International Journal of

Inflammatory Bowel Disease

Official Publication of the Brazilian Study Group of Inflammatory Bowel Disease Volume 1 Number 1 May-August 2014

PERMANYER BRASIL
www.permanyer.com
 Para pacientes adultos com Doena de Crohn ativa moderada a grave1
O tratamento da Doena Pentasa proporciona ADHERE5
Inflamatria
Quando Intestinal
a terapia (DII)
convencional falha... exibilidade posolgica 4
ANOS
precisa ser, alm de ecaz,
1,2

e tratamento individualizado
3
Remisso Clnica
Sustentada
conveniente* para o paciente. EXTEND6

SEMANA
1,2,3
HUMIRA eficaz 52
Cicatrizao de Mucosa
CHARM7

SEMANA
26/56
Reduo de Hospitalizaes
e Cirurgias
CLASSIC II8

SEMANA
12
SACH SACH COMPRIMIDO SUPOSITRIO ENEMA LQUIDO
2g 1g 500 mg
Qualidade de Vida 1g 1 g em 100 mL
Convenincia e eficcia: cx. com 30 sachs cx. com 50 sachs cx.I2com 50 compr.
CLASSIC cx. com 28 sup. cx. com 7 frascos

sachs em dose nica. ** 1-3

SEMANA
DISPONVEL NO SISTEMA PBLICO
4

4
Induo da Remisso
Clnica
GAIN4

SEMANA
Pentasa Sach 1x ao dia vs Referncias bibliogrficas: 1) Dignass AU, Bokemeyer B, Adamek
H. Mesalamine once daily is more effective than twice daily in patients with
H, Mross M, Vinter-Jensen L, Bner N, Silvennoinen J, Tan G, Pool MO, Stijnen T, Dietel P, Klugmann T, Vermeire S, Bhatt A, Veerman
1 quiescent ulcerative colitis. Clin Gastroenterol Hepatol. 2009 Jul;7(7):762-9. 2) Philip Miner, MD, Stephen Hanauer, MD, Malcolm
5
2x ao dia em RCU leve a moderada
Robinson, MD, Jerrold Schwartz, MD, Sanjeev Arora, MD, And Pentasa UC Maintenance Study Group. Safety and Efficacy of Controlled-Release Mesalamine for Maintenance of Remission in Ulcerative
Colitis. Digestive Diseases and Sciences, 1Iol. 40, No. 2Resposta Clnicapp.
(February 1995), na296-304.
Semana 3) 1 Bula do produto conforme registro na ANVISA N MS 1.2876.0002. 4) BRASIL. Ministrio da Sade. Aprova o
Componente de Medicamentos de Dispensao Excepcional. Portaria n. 2.577, de 27 de outubro de 2006. 5) B. Flourie, H. Hagege, G. Tucat, D. Maetz, X. Hebuterne, J. P. Kuyvenhoven, T. G. Tan, M. J.
Pierik, A. A. M. Masclee, O. Dewit, C. S. Probert & D. Aoucheta on behalf of the MOTUS study investigators. Randomised clinical trial: once- vs. twice-daily prolongedrelease mesalazine for active ulcerative
HUMIRA (adalimumabe) MS: 1.0553.0294. Indicaes: Artrite Reumatoide, Artrite Psorisica, Espondilite Anquilosante, Doena de Crohn, Psorase em Placas, Artrite Idioptica Juvenil Poliarticular. Contraindicaes: pacientes com conhecida colitis.leucocitose,
trombocitopenia, Aliment Pharmacol Ther 2013;
hipersensibilidade 37:
e alergia, 767775.
urticria, insuficincia renal, alteraes da coagulao e distrbios hemorrgicos, teste para autoanticorpos positivo, linfoma, neoplasia de rgos slidos, melanoma, prpura trombocitopnica
hipersensibilidade ao adalimumabe ou quaisquer componentes da frmula do produto. Advertncias e Precaues: Infeces: foram relatadas infeces graves devido a bactrias, micobactrias, fungos, vrus, parasitas ou outras infeces idioptica, arritmia,
Pentasa insuficincia

