Efeitos da Terapia com Anti-TNF alfa na Pressão Arterial em Pacientes com Hipertensão Resistente: Um Estudo Piloto Randomizado, Duplo-Cego e Controlado por Placebo

Ana Paula de Faria; Alessandra M V Ritter; Arthur Santa-Catharina; Débora P Souza; Estephania P Naseri; Manoel B Bertolo; Mariana Rodrigues Pioli; Caio C Carvalho; Rodrigo Modolo; Heitor Moreno

doi:10.36660/abc.202190703

. 2021 Mar 3;116(3):443–451. [Article in Portuguese] doi: 10.36660/abc.202190703

View full-text in English

Efeitos da Terapia com Anti-TNF alfa na Pressão Arterial em Pacientes com Hipertensão Resistente: Um Estudo Piloto Randomizado, Duplo-Cego e Controlado por Placebo

Ana Paula de Faria ^1,^✉, Alessandra M V Ritter ¹, Arthur Santa-Catharina ¹, Débora P Souza ¹, Estephania P Naseri ¹, Manoel B Bertolo ¹, Mariana Rodrigues Pioli ¹, Caio C Carvalho ², Rodrigo Modolo ¹, Heitor Moreno ¹

PMCID: PMC8159563 PMID: 33909773

Resumo

Fundamento:

A citocina fator de necrose tumoral alfa (TNF-α) é elevada na hipertensão resistente (HAR), mas os efeitos dos inibidores de TNF-α nessa população ainda são desconhecidos.

Objetivos:

O objetivo deste estudo foi avaliar se uma única dose de infliximabe controlada por placebo reduz a pressão arterial (PA) de forma aguda em pacientes com HAR.

Métodos:

Realizamos um estudo cruzado, randomizado, duplo-cego e controlado por placebo em que pacientes com HAR receberam infliximabe ou placebo. O desfecho primário foi a alteração dos níveis de PA média em relação ao basal imediatamente após a infusão, obtida por avaliação hemodinâmica não invasiva contínua, batimento a batimento. Os desfechos secundários incluíram alterações em medidas de PA central, ambulatorial e em consultório, na função endotelial, e nos biomarcadores inflamatórios após 7 dias. O nível de significância aceito foi alfa=0,05.

Resultados:

Foram incluídos dez portadores de HAR. O resultado do desfecho primário demonstrou uma redução aguda dos níveis de PA média (média das diferenças ± desvio padrão = -6,3 ± 7,2 mmHg, p=0,02) em relação ao basal, após o uso de infliximabe, em comparação com o placebo. Os níveis de PA diastólica (-4,9 ± 5,5 mmHg, p=0,02), mas não os níveis de PA sistólica (-9,4 ± 19,7 mmHg, p=0,16), reduziram após a infusão de infliximabe. Não foram identificadas diferenças significativas nos demais parâmetros hemodinâmicos, nem nos resultados dos desfechos secundários, com exceção dos níveis de TNF-α, que aumentaram continuamente após o uso de infliximabe. Não foram relatados eventos adversos durante o protocolo.

Conclusões:

Uma dose única de infliximabe reduziu os níveis de PA média e diastólica imediatamente após sua infusão, em comparação com placebo em HAR. A terapia com anti-TNF-α foi considerada segura e bem tolerada. Os resultados desse estudo prova de conceito são geradores de hipótese e precisam ser investigados em maior detalhe. (Arq Bras Cardiol. 2021; 116(3):443-451)

Palavras-chave: Hipertensão, Pressão Arterial, Infliximab/uso terapêutico, Ensaio Clínico Controlado Randomizado, Inflamação

Introdução

É sabido que a inflamação sistêmica de grau baixo é subjacente à fisiopatologia da hipertensão resistente (HAR) devido à falta de controle de pressão arterial (PA), juntamente com condições coexistentes, tais como obesidade, diabetes tipo 2 (DT2) e síndrome metabólica. Recentemente, nosso grupo de pesquisa explorou o papel das citocinas inflamatórias nessa população de alto risco. Um escore inflamatório alto, incluindo, entre outros, a citocina pró-inflamatória fator de necrose tumoral alfa (TNF-α), foi proposto a pacientes obesos com HAR em comparação com pacientes obesos com hipertensão controlada.¹ Além disso, altos níveis de TNF-α foi associado a danos vasculares nesses pacientes com HAR.²

Apesar da indicação do uso de inibidores de TNF-α ser bem estabelecida para o tratamento de algumas doenças autoimunes, estudos experimentais e clínicos demonstraram seu uso efetivo para condições relacionadas ao sistema cardiovascular (CV), tais como a prevenção da hipertensão,³ e a redução de lesão de órgãos-alvo (LOA).⁴^,⁵ O infliximabe apresentou benefícios cardiovasculares como um agente neutralizador de TNF-α capaz de reduzir os níveis de PA sistólica (PAS) e o remodelamento cardíaco em ratos espontaneamente hipertensos.⁶

Como o processo inflamatório é parte da HAR e o TNF-α está implicado em disfunções cardiovasculares, o objetivo deste estudo piloto de prova de conceito foi avaliar se uma única dose do inibidor de TNF-α, infliximabe, controlada por placebo, reduz os níveis de PA em pacientes com HAR.

Métodos

Desenho do estudo

Com o uso de um desenho cruzado de intervenção, randomizado, duplo-cego e controlado por placebo, foram explorados os efeitos agudos do infliximabe, um inibidor de TNF-α, e seu comparador, placebo constituído de soro fisiológico, como uma terapia adicional ao tratamento padrão para a população com HAR. Um esquema de randomização em blocos foi criado utilizando-se um código gerado por computador. Os pacientes com HAR foram designados aleatoriamente, na inclusão, a receber ou (1) infusão de placebo seguida de infusão de infliximabe depois de um período de wash-out de 40 dias, ou (2) infliximabe seguido de placebo depois de um período de wash-out de 40 dias. Um farmacêutico alocou, de forma não cega, os voluntários do estudo e manteve consigo os códigos de tratamento até o encerramento do estudo. O enfermeiro que preparou as infusões também o fez de forma não cega. Nenhum dos dois profissionais estava envolvido na coleta, análise ou interpretação dos dados. Um médico fez a inclusão de forma cega dos sujeitos no estudo. Os participantes, o médico avaliador e os pesquisadores que avaliaram os resultados permaneceram de forma cega após a designação das intervenções.

O estudo piloto foi de iniciativa do investigador, desenhado pelos investigadores e não houve apoio de nenhuma entidade comercial. Todos os autores garantiram que os dados e análises estivessem completos e acurados, e certificaram a aderência do estudo ao protocolo.

O estudo foi aprovado pelo Comitê de Ética em Pesquisa (número de aprovação 710.449, CAAE 30811214.9.0000.5404, da Faculdade de Ciências Médicas da Universidade Estadual de Campinas-FCM/UNICAMP, Brasil), e registrado no clinicaltrials.gov (NCT02743390). O estudo foi realizado de acordo com princípios éticos para pesquisas médicas em seres humanos da Associação Médica Mundial (Declaração de Helsinki), e todos os participantes assinaram o termo de consentimento livre e esclarecido antes de serem incluídos no estudo. Também foram seguidas as recomendações do documento Consolidated Standards of Reporting Trials (CONSORT).

