enzyme-linked immunosorbent assay. Oxygen consumption (VO2) was estimated by a portable gas analysis system, heart rate (HR) was measured using a HR monitor, and perceived exertion (RPE) was evaluated using the Borg scale of perceived exertion. Acutely mild WBV increased VO2 and HR similarly in both groups. There was an interaction (disease vs vibration) in RPE (P=0.0078), showing a higher RPE in FM compared to HW at rest, which further increased in FM after acute WBV, whereas it remained unchanged in HW. In addition, there was an interaction (disease vs vibration) in plasma levels of adiponectin (P=0.0001), sTNFR1 (P=0.000001), sTNFR2 (P=0.0052), leptin (P=0.0007), resistin (P=0.0166), and BDNF (P=0.0179). In conclusion, a single acute session of mild and short WBV can improve the inflammatory status in patients with FM, reaching values close to those of matched HW at their basal status. The neuroendocrine mechanism seems to be an exercise-induced modulation towards greater adaptation to stress response in these patients.

Incidence of tuberculosis among patients with rheumatoid arthritis using TNF blockers in Brazil: data from the Brazilian Registry of Biological Therapies in Rheumatic Diseases (Registro Brasileiro de Monitoração de Terapias Biológicas - BiobadaBrasil) / Incidência de tuberculose em pacientes com artrite reumatoide em uso de bloqueadores do TNF no Brasil: dados do Registro Brasileiro de Monitoração de Terapias Biológicas BiobadaBrasil

Abstract Objectives To assess the incidence of tuberculosis and to screen for latent tuberculosis infection among Brazilians with rheumatoid arthritis using biologics in clinical practice. Patients and methods This cohort study used data from the Brazilian Registry of Biological Therapies in Rheumatic Diseases (Registro Brasileiro de Monitoração de Terapias Biológicas - BiobadaBrasil), from 01/2009 to 05/2013, encompassing 1552 treatments, including 415 with only synthetic disease-modifying anti-rheumatic drugs, 942 synthetic DMARDs combined with anti-tumor necrosis factor (etanercept, infliximab, adalimumab) and 195 synthetic DMARDs combined with other biologics (abatacept, rituximab and tocilizumab). The occurrence of tuberculosis and the drug exposure time were assessed, and screening for tuberculosis was performed. Statistical analysis: Unpaired t-test and Fisher's two-tailed test; p < 0.05. Results The exposure times were 981 patient-years in the controls, 1744 patient-years in the anti-TNF group (adalimumab = 676, infliximab = 547 and etanercept = 521 patient-years) and 336 patient-years in the other biologics group. The incidence rates of tuberculosis were 1.01/1000 patient-years in the controls and 2.87 patient-years among anti-TNF users (adalimumab = 4.43/1000 patient-years; etanercept = 1.92/1000 patient-years and infliximab = 1.82/1000 patient-years). No cases of tuberculosis occurred in the other biologics group. The mean drug exposure time until the occurrence of tuberculosis was 27(11) months for the anti-TNF group. Conclusions The incidence of tuberculosis was higher among users of synthetic DMARDs and anti-TNF than among users of synthetic DMARDs and synthetic DMARDs and non-anti-TNF biologics and also occurred later, suggesting infection during treatment and no screening failure.

Resumo Objetivos Avaliar incidência de tuberculose e triagem para tuberculose latente em brasileiros com artrite reumatoide em uso de agentes biológicos na prática clinica. Pacientes e métodos Estudo de coorte com dados do Registro Brasileiro de Monitoração de Terapias Biológicas (BiobadaBrasil), de 01/2009 a 05/2013, abrangeu 1.552 tratamentos, 415 somente com drogas modificadoras do curso da doença (MMCDs) sintéticas, 942 MMCDs sintéticas em associação com anti-TNF (etanercepte, infliximabe, adalimumabe) e 195 MMCDs sintéticas em associação com outros biológicos (abatacepte, rituximabe e tocilizumabe). Avaliaram-se ocorrência de tuberculose, tempo de exposição às drogas e triagem para TB. Análise estatística: teste t não pareado e teste de Fisher bicaudal; p < 0,05. Resultados O tempo de exposição dos controles foi de 981 pacientes-ano, do grupo de anti-TNF foi de 1.744 pacientes-ano (adalimumabe = 676, infliximabe = 547 e etanercepte = 521 pacientes-ano) e o de outros biológicos de 336 pacientes-ano. A incidência de TB foi de 1,01/1.000 pacientes-ano nos controles e de 2,87 pacientes-ano nos usuários de anti-TNF (adalimumabe = 4,43/1.000 pacientes-ano; etanercepte = 1,92/1.000 pacientes-ano e infliximabe = 1,82/1.000 pacientes-ano). Não houve casos de tuberculose no grupo de outros biológicos. O tempo médio de exposição até a ocorrência de tuberculose foi de 27(11) meses para o grupo anti-TNF. Conclusões A incidência de tuberculose foi maior nos usuários de MMCDs sintéticas e anti-TNF do que nos usuários de MMCDs sintéticas e de MMCDs sintéticas e biológicos não anti-TNF, e também mais tardia, sugerindo infecção durante o tratamento, e não falha na triagem.