mesalazinacardacacongestiva, ocluso arterial
Comprimidos: USO vascular,
ADULTOtromboflebite,
E PEDITRICO aneurisma (em artico, doena acima
crianas pulmonarde obstrutiva crnica,depneumopatia
dois anos intersticial,Sach
idade). Enema, pneumonite, pancreatite, aumento
e Supositrios: USOdaADULTO.
bilirrubina,INDICAES:
esteatose heptica,
oportunistas. Pacientes que desenvolvem uma infeco fngica grave so tambm advertidos a interromper o uso de bloqueadores de TNF at que a infeco seja controlada. O tratamento com HUMIRA (adalimumabe) no deve ser iniciado ou rabdomilise, lpus eritematoso Enema
Comprimidos, sistmico, epancitopenia,
Supositrios:escleroseDoena
mltipla,Infl
parada cardaca,
amatria cicatrizao
Intestinal (Crohn e RCU).Reaes
prejudicada. Sach:adversas de ps comercializao: diverticulite,
RCUI. CONTRAINDICAES: linfoma hepatoesplnico
hipersensibilidade aos salicilatosde ouclulas T, leucemia,componente
a qualquer carcinoma de dasclulas
continuado em pacientes com infeces ativas, at que as infeces estejam controladas. Recomenda-se cautela ao uso em pacientes com histrico de infeces de repetio ou com doena de base que possa predispor o paciente a infeces. de Merkel (carcinoma
formulaes; neuroendcrino
em casoscutneo), anafilaxia,
de doenas renaissarcoidose, doenas
ou hepticas desmielinizantes,
severas. CUIDADOS acidente vascular cerebral, embolismo
E ADVERTNCIAS: pacientes pulmonar, derrame
alrgicos pleural, fibrosedevem
sulfassalazina pulmonar,
ter perfurao
cautela com intestinal,
uso dereativao
Pentasada hepatite B, insuficincia heptica,
; descontinuar em caso de
Tuberculose: foram relatados casos de tuberculose incluindo reativao e nova manifestao de tuberculose pulmonar e extrapulmonar (disseminada). . Antes de iniciar o tratamento todos os pacientes devem ser avaliados quanto presena de hepatite, vasculite
reaescutnea, sndrome aguda,
de intolerncia de Stevens-Johnson, angioedema,
clicas abdominais, novo aparecimento
dor abdominal aguda, ou piorador
febre, da de
psorase;
cabeaeritema
severamultiforme,
e erupoalopecia,
cutnea,sndrome
discrasialpus smile, infarto
sanguinea, mio edopericardite.
miocrdio, Usar
febre.com Posologia:
cautela Artrite
quando Reumatoide, Artrite funo
coexistir asma, Psorisica,
tuberculose ativa ou inativa (latente).Se a tuberculose ativa for diagnosticada, o tratamento com HUMIRA (adalimumabe) no deve ser iniciado. Se for diagnosticada tuberculose latente, o tratamento apropriado deve ser iniciado com profilaxia Espondilite Anquilosante:
heptica ou arenal doseprejudicada.
para pacientesUso
adultos de 40 amg,
durante administrados
gravidez em dose nica
e lactao: por via subcutnea,
Pentasa a cada 14
deve ser utilizado comdias. Doenadurante
cautela de Crohn: incio do tratamento
a gravidez e lactao. Semana
Efeito na 0: 160 mg por via subcutnea
capacidade de dirigir; Semana
e operar 2: 80mquinas:
mg; Manuteno
antituberculose. Reativao da Hepatite B: o uso de inibidores de TNF foi associado reativao do vrus da hepatite B (HBV) em pacientes portadores crnicos deste vrus podendo ser fatal. Deve-se ter cautela ao administrar inibidores de TNF do tratamento: a partir da Semana
O tratamento com Pentasa4, 40 mg
a cada
no 14 dias.
parece terPsorase:
efeito napara pacientes adultos
capacidade dee/ou
de dirigir uma operar
dose inicial de 80 mgUso
mquinas. por em idosos, crianas
via subcutnea, ou outros
seguida de doses de 40 mggrupos de risco:
administradas Comprimidos:
em semanas alternadas, comeando na semana seguinte
No recomendado o uso
em pacientes portadores do vrus da hepatite B. Eventos neurolgicos: com exacerbao de sintomas e/ou evidncia radiolgica de doena desmielinizante, Deve-se ter cautela ao considerar o uso de HUMIRA (adalimumabe) em pacientes com dose inicial.de Pentasa
Artrite comprimidos
idioptica

em crianas
juvenil poliarticular: com menos
para pacientes de superior
com idade dois anos a 13deanos de Enema,
idade. 40 mg soluoSach e Supositrios:
injetvel, administrados emNo dose nica
recomendado o uso dea cada
por via subcutnea, Pentasa emVENDA
14 dias.

