Colite Ulcerativa

Fatos sobre colite ulcerativa

Acredita-se que a causa da colite ulcerativa esteja de alguma forma relacionada a reações imunológicas anormais do corpo às bactérias normalmente encontradas no cólon.

• A colite ulcerativa (UC) é uma inflamação do intestino grosso (cólon).
• A causa da colite ulcerativa é desconhecida.
• Sangramento retal intermitente, dor abdominal em cólica e diarreia geralmente são sintomas de colite ulcerativa.
• O diagnóstico de colite ulcerativa pode ser feito com um enema de bário, mas a visualização direta (sigmoidoscopia ou colonoscopia) é o meio de diagnóstico mais preciso.
• A colite ulcerativa de longa duração é um fator de risco para câncer de cólon.
• O tratamento da colite ulcerativa pode envolver medicamentos e cirurgia.
• A colite ulcerativa também pode causar inflamação nas articulações, coluna, pele, olhos, fígado e seus ductos biliares.

Dieta para colite ulcerativa

Não há evidências clínicas ou científicas que sustentem a teoria de que uma dieta especializada possa causar ou beneficiar indivíduos com colite ulcerativa (CU). No entanto, os pacientes podem achar que certos alimentos agravam os sintomas da colite ulcerativa e devem evitar esses alimentos. Os sintomas mais comuns da colite ulcerativa são sangramento retal, cólicas abdominais e diarreia. Algumas pessoas recomendam evitar uma dieta rica em fibras (como frutas cruas, vegetais, sementes, nozes, etc.), além de outros alimentos que agravam os sintomas. Pode ser razoável manter um diário alimentar para rastrear quais alimentos agravam os sintomas e alimentos que não agravam os sintomas (por exemplo, bananas, arroz branco, pão branco, compota de maçã, alimentos leves e macios, etc.) Discuta suas necessidades dietéticas com seu médico ou nutricionista especializado em colite ulcerativa e dieta.

O que é colite ulcerativa?

A colite ulcerosa é considerada relacionada com a doença de Crohn, outra doença inflamatória crónica dos intestinos (ambas são referidas como doença inflamatória intestinal).


A colite ulcerativa é uma inflamação crônica do intestino grosso (cólon). O cólon é a parte do sistema digestivo onde a água é removida do material não digerido e o material residual restante é armazenado. O reto é a extremidade do cólon adjacente ao ânus. Em pacientes com colite ulcerativa, úlceras e inflamação do revestimento interno do cólon levam a sintomas de dor abdominal, diarreia e sangramento retal.

A colite ulcerativa está intimamente relacionada a outra condição de inflamação dos intestinos chamada doença de Crohn. Juntos, eles são frequentemente referidos como doença inflamatória intestinal (DII). A colite ulcerativa e as doenças de Crohn são condições crônicas. A doença de Crohn pode afetar qualquer porção do trato gastrointestinal, incluindo todas as camadas da parede intestinal. Pode não estar limitado ao trato GI (afetando o fígado, a pele, os olhos e as articulações). A UC afeta apenas o revestimento do cólon (intestino grosso). Homens e mulheres são afetados igualmente. Os mais comuns começam durante a adolescência e início da idade adulta, mas também podem começar durante a infância e mais tarde na vida.

A UC é encontrada em todo o mundo, mas é mais comum nos Estados Unidos, Inglaterra e norte da Europa. É especialmente comum em pessoas de ascendência judaica. A colite ulcerativa raramente é vista na Europa Oriental, Ásia e América do Sul, e é rara na população negra. Por razões desconhecidas, um aumento da frequência dessa condição foi observado recentemente em nações em desenvolvimento.

Parentes de primeiro grau de pessoas com colite ulcerativa têm um risco aumentado de desenvolver a doença ao longo da vida, mas o risco geral permanece pequeno.

Quais são os sintomas de colite ulcerativa?

Ilustração de colite ulcerativa


Os sintomas comuns da colite ulcerativa incluem sangramento retal, dor abdominal e diarreia, mas há uma ampla gama de sintomas entre os pacientes com esta doença. A variabilidade dos sintomas reflete as diferenças na extensão da doença (a quantidade do cólon e do reto que está inflamada) e a intensidade da inflamação. Geralmente, pacientes com inflamação confinada ao reto e um segmento curto do cólon adjacente ao reto apresentam sintomas mais leves e um prognóstico melhor do que pacientes com inflamação do cólon mais disseminada. Os diferentes tipos de colite ulcerativa são classificados de acordo com a localização e a extensão da inflamação:

1. Proctite ulcerativa refere-se à inflamação que é limitada ao reto. Em muitos pacientes com proctite ulcerativa, sangramento retal intermitente leve pode ser o único sintoma. Outros pacientes com inflamação retal mais grave podem, além disso, sentir dor retal, urgência (sensação súbita de ter que defecar e necessidade de correr para o banheiro por medo de se sujar) e tenesmo (necessidade ineficaz e dolorosa de evacuar causada pela inflamação).
2. Proctossigmoidite envolve inflamação do reto e do cólon sigmóide (um segmento curto do cólon contíguo ao reto). Os sintomas da proctossigmoidite, como os da proctite, incluem sangramento retal, urgência e tenesmo. Alguns pacientes com proctossigmoidite também desenvolvem diarreia sanguinolenta e cólicas.
3. Colite do lado esquerdo envolve inflamação que começa no reto e se estende até o cólon esquerdo (cólon sigmóide e cólon descendente). Os sintomas da colite do lado esquerdo incluem diarreia sanguinolenta, cólicas abdominais, perda de peso e dor abdominal do lado esquerdo.
4. Pancolite ou colite universal refere-se à inflamação que afeta todo o cólon (cólon direito, cólon esquerdo, cólon transverso e reto). Os sintomas da pancolite incluem diarreia sanguinolenta, dor e cólicas abdominais, perda de peso, fadiga, febre e suores noturnos. Alguns pacientes com pancolite apresentam inflamação de baixo grau e sintomas leves que respondem prontamente aos medicamentos. Geralmente, no entanto, os pacientes com pancolite sofrem de doença mais grave e são mais difíceis de tratar do que aqueles com formas mais limitadas de colite ulcerativa.
5. Colite fulminante é uma forma rara, mas grave de pancolite. Os pacientes com colite fulminante ficam extremamente doentes com desidratação, dor abdominal intensa, diarreia prolongada com sangramento e até choque. Eles correm o risco de desenvolver megacólon tóxico (dilatação acentuada do cólon devido à inflamação grave) e ruptura do cólon (perfuração). Pacientes com colite fulminante e megacólon tóxico são tratados no hospital com medicamentos intravenosos potentes. A menos que respondam prontamente ao tratamento, a remoção cirúrgica do cólon doente é necessária para evitar a ruptura do cólon.

Enquanto a intensidade da inflamação do cólon na colite ulcerativa aumenta e diminui ao longo do tempo, a localização e a extensão da doença em um paciente geralmente permanecem constantes. Portanto, quando um paciente com proctite ulcerativa desenvolve uma recaída de sua doença, a inflamação geralmente fica confinada ao reto. No entanto, um pequeno número de pacientes (menos de 10%) com proctite ulcerativa ou proctossigmoidite pode desenvolver colite mais extensa posteriormente. Assim, pacientes que inicialmente apresentam apenas proctite ulcerativa podem desenvolver posteriormente colite do lado esquerdo ou mesmo pancolite.

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O que causa a colite ulcerativa?

A causa da colite ulcerativa não é conhecida. Até o momento, não há evidências convincentes de que seja causada por infecção ou seja contagiosa.