População

Pacientes com diagnóstico confirmado de HAR foram recrutados de uma população pré-selecionada do Ambulatório Especializado em Hipertensão Resistente do Hospital de Clínicas da Universidade Estadual de Campinas (UNICAMP, Campinas, Brasil). A HAR foi definida de acordo com a diretriz da American Heart Association.⁷ Foi realizado um diagnóstico preciso de HAR com um período de acompanhamento clínico de 6 meses para a triagem e a exclusão de causas secundárias de hipertensão [estenose de artéria renal (US-Doppler), feocromocitoma (metanefrinas urinárias e tomografia computadorizada), hiperaldosteronismo primário (relação aldosterona-renina>20 ng dl⁻¹ por ng ml⁻¹ h⁻¹), síndrome de Cushing (cortisol e níveis de ACTH), apneia obstrutiva do sono (classificada como “alto risco” no questionário de Berlin)], e pseudorresistência (monitorização ambulatorial da pressão arterial (MAPA) e contagem de comprimidos para excluir a hipertensão do jaleco branco e a não aderência à medicação, respectivamente).

Os critérios de exclusão foram doença cardíaca isquêmica sintomática, função renal comprometida, histórico de acidente vascular, infarto do miocárdio e doenças vasculares periféricas, diabetes tipo 1, gravidez, tabagismo, doenças autoimunes, ou contraindicação ao uso de infliximabe. Pacientes não qualificados para o estudo também incluíram os que tinham testes tuberculínicos positivos ou inativos (latentes) ou com radiografia torácica póstero-anterior anormal - avaliada por radiologista e reumatologista especialista em infusão de TNF-α (EP).

Protocolo e avaliações do estudo

O protocolo foi realizado com os participantes recebendo uma única infusão de infliximabe (Remicade®, 100 mg, Janssen-Cilag Farmacêutica Ltda.) na dose de 3 mg/Kg, que foi primeiro reconstituída com 10 mL de água estéril para injeção e, em seguida, diluída com 250 mL de cloreto de sódio 0,9% estéril para injeção, de acordo com as instruções do fabricante; ou recebendo uma única infusão de placebo que consistia 250 mL de cloreto de sódio 0,9% estéril para injeção. Os pacientes receberam as infusões intravenosas em um período de 2 horas, com uma vazão de 125 ml/h. Não foi coadministrada nenhuma outra medicação. O cruzamento para o braço de tratamento seguinte (infusão de placebo ou infliximabe) foi feito depois de um período de wash-out de 40 dias.

As avaliações do estudo incluíam 3 etapas (avaliação no basal, imediatamente após a infusão, e 7 dias após a infusão). Na visita para avaliação do basal (antes das infusões - T0) foram avaliados indicadores antropométricos, as PA de consultório, central (análise de onda de pulso - AOP) e níveis de MAPA, e dilatação mediada por fluxo (DMF). Além disso, foram coletadas amostras de sangue para determinar biomarcadores adicionais. Os registros hemodinâmicos não invasivos contínuos batimento a batimento foram avaliados por 15 minutos no basal (T0) e imediatamente após (T1) em ambas as infusões. A PA de consultório e a coleta de sangue também foram examinadas imediatamente após ambas as infusões (T1). Para avaliar a resposta de curto prazo devido à meia-vida longa do infliximabe (aproximadamente 8 dias),⁸ 7 dias após as infusões (T2), as PA de consultório, central e MAPA, DMF e a coleta de sangue foram reavaliadas (Figura suplementar).

Depois das avaliações do ensaio, foi respeitado um período de wash-out de 40 dias. Em seguida, o tratamento foi trocado (o que significa que participantes que receberam a primeira infusão de soro fisiológico, depois do período de wash-out de 40 dias, receberam infusão de infliximabe; e os participantes que receberam a primeira infusão de infliximabe, depois do período de wash-out de 40 dias, receberam infusão de soro fisiológico), e as avaliações de ensaio foram repetidas. (Figura suplementar).

Nenhum dos participantes alterou sua medicação anti-hipertensiva durante o período do estudo. Todos os procedimentos iniciaram às 08:00, e os parâmetros foram avaliados após 8 horas de jejum noturno. Depois do protocolo, os pacientes ainda permaneceram sob observação por 1 hora antes de serem liberados. Os participantes foram instruídos a relatar os efeitos colaterais comuns do infliximabe ou qualquer outro evento adverso que eles experimentassem em qualquer momento durante o estudo.

Pressão arterial, função endotelial e avaliações bioquímicas

A PAS e a PA diastólica (PAD) de consultório foram avaliadas em 3 etapas do estudo – basal, imediatamente após a infusão, e 7 dias após a infusão (infliximabe e placebo) – por um profissional de saúde treinado, de acordo com as diretrizes europeias e brasileiras de hipertensão arterial. Utilizamos um esfigmomanômetro digital validado (HEM-907XL, OMRON Healthcare Inc., Bannockburn, IL, EUA). A PA ambulatorial foi medida em 2 etapas do estudo – basal e 7 dias após a infusão (infliximabe e placebo) – e foi realizada utilizando-se um monitor oscilométrico automático (Spacelabs90207, Spacelabs Inc, Redmon, WA). Os pacientes foram instruídos a manter suas atividades normais diárias e a registrar suas atividades de 24 horas em um diário pessoal.

A PAS e PAD, e a pressão de pulso foram avaliadas em 2 etapas do estudo – basal e 7 dias após a infusão (infliximabe e placebo) – e foram determinadas por AOP com o sistema Sphygmocor (Artcor, Sidney, Austrália).⁹ A onda de pulso foi obtida pelo método de tonometria de aplanação da artéria radial. O equipamento também fornece dados adicionais em relação à medição da rigidez arterial pelo índice de incremento (AIx), além do AIx corrigido para a frequência cardíaca de 75 bpm (AIx@75). O AIx é definido pela razão entre as ondas refletidas e de ejeção (onda de pulso que percorre as artérias carótida e femoral).

Os dados da avaliação hemodinâmica não invasiva contínua, batimento a batimento, foram avaliados em 2 etapas do estudo – basal e imediatamente após a infusão (infliximabe e placebo) – e foram obtidos utilizando-se o dispositivo Finometer® (Finapres Medical Systems; Amsterdam, Holanda) e o software Finometer® Beatscope Easy versão 02.10 (Finapres Medical Systems, Amsterdam, Holanda). Um manguito de dimensões apropriadas foi colocado no terceiro ou quarto dedo da mão esquerda e o braço foi deixado em repouso sobre uma mesa, com o paciente sentado. Os níveis de PA sistólica (PAS em mmHg), diastólica (PAD em mmHg), e média (PAM em mm), débito cardíaco (DC em l/min), e resistência vascular periférica total (RVPT em dyn.s/cm⁻⁵) foram registrados durante 15 minutos antes de imediatamente após o protocolo de infusões. Para as análises, foram utilizadas as seções estáveis de registros (os 10 minutos iniciais dos registros foram excluídos das análises). O dispositivo Finometer® utiliza o método de fotopletismografia, e fornece medidas hemodinâmicas confiáveis conforme mostrado anteriormente.¹⁰^,¹¹

A função endotelial foi avaliada em 2 etapas do estudo – basal e 7 dias após a infusão (infliximabe e placebo) – e foi determinada pelo método DMF, de acordo com as diretrizes atuais.¹²^,¹³ Foi utilizado um transdutor vascular linear (7–12MHz, Toshiba Powervision 6000, Tóquio, Japão) sincronizado com sinal de eletrocardiograma (ECG) no protocolo. Os pacientes, em posição supina, em uma sala silenciosa e com ar-condicionado (22–24 °C), foram submetidos a oclusão da artéria braquial por cinco minutos, utilizando um esfigmomanômetro aneróide. O diâmetro da artéria braquial foi registrado antes e depois da compressão com manguito. A alteração do diâmetro da artéria braquial foi expressa como uma porcentagem de alteração relativa ao diâmetro do vaso imediatamente antes da inflação do manguito. O exame da função vascular foi realizado por um único examinador experiente, de forma cega. O coeficiente de variação intraobservador foi de 1,6%.