Inflammation and oxidative stress in heart failure: effects of exercise intensity and duration

Although acute exercise is apparently pro-inflammatory and increases oxidative stress, it can promote the necessary stress stimulus to train chronic adaptations in patients with chronic heart failure (CHF). This study aimed to compare the effects of exercise intensity and duration on the inflammatory markers soluble tumor necrosis factor receptor (sTNFR1) and interleukin-6 (IL-6), and on oxidative stress [malondialdehyde (MDA) and antioxidant enzymes: catalase (CAT) and superoxide dismutase (SOD)] in individuals with CHF. Eighteen patients performed three exercise sessions: 30 min of moderate-intensity (M30) exercise, 30 min of low-intensity (L30) exercise, and 45 min of low-intensity (L45) exercise. Blood analysis was performed before exercise (baseline), immediately after each session (after), and 1 h after the end of each session (1h after). Thirty min of M30 exercise promoted a larger stressor stimulus, both pro-inflammatory and pro-oxidative, than that promoted by exercises L30 and L45. This was evidenced by increased sTNFR1 and MDA levels after exercise M30. In response to this stressor stimulus, 1 h after exercise, there was an increase in IL-6 and CAT levels, and a return of sTNFR1 to baseline levels. These findings suggest that compared with the duration of exercise, the exercise intensity was an important factor of physiologic adjustments.

Associated clinical and laboratory markers of donor on allograft function after heart transplant

Abstract Introduction: Primary graft dysfunction is a major cause of mortality after heart transplantation. Objective: To evaluate correlations between donor-related clinical/biochemical markers and the occurrence of primary graft dysfunction/clinical outcomes of recipients within 30 days of transplant. Methods: The prospective study involved 43 donor/recipient pairs. Data collected from donors included demographic and echocardiographic information, noradrenaline administration rates and concentrations of soluble tumor necrosis factor receptors (sTNFR1 and sTNFR2), interleukins (IL-6 and IL-10), monocyte chemoattractant protein-1, C-reactive protein and cardiac troponin I. Data collected from recipients included operating, cardiopulmonary bypass, intensive care unit and hospitalization times, inotrope administration and left/right ventricular function through echocardiography. Results: Recipients who developed moderate/severe left ventricular dysfunction had received organs from significantly older donors (P =0.020). Recipients from donors who required moderate/high doses of noradrenaline (>0.23 µg/kg/min) around harvesting time exhibited lower post-transplant ventricular ejection fractions (P =0.002) and required longer CPB times (P =0.039). Significantly higher concentrations of sTNFR1 (P =0.014) and sTNFR2 (P =0.030) in donors were associated with reduced intensive care unit times (≤5 days) in recipients, while higher donor IL-6 (P =0.029) and IL-10 (P =0.037) levels were correlated with reduced hospitalization times (≤25 days) in recipients. Recipients who required moderate/high levels of noradrenaline for weaning off cardiopulmonary bypass were associated with lower donor concentrations of sTNFR2 (P =0.028) and IL-6 (P =0.001). Conclusion: High levels of sTNFR1, sTNFR2, IL-6 and IL-10 in donors were associated with enhanced evolution in recipients. Allografts from older donors, or from those treated with noradrenaline doses >0.23 µg/kg/min, were more frequently affected by primary graft dysfunction within 30 days of surgery.

Indirect and direct costs of treating patients with ankylosing spondylitis in the Brazilian public health system / Custos diretos e indiretos do tratamento de pacientes com espondilite anquilosante pelo sistema público de saúde brasileiro

ABSTRACT Introduction: Patients with Ankylosing Spondylitis (AS) require a team approach from multiple professionals, various treatment modalities for continuous periods of time, and can lead to the loss of labour capacity in a young population. So, it is necessary to measure its socio-economic impact. Objectives: To describe the use of public resources to treat AS in a tertiary hospital after the use of biological medications was approved for treating spondyloarthritis in the Health Public System, establishing approximate values for the direct and indirect costs of treating this illness in Brazil. Material and methods: 93 patients selected from the ambulatory spondyloarthritis clinic at the Hospital de Clínicas of the Federal University of Paraná between September 2011 and September 2012 had their direct costs indirect treatment costs estimation. Results: 70 patients (75.28%) were male and 23 (24.72%) female. The mean age was 43.95 years. The disease duration was calculated based on the age of diagnosis and the mean was 8.92 years (standard deviation: 7.32); 63.44% were using anti-TNF drugs. Comparing male and female patients the mean BASDAI was 4.64 and 5.49 while the mean BASFI was 5.03 and 6.35 respectively. Conclusions: The Brazilian public health system's spending related to ankylosing spondylitis has increased in recent years. An important part of these costs is due to the introduction of new, more expensive health technologies, as in the case of nuclear magnetic resonance and, mainly, the incorporation of anti-TNF therapy into the therapeutic arsenal. The mean annual direct and indirect cost to the Brazilian public health system to treat a patient with ankylosing spondylitis, according to our findings, is US$ 23,183.56.