A colite ulcerativa provavelmente envolve a ativação anormal do sistema imunológico nos intestinos. Este sistema deve defender o corpo contra bactérias nocivas, vírus, fungos e outros invasores estrangeiros. Normalmente, o sistema imunológico é ativado apenas quando o corpo é exposto a invasores nocivos. Em pacientes com colite ulcerativa, no entanto, o sistema imunológico é ativado de forma anormal e crônica na ausência de qualquer invasor conhecido. A ativação anormal contínua do sistema imunológico causa inflamação crônica e ulceração das porções do intestino grosso. Essa suscetibilidade à ativação anormal do sistema imunológico é herdada geneticamente. Parentes de primeiro grau (irmãos, irmãs, filhos e pais) de pacientes com DII são, portanto, mais propensos a desenvolver essas doenças.

Houve vários estudos usando varreduras de associação ampla do genoma investigando a suscetibilidade genética na colite ulcerativa. Esses estudos descobriram que existem aproximadamente 30 genes que podem aumentar a suscetibilidade à colite ulcerativa, incluindo o gene do receptor de imunoglobulina FCGR2A, 5p15, 2p16, ORMDL3, ECM1, bem como regiões nos cromossomos 1p36, 12q15, 7q22, 22q13 e IL23R. Neste ponto inicial da pesquisa, ainda não está claro como essas associações genéticas serão aplicadas no tratamento da doença, mas elas podem ter implicações futuras para entender a patogênese e criar novos tratamentos.

Como é feito o diagnóstico de colite ulcerativa?

O diagnóstico de colite ulcerativa é sugerido pelos sintomas de dor abdominal, sangramento retal e diarreia. Como não há padrão-ouro para o diagnóstico, o diagnóstico final depende de uma combinação de sintomas, a aparência do revestimento do cólon no momento da endoscopia, características histológicas de biópsias do revestimento do cólon e estudos de fezes para excluir a presença de infecções infecciosas. agentes que podem estar causando a inflamação.

• Amostras de fezes são coletados para análise para excluir infecção e parasitas, pois essas condições podem causar colite que imita a colite ulcerativa.
• Exames de sangue pode mostrar anemia (uma contagem baixa de glóbulos vermelhos) e uma contagem elevada de glóbulos brancos e/ou uma taxa de sedimentação elevada (comumente referida como "taxa de sed"). Uma contagem elevada de glóbulos brancos e uma taxa de sed refletem a inflamação contínua que pode estar associada à infecção ou a qualquer tipo de inflamação crônica, incluindo UC e doença de Crohn. A anemia, especialmente em um jovem do sexo masculino com dor crônica e diarreia, deve levantar a suspeita de DII para o médico.
• Outros exames de sangue também pode ser verificado, incluindo função renal, testes de função hepática, estudos de ferro e proteína C reativa (outro sinal de inflamação).
• Há algumas evidências de que um teste de fezes para uma proteína chamada calprotectina pode ser útil na identificação de pacientes que se beneficiariam da colonoscopia. A calprotectina parece ser um marcador sensível de inflamação intestinal, o que significa que pode ser elevada antes que os sintomas se tornem graves e os sinais de inflamação não sejam claros. No cenário certo, particularmente no início do curso da DII, níveis elevados podem sugerir doença inflamatória intestinal. Este teste sozinho, no entanto, não pode distinguir entre as diferentes doenças que causam a inflamação, portanto, deve ser usado com cautela.
• A confirmação da colite ulcerativa requer um teste para visualizar o intestino grosso. Tubos flexíveis inseridos pelo reto ( c olonoscópio) permitem a visualização direta do interior do cólon para estabelecer o diagnóstico e determinar a extensão da colite. Pequenas amostras de tecido (biópsias) podem ser obtidas durante o procedimento para determinar a gravidade da colite.
• Um raio X de enema de bário também pode indicar o diagnóstico de colite ulcerativa. Durante um enema de bário, uma substância líquida calcária é administrada no reto e injetada no cólon. O bário é tão denso que os raios X não passam por ele, de modo que o contorno do cólon pode ser visto nas imagens de raios X. Um enema de bário é menos preciso e útil do que a visualização direta (sigmoidoscopia ou colonoscopia) no diagnóstico de CU. Se for realizado um enema de bário e houver suspeita de colite ulcerativa, é necessária uma colonoscopia para verificar o diagnóstico.

O conhecimento da extensão e gravidade da colite é importante na escolha entre as opções de tratamento.

Algumas modalidades de diagnóstico mais recentes incluem endoscopia por cápsula de vídeo e enterografia por TC/RM. A videocápsula endoscópica (VCE) pode ser útil para a detecção de doença do intestino delgado em pacientes com diagnóstico de CU com características atípicas e que podem ser suspeitos de realmente ter doença de Crohn. Com o VCE, os pacientes engolem uma cápsula que contém uma câmera que tira fotos enquanto viaja pelos intestinos e envia as fotos sem fio para um gravador. As fotos são então revisadas. Em um estudo de 2007, a VCE confirmou a presença de doença do intestino delgado em cerca de 15% dos pacientes com colite ulcerativa com características atípicas ou doença inflamatória intestinal não classificada, alterando o diagnóstico para doença de Crohn (que não se limita ao intestino grosso como na UC). Esta pode ser uma modalidade diagnóstica útil nesta população específica de pacientes.

A enterografia por TC e RM são técnicas de imagem que utilizam agentes de contraste líquido oral constituídos por soluções de PEG ou baixa concentração de bário para proporcionar uma distensão mais adequada do cólon e do intestino delgado. Estes foram relatados como superiores às técnicas de imagem padrão na avaliação da patologia do intestino delgado em pacientes com doença de Crohn. Eles também demonstraram fornecer estimativas adequadas da gravidade da doença na colite ulcerativa (com algumas sub e superestimativas).

Quais são as complicações da colite ulcerativa?

Transfusões de sangue, pancolite e megacólon tóxico

Pacientes com colite ulcerativa limitada ao reto (proctite) ou colite limitada ao final do cólon esquerdo (proctossigmoidite) geralmente se saem muito bem. Tratamentos periódicos breves usando medicamentos orais ou enemas podem ser suficientes. Complicações graves são raras nesses pacientes. Naqueles com doença mais extensa, a perda de sangue dos intestinos inflamados pode levar à anemia e pode exigir tratamento com suplementos de ferro ou mesmo transfusões de sangue. Raramente, o cólon pode dilatar agudamente para um tamanho grande quando a inflamação se torna muito grave. Essa condição é chamada de megacólon tóxico. Pacientes com megacólon tóxico estão extremamente doentes com febre, dor e distensão abdominal, desidratação e desnutrição. A menos que o paciente melhore rapidamente com a medicação, a cirurgia geralmente é necessária para evitar a ruptura do cólon.

Em um estudo escandinavo publicado com mais de 500 pacientes com colite ulcerativa acompanhados por até 10 anos após o diagnóstico, descobriu-se que sua taxa de mortalidade não diferia da população geral. Além disso, a necessidade cumulativa de colectomia após 10 anos foi de 9,8%, quase 50% dos pacientes estavam livres de recidiva nos últimos cinco anos do estudo e apenas 20% dos pacientes com proctite ou doença do lado esquerdo evoluíram para pancolite.

Câncer

O câncer de cólon é uma complicação reconhecida da colite ulcerativa crônica. O risco de câncer começa a aumentar após oito a dez anos de colite. Pacientes com apenas proctite ulcerativa provavelmente não apresentam risco aumentado de câncer de cólon em comparação com a população geral. Entre os pacientes com pancolite ativa (envolvendo todo o cólon) por 10 anos ou mais, o risco de câncer de cólon é maior em comparação com a população geral. Em pacientes com colite limitada ao lado esquerdo do cólon, o risco de câncer de cólon é aumentado, mas não tão alto quanto em pacientes com pancolite crônica.

Os pacientes com maior risco de câncer são pacientes com história familiar positiva de câncer de cólon, colite de longa duração, envolvimento extenso do cólon e colangite esclerosante primária (CEP), outra complicação da colite ulcerativa.