Foram coletadas amostras de sangue para avaliação em 3 etapas do estudo – basal, imediatamente após a infusão, e 7 dias após a infusão (infliximabe e placebo) – dos níveis plasmáticos de nitrato/nitrito, biomarcadores inflamatórios, tais como o TNF-α, interleucinas-6 (IL-6) e -10 (IL-10), adiponectina, proteína quimiotática de monócitos 1 (MCP-1), e os hormônios cortisol e aldosterona. Para as medições de nitrato e nitrito, foi coletado plasma heparinizado e imediatamente misturado com uma solução padrão de nitrito diluída a 5:1 contendo 0.8M de ferricianeto e 1% de NP-40.¹⁴ As amostras foram desproteinizadas com metanol (1:1) e centrifugadas a 14.000 g por 5 min. Depois disso, foram injetados 300 μl de sobrenadante na solução de tri-iodeto acidificada, que foi purgada com nitrogênio com um analisador de quimiluminescência em fase gasosa de óxido nítrico (ON) (Sievers Model 280i NO Analyzer, Boulder, CO, EUA). Biomarcadores inflamatórios e hormônios foram medidos em amostras de plasma coletada em EDTA e analisados pelo ensaio de imunoabsorção enzimática (R&D Systems, Minneapolis, MN, EUA), de acordo com as instruções do fabricante.

Desfechos primário e secundários

O desfecho primário foi a alteração aguda (de T0 a T1) dos níveis de PA média em relação ao basal imediatamente após a infusão, obtida por avaliação hemodinâmica não invasiva contínua, batimento a batimento.

Os desfechos secundários incluíram alterações em: (1) níveis de PA determinados em consultório em todos os momentos de avaliação do protocolo, pela MAPA e PA central depois de 7 dias; (2) função endotelial após 7 dias; e (3) biomarcadores inflamatórios em todos os momentos de avaliação do protocolo, depois da infusão de infliximabe em comparação com placebo. Todos os resultados secundários foram exploratórios, mas foram considerados relevantes para essa população devido à natureza do ensaio – prova de conceito piloto.

Análises estatísticas

Foi estimada uma amostra mínima de 10 pacientes com HAR para se detectar uma diferença clínica na PA média de 10 mmHg (desvio padrão de 10 mmHg) — entre infliximabe e placebo — com poder de 80% e erro tipo alfa de 0,05.

As variáveis contínuas foram expressas como média e desvio padrão (DP), devido à distribuição normal avaliada pelo teste Kolmogorov–Smirnov. As variáveis categóricas foram apresentadas como frequências e porcentagens. O teste t de Student pareado foi aplicado para comparar os valores de delta (distribuição normal) entre o infliximabe e o placebo nos mesmos pacientes (desenho cruzado). Foi realizado o teste ANOVA de dois fatores para medidas repetidas seguido do teste de comparação múltipla post hoc de Sidak para identificar as diferenças entre os tratamentos (infliximabe X placebo) nos valores delta dos momentos da avaliação (ou seja, T1-T0 – agudo, e T2-T0 – 7 dias).

As análises foram realizadas utilizando-se os softwares SPSS (IBM SPSS Statistics for Mac, Versão 21.0. Armonk, NY: IBM Corp. Lançado em 2012) e GraphPad Prism (versão 7.00 para Windows, GraphPad Software, La Jolla California EUA, www.graphpad.com). O nível de significância aceito foi alfa=0,05.

Resultados

De março de 2015 a julho de 2017, foram incluídos, no total, 10 pacientes com HAR e todos os pacientes concluíram este ensaio de prova de conceito - Figura 1. As características basais dos pacientes com HAR são apresentadas na Tabela 1. A maioria dos participantes eram do sexo masculino e não brancos. Como o esperado, a maioria era obesa com DT2 e estavam tomando diuréticos e uma grande proporção de β-bloqueadores, antagonistas dos receptores de angiotensina II, e bloqueadores dos canais de cálcio.

Tabela 1. Características da linha de base da população do estudo.

	HAR (N=10)
Dados clínicos
Idade (anos)	61,8 ± 8,5
Sexo (feminino)	40% (4)
IMC (Kg/m²)	31,9 ± 5,9
Diabetes tipo 2, (n)	70% (7)
Não brancos, (n)	60% (6)
Medicamentos anti-HA
Número total	4,4 ± 0,7
Diuréticos, (n)	100% (10)
Espironolactona, (n)	50% (5)
β-bloqueadores, (n)	80% (8)
IECA, (n)	30% (3)
ARA II, (n)	70% (7)
BCC, (n)	90% (9)
Agonistas alfa-2, (n)	12% (1)

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Os dados foram expressos como média e desvio padrão, ou porcentagem e número absoluto. HAR: hipertensão resistente; IMC: índice de massa corporal; Anti-HA: anti-hipertensivos; IECA: inibidores da enzima conversora de angiotensina; ARA II: antagonistas dos receptores de angiotensina II; BCC: bloqueadores dos canais de cálcio.

A análise do resultado do desfecho primário demonstrou uma redução aguda dos níveis de PA média em relação ao basal, após o uso de infliximabe, em comparação com o placebo (média das diferenças ±DP foi -6,3 ±7,2 mmHg, p=0,02). Valores absolutos de delta de PA média em relação ao basal imediatamente após as infusões de placebo e infliximabe nos pacientes estudados são apresentados na Figura 2, e os demais parâmetros hemodinâmicos, na Figura 3. Além da redução dos valores de PA médios, também foi identificada uma redução dos níveis de PAD (-4,9± 5,5 mmHg, p=0,02) em relação ao basal, após o uso de infliximabe, em comparação com o placebo. Não foram identificadas diferenças estatisticamente significativas em PAS, DC e RVPT.

Os resultados dos desfechos secundários são apresentados nas Tabelas suplementares 1 e 2. Não foram identificadas alterações em PA e FC em relação aos tempos delta avaliados, T1-T0 e T2-T0, após os tratamentos. Da mesma forma, os níveis plasmáticos não apresentaram nenhuma alteração nem nos parâmetros inflamatórios nem nos hormonais, nos tempos delta avaliados, com exceção do TNF-α, que aumentou continuamente após a dose única de infliximabe, em comparação com o placebo (Tabela suplementar 1). Não foram identificadas alterações nos valores delta dos níveis de PA ambulatorial e central 7 dias após as infusões (T2-T0). A função endotelial avaliada por DMF também permaneceu inalterada (Tabela suplementar 2).

Por fim, não foram relatados pelos voluntários eventos adversos durante o protocolo das infusões, nem durante o período do ensaio. Não houve reações alérgicas ao infliximabe, e nenhum paciente abandonou o estudo devido à toxicidade.

Discussão

O principal achado deste estudo piloto de prova de conceito foi que uma dose única de infliximabe reduziu os níveis de PA média em comparação com placebo, em pacientes com HAR. Secundariamente, o infliximabe também reduziu a PA diastólica. Até onde sabemos, o presente estudo é o primeiro a investigar os efeitos da infusão de um medicamento biológico de anticorpos monoclonais em população portadora de HAR.