crianas. InteraesMDICA.
SOB PRESCRIO medicamentosas e
Registrado por: Abbott
doenas desmielinizantes do sistema nervoso perifrico ou central. Malignidades: foi observado maior nmero de casos de linfoma entre os pacientes que receberam antagonistas de TNF. Malignidades, algumas fatais, foram relatadas entre crianas Laboratrioscom exames
do Brasil Ltda.- Rua laboratoriais:
Michigan, 735 A So
terapia
Paulocombinada
SP - CNPJ:de56.998.701/0001-16.
Pentasa com azatioprina ou 6-mercaptopurina
ABBVIE LINE: 0800 022 2843. BU19 ou tioguanina mostra maior frequncia de mielossupresso; raramente pode ocorrer alterao nas
e adolescentes que foram tratados com agentes bloqueadores de TNF. A maioria dos pacientes estava tomando concomitantemente imunossupressores. Casos muito raros de linfoma hepatoesplnico de clulas T, foram identificados em pacientes funes hepticas e renais. Interao com alimento: Comprimidos e Sach: O trnsito e a liberao de mesalazina aps administrao oral so independentes da coadministrao de alimento,
Assim como observado com outros antagonistas de TNF, foram relatados casos de tuberculose associados ao Humira (adalimumabe).
61 dos pacientes atingiram a
recebendo adalimumabe. O risco potencial com a combinao de azatioprina ou 6-mercaptopurina e HUMIRA (adalimumabe) deve ser cuidadosamente considerado. Alergia: durante estudos clnicos, reaes alrgicas graves foram relatadas incluindo
% imediatamente e deve-se iniciar o tratamento apropriado. Eventos hematolgicos: raros relatos de
reao anafiltica. Se uma reao anafiltica ou outra reao alrgica grave ocorrer, a administrao de HUMIRA (adalimumabe) deve ser interrompida
enquanto que a absoro sistmica ser reduzida. Enema e Supositrios: No h dados disponveis at o momento sobre a interao de Pentasa com alimentos. Reaes adversas: diarreia, nusea,
A administrao concomitante de antagonistas de TNF e abatacept tem sido associada a aumento do risco de infeces, incluindo
dor abdominal, cefaleia, vmitos, eczema e erupo cutnea; reaes de hipersensibilidade; como prurido, desconforto retal e urgncia podem ocorrer. POSOLOGIA: Comprimidos: Retocolite Ulcerativa
Adultos: Tratamento agudo: Dose individual de at 4 gramas divididas ao longo do dia. Tratamento de manuteno: Dose inicial recomendada de 2 g uma vez ao dia; Retocolite ulcerativa - Crianas com
remisso clnica e endoscpica
pancitopenia, incluindo anemia aplstica. A descontinuao da terapia deve ser considerada em pacientes com anormalidades hematolgicas significativas confirmadas. Insuficincia cardaca congestiva: Casos de piora da ICC tambm foram relatados
Processos autoimunes: pode ocorrer a formao de anticorpos autoimunes. Se um paciente desenvolver sintomas que sugiram sndrome Lpus smile, o tratamento deve ser descontinuado. Uso em idosos: a frequncia de infeces graves entre infeces srias, quando comparada a antagonistas de TNF isolado.
mais de dois anos de idade: Tratamento agudo e de manuteno: Dose individual recomendada de 20 a 30 mg/kg de peso corpreo ao dia, em doses divididas; Doena de Crohn - Adultos: Tratamento
5 agudo e de manuteno: dosagem individual de at 4 g ao dia, em doses divididas; Doena de Crohn - Crianas com mais de dois anos de idade: Tratamento agudo e de manuteno: Dose individual
com Pentasa Sach 4g 1x ao dia
pacientes com mais de 65 anos de idade tratados com HUMIRA (adalimumabe) foi maior do que para os sujeitos com menos de 65 anos de idade. Deve-se ter cautela quandodo tratamento de pacientes idosos. Uso na gravidez: este medicamento
s deve ser usado durante a gravidez quando, na opinio do mdico, os benefcios potenciais claramente justificarem os possveis riscos ao feto. Mulheres em idade reprodutiva devem ser advertidas a no engravidar durante o tratamento com
Referncias:
Gatroenterology
1. Bula do produto
recomendada
idade):2006;
de 20
130:323-333.
Tratamento
HUMIRA (adalimumabe).
a 30 mg/kg
3. Colombel
agudo:
de peso 2. Hanauer
J-F, Sandborn
Dose individual
corpreoSB,aoSandborn
de WJ,
at Rutgeerts
dia, emWJ,doses
4 gramasP, etdivididas
Rutgeerts
al. Adalimumab
ao longo
P, Fedorak
divididas. RN, Lukas
Enema:
for maintenance
do dia (4 sachs
M, Macintosh
Para adultos: Um
of clinical
de response
D, etenema
1g ou 2and
al. Human
aoAnti-tumor
remission
sachs in patients
de 2g).
NecrosisRetocolite
deitar. Sach: Factor Monoclonal
with Crohns
Tratamento
Antibody
Ulcerativa
disease: the CHARM
de manuteno:
(Adalimumab)
Adultos in Crohns Disease:
(em pacientes
trial. Gastroenterology.
Dose inicial recomendada2007;
acima de The18
de 2132(1):52-65.
g uma vez ao
CLASSIC
anosldeTrial.
4. dia
Sandborn
(2
HUMIRA (adalimumabe). A administrao de vacinas vivas em recm-nascidos expostos ao adalimumabe no tero no recomendada por 05 meses aps a ltima injeo de adalimumabe da me durante a gravidez. Este medicamento no deve ser WJ, Rugteertssachs
P, EnnsdeR, 1g
et al.ouAdalimumab
1 sach de 2g). Supositrios:
induction therapy for Crohn Proctite ulcerativatreated
disease previously - Adultos: Um supositrio,
with infliximab: umatrial.
a randomized a duas vezesMed.
Ann Intern ao dia 4 semanas. / VENDA
por146(12):829-838.
2007; SOB PRESCRIO
5. R Panaccione, J-F Colombel, WJMDICA
Sandborn, /G Material
DHaens, QdeZhou,
uso PFexclusivo
Pollack, RB
utilizado por mulheres grvidas sem orientao mdica ou do cirurgio-dentista. Uso na lactao: recomenda-se decidir entre descontinuar o tratamento com HUMIRA (adalimumabe) ou interromper o aleitamento, levando em conta a importncia do Thakkar andAM classe mdica
Robinson. / SE PERSISTIREM
Alimentary OS SINTOMAS,
Pharmacology and Therapeutics O MDICO DEVER
2013; 38(10):1236-1247. SER CONSULTADO.
6. Paul Rutgeerts, Geert R DHaens, Gert/ Reg.
A VanMS: 1.2876.0002
Assche, / Farm.
William J Sandborn, Resp.:
Douglas Helena
C Wolf, Satie Komatsu
Jean-Frederic Colombel,- Walter
CRF/SP: 19.714
Reinisch, Karel-Geboes,
Laboratrios
Mahmudul
medicamento para a me. O aleitamento no recomendado por pelo menos 05 meses aps a ltima administrao de HUMIRA (adalimumabe). Interaes Medicamentosas: Metotrexato: no h necessidade de ajuste de doses de nenhum dos Khan, AndreasFerring
Lazar,Ltda. Praa So
Anne Camez, Paul Marcos,
F Pollack. 624 - 05455-050
Gastroenterology 2012;-142:
So1102-11.
Paulo 7.SP / CNPJ:
Feagan Brian74.232.034/0001-48.
G et al. Gastroenterology 2008;(CCDS135: 2011/06_v10_2). Cd. PEN-20
1493-1499. 8. WJ Sandborn, SB Hanauer,MAIO/2014.
P Rutgeerts, RN Fedorak, M Lukas, DG MacIntosh, R Panaccione, D
dois medicamentos. Outras: o uso concomitante de HUMIRA (adalimumabe) e outros DMARDs (por exemplo, anacinra e abatacepte) no recomendado. Vacinas vivas no devem ser administradas concomitantemente a HUMIRA (adalimumabe). Wolf, JD Kent, B Bittle, J Li, PF Pollack. Gut 2007; 56;1232-1239.
No foram observadas interaes com DMARDs (sulfassalazina, hidroxicloroquina, leflunomida e ouro parenteral), glicocorticoides, salicilatos, anti-inflamatrios no esteroidais ou analgsicos. Reaes Adversas: infeces no trato respiratrio,
leucopenia, anemia, aumento de lipdeos, dor de cabea, dor abdominal, nusea, vmito, elevao de enzimas hepticas, rash, dor musculoesqueltica, reao no local da injeo, infeces, neoplasia benigna , cncer de pele no melanoma,
CONTRAINDICAES: hipersensibilidade aos salicilatos ou qualquer componente da formulao. Interaes medicamentosas:
Material destinado a profissionais da sade prescritores. Reproduo proibida. Produzido em Maio/2014.
A terapia combinada de Pentasa com azatioprina ou 6-mercaptopurina ou tioguanina mostra maior frequncia de mielossupresso.