Uma vez que esses cânceres têm um resultado mais favorável quando diagnosticados e tratados em um estágio mais precoce, exames de cólon anuais podem ser recomendados após oito anos de doença extensa conhecida. Durante esses exames, amostras de tecido (biópsias) podem ser coletadas para procurar alterações pré-cancerosas nas células de revestimento do cólon. Quando alterações pré-cancerosas são encontradas, a remoção do cólon pode ser necessária para prevenir o câncer de cólon.

Outras complicações da colite ulcerativa

As complicações da colite ulcerativa podem envolver outras partes do corpo.

• Dez por cento dos pacientes podem desenvolver inflamação das articulações (artrite).
• Alguns pacientes têm dor lombar devido à artrite das articulações sacroilíacas.
• A espondilite anquilosante (EA) é um tipo de artrite que afeta as articulações vertebrais dos indivíduos afetados. Parece haver uma incidência aumentada de espondilite anquilosante entre pacientes com doença inflamatória intestinal.
• Raramente, os pacientes podem desenvolver nódulos cutâneos dolorosos e vermelhos (eritema nodoso). Outros podem ter olhos vermelhos e dolorosos (uveíte, episclerite). Como essas complicações específicas podem causar comprometimento permanente da visão, dor nos olhos ou vermelhidão são sintomas que exigem avaliação médica.
• As doenças do fígado e dos ductos biliares também podem estar associadas à colite ulcerativa. Por exemplo, em pacientes com uma condição rara chamada colangite esclerosante, infecções repetidas e inflamação nos ductos biliares podem levar a febre recorrente, amarelecimento da pele (icterícia), cirrose e necessidade de transplante de fígado.
• Finalmente, os pacientes com colite ulcerativa também podem ter uma tendência aumentada de formar coágulos sanguíneos, especialmente no cenário de doença ativa.

Quais são os tratamentos para colite ulcerativa?

Tanto os medicamentos quanto a cirurgia têm sido usados ​​para tratar a colite ulcerativa. No entanto, a cirurgia é reservada para aqueles com inflamação grave e complicações com risco de vida. Não há medicamento que possa curar a colite ulcerativa. Pacientes com colite ulcerativa normalmente experimentam períodos de recaída (agravamento da inflamação) seguidos por períodos de remissão (resolução da inflamação) com duração de meses a anos. Durante as recaídas, os sintomas de dor abdominal, diarreia e sangramento retal pioram. Durante as remissões, esses sintomas desaparecem. As remissões geralmente ocorrem devido ao tratamento com medicamentos ou cirurgia, mas ocasionalmente ocorrem de forma espontânea, ou seja, sem nenhum tratamento.

O que são medicamentos para colite ulcerativa ?

Como a colite ulcerativa não pode ser curada por medicamentos, os objetivos do tratamento com medicamentos são 1) induzir remissões, 2) manter as remissões, 3) minimizar os efeitos colaterais do tratamento, 4) melhorar a qualidade de vida e 5) minimizar o risco de câncer . O tratamento da colite ulcerativa com medicamentos é semelhante, embora nem sempre idêntico, ao tratamento da doença de Crohn.

Os medicamentos para o tratamento da colite ulcerativa incluem 1) agentes anti-inflamatórios, como compostos 5-ASA, corticosteróides sistêmicos, corticosteróides tópicos e 2) imunomoduladores.

Medicamentos anti-inflamatórios que diminuem a inflamação intestinal são análogos aos medicamentos para artrite que diminuem a inflamação das articulações (artrite). Os medicamentos anti-inflamatórios usados ​​no tratamento da colite ulcerativa são:

• Compostos 5-ASA tópicos como sulfassalazina (Azulfidine), olsalazina (Dipentum) e mesalamina (Pentasa, Asacol, Lialda, Apriso Rowasa enema) que precisam de contato direto com o tecido inflamado para serem eficazes.
• Medicamentos anti-inflamatórios sistêmicos, como corticosteróides que diminuem a inflamação em todo o corpo sem contato direto com o tecido inflamado. Os corticosteroides sistêmicos têm efeitos colaterais previsíveis com o uso a longo prazo.

Os imunomoduladores são medicamentos que suprimem o sistema imunológico do corpo, seja reduzindo as células responsáveis ​​pela imunidade ou interferindo em proteínas importantes na promoção da inflamação. Os imunomoduladores estão se tornando cada vez mais importantes tratamentos para pacientes com colite ulcerativa grave que não respondem adequadamente aos agentes anti-inflamatórios. Exemplos de imunomoduladores incluem 6-mercaptopurina (6-MP), azatioprina (Imuran), metotrexato (Rheumatrex, Trexall), ciclosporina (Gengraf, Neoral).

Há muito se observa que o risco de colite ulcerativa parece ser maior em não fumantes e em ex-fumantes. Em certas circunstâncias, os pacientes melhoram quando tratados com nicotina.

Compostos de 5-ASA

O 5-ASA (ácido 5-aminossalicílico), também chamado de mesalamina, é quimicamente semelhante à aspirina. A aspirina (ácido acetilsalicílico) tem sido usada por muitos anos no tratamento de artrite, bursite e tendinite (condições de inflamação dos tecidos). A aspirina, no entanto, não é eficaz no tratamento da colite ulcerativa. Por outro lado, o 5-ASA pode ser eficaz no tratamento da colite ulcerativa se o fármaco puder ser administrado diretamente (topicamente) no revestimento do cólon inflamado. Por exemplo, o enema Rowasa é uma solução de 5-ASA que é eficaz no tratamento da inflamação no reto e próximo ao reto (proctite ulcerativa e proctosigmoidite ulcerativa). No entanto, a solução de enema não pode atingir o suficiente para tratar a inflamação na parte superior do cólon. Portanto, para a maioria dos pacientes com colite ulcerativa, o 5-ASA deve ser administrado por via oral. Quando o 5-ASA puro é tomado por via oral, no entanto, o estômago e o intestino delgado superior absorvem a maior parte da droga antes de atingir o cólon. Portanto, para ser eficaz como agente oral para colite ulcerativa, o 5-ASA deve ser modificado quimicamente para escapar da absorção pelo estômago e intestinos superiores. Esses compostos de 5-ASA modificados são sulfassalazina (Azulfidina), mesalamina (Pentasa, Rowasa, Asacol, Lialda, Apriso) e olsalazina (Dipentum).

Azulfidina

A sulfassalazina (Azulfidina) tem sido usada com sucesso por muitos anos na indução de remissão em pacientes com colite ulcerativa leve a moderada. Induzir a remissão significa diminuir a inflamação intestinal e aliviar os sintomas de dor abdominal, diarreia e sangramento retal. A sulfassalazina também tem sido usada por períodos prolongados para manter as remissões.

A sulfassalazina consiste em uma molécula de 5-ASA ligada quimicamente a uma molécula de sulfapiridina. (A sulfapiridina é um antibiótico sulfa). Conectar as duas moléculas impede a absorção pelo estômago e intestinos superiores antes de atingir o cólon. Quando a sulfassalazina atinge o cólon, as bactérias no cólon quebram a ligação entre as duas moléculas. Após romper com o 5-ASA, a sulfapiridina é absorvida pelo corpo e então excretada na urina. A maior parte do fármaco 5-ASA ativo, no entanto, permanece no cólon para tratar a colite.

A maioria dos efeitos colaterais da sulfassalazina são devidos à molécula de sulfapiridina. Esses efeitos colaterais incluem náusea, azia, dor de cabeça, anemia, erupções cutâneas e, em casos raros, hepatite e inflamação renal. Nos homens, a sulfassalazina pode reduzir a contagem de espermatozóides. A redução na contagem de espermatozóides é reversível, e a contagem geralmente volta ao normal após a descontinuação da sulfassalazina ou pela mudança para um composto 5-ASA diferente.