Vários estudos clínicos e experimentais demonstraram o papel da citocina pró-inflamatória TNF-α na hipertensão.³^,¹⁵ Uma relação entre o TNF-α e o sistema renina-angiotensina-aldosterona (SRAA) foi corroborada pela literatura destacando sua interação na modulação da resposta hipertensiva e da LOA a ela relacionada.³ Está bem estabelecido que a HAR com comorbidades existentes, tais como obesidade, DT2 e síndrome metabólica,¹⁶^,¹⁷ apresenta hiperativação do sistema nervoso simpático (SNS) e do SRAA. Portanto, presume-se que o TNF-α seria aumentado nessa população de alto risco. Na verdade, este grupo de pesquisa já demonstrou anteriormente que os níveis de TNF-α estão aumentados em HAR em comparação com normotensos, e que essa citocina estava associada ao aumento da rigidez arterial.² Recentemente, demonstrou-se também que um escore inflamatório elevado, combinando várias citocinas circulantes, tais como o TNF-α, está relacionado à HAR de maneira dependente da obesidade, em comparação com sujeitos hipertensos controlados.¹

O uso dos inibidores de TNF-α já foi reconhecido mundialmente para tratamento de doenças autoimunes, especialmente no cenário da reumatologia.¹⁸^,¹⁹ O infliximabe é um medicamento biológico contendo anticorpo monoclonal quimérico humano-murino que neutraliza a atividade do TNF-α. Ao realizar uma ligação com alta afinidade às formas solúveis e transmembranares do TNF-α, o infliximabe consegue inibir a ligação do TNF-α a seus receptores.²⁰ Além dos benefícios clínicos observados após o uso do infliximabe para aliviar os sintomas ou evitar o avanço de doenças autoimunes, sua administração também revelou o potencial para reduzir risco cardiovascular. Por exemplo, resultados de estudos de coorte indicaram a redução na incidência de eventos CV em sujeitos com artrite reumatoide (AR) em uso de terapia anti-TNF-α.²¹^,²²

Os efeitos da inibição de TNF-α para prevenir o aumento dos níveis de PA e lesões a órgãos foram relatados em modelos hipertensivos.⁶^,²³ Este grupo de pesquisa detectou a redução na PAS e hipertrofia ventricular esquerda em ratos espontaneamente hipertensos após 8 semanas de tratamento com infliximabe (nas doses de 1,5 e 6mg/kg/semana). Esses benefícios cardiovasculares provavelmente foram alcançados devido a um mecanismo dependente de vasodilatação, em que a neutralização de TNF-α foi capaz de induzir a síntese do NO.⁶ No cenário clínico, o infliximabe (inicialmente 3mg/Kg a cada 8 semanas durante o período de monitoramento de 1 ano) diminuiu os níveis de PAS e PAD em pacientes com AR recém diagnosticada.²⁴ Além disso, depois de 2 semanas de terapia, o infliximabe (3mg/kg) reduziu a PA sistólica de 24 horas em pacientes com AR, especialmente durante o período diurno. Este estudo também identificou a redução nos níveis de norepinefrina plasmática e atividade de renina plasmática, sugerindo alterações relacionadas ao infliximabe no SNS e SRAA.²⁵ Os achados do presente estudo são, em parte, compatíveis com os de estudos anteriores, pois revelam um efeito modesto de uma dose única da terapia com infliximabe e de 3 mg/kg na redução dos níveis de PA imediatamente após sua infusão em uma população de risco tão alto como os portadores de HAR. Entretanto, reconhecemos a impossibilidade de atingir a meta de diferença clínica de 10 mmHg projetada neste estudo.

A inibição da via inflamatória pelo infliximabe em nosso estudo pode ter evocado de forma aguda algumas alterações funcionais/bioquímicas, e, consequentemente, acarretado esses níveis de PA reduzidos. Como bem se sabe, o TNF-α é capaz de induzir a disfunção endotelial²⁶ (i) estimulando a liberação de micropartículas endoteliais e a produção de espécies reativas do oxigênio,²⁷ e (ii) reduzindo a expressão de eNOS constitutiva,²⁸ que reduz a biodisponibilidade de NO. Neste estudo, os resultados de DMF não apresentaram diferenças estatísticas 7 dias após a administração aguda de infliximabe, bem como os níveis de metabólitos de NO (nitrato/nitrito) em qualquer um dos dois momentos de avaliação. Embora a inibição de TNF-α tenha sido relatada como possível estratégia para melhorar a função endotelial,²⁹ os resultados negativos podem ser explicados, já que foi demonstrado anteriormente que os pacientes com HAR têm vasodilatação gravemente prejudicada associada a maior rigidez vascular³⁰ e a níveis mais altos de 8-isoprostano³¹ – um marcador proposto de stress oxidativo in vivo – comparado com hipertensos controlados. Por outro lado, ainda é possível que os níveis de NO imediatamente após o uso de infliximabe estivessem reduzidos em artérias de resistência - que este estudo não conseguiu avaliar - causando as reduções de RVPT e PA, embora esse primeiro parâmetro não tenha sido considerado significativo. Outra hipótese que corrobora nossos achados é a relação entre TNF-α e SRAA, como mencionado acima. Essa citocina pró-inflamatória pode estimular a expressão de receptores de angiotensina tipo 1,¹⁵ e do gene angiotensinogênio no fígado,³² este último levando fisiologicamente níveis altos de angiotensina II, e a secreção de aldosterona. Apenas os níveis de aldosterona foram avaliados neste estudo. Embora o resultado tenha permanecido limítrofe e o hormônio possa agir na regulação de longo prazo da PA, foi possível observar uma tendência a uma maior redução de aldosterona nos dois momentos de avaliação após o uso do infliximabe, comparado ao placebo.

É interessante que os níveis de TNF-α tenham aumentado gradualmente nos momentos da avaliação após o uso do infliximabe, em comparação com o placebo. Da mesma forma, alguns estudos detectaram o aumento em seus níveis após a terapia anti-TNF-α,²⁹^,³³ embora os mecanismos dessa elevação ainda sejam desconhecidos. Ela possivelmente pode ser explicada pelo prolongamento da meia-vida do TNF-α pelo tratamento – conforme previamente observado nos estudos que exploram outras terapias anti-TNF-α³⁴^,³⁵ – apesar de ter bloqueado a atividade do TNF-α.³⁴ Por outro lado, um tratamento crônico foi associado à redução de níveis do TNF-α, atingindo um nível de equilíbrio estável mais baixo, o que pode refletir um equilíbrio entre a produção de tecido e a eliminação do TNF-α.³⁶ Curiosamente, foi observada uma diminuição aguda dos níveis de PA, que não se manteve após 7 dias de acompanhamento. Como sabemos que neste estudo os níveis de TNF-α aumentaram na semana seguinte à infusão de infliximabe, e que o tratamento crônico tende a diminuir seus níveis, é razoável pressupor que um tratamento crônico poderia ser acompanhado da redução sustentada dos níveis de PA. Entretanto, isso precisa ser provado em um período de acompanhamento mais longo após a infusão.