RESUMO Introdução: Os pacientes com espondilite anquilosante (EA) exigem uma abordagem de equipe com vários profissionais e várias modalidades de tratamento, continuamente; além disso, a doença pode levar à perda da capacidade de trabalho em uma população jovem, de modo que é necessário medir o seu impacto socioeconômico. Objetivos: Descrever o uso de recursos públicos para o tratamento da EA em um hospital terciário após o uso dos fármacos biológicos ter sido aprovado para o tratamento das espondiloartrites pelo Sistema Público de Saúde e estabelecer valores aproximados para os custos diretos e indiretos do tratamento dessa doença no Brasil. Material e métodos: Foram estimados os custos de tratamento diretos e indiretos de 93 pacientes com EA do ambulatório de espondiloartrite do Hospital de Clínicas da Universidade Federal do Paraná, entre setembro de 2011 e setembro 2012. Resultados: Dos pacientes, 70 (75,28%) eram do sexo masculino e 23 (24,72%) do feminino. A idade média foi de 43,95 anos. A duração da doença foi calculada com base na idade do diagnóstico e a média foi de 8,92 anos (desvio padrão: 7,32); 63,44% dos indivíduos usavam fármacos anti-TNF. Na comparação dos pacientes dos sexos masculino e feminino, a média no Bath Ankylosing Spondylitis Disease Activity Index (Basdai) foi de 4,64 e 5,49, enquanto a média no Bath Ankylosing Spondylitis Functional Index (Basfi) foi de 5,03 e 6,35, respectivamente. Conclusões: Os gastos do sistema público de saúde brasileiro relacionados com a espondilite anquilosante aumentaram nos últimos anos. Uma parte importante desses custos deve-se à introdução das novas tecnologias de saúde, mais dispendiosas, como no caso da ressonância nuclear magnética e, principalmente, da incorporação da terapia anti-TNF ao arsenal terapêutico. O custo médio anual direto e indireto do sistema público de saúde brasileiro para tratar de um paciente com espondilite anquilosante, de acordo com os resultados deste estudo, é de US$ 23.183,56.

Depression as a Clinical Determinant of Dependence and Low Quality of Life in Elderly Patients with Cardiovascular Disease / Depressão como Determinante Clínico de Dependência e Baixa Qualidade de Vida em Idosos Cardiopatas

Background: The aging process promotes a progressive increase in chronic-degenerative diseases. The effect of these diseases on the functional capacity has been well recognized. Another health parameter concerns “quality of life related to health”. Among the elderly population, cardiovascular diseases stand out due to the epidemiological and clinical impact. Usually, these diseases have been associated with others. This set of problems may compromise both independence and quality of life in elderly patients who seek cardiologic treatment. These health parameters have not been well contemplated by cardiologists. Objective: Evaluating, among the elderly population with cardiovascular disease, which are the most relevant clinical determinants regarding dependence and quality of life. Methods: This group was randomly and consecutively selected and four questionnaires were applied: HAQ, SF-36, PRIME-MD e Mini Mental State. Results: The study included 1,020 elderly patients, 63.3% women. The group had been between 60 and 97 years-old (mean: 75.56 ± 6.62 years-old). 61.4% were independent or mild dependence. The quality of life total score was high (HAQ: 88.66 ± 2.68). 87.8% of patients had a SF-36 total score > 66. In the multivariate analysis, the association between diagnoses and high degrees of dependence was significant only for previous stroke (p = 0.014), obesity (p < 0.001), lack of physical activity (p = 0.016), osteoarthritis (p < 0.001), cognitive impairment (p < 0.001), and major depression (p < 0.001). Analyzing the quality of life, major depression and physical illness for depression was significantly associated with all domains of the SF-36. Conclusion: Among an elderly outpatient cardiology population, dependence and quality of life clinical determinants are not cardiovascular comorbidities, especially the depression. .