Os benefícios da sulfassalazina geralmente estão relacionados à dose. Portanto, altas doses de sulfassalazina podem ser necessárias para induzir a remissão. Alguns pacientes não podem tolerar altas doses por causa de náuseas e dores de estômago. Para minimizar o desconforto estomacal, a sulfassalazina geralmente é tomada após ou com as refeições. Alguns pacientes acham mais fácil tomar Azulfidine-EN (forma de sulfassalazina com revestimento entérico). O revestimento entérico ajuda a diminuir a dor de estômago. Os novos compostos 5-ASA não têm o componente sulfapiridina e têm menos efeitos colaterais do que a sulfassalazina.

Asacol

Asacol é um comprimido que consiste no composto 5-ASA, mesalamina, envolvido por um revestimento de resina acrílica. (Asacol é livre de sulfa.) O revestimento de resina evita que o 5-ASA seja absorvido ao passar pelo estômago e intestino delgado. Quando o comprimido atinge o íleo terminal e o cólon, o revestimento de resina se dissolve, liberando assim 5-ASA no cólon.

Asacol é eficaz na indução de remissões em pacientes com colite ulcerativa leve a moderada. Também é eficaz quando usado por períodos prolongados para manter as remissões. A dose recomendada de Asacol para induzir a remissão é de dois comprimidos de 400 mg três vezes ao dia (total de 2,4 gramas por dia). Dois comprimidos de Asacol duas vezes ao dia (1,6 gramas por dia) são recomendados para manter a remissão. Ocasionalmente, a dose de manutenção é maior.

As with Azulfidine, the benefits of Asacol are dose-related. If patients do not respond to 2.4 grams a day of Asacol, the dose frequently is increased to 3.6 grams a day (and sometimes even higher) to induce remission. If patients fail to respond to the higher doses of Asacol, then alternatives, such as corticosteroids, are considered.

Lialda

Lialda (mesalamine multi matrix, MMX) is an extended release formulation. It is a 5-ASA medication within an inert matrix that is surrounded by a coating. When the capsule reaches the distal ileum, the outer coating (the capsule) dissolves. The intestinal fluid then is absorbed into the matrix forming a gel-like substance which prolongs the contact of the medication with the colonic wall as the mesalamine slowly separates from the matrix. This extended release formulation allows for higher doses to be taken less frequently throughout the day and might and improve compliance.

The most common side effects experienced while taking Lialda are flatulence, abdominal pain, headache, nausea, and dyspepsia.

Apriso

Apriso is another formulation of 5-ASA that consists of extended-release mesalamine granules encased in microcrystalline cellulose within a capsule. Dissolution of the capsule occurs in the distal ileum, and, since the granules are encased in the cellulose and only slowly separates from the cellulose, there is prolonged delivery of medication as the cellulose and mesalamine travel through the colon.

The most common side effects of this medication are headache, diarrhea, abdominal pain, nausea, nasopharyngitis, influenza-like illness, and sinusitis.

Pentasa

Pentasa is a capsule consisting of the 5-ASA compound mesalamine inside controlled-release spheres. Like Asacol, it is sulfa free. As the capsule travels down the intestines, the 5-ASA inside the spheres is slowly released into the intestines. Unlike Asacol, the mesalamine in Pentasa is released into the small intestine as well as the colon. Therefore, Pentasa can be effective in treating inflammation in the small intestine and the colon. Pentasa is currently the most logical 5-ASA compound for treating mild to moderate Crohn's disease involving the small intestine. Pentasa also is used to induce remission and maintain remission among patients with mild to moderate ulcerative colitis.

Olsalazine (Dipentum)

Olsalazine (Dipentum) consists of two 5-ASA molecules linked together. It is sulfa free. The linked 5-ASA molecules travel through the stomach and the small intestine unabsorbed. When the drug reaches the terminal ileum and the colon, the normal bacteria in the intestine break the linkage and release the active drug into the colon and the terminal ileum. Olsalazine has been used in treating ulcerative colitis and in maintaining remissions. A side effect unique to olsalazine is secretory diarrhea (diarrhea resulting from excessive production of fluid in the intestines). This condition occurs in some patients, and the diarrhea sometimes can be severe.

Balsalazide (Colazal

Balsalazide (Colazal) is a capsule in which the 5-ASA is linked by a chemical bond to another molecule that is inert (without effect on the intestine) and prevents the 5-ASA from being absorbed. This drug is able to travel through the intestine unchanged until it reaches the end of the small bowel (terminal ileum) and colon. There, intestinal bacteria break apart the 5-ASA and the inert molecule, releasing the 5-ASA. Because intestinal bacteria are most abundant in the terminal ileum and colon, Colazal is used to treat inflammation predominantly localized to the colon.

More clinical trials are needed to compare the effectiveness of Colazal to the other mesalamine compounds such as Asacol in treating ulcerative colitis. Therefore in the United States, choosing which 5-ASA compound has to be individualized. Some doctors prescribe Colazal for patients who cannot tolerate or fail to respond to Asacol. Others prescribe Colazal for patients with predominantly left sided colitis, since some studies seem to indicate that Colazal is effective in treating left sided colitis.

Side Effects of 5-ASA Compounds

The sulfa-free 5-ASA compounds have fewer side effects than sulfasalazine and also do not impair male fertility. In general, they are safe medications for long-term use and are well-tolerated.

Patients allergic to aspirin should avoid 5-ASA compounds because they are chemically similar to aspirin.

Rare kidney inflammation has been reported with the use of 5-ASA compounds. These compounds should be used with caution in patients with known kidney disease. It also is recommended that blood tests of kidney function be obtained before starting and periodically during treatment.

Rare instances of acute worsening of diarrhea, cramps, and abdominal pain may occur which is at times may be accompanied by fever, rash, and malaise. This reaction is believed to represent an allergy to the 5-ASA compound.

Rowasa Enema

Rowasa is the 5-ASA compound mesalamine in enema form and is effective in ulcerative proctitis and ulcerative proctosigmoiditis (two conditions where active 5-ASA drugs taken as enemas can easily reach the inflamed tissues directly). Each Rowasa enema contains 4 grams of mesalamine in 60 cc of fluid. The enema usually is administered at bedtime, and patients are encouraged to retain the enema through the night.

The enema contains sulfite and should not be used by patients with sulfite allergy. Otherwise, Rowasa enemas are safe and well-tolerated.

Rowasa also comes in suppository form for treating limited proctitis. Each suppository contains 500 mg of mesalamine and usually is administered twice daily.

While some patients improve within several days of starting Rowasa, the usual course of treatment is three to six weeks. Some patients may need even longer courses of treatment for optimal benefit. In patients who do not respond to Rowasa, oral 5-ASA compounds (such as Asacol) can be added. Some studies have reported increased effectiveness in treating ulcerative proctitis and proctosigmoiditis by combining oral 5-ASA compounds with Rowasa enemas. Oral 5-ASA compounds also are used to maintain remission in ulcerative proctitis and proctosigmoiditis.

Another alternative for patients who fail to respond to Rowasa or who cannot use Rowasa is cortisone enemas (Cortenema). Cortisone is a potent anti-inflammatory agent. Oral corticosteroids are systemic drugs with serious and predictable long-term side effects. Cortenema is a topical corticosteroid that has less absorption into the body than oral corticosteroids, and, therefore, it has fewer and less severe side effects.

Systemic corticosteroids (including side effects)

Corticosteroids (Prednisone, prednisolone, hydrocortisone, etc.) have been used for many years in the treatment of patients with moderate to severe Crohn's disease and ulcerative colitis or who fail to respond to optimal doses of 5-ASA compounds. Unlike the 5-ASA compounds, corticosteroids do not require direct contact with the inflamed intestinal tissues to be effective. Oral corticosteroids are potent anti-inflammatory agents. After absorption, corticosteroids exert prompt anti-inflammatory action throughout the body. Consequently, they are used in treating Crohn's enteritis, ileitis, and ileocolitis, as well as ulcerative and Crohn's colitis. In critically ill patients, intravenous corticosteroids (such as hydrocortisone) can be given in the hospital.