O presente estudo tem várias limitações inerentes aos estudos piloto de prova de conceito. A limitação mais importante é o tamanho da amostra. É importante mencionar que a população estudada representa um subconjunto muito específico de hipertensos com baixa prevalência global.¹⁶ Além disso, tivemos uma grande proporção de pacientes com resultados positivos nos testes de tuberculose e, então, foram excluídos do estudo (n=9). Nossos achados negativos em desfechos secundários nos dois momentos de avaliação podem ter acontecido por não ter poder estatístico suficiente (erro tipo II). Uma dose única de 3 mg/kg pode não ter sido suficiente para causar o efeito clínico esperado imediatamente após a infusão ou qualquer efeito na avaliação de curto prazo (7 dias após a infusão). Embora não tenhamos alcançado a meta de diferença de 10 mmHg na PA média depois do infliximabe em comparação com o placebo [na verdade, a média das diferenças foi de -6,3 (DP=7,2)], o poder do estudo foi de 70%, e pode, portanto, ser considerado satisfatório, já que este foi um estudo piloto. Um desenho cruzado pode, reconhecidamente, implicar a possível existência de efeitos residuais da medicação. Na tentativa de superar esse problema, e considerando a meia-vida longa do infliximabe (a meia-vida de eliminação média é de cerca de 8 dias),⁸ um período de wash-out de 40 dias (5x meias-vidas) seria seguro. Como este estudo utilizou dose única, não é possível garantir que os efeitos da redução dos níveis de PA sejam sustentados durante o período de uso crônico do infliximabe. Por fim, para garantir as validades internas e externas, estudos de larga escala são necessários para estabelecer a segurança clínica e a eficácia de um inibidor de TNF-α no manejo da HAR.

Conclusões

Este estudo piloto prova de conceito demonstrou que uma dose única de infliximabe reduziu os níveis de PA média e diastólica imediatamente após sua infusão, em comparação com placebo. A terapia com anti-TNF-α foi considerada segura e bem tolerada. Ela acrescenta uma perspectiva clínica às terapias direcionadas ao processo inflamatório para tratar da hipertensão de difícil controle. Devido ao tamanho pequeno da amostra e ao poder abaixo do pré-especificado, os achados devem ser interpretados como exploratórios e geradores de hipótese.

Agradecimentos

Os autores agradecem ao Centro de Medicamentos de Alta Complexidade (CEDMAC) - Hospital das Clínicas/Universidade Estadual de Campinas (UNICAMP) pelo apoio técnico e por fornecer a medicação.

Funding Statement

O presente estudo foi financiado pela FAPESP (2015/17151-7) e parcialmente financiado pelo CNPq e CAPES.

Footnotes

Fontes de financiamento

O presente estudo foi financiado pela FAPESP (2015/17151-7) e parcialmente financiado pelo CNPq e CAPES.

Vinculação acadêmica

Não há vinculação deste estudo a programas de pós-graduação.

*Material suplementar

Para informação adicional, por favor, clique aqui.

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Arq Bras Cardiol. 2021 Mar 3;116(3):443–451. [Article in English]

Effects of Anti-TNF alpha Therapy on Blood Pressure in Resistant Hypertensive Subjects: A Randomized, Double-Blind, Placebo-Controlled Pilot Study

Abstract

Background:

The cytokine tumor necrosis factor-alpha (TNF-α) is elevated in resistant hypertension (RH), but the effects of a TNF-α inhibitor in this population is unknown.

Objective:

The aim of this trial was to evaluate whether a single dose of infliximab controlled by placebo acutely reduces blood pressure (BP) in RH subjects.

Methods:

A double-blind, placebo-controlled, crossover trial was conducted, and randomized RH subjects received either infliximab or placebo. The primary endpoint was the change in mean BP levels relative to the baseline immediately after the infusion obtained by continuously beat-to-beat non-invasive hemodynamic assessment. Secondary endpoints included changes in office, ambulatory and central BP measurements; endothelial function; and inflammatory biomarkers after 7 days. The level of significance accepted was alpha=0.05.

Results:

Ten RH subjects were enrolled. The primary endpoint analysis showed an acute decrease in mean BP values (mean of differences ± standard deviation = -6.3 ± 7.2 mmHg, p=0.02) from baseline, after the application of infliximab compared with placebo. Diastolic BP levels (-4.9 ± 5.5 mmHg, p=0.02), but not systolic BP levels (-9.4 ± 19.7 mmHg, p=0.16), lowered after infliximab infusion. No further significant differences were identified in either the other hemodynamic parameters or in secondary endpoints, except for TNF-α levels, which increased continuously after infliximab infusion. No adverse events were reported during the protocol.

Conclusions:

A single-dose of infliximab decreased the mean and diastolic BP levels immediately after its infusion, when compared to the placebo in RH. The anti-TNF-α therapy was found to be safe and well-tolerated. The results of this proof-of-concept are hypothesis-generating and need to be further investigated. (Arq Bras Cardiol. 2021; 116(3):443-451)

Keywords: Hypertension, Blood Pressure, Infliximb/therapeutic use, Randomized Controlled Trial, Inflammation

Introduction

Low-grade systemic inflammation has proven to be an underlying factor of the pathophysiology of resistant hypertension (RH) due to the lack of blood pressure (BP) control, along with coexisting conditions, such as obesity, type 2 diabetes (T2D), and metabolic syndrome. Recently, our research group has explored the role of inflammatory cytokines in this high-risk population. An elevated inflammatory score, including, among others, the proinflammatory cytokine tumor necrosis factor-alpha (TNF-α), was proposed in obese resistant subjects, when compared to controlled obese hypertensive subjects.¹ In addition, higher levels of TNF-α have been associated with vascular damage in these RH subjects.²

While the recommendation for TNF-α inhibitor use is well established for treating some autoimmune diseases, experimental and clinical studies have demonstrated its effective use for cardiovascular (CV) system-related parameters, such as in preventing hypertension³ and reducing target organ damage (TOD).⁴^,⁵ In fact, infliximab has revealed CV benefits as a TNF-α-neutralizing agent able to reduce systolic BP (SBP) levels and cardiac remodeling in spontaneously hypertensive rats.⁶

Since the inflammatory process is part of RH and TNF-α is implicated in CV derangements, the purpose of this proof-of-concept pilot trial was to evaluate whether a single dose of the TNF-α inhibitor, infliximab, controlled by placebo reduces BP levels in RH subjects.

Methods

Trial design

With the use of a randomized, double-blind, placebo-controlled interventional crossover design,this study explored the acute effects of infliximab, a TNF-α inhibitor, and its comparator placebo saline solution, as an add−on therapy to standard treatment in the population with RH. A blocked randomization scheme was created using a computer-generated code. RH subjects were randomly assigned upon enrollment to receive either (1) placebo infusion followed by infliximab infusion after a 40-day period of washout or (2) infliximab followed by placebo after a 40-day period of washout. An unblinded pharmacist distributed the study volunteers and remained with the treatment codes until study closure. The nurse who prepared the infusions was also not blinded. Both were not involved in data collection, analysis, or interpretation. A masked physician enrolled subjects into the study. Participants, evaluator physician, and the researchers assessing outcomes remained blinded after assignment to interventions.

This pilot trial was an investigator-initiated study, designed by the investigators, and no support from a commercial entity was provided. All authors certified the completeness and accuracy of the data and analyses, as well as for the adherence of the trial to the protocol.

The present study was approved by the local Research Ethic Committee (approval number 710.449, CAAE 30811214.9.0000.5404, from the School of Medical Sciences of University of Campinas-FCM/UNICAMP, Brazil) and registered in clinicaltrials.gov (NCT02743390). It was conducted in accordance with ethical principles for medical research involving human subjects established by the World Medical Association (Declaration of Helsinki), and all participants provided informed written consent before enrolling in the study. The recommendations of the Consolidated Standards of Reporting Trials (CONSORT) statement were also followed.