Fundamento: Com o envelhecimento, a prevalência de doenças crônico-degenerativas sofreu aumento progressivo. A repercussão dessas doenças sobre a capacidade funcional foi reconhecida. Outro parâmetro de saúde é a “qualidade de vida relacionada à saúde”. Na população idosa, as doenças cardiovasculares destacam-se pelo impacto epidemiológico e clínico. Elas, geralmente, vêm associadas a outras afecções. Esse conjunto de problemas pode comprometer a independência e a qualidade de vida do idoso que busca tratamento cardiológico. Objetivo: Avaliar, em uma população de idosos cardiopatas, quais são os determinantes clínicos mais relevantes de dependência e de qualidade de vida. Métodos: O grupo foi selecionado aleatória e consecutivamente, sendo aplicados quatro questionários: HAQ, SF-36, PRIME‑MD e Mini Exame do Estado Mental. Resultados: Incluiu-se 1020 idosos, 63,3% mulheres. O grupo tinha em média 75,56 ± 6,62 anos. 61,4% mostrou-se independente ou com dependência leve. O escore de qualidade de vida foi elevado (HAQ: 88,66 ± 2,68). 87,8% dos pacientes apresentou escore total do SF-36 ≥ 66. À análise multivariada, a associação entre os diagnósticos e graus elevados de dependência foi significante apenas para acidente vascular cerebral prévio (p = 0,014), obesidade (p < 0,001), sedentarismo (p = 0,016), osteoartrite (p < 0,001), déficit cognitivo (p < 0,001), e depressão maior (p < 0,001). Ao analisarmos a qualidade de vida, a depressão maior e a depressão por doença física associou-se significativamente com todos os domínios do SF-36. Conclusão: Em uma população de idosos cardiopatas, os determinantes clínicos mais relevantes de prejuízos para dependência e qualidade de vida foram as comorbidades não cardiovasculares, particularmente a depressão. .

Expression of lymphatic markers and lymphatic growth factors in psoriasis before and after anti-TNF treatment

BACKGROUND: Angiogenesis is an early stage of psoriatic lesion development, but less is known about lymphagiogenesis and its role in the development of psoriasis. OBJECTIVE: To examine the expression of specific lymphatic markers and lymphatic growth factors in untreated psoriatic skin, in the unaffected skin of patients and skin of healthy volunteers, as well as their alteration after treatment with an anti-TNF agent. METHODS: Immunohistochemistry for the lymphatic markers D2-40 and LYVE-1, in addition to the VEGF-C and VEGF-D growth factors, was performed in the skin biopsies of psoriatic lesions and adjacent non-psoriatic skin of 19 patients before and after treatment with etanercept, as well as in the skin biopsies of 10 healthy volunteers. RESULTS: The expressions of D2-40, VEGF-C and VEGF-D on lymphatic vessels underwent statistically significant increases in untreated psoriatic skin compared with non-lesional skin, in contrast to LYVE-1, which did not involve significant increase in expression in psoriatic skin. VEGF-C expression on lymphatic vessels diminished after treatment with etanercept. Moreover VEGF-C and VEGF-D staining on fibroblasts presented with higher expression in lesional skin than in non-lesional adjacent skin. CONCLUSION: Remodeling of lymphatic vessels possibly occurs during psoriatic lesion development, parallel to blood vessel formation. The exact role of this alteration is not yet clear and more studies are necessary to confirm these results. .

Two cases of renal cell cancer during immunobiologic therapy for psoriasis

Immunobiologic therapy is indicated for severe forms of psoriasis, resistant to conventional therapy. There is growing concern about their safety profile and possible association with cancer development. This article documents two cases of renal cell cancer during treatment with biologic therapy, reviewing what is described in the literature . The risk of solid tumors as a complication of using TNF-alpha inhibitors is controversial. No conclusion can be drawn from the data in the literature, however, we believe that special attention should be given to those with known risk factors for a specific neoplasm.

Anti-TNFα therapy in the management of psoriasis: experience of a state referral center

BACKGROUND: Psoriasis is a chronic immune-mediated disease, characterized by increased levels of TNFα. Anti-TNFα agents have revolutionized the treatment of severe psoriasis by targeting an important molecule involved in its pathogenesis. OBJECTIVES: We report the experience of a state referral center that uses anti-TNFα agents for psoriasis. METHODS: We conducted a retrospective case series. Seventy-four out of 120 patients met the inclusion criteria. Clinical and laboratory data was analyzed using the chi-squared, Wicoxon and McNemar's tests. Associations were considered statistically significant when p-value<0.05. RESULTS: Forty-one subjects (55.40%) were male, with a mean age of 47.69±14.99 years. Median disease duration and pre-treatment PASI were 14.0 months (IQR 9.0-20.0), and 13.55 points (IQR 8.5-20.32). Sixty patients (81.10%) had arthropathic psoriasis. Forty-six subjects (62.20%) had comorbidities; the most frequent was dyslipidemia (25.70%). In 55.40% of patients, insufficient response to conventional therapies was the principal indication for using anti-TNFα drugs. Clinical improvement occurred in 93.20% of cases, and the post-treatment PASI median was 0.0 points (IQR 0.0-0.0). Adverse effects occurred in 6.80% of patients. Infections and elevation of transaminases occurred in 28.40% and 8.10% of cases, respectively. CONCLUSION: Post-treatment reduction in PASI was satisfactory and the occurrence of adverse effects was minor, mostly mild infusion effects and local reactions at drug administration sites. .