Corticosteroids are faster acting than the 5-ASA compounds. Patients frequently experience improvement in their symptoms within days of starting corticosteroids. Corticosteroids, however, do not appear to be useful in maintaining remissions in ulcerative colitis.

Corticosteroid side effects

Side effects of corticosteroids depend on the dose and duration of use. Short courses of prednisone, for example, usually are well tolerated with few and mild side effects. Long term, high doses of corticosteroids usually produce predictable and potentially serious side effects. Common side effects include rounding of the face (moon face), acne, increased body hair, diabetes, weight gain, high blood pressure, cataracts, glaucoma, increased susceptibility to infections, muscle weakness, depression, insomnia, mood swings, personality changes, irritability, and thinning of the bones (osteoporosis) with an accompanying increased risk of compression fractures of the spine. Children on corticosteroids can experience stunted growth.

The most serious complication from long term corticosteroid use is aseptic necrosis of the hip joints. Aseptic necrosis means death of bone tissue. It is a painful condition that can ultimately lead to the need for surgical replacement of the hips. Aseptic necrosis also has been reported in knee joints. It is unknown how corticosteroids cause aseptic necrosis. Patients on corticosteroids who develop pain in the hips or knees should report the pain to their doctors promptly. Early diagnosis of aseptic necrosis with cessation of corticosteroids has been reported in some patients to decrease the severity of the condition and possibly help avoid hip replacement.

Prolonged use of corticosteroids can depress the ability of the body's adrenal glands to produce cortisol (a natural corticosteroid necessary for proper functioning of the body). Abruptly discontinuing corticosteroids can cause symptoms due to a lack of natural cortisol (a condition called adrenal insufficiency). Symptoms of adrenal insufficiency include nausea, vomiting, and even shock. Withdrawing corticosteroids too quickly also can produce symptoms of joint aches, fever, and malaise. Therefore, corticosteroids need to be gradually reduced rather than abruptly stopped.

Even after the corticosteroids are discontinued, the adrenal glands' ability to produce cortisol can remain depressed for months to two years. The depressed adrenal glands may not be able to produce enough cortisol to help the body handle stress such as accidents, surgery, and infections. These patients will need treatment with corticosteroids (prednisone, hydrocortisone, etc.) during stressful situations to avoid developing adrenal insufficiency.

Because corticosteroids are not useful in maintaining remission in ulcerative colitis and Crohn's disease and because they have predictable and potentially serious side effects, these drugs should be used for the shortest possible length of time.

Proper Use of Corticosteroids

Once the decision is made to use oral corticosteroids, treatment usually is initiated with prednisone, 40-60 mg daily. The majority of patients with ulcerative colitis respond with an improvement in symptoms. Once symptoms improve, prednisone is reduced by 5-10 mg per week until the dose of 20 mg per day is reached. The dose then is tapered at a slower rate until the prednisone ultimately is discontinued. Gradually reducing corticosteroids not only minimizes the symptoms of adrenal insufficiency, it also reduces the chances of abrupt relapse of the colitis.

Many doctors use 5-ASA compounds at the same time as corticosteroids. In patients who achieve remission with systemic corticosteroids, 5-ASA compounds such as Asacol are often continued to maintain remissions.

In patients whose symptoms return during reduction of the dose of corticosteroid, the dose of corticosteroids is increased slightly to control the symptoms. Once the symptoms are under control, the reduction can resume at a slower pace. Some patients become corticosteroid dependent. These patients consistently develop symptoms of colitis whenever the corticosteroid dose reaches below a certain level. In patients who are corticosteroid dependent or who are unresponsive to corticosteroids, other anti-inflammatory medications, immunomodulator medications or surgery are considered.

The management of patients who are corticosteroid dependent or patients with severe disease which responds poorly to medications is complex. Doctors who are experienced in treating inflammatory bowel disease and in using the immunomodulators should evaluate these patients.

Preventing Corticosteroid-induced Osteoporosis

Long-term use of corticosteroids such as prednisolone or prednisone can cause osteoporosis . Corticosteroids cause decreased calcium absorption from the intestines and increased loss of calcium from the kidneys and bones. Increasing dietary calcium intake is important but alone cannot halt corticosteroid-induced bone loss. Management of patients on long term corticosteroids should include:

• Adequate calcium (1000 mg daily if premenopausal, 1500 mg daily if postmenopausal) and vitamin D (800 units daily) intake.
• Periodic review with the doctor on the need for continued corticosteroid treatment and the lowest effective dose if continued treatment is necessary.
• A bone density study to measure the extent of bone loss in patients taking corticosteroids for more than three months.
• Regular weight-bearing exercise, and stop smoking cigarettes.
• Discussion with the doctor regarding the use of alendronate (Fosamax) or risedronate (Actonel) in the prevention and the treatment of corticosteroid induced osteoporosis.

Budesonide (Entocort EC)

Oral budesonide (Entocort EC) is a topically acting corticosteroid which was been shown to be effective in Crohn's disease, and in enema formulation for left-sided ulcerative colitis with fewer side effects than oral steroids. In a recent meta-analysis, however, it was found to be significantly less likely to induce clinical remission in patients with ulcerative colitis than oral mesalamine after 8 weeks of therapy. Therefore, use of this medication is not recommended at this time to treat flares of ulcerative colitis.

Golimumab (Simponi)

Golimumab is an injectable man-made protein that binds to tumor necrosis factor alpha in the body, and blocks the effects of tumor necrosis factor alfa in patients with ulcerative colitis. Golimumab is injected under the skin, and injection sites should be rotated. Golimumab interacts with several drugs and has several side effects. Consult with your prescribing physician or pharmacist to discuss these potential drug interactions and side effects.

What are immunomodulator medications?

Immunomodulators are medications that weaken the body's immune system. The immune system is composed of immune cells and the proteins that these cells produce. These cells and proteins serve to defend the body against harmful bacteria, viruses, fungi, and other foreign invaders. Activation of the immune system causes inflammation within the tissues where the activation occurs. (Inflammation is, in fact, an important mechanism to defend the body used by the immune system.) Normally, the immune system is activated only when the body is exposed to harmful invaders. In patients with Crohn's disease and ulcerative colitis, however, the immune system is abnormally and chronically activated in the absence of any known invader. Immunomodulators decrease tissue inflammation by reducing the population of immune cells and/or by interfering with their production of proteins that promote immune activation and inflammation. Generally, the benefits of controlling moderate to severe ulcerative colitis outweigh the risks of infection due to weakened immunity. Examples of immunomodulators include azathioprine (Imuran), 6-mercaptopurine (6-MP, Purinethol), cyclosporine (Sandimmune), and methotrexate (Rheumatrex, Trexall).

Azathioprine (Imuran) and 6-MP (Purinethol)

Azathioprine and 6-mercaptopurine (6-MP) are medications that weaken the body's immunity by reducing the population of a class of immune cells called lymphocytes. Azathioprine and 6-MP are related chemically. Specifically, azathioprine is converted into 6-MP inside the body. In high doses, these two drugs have been useful in preventing rejection of transplanted organs and in treating leukemia. In low doses, they have been used for many years to treat patients with moderate to severe Crohn's disease and ulcerative colitis.

Azathioprine and 6-MP are increasingly recognized by doctors as valuable drugs in treating Crohn's disease and ulcerative colitis. Some 70% of patients with moderate to severe disease will benefit from these drugs. Because of the slow onset of action and the potential for side effects, however, 6-MP and azathioprine are used mainly in the following situations:

• Patients with ulcerative colitis and Crohn's disease not responding to corticosteroids.
• Patients who are experiencing undesirable corticosteroid-related sideeffects.
• Patients who are dependent on corticosteroids and are unable to discontinue them without developing relapses.