Adaptado de Flouri B. et al, 20135.

*comodidade posolgica: uma vez ao dia3. **no tratamento de manuteno da Retocolite Ulcerativa (RCU)
a de Crohn ativa moderada a grave1
ADHERE5

4
ANOS
Remisso Clnica
Sustentada
EXTEND6

SEMANA
52
Cicatrizao de Mucosa
CHARM7

SEMANA
26/56
Reduo de Hospitalizaes
e Cirurgias
CLASSIC II8

SEMANA
12
Qualidade de Vida
CLASSIC I2

SEMANA
4
Induo da Remisso
Clnica
GAIN4

SEMANA
1
Resposta Clnica na Semana 1

trombocitopenia, leucocitose, hipersensibilidade e alergia, urticria, insuficincia renal, alteraes da coagulao e distrbios hemorrgicos, teste para autoanticorpos positivo, linfoma, neoplasia de rgos slidos, melanoma, prpura trombocitopnica
idioptica, arritmia, insuficincia cardaca congestiva, ocluso arterial vascular, tromboflebite, aneurisma artico, doena pulmonar obstrutiva crnica, pneumopatia intersticial, pneumonite, pancreatite, aumento da bilirrubina, esteatose heptica,
rabdomilise, lpus eritematoso sistmico, pancitopenia, esclerose mltipla, parada cardaca, cicatrizao prejudicada. Reaes adversas de ps comercializao: diverticulite, linfoma hepatoesplnico de clulas T, leucemia, carcinoma de clulas
de Merkel (carcinoma neuroendcrino cutneo), anafilaxia, sarcoidose, doenas desmielinizantes, acidente vascular cerebral, embolismo pulmonar, derrame pleural, fibrose pulmonar, perfurao intestinal, reativao da hepatite B, insuficincia heptica,
hepatite, vasculite cutnea, sndrome de Stevens-Johnson, angioedema, novo aparecimento ou piora da psorase; eritema multiforme, alopecia, sndrome lpus smile, infarto do miocrdio, febre. Posologia: Artrite Reumatoide, Artrite Psorisica,
Espondilite Anquilosante: a dose para pacientes adultos de 40 mg, administrados em dose nica por via subcutnea, a cada 14 dias. Doena de Crohn: incio do tratamento Semana 0: 160 mg por via subcutnea ; Semana 2: 80 mg; Manuteno
do tratamento: a partir da Semana 4, 40 mg a cada 14 dias. Psorase: para pacientes adultos de uma dose inicial de 80 mg por via subcutnea, seguida de doses de 40 mg administradas em semanas alternadas, comeando na semana seguinte
dose inicial. Artrite idioptica juvenil poliarticular: para pacientes com idade superior a 13 anos de 40 mg soluo injetvel, administrados em dose nica por via subcutnea, a cada 14 dias. VENDA SOB PRESCRIO MDICA. Registrado por: Abbott
Laboratrios do Brasil Ltda.- Rua Michigan, 735 So Paulo SP - CNPJ: 56.998.701/0001-16. ABBVIE LINE: 0800 022 2843. BU19
Assim como observado com outros antagonistas de TNF, foram relatados casos de tuberculose associados ao Humira (adalimumabe).