Systemic sarcoidosis induced by etanercept: first Brazilian case report / Sarcoidose sistemica induzida por etanercepte: primeiro relato de caso brasileiro

The antagonists of tumor necrosis factor alpha (TNF-α) are increasingly being used in the treatment of inflammatory and autoimmune diseases. Several adverse effects of these drugs have been reported, including the paradoxical development of sarcoidosis, especially with the use of etanercept. We present the first Brazilian case report of systemic sarcoidosis induced by etanercept and a literature review.

Os medicamentos antagonistas do fator de necrose tumoral alfa (TNF-α) estão sendo cada vez mais utilizados no tratamento de doenças inflamatórias e autoimunes. Efeitos adversos desses medicamentos vem sendo relatados, incluindo o desenvolvimento paradoxal de sarcoidose, principalmente com o uso do etanercepte. Apresentamos o primeiro relato de caso brasileiro de sarcoidose sistêmica induzida por etanercepte e uma revisão da literatura.

O etanercepte induz QRS de baixa tensão e disfunção autonômica em camundongos com doença de Chagas experimental / Etanercept induces low QRS voltage and autonomic dysfunction in mice with experimental Chagas disease

FUNDAMENTO: A doença de Chagas é uma doença parasitária tropical causada pelo protozoário flagelado Trypanosoma cruzi. A cardiomiopatia chagásica é caracterizada por distúrbios na regulação autonômica e na condução do potencial de ação nas fases aguda e crônica da infecção. Embora o fator de necrose tumoral alfa (TNF-α) tenha sido associadoà cardiomiopatia em modelos experimentais e em pacientes com doença de Chagas, outros relatos sugerem que o TNF-α pode exercer ações antiparasitárias durante a fase aguda da infecção. OBJETIVOS: Este estudo teve como objetivo determinar os efeitos de um blocker TNF-α solúvel, o etanercepte, em parâmetros eletrocardiográficos na fase aguda da infecção experimental com Trypanosoma cruzi. MÉTODOS: Foram feitos eletrocardiogramas em camundongos infectados não tratados e camundongos infectados que foram tratados com etanercepte 7 dias após a infecção. Os parâmetros de variabilidade onda do eletrocardiograma e frequência cardíaca foram determinados utilizando o Chart para Windows. RESULTADOS: O tratamento com etanercepte resultou em uma baixa tensão do complexo QRS e uma redução da variabilidade da frequência cardíaca em comparação com a ausência de tratamento. No entanto, os camundongos tratados apresentaram um atraso na queda da curva de sobrevivência durante a fase aguda. CONCLUSÃO: Os resultados deste estudo sugerem que, embora o tratamento com etanercepte promova a sobrevivência em camundongos infectados com uma linhagem virulenta de T. cruzi, o bloqueio do TNF-α gera um complexo de baixa tensão e disfunção autonômica durante a fase aguda da infecção. Esses resultados indicam que a mortalidade durante a fase aguda pode ser atribuída a uma resposta inflamatória sistêmica, em vez da disfunção cardíaca.

BACKGROUND: Chagas disease is a tropical parasitic disease caused by the flagellate protozoan Trypanosoma cruzi. Chagasic cardiomyopathy is characterized by disorders of autonomic regulation and action potential conduction in the acute and chronic phases of infection. Although tumor necrosis factor alpha (TNF-α) has been linked to cardiomyopathy in experimental models and in patients with Chagas disease, other reports suggest that TNF-α may exert anti-parasitic actions during the acute phase of infection. OBJECTIVES: This study aimed to determine the effects of a soluble TNF-α agonist, etanercept, on electrocardiographic parameters in the acute phase of experimental infection with Trypanosoma cruzi. METHODS: Electrocardiograms were obtained from untreated infected mice and infected mice who were treated with etanercept 7 days after infection. ECG wave and heart rate variability parameters were determined using Chart for Windows. RESULTS: Etanercept treatment resulted in a low QRS voltage and decreased heart rate variability compared with no treatment. However, the treated mice exhibited a delay in the fall of the survival curve during the acute phase. CONCLUSION: The results of this study suggest that although etanercept treatment promotes survival in mice infected with a virulent T. cruzi strain, TNF-α blockade generates a low voltage complex and autonomic dysfunction during the acute phase of infection. These findings indicate that mortality during the acute phase can be attributed to a systemic inflammatory response rather than cardiac dysfunction.).