When azathioprine and 6-MP are added to corticosteroids in the treatment of ulcerative colitis patients who do not respond to corticosteroids alone, there may be an improved response or smaller doses and shorter courses of corticosteroids may be effective. Some patients can discontinue corticosteroids altogether without experiencing relapses. The ability to reduce corticosteroid requirements has earned 6-MP and azathioprine their reputation as "steroid-sparing" medications.

In patients with severe ulcerative colitis who suffer frequent relapses, 5-ASA may not be sufficient, and more potent azathioprine and 6-MP will be necessary to maintain remissions. In the doses used for treating ulcerative colitis and Crohn's disease, the long-term side effects of azathioprine and 6-MP are less serious than long-term oral corticosteroids or repeated courses of oral corticosteroids.

What Are the Side Effects of 6-MP and Azathioprine?

Side effects of 6-MP and azathioprine include increased vulnerability to infections, inflammation of the liver (hepatitis) and pancreas, (pancreatitis), and bone marrow toxicity (interfering with the formation of cells that circulate in the blood).

The goal of treatment with 6-MP and azathioprine is to weaken the body's immune system in order to decrease the intensity of inflammation in the intestines; however, weakening the immune system increases the patient's vulnerability to infections. For example, in a group of patients with severe Crohn's disease unresponsive to standard doses of azathioprine, raising the dose of azathioprine helped to control the disease, but two patients developed cytomegalovirus (CMV) infection. CMV usually infects individuals with weakened immune systems such as patients with AIDS or cancer, especially if they are receiving chemotherapy, which further weakens the immune system.

Azathioprine and 6-MP-induced inflammation of the liver (hepatitis) and pancreas (pancreatitis) are rare. Pancreatitis typically causes severe abdominal pain and sometimes vomiting. Pancreatitis due to 6-MP or azathioprine occurs in a small percentage of patients, usually during the first several weeks of treatment. Patients who develop pancreatitis should not receive either of these two medications again.

Azathioprine and 6-MP also suppress the bone marrow. The bone marrow is where red blood cells, white blood cells, and platelets are made. Actually, a slight reduction in the white blood cell count during treatment is desirable since it indicates that the dose of 6-MP or azathioprine is high enough to have an effect; however, excessively low red or white blood cell counts indicates bone marrow toxicity. Therefore, patients on 6-MP and azathioprine should have periodic blood counts (usually every two weeks initially and then every 3 months during maintenance) to monitor the effect of the drugs on their bone marrow.

6-MP can reduce the sperm count in men. When the partners of male patients on 6-MP conceive, there is a higher incidence of miscarriages and vaginal bleeding. There also are respiratory difficulties in the newborn. Therefore, it is recommended that whenever feasible, male patients should stop 6-MP and azathioprine for three months before attempting to conceive.

Patients on long-term, high dose azathioprine to prevent rejection of the kidney after kidney transplantation have an increased risk of developing lymphoma, a malignant disease of lymphatic cells. There is no evidence at present that long term use of azathioprine and 6-MP in the low doses used in IBD increases the risk for lymphoma, leukemia or other malignancies.

Other Issues in the Use of 6-MP

One problem with 6-MP and azathioprine is their slow onset of action. Typically, full benefit of these drugs is not realized for three months or longer. During this time, corticosteroids frequently have to be maintained at high levels to control inflammation.

The reason for this slow onset of action is partly due to the way doctors prescribe 6-MP. Typically, 6-MP is started at a dose of 50 mg daily. The blood count is then checked two weeks later. If the white blood cell count (specifically the lymphocyte count) is not reduced, the dose is increased. This cautious, stepwise approach helps prevent severe bone marrow and liver toxicity, but also delays benefit from the drug.

Studies have shown that giving higher doses of 6-MP early can speed up the benefit of 6-MP without increased toxicity in most patients, but some patients do develop severe bone marrow toxicity. Therefore, the dose of 6-MP has to be individualized. Scientists now believe that an individual's vulnerability to 6-MP toxicity is genetically inherited. Blood tests can be performed to identify those individuals with increased vulnerability to 6-MP toxicity. In these individuals, lower initial doses can be used. Blood tests can also be performed to measure the levels of certain by-products of 6-MP. The levels of these by-products in the blood help doctors more quickly determine whether the dose of 6-MP is right for the patient.

TPMT genetics and safety of azathioprine and 6-MP

Azathioprine is converted into 6-MP in the body, and 6-MP then is partially converted into other chemicals by an enzyme called thiopurine methyltransferase (TPMT). These chemicals then are eliminated from the body. The activity of TPMT that determines the ability to convert 6-MP into other chemicals is genetically determined, and approximately 10% of the population in the United States has reduced or absent TPMT activity. In this 10% of patients, 6-MP and another related chemical (6-thioguanine or 6-TG) accumulate and are toxic to the bone marrow where blood cells are produced. Thus, when given normal doses of azathioprine or 6-MP, these patients with reduced or absent TPMT activity can develop seriously low white blood cell counts for prolonged periods of time, exposing them to serious life-threatening infections.

The Food and Drug Administration now recommends that doctors check TPMT levels prior to starting treatment with azathioprine or 6-MP. Patients found to have genes associated with reduced or absent TPMT activity are treated with alternative medications or are prescribed substantially lower than normal doses of 6-MP or azathioprine.

A word of caution is in order, however. Having normal TPMT genes is no guarantee against azathioprine or 6-MP toxicity. Rarely, a patient with normal TPMT genes can develop severe toxicity in the bone marrow and a low white blood cell count even with normal doses of 6-MP or azathioprine. In addition, with normal levels of TPMT activity, liver toxicity, another toxic effect of 6-MP, can still occur. Therefore, all patients taking 6-MP or azathioprine (regardless of TPMT genetics) have to be closely monitored by a doctor who will order periodic blood counts, and liver enzyme tests for as long as the medication is taken.

Another cautionary note:allopurinol (Zyloprim), used in treating high blood uric acids levels and gout, can induce bone marrow toxicity when used together with azathioprine or 6-MP. This occurs because allopurinol reduces TMPT activity. The combination of genetically-reduced TMPT activity and further reduction of TMPT activity by the allopurinol increases greatly the risk of bone marrow toxicity.

6-MP metabolite levels

In addition to monitoring blood cell counts and liver tests, doctors also may measure blood levels of the chemicals that are formed from 6-MP (6-MP metabolites), which can be helpful in several situations such as:

1. If a patient's disease is not responding to standard doses of 6-MP or azathioprine and his/her 6-MP blood metabolite levels are low, compliance should be checked, and if satisfactory, the dose of 6-MP or azathioprine may be increased.
2. If a patient's disease does not respond to treatment and his/her 6-MP blood metabolite levels are very low, it is most likely that he/she is not taking his/her medication. The lack of response in this case is due to patient non-compliance.

How Long Can Patients Continue on 6-MP?

Patients have been maintained on 6-MP or azathioprine for years without any important long-term side effects. Their doctors, however, should closely monitor their patients on long-term 6-MP. There is data suggesting that patients on long-term maintenance with 6-MP or azathioprine fare better than those who stop these medications. Those who stop 6-MP or azathioprine are more likely to experience relapses, more likely to need corticosteroids or undergo surgery.

Methotrexate

Methotrexate (Rheumatrex, Trexall) is an immunomodulator and anti-inflammatory medication. Methotrexate has been used for many years in the treatment of severe rheumatoid arthritis and psoriasis. It has been helpful in treating patients with moderate to severe Crohn's disease who are either not responding to 6-MP and azathioprine or are intolerant of these two medications. Methotrexate also may be effective in patients with moderate to severe ulcerative colitis who are not responding to corticosteroids or 6-MP and azathioprine. It can be given orally or by weekly injections under the skin or into the muscles. It is more reliably absorbed with the injections.

One major complication of methotrexate is the development of liver cirrhosis when the medication is given over a prolonged period of time (years). The risk of liver damage is higher in patients who also abuse alcohol or have morbid (severe) obesity. Generally, periodic liver biopsies are recommended for a patient who has received a cumulative (total) methotrexate dose of 1.5 grams and higher.