A administrao concomitante de antagonistas de TNF e abatacept tem sido associada a aumento do risco de infeces, incluindo
infeces srias, quando comparada a antagonistas de TNF isolado.
Referncias: 1. Bula do produto HUMIRA (adalimumabe). 2. Hanauer SB, Sandborn WJ, Rutgeerts P, Fedorak RN, Lukas M, Macintosh D, et al. Human Anti-tumor Necrosis Factor Monoclonal Antibody (Adalimumab) in Crohns Disease: The CLASSIC l Trial.
Gatroenterology 2006; 130:323-333. 3. Colombel J-F, Sandborn WJ, Rutgeerts P, et al. Adalimumab for maintenance of clinical response and remission in patients with Crohns disease: the CHARM trial. Gastroenterology. 2007; 132(1):52-65. 4. Sandborn
WJ, Rugteerts P, Enns R, et al. Adalimumab induction therapy for Crohn disease previously treated with infliximab: a randomized trial. Ann Intern Med. 2007; 146(12):829-838. 5. R Panaccione, J-F Colombel, WJ Sandborn, G DHaens, Q Zhou, PF Pollack, RB
Thakkar and AM Robinson. Alimentary Pharmacology and Therapeutics 2013; 38(10):1236-1247. 6. Paul Rutgeerts, Geert R DHaens, Gert A Van Assche, William J Sandborn, Douglas C Wolf, Jean-Frederic Colombel, Walter Reinisch, Karel Geboes, Mahmudul
Khan, Andreas Lazar, Anne Camez, Paul F Pollack. Gastroenterology 2012; 142: 1102-11. 7. Feagan Brian G et al. Gastroenterology 2008; 135: 1493-1499. 8. WJ Sandborn, SB Hanauer, P Rutgeerts, RN Fedorak, M Lukas, DG MacIntosh, R Panaccione, D
Wolf, JD Kent, B Bittle, J Li, PF Pollack. Gut 2007; 56;1232-1239.
Material destinado a profissionais da sade prescritores. Reproduo proibida. Produzido em Maio/2014.
 A ADESO QUE A TECNOLOGIA OFERECE5
Contraindicao: Mesacol MMX no recomendado em casos de hipersensibilidade a salicilatos.
InteraoMedicamentosa: a administrao da mesalazina pode potencializar a toxicidade do metotrexato.
Mesacol MMX mesalazina USO ORAL. USO ADULTO ACIMA DE 18 ANOS. Apresentaes e composio: Comprimidos revestidos de liberao prolongada, com 1,2 g de mesalazina cada. Embalagens com 10 e 30 unidades. Indicaes: anti-inflamatrio
de ao local no tratamento da colite ulcerativa ativa leve a moderada, na fase aguda (induo da remisso) e na manuteno da remisso. Contraindicaes: Este medicamento no deve ser usado por pacientes com histria de hipersensibilidade aos salicilatos (que
inclui o cido acetilsaliclico), mesalazina, sulfassalazina ou a qualquer dos componentes da frmula; pacientes com insuficincia heptica e/ou renal graves; pacientes com lcera gstrica e duodenal ativa; pacientes com tendncia elevada a sangramento. Este
medicamento contraindicado para menores de 18 anos. Precaues e advertncias: As mesmas precaues e advertncias relacionadas com o uso de preparados contendo mesalazina ou pr-drogas de mesalazina devem ser consideradas para Mesacol
MMX. A maioria dos pacientes intolerantes sulfassalazina pode administrar mesalazina sem que haja risco de reaes cruzadas, porm, deve-se ter cuidado ao administrar mesalazina a esses pacientes. Assim como todos os salicilatos, a mesalazina deve ser utilizada
com cautela em pacientes com histria de lcera gstrica ou duodenal, por pacientes asmticos (em razo das reaes de hipersensibilidade), com disfuno renal ou heptica (leve a moderada), ou com histria de miocardite ou pericardite. A mesalazina pode estar
associada Sndrome da Intolerncia Aguda, que pode ser difcil de ser distinguida de uma doena inflamatria intestinal. Apesar de a frequncia no estar ainda bem estabelecida, esse fato ocorreu com 3% dos pacientes em estudos clnicos controlados com mesalazina
ou sulfassalazina. Os sintomas incluem clicas, dor abdominal aguda e diarreia com sangue, eventualmente febre, dor de cabea e erupo cutnea. Se h suspeita desta sndrome, necessria a interrupo imediata do tratamento. Obstruo orgnica ou funcional
do trato gastrointestinal pode retardar o incio de ao do produto. Interao com testes laboratoriais: O uso da mesalazina pode levar a resultados falsamente elevados quando se mede a normetanefrina urinria pelo mtodo laboratorial denominado cromatografia lquida