Perfil dos usuários de anticitocinas disponibilizadas pelo Sistema Único de Saúde no estado do Paraná para o tratamento da artrite reumatoide / Profile of users of anticytokines off ered by the health care system in the state of Paraná for the treatment of rheumatoid arthritis

INTRODUÇÃO: O tratamento da artrite reumatoide (AR) no âmbito do Sistema Único de Saúde (SUS) tem financiamento do Ministério da Saúde e cofinanciamento das Secretarias Estaduais. O Protocolo Clínico e Diretrizes Terapêuticas (PCDT) para o tratamento da AR descreve o esquema terapêutico para a patologia, inclusive com as anticitocinas adalimumabe, etanercepte ou infliximabe. OBJETIVO: Traçar o perfil dos usuários de anticitocinas, medicamentos biológicos cadastrados no Sistema de Informação do Componente Especializado da Assistência Farmacêutica, gerenciado pelo Centro de Medicamentos do Paraná. MÉTODOS: Foi realizado um estudo transversal tomando como referência o mês de março de 2010. Com base em dados de dispensação, foram coletadas informações relativas a idade, gênero, regional de saúde (RS), Código Internacional de Doenças (CID) e medicamento dispensado. Calculou-se também o custo mensal com anticitocinas para o SUS. RESULTADOS: No estado do Paraná foram encontrados 923 pacientes recebendo anticitocinas, dos quais 40 por cento recebiam adalimumabe, 44 por cento etanercepte e 16 por cento infliximabe, gerando um custo mensal de R$3.403.195,59. Com relação ao CID, 55 por cento dos indivíduos apresentavam CID M05.8, 27 por cento CID M06.0, 9 por cento CID M6.8, 8 por cento CID M5.0 e 1 por cento dos indivíduos apresentava os outros CIDs relacionados com a doença. As RS do Paraná com o maior número de indivíduos em tratamento com anticitocinas foram as de Ponta Grossa, Cornélio Procópio, Londrina, Cianorte, Maringá, Irati e Campo Mourão. CONCLUSÃO: Por meio deste estudo foi possível verificar a distribuição e o perfil dos usuários de anticitocinas para o tratamento da AR no Paraná no âmbito do SUS no mês de março de 2010.

INTRODUCTION: The Brazilian Unified Health Care System (SUS) offers treatment for patients with RA through federal funding (Ministry of Health) and state co-financing. The Clinical Protocol and Therapeutic Guidelines for the treatment of rheumatoid arthritis describe the therapeutic regimen for the disease, including the anticytokines adalimumab, etanercept or infliximab. OBJECTIVES: The aim of this study was to evaluate the profile of registered users of those anticytokines, biologics registered in the Information System of the Pharmaceutical Assistance Specialized Division, managed by the Paraná State Drug Center. METHODS: A cross-sectional study regarding data from March 2010 was conducted. Based on dispensation data, information regarding the following variables were collected: age; gender; regional health care centers; International Classification of Diseases (ICD); and drug dispensed. In addition, the monthly cost with anticytokines for the SUS was calculated. RESULTS: In the state of Paraná, 923 patients on anticytokines were identified, 40 percent, 44 percent and 16 percent of whom receiving adalimumab, etanercept and infliximab, respectively. This generated a monthly cost of R$3,403,195.59. Regarding the ICD, the distribution of patients was as follows: 55 percent had ICD M05.8; 27 percent, ICD M06.0; 9 percent, ICD M6.8; 8 percent, ICD M5.0; and 1 percent had other ICDs related to the disease. The regional health care centers of the state of Paraná with the largest number of patients on anticytokines were in the following municipalities: Ponta Grossa; Cornélio Procópio; Londrina; Cianorte; Maringá; Irati; and Campo Mourão. CONCLUSION: This study assessed the distribution and profile of users of anticytokines for the rheumatoid arthritis treatment covered by the SUS in the state of Paraná, in March 2010.

Severe cutaneous and arthritic psoriasis in patient with Aids: a good outcome with therapy using etanercept / Psoríase cutânea e artropática grave em paciente com Aids: boa resposta terapêutica com uso de terapia com etanercepte

We report the case of a patient with cutaneous and arthropathic psoriasis for eight years, whose sudden increased severity of the clinical picture led to a diagnosis of AIDS, emphasizing the importance of the specialist in the diagnosis of systemic diseases. The appropriate therapeutic interventions, including antiretroviral therapy and the immunobiological agent etanercept, enabled rapid improvement of symptoms and quality of life of the patient, besides contributing to delay in immunodeficiency progression.

Relata-se o caso de um paciente com psoríase cutânea e artropática há oito anos, cujo agravamento súbito do quadro clínico levou ao diagnóstico da Aids, ressaltando a importância do especialista no diagnóstico de doenças sistêmicas. A intervenção terapêutica apropriada, incluindo a terapia antirretroviral e agente imunobiológico - etanercepte - possibilitou a rápida melhora do quadro clínico e da qualidade de vida do paciente, além de contribuir para o retardo na progressão da imunodeficiência.

Psoriasis, lymphoma and etanercept: is there a correlation? / Psoríase, linfoma e etanercepte: existe correlação?

Psoriasis is a chronic inflammatory disease that can affect skin and joints. Their treatment varies depending on the severity and includes topical and systemic. Among the latter are the immunobiological that target the T cell We report a case that demonstrates the close relationship between psoriasis, lymphoma and biologic therapies.