Other side effects of methotrexate include low white blood cell counts and inflammation of the lungs.

Methotrexate should not be used in pregnancy.

Cyclosporine

Cyclosporine (Sandimmune) is a potent immunosuppressant used in preventing organ rejection after transplantation, for example, of the liver. It also has been used to treat patients with severe ulcerative colitis and Crohn's disease. Because of the approval of infliximab (Remicade) for treating severe Crohn's disease, cyclosporine probably will be used primarily in severe ulcerative colitis. Cyclosporine is useful in fulminant ulcerative colitis and in severely ill patients who are not responding to systemic corticosteroids. Administered intravenously, cyclosporine can be very effective in rapidly controlling severe colitis and avoiding or delaying surgery.

Cyclosporine also is available as an oral medication, but the relapse rate with oral cyclosporine is high. Therefore, cyclosporine seems most useful when administered intravenously in acute situations.

Side effects of cyclosporine include high blood pressure, impairment of kidney function, and tingling sensations in the extremities. More serious side effects include anaphylactic shock and seizures.

Infliximab (Remicade)

Infliximab (Remicade) is an antibody that attaches to a protein called tumor necrosis factor-alpha (TNF-alpha). TNF-alpha is one of the proteins produced by immune cells during activation of the immune system. TNF-alpha, in turn, stimulates other cells of the immune system to produce and release other proteins that promote inflammation. In Crohn's disease and in ulcerative colitis, there is continued production of TNF-alpha as part of the immune activation. Infliximab, by attaching to TNF-alpha, blocks its activity and in so doing decreases the inflammation.

Infliximab, an antibody to TNF-alpha, is produced by the immune system of mice after the mice are injected with human TNF-alpha. The mouse antibody then is modified to make it look more like a human antibody, and this modified antibody is infliximab. Such modifications are necessary to decrease the likelihood of allergic reactions when the antibody is administered to humans. Infliximab is given by intravenous infusion over two hours. Patients are monitored throughout the infusion for side effects.

Infliximab has been used effectively for many years for the treatment of moderate to severe Crohn's disease that was not responding to corticosteroids or immuno-modulators. In Crohn's disease patients, a majority experienced improvement in their disease after one infusion of infliximab. Some patients noticed improvement in symptoms within days of the infusion. Most patients experienced improvement within two weeks. In patients who respond to infliximab, the improvements in symptoms can be dramatic. Moreover, there can be impressively rapid healing of the ulcers and the inflammation in the intestines after just one infusion.

Only over the last few years infliximab also has been used to treat severe UCs. In a study of over 700 patients with moderate to severe UC, for example, infliximab was found to be more effective than placebo in inducing and maintaining remission.

Infliximab is typically given to induce remission in three doses - at time zero and then two weeks and four weeks later. After remission is attained, maintenance doses can be given every other month.

Side effects of infliximab

Infliximab, generally, is well tolerated. There have been rare reports of side effects during infusions, including chest pain, shortness of breath, and nausea. These effects usually resolve spontaneously within minutes if the infusion is stopped. Other commonly reported side effects include headache and upper respiratory tract infection.

Infliximab, like immuno-modulators, increases the risk for infection. One case of salmonella colitis and several cases of pneumonia have been reported with the use of infliximab. There also have been cases of tuberculosis (TB) reported after the use of infliximab.

Because infliximab is partly a mouse protein, it may induce an immune reaction when given to humans, especially with repeated infusions. In addition to the side effects that occur while the infusion is being given, patients also may develop a "delayed allergic reaction" that occurs 7-10 days after receiving the infliximab. This type of reaction may cause flu-like symptoms with fever, joint pain and swelling, and a worsening of Crohn's disease symptoms. It can be serious, and if it occurs, a physician should be contacted. Paradoxically, those patients who have more frequent infusions of Remicade are less likely to develop this type of delayed reaction compared to those patients who receive infusions separated by long intervals (6-12 months).

There are some reports of worsening heart disease in patients who have received Remicade. The precise mechanism and role of infliximab in the development of this side effect is unclear. As a precaution, individuals with heart disease should inform their physician of this condition before receiving infliximab.

There have been rare reports of nerve damage such as optic neuritis (inflammation of the nerve of the eye) and motor neuropathy (damage to the nerves controlling muscles).

There have also been rare reports of patients developing viral colitis (cytomegalovirus and herpes simplex virus) while on immunosuppressive medications. These viral infections can mimic a flare of ulcerative colitis and mistakenly suggest resistance to therapy. Before increasing the dose or changing the medication being used to treat the ulcerative colitis, patients should have a thorough evaluation including flexible sigmoidoscopy or limited colonoscopy with biopsies to help make the diagnosis of viral colitis.

Precautions with infliximab

Infliximab can aggravate and cause the spread of an existing infection. Therefore, it should not be given to patients with pneumonia, urinary tract infection or abscess (localized collection of pus).

It now is recommended that patients be tested for TB prior to receiving infliximab. Patients who previously had TB should inform their physician of this before they receive infliximab.

Infliximab can cause the spread of cancer cells; therefore, it should not be given to patients with cancer.

The effects of infliximab on the fetus are not known although the literature suggests that this medication is safe for women to continue until week 32 of pregnancy. At that time, the risk of exposure of the fetus to this medication by placental transfer is increased. Infliximab is listed as a pregnancy category B drug by the FDA (meaning there has been no documented human toxicity).

Because infliximab is partly a mouse protein, some patients can develop antibodies against infliximab with repeated infusions. The development of these antibodies can decrease the effectiveness of the drug. The chances of developing these antibodies can be decreased by concomitant use of 6-MP and corticosteroids. There are ongoing studies in patients who have lost their initial response to infliximab to determine whether measurement of antibody titers will be helpful in guiding further treatment. Results of these studies are not yet available.

While infliximab represents an exciting new class of medications in the fight against Crohn's disease and ulcerative colitis, caution is warranted because of potentially serious side effects. Doctors are using infliximab in moderate to severe ulcerative colitis not responding to other medications.

Other biological therapies under development

Adalimumab

Adalimumab is an anti-TNF drug similar to infliximab. It decreases inflammation by blocking tumor necrosis factor (TNF-alpha). In contrast to infliximab, adalimumab is a fully humanized anti-TNF antibody containing no mouse protein and, therefore, might cause less of an immune reaction. Adalimumab is administered subcutaneously (under the skin) instead of intravenously as in the case of infliximab.

Rheumatologists have been using adalimumab for treating inflammation of the joints in patients with rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis. It was also approved by the FDA in 2007 for the treatment of moderately to severely active Crohn's disease. Though not approved formally by the FDA for treatment of ulcerative colitis, a few studies have shown it to have some efficacy in treating patients with ulcerative colitis who are refractory to or have lost their response to infliximab. More information will be required before recommending this as a standard therapy.

Visilizumab (anti-CD3 antibody)

Visilizumab is a humanized antibody that specifically binds to human CD3 expressing T cells, that inhibits the activity of the cells. (CD3 expressing T cells are part of the immune system and seem to play an important role in promoting the inflammation of ulcerative colitis.). In a phase 1 open-label study evaluating the safety and tolerability of this medication, 32 subjects received visilizumab. Results showed that 84% of these patients achieved a clinical response by day 30, 41% achieved clinical remission, and 44% achieved endoscopic remission. Main side effects were decreased CD4 counts and cytokine release syndromes (flu-like symptoms, etc), though there were no serious infections. Initial data seems promising though more must be learned about this medication before it can be used routinely. This medication is not yet approved by the FDA for treatment of ulcerative colitis.