com deteco eletroqumica, devido semelhana dos cromatogramas da normetanefrina e do principal metablito da mesalazina, o cido N-acetilaminosalicilico (N-Ac-5-ASA). Uma alternativa para a anlise seletiva da normetanefrina deve ser considerada. Mesalazina
no recomendada para pacientes com disfuno renal grave, e deve-se ter cautela com pacientes com nveis sanguneos aumentados de ureia ou com proteinria. A mesalazina rapidamente excretada pelos rins, principalmente o seu metablito cido N-acetil-5-
aminossaliclico. Em ratos, altas doses da mesalazina administradas por via intravenosa causaram intoxicao tubular e glomerular. Em caso de aparecimento de disfuno renal durante o tratamento, deve-se suspeitar de nefrotoxicidade induzida pela mesalazina. Nestes
casos recomenda-se monitorar a funo renal, especialmente no incio do tratamento. Durante tratamento prolongado tambm necessrio monitorar regularmente a funo renal (creatinina srica). Ainda no est estabelecida a segurana do produto em crianas.
Gravidez e lactao: Mesacol MMX est classificado na categoria B de risco de frmacos destinados ao uso em grvidas. Em princpio, o produto no deve ser empregado em gestantes e lactantes, exceto quando absolutamente necessrio. A segurana de Mesacol
MMX para uso durante a gravidez ou amamentao ainda no foi estabelecida, mas sabe-se que a mesalazina atravessa a placenta e excretada pelo leite materno em pequenas quantidades. Estudos pr-clnicos no revelaram evidncia de efeitos teratognicos ou
de toxicidade fetal oriundos da mesalazina, nem na evoluo da gestao ou no desenvolvimento perinatal e ps-natal. A pequena experincia de uso da mesalazina em outras formulaes durante a gravidez no revelou efeito prejudicial ao feto, entretanto, a mesalazina
deve ser usada com cautela durante a gravidez e somente quando os benefcios para a me forem superiores aos riscos potenciais ao feto. Detectaram-se baixas concentraes de mesalazina e concentraes mais elevadas de seu metablito N-acetilado no leite
materno, mas o significado clnico desta evidncia ainda no foi determinado. Portanto, deve-se ter cautela na administrao da mesalazina a lactantes. Categoria B de risco na gravidez Este medicamento no deve ser utilizado por mulheres grvidas sem orientao
mdica ou do cirurgio-dentista. Pacientes peditricos: Devido falta de dados sobre a administrao da mesalazina em altas doses na populao peditrica, Mesacol MMX no recomendado para pacientes menores de 18 anos. Pacientes idosos: A exposio
sistmica a mesalazina aumentada em at 2 vezes em indivduos idosos (> 65 anos) em comparao com indivduos mais jovens adultos (18-35 anos) aps uma dose nica de 4,8 g do medicamento. A exposio sistmica nestes indivduos foi inversamente
correlacionada com a funo renal, avaliada pelo clearance de creatinina estimado. O impacto potencial sobre o uso seguro da mesalazina na populao idosa deve ser avaliado na prtica clnica. Pacientes com insuficincia renal: A mesalazina deve ser administrada
com precauo em pacientes com disfuno renal leve a moderada. Seu uso contraindicado para pacientes com insuficincia renal grave. Vide itens 4 Contraindicaes e 5 Advertncias e Precaues. Relatos de diminuio da funo renal (incluindo nefropatia,
nefrite intersticial aguda/crnica e insuficincia renal) com alteraes mnimas tm sido associados a preparaes contendo mesalazina e pr-frmacos da mesalazina. Pacientes com insuficincia heptica: A mesalazina deve ser administrada com precauo em
pacientes com insuficincia heptica leve a moderada. Seu uso contraindicado para pacientes com insuficincia heptica grave. Dirigir e operar mquinas: improvvel que o uso deste medicamento tenha qualquer efeito sobre a capacidade de dirigir veculos ou de