A psoríase é uma doença inflamatória crônica que pode afetar a pele e as articulações. Seu tratamento varia conforme a gravidade e inclui medicamentos tópicos e sistêmicos. Dentre os últimos estão os imunobiológicos, que têm como alvo a célula T. Relatamos um caso que demonstra a estreita relação entre a psoríase, o linfoma e os imunobiológicos.

Leucopenia e trombocitopenia induzidas por etanercepte: relato de dois casos e revisão da literatura / Leukopenia and thrombocytopenia induced by etanercept: two case reports and literature review

O fator de necrose tumoral alfa (TNF-alfa) é uma citocina pró-inflamatória, e seu excesso pode levar a sérias consequências. Esses efeitos são conhecidos por serem antagonizados por inibidores da atividade do TNF-alfa. O etanercepte é uma proteína de fusão que inibe a ação do TNF-alfa. Como a regulação do TNF-alfa está relacionada à diferenciação celular de várias células envolvidas na resposta imunológica por meio da expressão de várias outras citocinas, é possível que o uso de inibidores dessa citocina possa causar citopenia. Relatamos dois casos de bicitopenia induzidos por etanercepte. Em ambos os casos houve melhora clínica do quadro após a retirada da medicação. Discutimos a necessidade da introdução de testes laboratoriais de rotina em pacientes que usam terapia anti-TNF, para identificar possíveis alterações hematológicas.

Tumor necrosis factor-alpha (TNF-alpha) is a proinflammatory cytokine, and its excess can lead to severe consequences. Those effects are known to be antagonized by TNF-alpha inhibitors. Etanercept is a fusion protein that inhibits TNF-alpha action. As TNF-alpha regulation is related to cellular differentiation of various cellular types involved in immune response through expression of several other cytokines, it is possible that the use of its inhibitors may cause cytopenia. We report two cases of bicytopenia induced by etanercept. Both cases recovered after drug withdrawal. We discuss the need of introduction of routine laboratorial tests in patients using anti-TNF therapy, in order to identify possible hematological changes.

Efectividad y seguridad de terapia biológica en pacientes con artritis idiopática juvenil del Hospital san Juan de Dios (HSJD) durante 2008-2012 / Effectiveness and safety of biological therapy in patients with juvenile idiopathic arthritis at San Juan de Dios Hospital (HSJD) during 2008-2012

Introducción: La artritis idiopática juvenil (AIJ) es la enfermedad reumatológica más prevalente en la infancia y en Chile es incorporada al GES en 2010, permitiendo el acceso a terapia biológica. Materiales y métodos: Estudio retrospectivo de pacientes con AIJ refractarios a terapia habitual que iniciaron terapia biológica en el HSJD desde 2008. Se revisaron las fichas clínicas de todos los pacientes, se evaluó la mejoría clínica alcanzada mediante el índice ACR30/50 (American College of Rheumatology) y efectos adversos previo y posterior al uso de biológicos. Resultados: Han recibido terapia biológica 14 pacientes desde 2008, 76 por ciento mujeres. La edad promedio de inicio de la enfermedad fue de 7,8 años, con una duración promedio de la enfermedad de 5,9 meses al diagnóstico. Todos recibieron etanercept. El 71 por ciento recibió etanercept antes de los cinco años del diagnóstico y el 86 por ciento tenía más de 10 años. El 50 por ciento presentaba AIJ de tipo poliarticular, 36 por ciento asociada a entesitis, 5 por ciento sistémica y 5 por ciento indiferenciada. Primero recibieron tratamiento con metotrexato, sulfasalazina, corticoides y/o AINE. Se consignaron 37 reacciones adversas a fármacos (54 por ciento infecciones virales, 41 por ciento bacterianas, 5 por ciento hepatotoxicidad). Durante el uso de terapia biológica ocurrieron 27 reacciones adversas (56 por ciento infecciones bacterianas, 44 por ciento virales). La incidencia de reacciones adversas con uso exclusivo de DMARD fue de 0,0698 mensual y en tratamiento combinado de biológicos con DMARD (en menor dosis) fue de 0,0683 (sin diferencias significativas). Un 69 por ciento y 82 por ciento de los pacientes lograron un índice de ACR30 a los seis y 12 meses de terapia, respectivamente, y ACR50, 62 por ciento y 73 por ciento, respectivamente. Conclusión: La terapia biológica fue efectiva y segura en la mayoría de los pacientes, comparable a lo reportado a nivel internacional.