Population

Subjects with confirmed diagnosis of RH were recruited from a prescreened population of the Specialized Outpatient Clinic in RH at the University of Campinas (UNICAMP, Campinas, Brazil). RH was defined according to American Heart Association Statement.⁷ A precise diagnosis of RH with a 6-month clinical follow-up was performed to screen and exclude secondary causes of hypertension [renal artery stenosis (US-Doppler), pheochromocytoma (urinary metanephrines and computed tomography), primary hyperaldosteronism (aldosterone renin ratio>20 ng dl⁻¹ per ng ml⁻¹ h⁻¹), cushing syndrome (cortisol and ACTH levels), obstructive sleep apnea (classified as “high risk” at Berlin questionnaire)], and pseudo resistance (ambulatory BP monitoring (ABPM) and pill count to exclude white-coat hypertension and medication nonadherence, respectively).

Exclusion criteria were symptomatic ischemic heart disease, impaired renal function, liver disease, history of stroke, myocardial infarction and peripheral vascular diseases, type I diabetes, pregnant women, smoking, autoimmune diseases, or those who presented a contraindication to infliximab use. Non-eligible patients also consisted of those with a positive or inactive (latent) skin test for tuberculosis or with an abnormal posteroanterior chest radiography (chest X-ray) – evaluated by radiology and rheumatology specialists in TNF-alpha infusion (EP).

Trial protocol and assessments

The protocol was performed with the participants, receiving either a single infliximab infusion (Remicade®, 100 mg, Janssen-Cilag Farmacêutica Ltda.) at a dose of 3 mg/Kg, which was first reconstituted with 10 mL of sterile water for injection and then diluted to 250 mL with sterile 0.9% sodium chloride for injection according to manufacturer’s instructions; or receiving a single-infusion placebo, consisting of 250 mL, with sterile 0.9% sodium chloride for injection. Subjects received the intravenous infusions over a two-hour period with a flow rate of 125 ml/h. No other drug was co-administered. Crossover to the following arm of treatment (placebo or infliximab infusion) was made after a washout period of 40 days.

Trial assessments of the study consisted of three steps (assessments in the baseline, immediately after infusion, and seven days after infusion). At the baseline visit (before infusions - T0), anthropometric, office, central (pulse wave analysis-PWA) BP, and ABPM levels and flow-mediated dilation (FMD) were assessed. Morevoer, blood samples were collected to further determine inflammatory biomarkers. Continuous beat-to-beat noninvasive hemodynamic recording were evaluated for 15 minutes in the baseline (T0) and immediately after (T1) both infusions. Office BP and blood collection were also examined immediately after both infusions (T1). To assess a short-term response due to the long half-life of infliximab (around 8 days),⁸ seven days after the infusions (T2), office, central, ABPM BP, FMD, and blood collection were revaluated (Supplementary Figure).

After the trial assessments, a 40-day period of washout was conducted. The treatment was then changed (meaning that the participant who had received saline infusion, after a 40-day period of washout, received infliximab infusion, and vice-versa; the participant who had received infliximab infusion, after a 40-day period of washout, received saline infusion), and the trial assessments were repeated (Supplementary Figure).

No participant changed their antihypertensive medication during the period of the trial. All procedures were begun at 08:00 a.m., and the parameters were evaluated after 8 hours of overnight fasting. After the protocol, patients still remained under observation for 1h before being discharged. Participants were instructed to report either common side effects of infliximab or any adverse event they could have at any time during the study.

Blood pressure, endothelial function, and biochemical assessments

Office SBP and diastolic BP (DBP) were assessed in three steps of the study – in the baseline, immediately after infusion, and seven days after infusion (infliximab and placebo) – by a trained health professional, following the European and Brazilian guidelines of arterial hypertension. A validated digital sphygmomanometer (HEM-907XL, OMRON Healthcare Inc., Bannockburn, IL, USA) was used. Ambulatory BP measurement was assessed in two steps of the study – in the baseline and seven days after infusion (infliximab and placebo) – and performed using an automatic oscillometric monitor (Spacelabs90207, Spacelabs Inc, Redmon, WA). Patients were instructed to maintain normal daily activities and record their 24-hour activities in a personal diary.

Central systolic and diastolic aortic BP and pulse pressure were assessed in two steps of the study – in the baseline and seven days after infusion (infliximab and placebo) – and determined by PWA, using the Sphygmocor system (Artcor, Sidney, Australia).⁹ The pulse wave was obtained by the method of applanation tonometry of the radial artery. The equipment also provides additional data regarding the measurement of arterial stiffness by the augmentation index (AIx) as well as by AIx corrected for heart rate of 75 bpm (AIx@75). AIx is defined by the ratio between the reflected and the ejection waves (pulse wave traveling from carotid to femoral arteries).

Continuous beat-to-beat non-invasive hemodynamic data were assessed in two steps of the study – in the baseline and immediately after infusion (infliximab and placebo) – and were obtained using the Finometer® device (Finapres Medical Systems; Amsterdam, Netherlands) and Finometer® Beatscope Easy software, version 02.10 (Finapres Medical Systems, Amsterdam, Netherlands). An appropriately sized cuff was placed on the third or fourth left finger, and the arm was rested on a table with the subject in a sitting position. Systolic (SBP in mmHg), diastolic (DBP in mmHg), and mean (MBP in mmHg) BP levels, cardiac output (CO in l/min), and total peripheral resistance (TPR in dyn.s/cm⁻⁵) were recorded for 15 minutes before and immediately after the protocol of infusions. For analyses, the stable section of beat-to-beat recordings were used (10 minutes at the beginning of recordings were excluded from these analyses). The Finometer® device makes use of the volume-clamp method and provides reliable hemodynamic measures, as previously shown.¹⁰^,¹¹

The endothelial function was assessed in two steps of the study – in the baseline and seven days after infusion (infliximab and placebo) – and was determined by the FMD method, in accordance with current guidelines.¹²^,¹³ Linear vascular transducer (7–12MHz, Toshiba Powervision 6000, Tokyo, Japan), synchronized with an electrocardiogram (ECG) signal, was used in the protocol. Subjects in a supine position in a quiet, air-conditioned room (22–24°C) were submitted to brachial artery occlusion for five minutes, using an aneroid sphygmomanometer. Brachial artery diameter was recorded before and after cuff compression. Change in the brachial artery diameter was expressed as a percentage change relative to the vessel diameter immediately before cuff inflation. The vascular function examination was performed by only one experienced blinded examiner. The intraobserver coefficient of variation was 1.6%.

Blood samples were collected for assessment in three steps of the study – in the baseline, immediately after infusion, and seven days after infusion (infliximab and placebo) – of the plasma levels of nitrate/nitrite; inflammatory biomarkers, such as TNF-α, interleukins-6 (IL-6), and -10 (IL-10); adiponectin; monocyte chemoattractant protein-1 (MCP-1); and the cortisol and aldosterone hormones. For nitrate and nitrite measurements, heparinized plasma was collected and immediately mixed with a nitrite-preserving solution in a 5:1 dilution, containing 0.8M ferricyanide and 1% NP-40.¹⁴ The samples were deproteinized with methanol (1:1) and centrifuged at 14,000g for 5 min. After, 300μl of supernatant were injected into the acidified triiodide solution and purged with nitrogen line with a gas-phase chemiluminescent nitric oxide (NO) analyzer (Sievers Model 280i NO Analyzer, Boulder, CO, USA). Inflammatory biomarkers and hormones were measured in EDTA-collected plasma samples and analyzed by enzyme-linked immunosorbent assay (R&D Systems, Minneapolis, MN, USA), according to manufacturer’s instructions.