Alpha-4 integrin blockade

Alpha-4 integrins on the surface of cells of the immune system help the cells to leave the blood and travel into the tissues where they promote inflammation. Antibodies against these integrins have been developed, to dampen the inflammatory response. Natalizumab is one such agent, and in small studies in patients with ulcerative colitis has been shown to have some efficacy in leading to clinical remission. Another more gut-selective humanized antibody (MLN02) has been evaluated in multi-center trials and has also been found to lead to clinical and endoscopic remission in more patients than placebo. More studies must be conducted to evaluate long term effectiveness and side effects of these medications. This medication is not yet approved by the FDA for treatment of ulcerative colitis.

Summary of medication treatment

• Azulfidine, Asacol, Pentasa, Dipentum, Colazal, and Rowasa all contain 5-ASA compounds which are topical anti-inflammatory ingredients. These medications are effective in inducing remission among patients with mild to moderate ulcerative colitis. They also are safe and effective in maintaining remission.
• Pentasa is more commonly used in treating Crohn's ileitis because the Pentasa capsules release more 5-ASA compounds into the small intestine than the Asacol tablets. Pentasa also can be used for treating mild to moderate ulcerative colitis.
• Rowasa enemas are safe and effective in treating ulcerative proctitis and proctosigmoiditis.
• The sulfa-free 5-ASA compounds (Asacol, Pentasa, Dipentum, Colazal, Rowasa) have fewer side effects than Azulfidine, which contains sulfa.
• Newer formulations of 5-ASA products (Lialda, Apriso) allow for higher doses to be taken less frequently throughout the day.
• In ulcerative colitis patients with moderate to severe disease and in patients who fail to respond to 5-ASA compounds, systemic (oral) corticosteroids can be used. Systemic corticosteroids (prednisone, prednisolone, cortisone, etc.) are potent and fast-acting anti-inflammatory agents for treating Crohn's ileitis, ileocolitis, and ulcerative colitis.
• Systemic corticosteroids are not effective in maintaining remission in patients with ulcerative colitis. Serious side effects can result from prolonged corticosteroid treatment.
• To minimize side effects, corticosteroids should be gradually reduced as soon as disease remission is achieved. In patients who become corticosteroid dependent or are unresponsive to corticosteroid treatment, surgery or immunomodulator treatments are considered.
• Immunomodulators used for treating severe ulcerative colitis include azathioprine/6-MP, methotrexate, and cyclosporine.
• Infliximab (Remicade) may be beneficial in controlling moderate to severe ulcerative colitis and in decreasing the need for urgent removal of the colon.
• Other biological agents are currently being studied, and with more research, might be approved for use in the future.

Surgery for ulcerative colitis

Surgery for ulcerative colitis usually involves removing the entire colon and the rectum. Removal of the colon and rectum is the only permanent cure for ulcerative colitis. This procedure also eliminates the risk of developing colon cancer. Surgery in ulcerative colitis is reserved for the following patients:

1. Patients with fulminant colitis and toxic megacolon who are not responding readily to medications.
2. Patients with long standing pancolitis or left-sided colitis who are at risk of developing colon cancers. Removal of the colon is important when changes are detected in the colon lining.
3. Patients who have had years of severe colitis which has responded poorly to medications.

Standard surgery involves the removal of the entire colon, including the rectum. A small opening is made in the abdominal wall and the end of the small intestine is attached to the skin of the abdomen to form an ileostomy. Stool collects in a bag that is attached over the ileostomy. Recent improvements in the construction of ileostomies have allowed for continent ileostomies. A continent ileostomy is a pouch created from the intestine. The pouch serves as a reservoir similar to a rectum, and is emptied on a regular basis with a small tube. Patients with continent ileostomies do not need to wear collecting bags.

More recently, a surgery has been developed which allows stool to be passed normally through the anus. In an ileo-anal anastomosis, the large intestine is removed and the small intestine is attached just above the anus. Only the diseased lining of the anus is removed and the muscles of the anus remain intact. In this "pull-through" procedure, the normal route of stool elimination is maintained. This procedure has a relatively good success rate, although pouchitis (inflammation of the distal ileum now acting as the rectum) is a well known complication (that should be confirmed by endoscopy) that is manifested by increased diarrhea, urgency, bleeding, and pain.

Treatment by disease severity and location (based on ACG Practice Guidelines)

Mild-moderate distal colitis

• Oral aminosalicylates, topical mesalamine, or topical steroids
• Combination of oral and topical aminosalicylates is better than either alone

For refractory cases, oral steroids or IV infliximab can be used (though this is less well studied in distal colitis)

Mild-moderate extensive colitis

• Oral sulfasalazine 4-6 g/day or alternative aminosalicylate 4.8 g/day
• Oral steroids for patients refractory to above therapy + topical therapy
• 6-MP or azathioprine for patients refractory to oral steroids, but not so severe as to require IV therapy
• Infliximab in patients who are steroid refractory/dependant on adequate doses of 6-MP/thiopurine or who are intolerant to these medications

Severe colitis

• Infliximab if urgent hospitalization is not needed
• If patient is toxic, should be admitted to the hospital for IV steroids
  • Failure to improve in 3-5 days is indication for colectomy or IV cyclosporine
• Maintenance 6-MP can also be added in these patients

Indications for Surgery

• Absolute:Hemorrhage, perforation, documented or strongly suspected cancer

Also, surgery is recommended for severe colitis refractory to medical therapy

Are there any special dietary requirements for persons with ulcerative colitis?

Although it seems plausible that a specialized diet might benefit patients with ulcerative colitis, there is actually no evidence to support treatment with dietary modification. Despite extensive research, no diet has been found to slow progression, treat, or cure the disease. It is recommended that patients stay on a balanced, healthy diet rich in fruits, vegetables, grains, lean meats, beans, fish, eggs, nuts. Patients should also try to limit foods with saturated fats high cholesterol. During flare-ups, patients should continue to eat as tolerated. The Crohn's and Colitis Foundation of America recommends a bland diet with soft food during a flare including hot cereals, boiled eggs, mashed potatoes, steamed vegetables, canned or cooked vegetables to minimize discomfort.

What research is being done regarding ulcerative colitis?

Active research is also ongoing to find other biological agents that are potentially more effective with fewer side effects in treating ulcerative colitis including adalimumab, visilizumab, and alpha-4 integrin blockers.

Research in ulcerative colitis is very active, and many questions remain to be answered. The cause, mechanism of inflammation, and optimal treatments have yet to be defined. Researchers have recently identified genetic differences among patients which may allow them to select certain subgroups of patients with ulcerative colitis who may respond differently to medications. Newer and safer medications are being developed. Improvements in surgical procedures to make them safer and more effective continue to emerge.

Health Maintenance

It is recommended that adults with inflammatory bowel disease generally follow the same vaccination schedules as the general population.

• Adults should receive a 1 time dose of Tdap, then Td booster every 10 years.
• Women between the ages of 9 and 26 should receive 3 doses of HPV vaccine (and consideration should be given to older patients who are HPV negative on Pap smear).
• Men in the same age range should also consider being vaccinated given the increased risk of HPV with immunosuppression.
• Influenza (flu) vaccine should be given annually to all patients (though the live intranasal vaccine is contraindicated in patients on immunosuppressive therapy).
• One dose of pneumococcal vaccine should be given between age 19-26 and then revaccination after 5 years.
• If not previously vaccinated, all adults should receive 2 doses of hepatitis A vaccine and 3 doses hepatitis B.
• Meningococcal vaccine is only recommended for patients with anatomic or functional asplenia, terminal complement deficiencies, or others at higher risk (college students, military recruits, etc).
• MMR, varicella, and zoster vaccines (shingles vaccine) are contraindicated for patients on biologic therapy, as they are all live vaccines.

Osteoporosis has also increasingly been recognized as a significant health problem in patients with IBD. IBD patients tend to have markedly reduced bone mineral densities. Screening with a bone density study is recommended in:

• postmenopausal woman,
• men> age 50,
• patients with prolonged steroid use (>3 consecutive months or recurrent courses),
• patients with a personal history of low-trauma fractures, and
• patients with hypogonadism.

For this reason, most patients with IBD should be on calcium and vitamin D supplementation.

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