Introduction: Juvenile idiopathic arthritis (JIA) is the most prevalent rheumatic disease in childhood and in Chile is included in the GES program since 2010, allowing access to biological therapy. Materials and methods: Is a retrospective study of patients with JIA refractory to standard therapy, who initiated biologic therapy in HSJD since 2008. We reviewed the medical data of all patients, clinical improvement was evaluated using the ACR30/50 (American College of Rheumatology) index and adverse effects before and after the use of biologics. Results: 14 patients received biological therapy since 2008, 76 percent female. The average age of disease onset was 7.8 years with a mean disease duration of 5.9 years at diagnosis. All received etanercept. 71 percent received it before 5 years of diagnosis and 86 percent had more than 10 years of diagnosis. 50 percent ad polyarticular JIA, 36 percent associated with enthesitis, 5 percent systemic JIA and 5 percent undifferentiated JIA. First they all received treatment with methotrexate, sulfasalazine, corticosteroids and/or NSAIDs. 37 had adverse drug reactions (95 percent viral or bacterial infections and 5 percent hepatotoxicity). During biologically therapy adverse reactions occurred 27 times (56 percent bacterial, 44 percent viral). The incidence of monthly adverse reactions only with DMARDs was 0.0698 and in the combined therapy (biological plus DMARDs at lower doses) was 0.0683 (no significant difference). 69 percent and 82 percent of patients achieved the ACR30 at 6 and 12 months of therapy respectively and 62 percent and 73 percent achieved ACR50 respectively. Conclusion: Biologic therapy was safe and effective in most patients, comparable to the worldwide reports.

Psoríase pustulosa palmoplantar tratada com etanercepte: relato de caso / Palmoplantar pustular psoriasis treated with etanercept

Contexto: A psoríase pustulosa palmoplantar (PPPP) é uma das apresentações clínicas da psoríase, muitas vezes de difícil tratamento, podendo-se utilizar diversos medicamentos tópicos e sistêmicos. O uso dos anti-TNFα no tratamento das formas pustulosas de psoríase é controverso, visto que a resposta clínica é variável, além desta classe de medicação biológica poder desencadear psoríase pustulosa. Descrição do Caso: Doente feminina, 60 anos, branca, com diagnóstico de PPPP há 12 anos e artrite psoriásica há seis anos. Antecedentes pessoais relevantes: hipertensão arterial sistêmica, hipertrigliceridemia e obesidade. Apresentou refratariedade tanto aos tratamentos tópicos instituídos (corticóides e emolientes) quanto aos sistêmicos (metotrexate, dapsona, colchinina e acitretina), tendo evoluído com excelente resposta terapêutica com etanercepte (administrado semanalmente, por via subcutânea, na dose de 50 mg). Discussão: Os anti-TNFα são eficazes no tratamento da psoríase em placas moderada a grave.Mas, o tratamento da PPPP com anti-TNFα não é classicamente preconizado. Segundo a literatura a resposta terapêutica com este tipo de medicamento é variável na PPPP. Além disso, os anti-TNFα podem desencadear quadro de pustulose palmoplantar. No entanto, há relatos de sucesso terapêutico com anti-TNFα em casos refratários de PPPP. Em função das comorbidades da paciente e após terem sido esgotadas as possibilidades terapêuticas clássicas, optamos pelo uso do etanercepte, que se mostrou eficaz.A doente iniciou tratamento em abril de 2008 e mantém o uso do etanercepte até a presente data, estando em remissão da doença. Conclusão: Destacamos a possibilidade do uso de anti-TNFα em paciente com PPPP refratária ao tratamento convencional. No nosso caso, o etanercepte mostrou-se eficaz e seguro, não tendo a doente apresentado nenhum efeito adverso grave.

Background: Palmoplantar pustular psoriasis (PPPP) is one of the clinical presentations of psoriasis, often difficult to treat, can be used several topical and systemic. The use of anti-tumor necrosis factor alpha (anti-TNFα) in the treatment of pustular forms of psoriasis is controversial, with a variable clinical response, outside this class of biological medication may trigger pustular psoriasis. CASE REPORT: Patient 60, female, white, with a diagnosis of PPPP for 12 years and psoriatic arthritis for 6 years. Relevant personal history: hypertension, hypertriglyceridemia andobesity. Presented refractory to topical treatments (corticosteroids and emollients) and systemic (methotrexate, dapsone, colchicineand acitretin), having evolved with excellent response to treatment with etanercept (administered weekly by subcutaneous injection at a dose of 50 mg). Discussion: The anti-TNFα are effective in the treatment of psoriasis in moderate to severe plaque. But, inthe treatment of PPPP is not classically recommended. According to the literature, the therapeutic response with this type of drug is variable in PPPP. In addition, anti-TNFα may trigger clinical of palmoplantar pustulosis. However, there are reports of therapeutic success with anti-TNFα in refractory cases of PPPP. Due to patient’s comorbidities, and after having exhausted the possibilities classical therapies, we chose the use of etanercept, which proved effective. The patient began treatment in April 2008 and keeps the use of etanercept until the present date, being in remission.Conclusion: We emphasize the possibility of using anti-TNFα in patients with PPPP refractory to conventional treatment. In our case, etanercept was effective and safe, not having the patient presented any serious adverse events.