Primary and secondary endpoints

Our primary endpoint was the acute change (from T0 to T1) in mean BP levels relative to the baseline immediately after the infusion, obtained by continuous beat-to-beat non-invasive hemodynamic assessment.

Secondary endpoints included changes in: (1) BP levels determined by office in all timelines, ambulatory, and central measurements after seven days; (2) endothelial function after 7 days; and (3) inflammatory biomarkers in all timelines, after infliximab infusion compared with placebo. All secondary outcomes were exploratory but were considered relevant in this population due to the nature of the trial – pilot proof-of-concept.

Statistical analyses

This study estimated a minimum sample size of 10 RH individuals, to detect a clinical difference in mean BP of 10 mmHg (standard deviation of 10 mmHg) — between infliximab and placebo — power of 80% and alpha error of 0.05.

Continuous variables were expressed as mean and standard deviation (SD), since their normal distribution was assessed by the Kolmogorov–Smirnov test. Categorical variables were presented in frequencies and percentages. Paired Student’s t-test was applied to compare delta values (normal distribution) between the application of infliximab and placebo in the same patients (crossover design). A two-way repeated measure ANOVA, followed by a Sidack’s post-hoc multiple comparison test, was performed to identify differences between the treatments (infliximab versus placebo) in the delta values of the evaluation times (i.e. T1-T0 – acute, and T2-T0 – 7 days).

The analyses were performed using the software SPSS (IBM SPSS Statistics for Mac, Version 21.0. Armonk, NY: IBM Corp. Released 2012) and GraphPad Prism (version 7.00 for Windows, GraphPad Software, La Jolla California USA, www.graphpad.com). The level of significance accepted was alpha=0.05.

Results

From March 2015 to July 2017, a total of 10 subjects with RH were included in this study, and all subjects completed this proof-of-concept interventional trial (Figure 1). Baseline characteristics of the RH subjects are presented in Table 1. Most participants were male and non-white. As expected, they were mainly obese with T2D, and taking diuretics and a great proportion of β-blockers, angiotensin II receptor antagonists, and calcium channel blockers.

Table 1. Baseline characteristics of the studied subjects.

	RH (N=10)
Clinical data
Age (years)	61.8 ± 8.5
Gender (Female)	40% (4)
BMI (Kg/m²)	31.9 ± 5.9
Type 2 Diabetes, (n)	70% (7)
Non-white, (n)	60% (6)
Anti-HA drugs
Total number	4.4 ± 0.7
Diuretics, (n)	100% (10)
Spironolactone, (n)	50% (5)
β-blockers, (n)	80% (8)
ACEis, (n)	30% (3)
ARAs II, (n)	70% (7)
CCBs, (n)	90% (9)
Alpha-2 agonists, (n)	12% (1)

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Data were expressed as mean and standard deviation, or percentage and absolute number. RH: resistant hypertension; BMI: body mass index; Anti-HA: antihypertensive; ACEis: angiotensin converting enzyme inhibitors; ARAs II: angiotensin II type I receptor antagonists; CCBs: calcium channel blockers.

The primary endpoint analysis showed an acute decrease in mean BP values from baseline after infliximab infusion, when compared to the placebo (the mean of differences ± SD was -6.3 ± 7.2 mmHg, p=0.02). Absolute delta mean BP values relative to baseline immediately after the placebo and infliximab infusions in the studied subjects are shown in Figure 2, while the other beat-to-beat hemodynamic parameters are shown in Figure 3. Apart from the decrease in mean BP, this study also found a reduction in diastolic BP levels (-4.9 ± 5.5 mmHg, p=0.02) from baseline, after infliximab, when compared to the placebo. No statistically significant differences were identified in SBP, CO, and TPR.

Secondary endpoints are shown in Supplementary Tables 1 and 2. No changes in office BP and HR relative to assessed delta times, T1-T0 and T2-T0, after the treatments were found. Similarly, plasma levels demonstrated no alteration in either inflammatory or hormonal parameters in assessed delta times, except for TNF-α, which increased continuously after a single dose of infliximab, when compared to the placebo (Supplementary Table 1). No difference in delta values of both ambulatory and central BP levels seven days after the infusions (T2-T0). The endothelial function assessed by FMD also remained unchanged (Supplementary Table 2).

Finally, no adverse events were reported by the volunteers during the protocol of the infusions, nor throughout the trial period. There were no overt allergic reactions to infliximab, and no patient withdrew from the study because of toxicity.

Discussion

The main finding of this proof-of-concept pilot trial was that a single dose of infliximab reduced the mean BP levels compared with placebo in subjects with RH. Secondarily, infliximab also reduced diastolic BP. To the best of our knowledge, the present study is the first to the investigate effects of the infusion of a monoclonal antibody biologic drug in the RH population.

Several experimental and clinical studies have demonstrated the role of the proinflammatory cytokine TNF-α on hypertension.³^,¹⁵ A crosstalk between TNF-α and renin-angiotensin-aldosterone system (RAAS) has been supported by the literature highlighting their interaction in modulating a hypertensive response and TOD related to it.³ It is well recognized that RH with coexisting comorbidities such as obesity, T2D, and metabolic syndrome,¹⁶^,¹⁷ presents overactivation of both the sympathetic nervous system (SNS) and RAAS. Therefore, it is presumed that TNF-α would be increased in this high-risk population. In fact, our research group has previously shown that TNF-α levels are increased in RH when compared to normotensives and that this cytokine was associated with increased arterial stiffness.² Recently, our research group also demonstrated that an elevated inflammatory score, combining several circulating cytokines, such as the TNF-α, relates to RH in an obesity-dependent manner, when compared to controlled hypertensives.¹

Inhibitors of TNF-α have been acknowledged worldwide to treat autoimmune diseases, mainly in a rheumatology setting.¹⁸^,¹⁹ Infliximab is a chimeric human-mouse monoclonal antibody biological drug that neutralizes the biological activity of TNF-α. Binding with high affinity to the soluble and transmembrane forms of TNF-α, infliximab is able to inhibit TNF-α binding with its receptors.²⁰ Besides the clinical benefits observed after infliximab use in relieving symptoms or avoiding the progression of autoimmune diseases, its administration has also revealed the potential to reduce CV risk. For instance, results from cohort studies have indicated a reduction in the incidence of CV events in subjects with rheumatoid arthritis (RA) who were taking anti-TNF-α therapy.²¹^,²²

TNF-α inhibition effects on preventing the rise in BP levels and organ damage have been reported in hypertensive models.⁶^,²³ Our research group found a reduction in SBP and left ventricular hypertrophy in spontaneously hypertensive rats after an 8-week treatment with infliximab (in both doses of 1.5 and 6mg/kg/week). These CV benefits were possibly achieved due to a vasodilation dependent-mechanism, in which the neutralization of TNF-α was able to induce the NO synthesis.⁶ In the clinical setting, infliximab (initially at 3mg/Kg every 8 weeks during a 1-year follow-up) decreased SBP and DBP levels in patients with recent-onset RA, apart from the reduction in disease activity.²⁴ In addition, after 2 weeks of therapy, infliximab (3mg/kg) reduced 24-h systolic BP in patients with RA, particularly during daytime. This study also found a reduction in plasma levels of norepinephrine and plasma renin activity, suggesting the infliximab-related changes in the SNS and RAAS.²⁵ Our findings are in part consistent with those previous studies, since they revealed a modest effect of a single dose of infliximab therapy at 3 mg/Kg on reducing BP levels immediately after its infusion in a high-risk population such as the RH. Nevertheless, we recognize the failure to reach the targeted clinical difference of 10 mmHg designed in this trial.

Inhibition of the inflammatory pathway by the anti-TNF-α infliximab in our study might have acutely evoked some functional/biochemical changes, and, consequently, provided these reduced BP levels. As is well-known, TNF-α is able to induce endothelial dysfunction²⁶ by (i) stimulating the release of endothelial microparticles and reactive oxygen species production²⁷ and (ii) downregulating the expression of constitutive eNOS,²⁸ which reduces NO bioavailability. In our study, FMD results showed no statistical difference seven days after the acute administration of infliximab, nor in the levels of NO metabolites (nitrate/nitrite), in either of two assessed times. Although TNF-α inhibition has been reported as a potential strategy to improve endothelial function,²⁹ our negative results might be explained by the fact that we have previously demonstrated that RH subjects have severely impaired vasodilation associated with greater vascular stiffness³⁰ and higher levels of 8-isoprostane,³¹ a proposed marker of oxidative stress in vivo, when compared to controlled hypertensives. On the other hand, it is still possible that NO levels immediately after infliximab infusion are reduced in small resistance arteries – which our study was unable to access – causing the TPR and BP reductions, although the first parameter proved to be insignificant. Another hypothesis to support our findings is the crosstalk between TNF-α and RAAS, as already mentioned above. This proinflammatory cytokine can stimulate both the expression of the angiotensin type 1 receptors¹⁵ and the angiotensinogen gene in the liver,³² the latter physiologically leading to high levels of angiotensin II and subsequent secretion of aldosterone. Only the aldosterone levels were assessed in our study. Although the aldosterone result was borderline, and this hormone may act in a long-term regulation of BP, a trend could be observed toward a greater reduction in aldosterone in both times assessed after infliximab, when compared theto placebo.

Interestingly, TNF-α levels gradually increased in the times assessed after infliximab use, when compared to the placebo. Similarly, some studies have found an increase in their levels after anti-TNF-α therapy,²⁹^,³³ although the mechanisms for this elevation are still unknown. This may well be explained by the prolongation of the TNF-α half-life by treatment – as previously observed in studies exploring other anti-TNF-α therapy³⁴^,³⁵ – despite having blocked the TNF-α activity.³⁴ On the other hand, a chronic treatment was associated with the decrease in TNF-α levels, achieving a lower steady state level, which may reflect an equilibrium between tissue production and the elimination of TNF-α.³⁶ Interestingly enough an acute decrease in BP levels was observed, which was not maintained after seven days of follow-up. Since it is known that the TNF-α levels increased in the week following infliximab infusion, and that chronic treatment tends to decrease its levels, it is reasonable to suppose that a chronic treatment could be accompanied by a sustained decrease in BP levels. However, this would need to be proven in a longer follow-up after infusion.

The present study has several limitations inherent to pilot, proof-of-concept studies. The most important limitation is the small sample size. It is worth mentioning that our studied population represents a very specific subset of hypertensive patients, with a low prevalence worldwide.¹⁶ Moreover, a great proportion of the subjects presented positive skin tests for tuberculosis and were excluded from the study (n=9). Our negative findings in secondary outcomes in the two assessed times may have been due to an insufficient statistical power (type II error). A single dose at 3mg/Kg may not have been enough to cause the clinical effect expected immediately after the infusion, nor any effect in the short-term evaluation (seven days after infusion). Although we did not find the targeted difference of 10 mmHg in mean BP after infliximab versus placebo [in fact, the mean of differences was -6.3 (SD=7.2)], our study power was 70% and may therefore be considered satisfactory, since it is a pilot trial. We recognize that a crossover design may imply the possible existence of carry-over effects. Trying to overcome this issue, and given the long half-life of infliximab (median elimination half-life is about eight days),⁸ a washout of 40 days (5x half-life) would be safe. Due to the single dose used in this trial, it is not possible to assure that the effects in reducing BP levels are sustained during the chronic use of infliximab. Finally, to guarantee internal and external validities larger-scale trials would be required to establish the clinical safety and efficacy of a TNF-α inhibitor in the management of RH.

Conclusions

This proof-of concept pilot trial showed that a single-dose infliximab reduced the mean and diastolic BP levels immediately after its infusion, when compared to the placebo. The anti-TNF-α therapy was found to be safe and well-tolerated. It adds clinical perspective on therapies targeting the inflammatory process to manage difficult-to-treat hypertension. Due to the small sample size and power below the pre-specified levels, the findings must be interpreted as exploratory and hypothesis-generating.

Acknowledgments

The authors acknowledge the Center for High Cost Medication (Centro de Medicamentos de Alta Complexidade - CEDMAC) - Clinical Hospital/University of Campinas (UNICAMP) for technician and medication support.

Funding Statement

This study was funded by FAPESP (2015/17151-7) and partially funded by CNPq and CAPES.

Footnotes

Sources of Funding

This study was funded by FAPESP (2015/17151-7) and partially funded by CNPq and CAPES.

Study Association

This study is not associated with any thesis or dissertation work.

*Supplemental Materials

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PERMALINK

Efeitos da Terapia com Anti-TNF alfa na Pressão Arterial em Pacientes com Hipertensão Resistente: Um Estudo Piloto Randomizado, Duplo-Cego e Controlado por Placebo

Ana Paula de Faria

Alessandra M V Ritter

Arthur Santa-Catharina

Débora P Souza

Estephania P Naseri

Manoel B Bertolo

Mariana Rodrigues Pioli

Caio C Carvalho

Rodrigo Modolo

Heitor Moreno

Resumo

Fundamento:

Objetivos:

Métodos:

Resultados:

Conclusões:

Introdução

Métodos

Desenho do estudo

População

Protocolo e avaliações do estudo

Pressão arterial, função endotelial e avaliações bioquímicas

Desfechos primário e secundários

Análises estatísticas

Resultados

Figura 1. Fluxograma do estudo.

Tabela 1. Características da linha de base da população do estudo.

Discussão

Conclusões

Agradecimentos

Funding Statement

Footnotes

Referências

Effects of Anti-TNF alpha Therapy on Blood Pressure in Resistant Hypertensive Subjects: A Randomized, Double-Blind, Placebo-Controlled Pilot Study

Ana Paula de Faria

Alessandra M V Ritter

Arthur Santa-Catharina

Débora P Souza

Estephania P Naseri

Manoel B Bertolo

Mariana Rodrigues Pioli

Caio C Carvalho

Rodrigo Modolo

Heitor Moreno

Abstract

Background:

Objective:

Methods:

Results:

Conclusions:

Introduction

Methods

Trial design

Population

Trial protocol and assessments

Blood pressure, endothelial function, and biochemical assessments

Primary and secondary endpoints

Statistical analyses

Results

Figure 1. Study flow diagram.

Table 1. Baseline characteristics of the studied subjects.

Discussion

Conclusions

Acknowledgments

Funding Statement

Footnotes

ACTIONS

PERMALINK

RESOURCES

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