operar mquinas. Interaes medicamentosas: Foram conduzidos estudos comparando a farmacocintica e a segurana da mesalazina e alguns antibiticos mais comumente utilizados. No foram observadas interaes relevantes clinicamente entre a mesalazina
com amoxicilina, ciprofloxacino XR, metronidazol ou sulfametoxazol. Existem tambm relatos de interao entre a mesalazina (outras formulaes) e outros medicamentos. O uso concomitante da mesalazina com agentes sabidamente nefrotxicos, inclusive com os
anti-inflamatrios no hormonais (AINHs como aspirina, ibuprofeno, diclofenaco etc.) e azatioprina pode aumentar o risco de reaes renais; o potencial para discrasias sanguneas da azatioprina e da 6-mercaptopurina pode aumentar; a ao hipoglicemiante das
sulfonilureias pode ser intensificada; a atividade anticoagulante dos derivados cumarnicos (varfarina) pode ser reduzida; a toxicidade do metotrexato pode ser potencializada; o efeito uricosrico da probenecida e da sulfimpirazona pode diminuir, assim como a ao
diurtica da furosemida e da espironolactona e a ao tuberculosttica da rifampicina. Em tese, a administrao concomitante de anticoagulantes orais deve ser feita com cautela. Substncias como a lactulose, que diminuem o pH do clon, podem reduzir a liberao
da mesalazina dos comprimidos revestidos de Mesacol MMX. Reaes adversas: A maioria das reaes adversas relatadas com Mesacol MMX foi transitria, e de intensidade leve a moderada. Foram descritas as seguintes reaes adversas, distribudas em
grupos de frequncias: Reao comum (> 1/100 e < 1/10): Gastrintestinal: flatulncia e nusea, vmito, dor abdominal, distenso abdominal, diarreia, dispepsia e colite. Sistema Nervoso: cefaleia. Musculoesquelticas: artralgia, lombalgia. Gerais: Astenia, fadiga,
pirexia. Distrbios do sistema imune: Hipersensibilidade (incluindo urticria, exantema, prurido e edema de face). Hepatobiliar: aumento das transaminases, anormalidades no teste da funo heptica. Estas reaes ocorreram em menos de 3% dos pacientes, sem
depender da dose administrada. Reao incomum (> 1/1.000 e < 1/100): Gastrintestinal: pancreatite e plipo retal. Sistema nervoso: tontura, sonolncia, tremores. Musculoesquelticas: mialgia. Cardiovascular: taquicardia, hipertenso e hipotenso arterial.
Respiratrio: dor faringolarngea. Ouvido e labirinto: otalgia. Pele e tecido subcutneo: acne, alopcia, prurigo. Sangue e linfa: reduo do nmero de plaquetas (trombocitopenia). Reao rara (> 1/10.000 e < 1/1000): Renais e urinrios: insuficincia renal. Sangue e
linfa: agranulocitose. H tambm relatos dos seguintes eventos adversos com a mesalazina: miocardite, pericardite, neuropatias, angioedema, lpus eritematoso, nefrite intersticial e sndrome nefrtica; reaes alrgicas com manifestaes pulmonares (como pneumonia
eosinoflica e broncoespasmo), hepatite, colelitase e discrasias sanguneas (tais como leucopenia, neutropenia, anemia aplstica e pancitopenia), reaes anafilticas, sndrome de Stevens-Johnson e sndrome da hipersensibilidade induzida por medicamentos.
Posologia e modo de usar: Mesacol MMX destina-se a uso exclusivo por via oral. Para o tratamento da colite ulcerativa leve a moderada, a dose usual para adultos acima de 18 anos de 2.400 mg a 4.800 mg (dois a quatro comprimidos) ao dia, administrada em
dose nica, de preferncia sempre mesma hora de cada dia, acompanhada de uma refeio. Caso o paciente esteja tomando a dose mais elevada (4.800 mg/dia), ele deve ser reavaliado aps oito semanas de tratamento. No apresentando mais sintomas, pode-se
prescrever uma dose diria de 2.400 mg (dois comprimidos) manuteno da remisso. A durao recomendada de oito semanas consecutivas, salvo critrio mdico diferente. Este medicamento no deve ser partido, mastigado ou dissolvido. AO
PERSISTIREM OS SINTOMAS, O MDICO DEVER SER CONSULTADO. MEDICAMENTO SOB PRESCRIO. Registro MS 1.0639. 0248. MEMX_0713_0813_VPS. Mesacol marca registrada da Takeda Pharma, MMX marca registrada da Cosmo Technologies
Ltda. e licenciada pela Takeda Pharma.
Referncias bibliogrficas: 1. Kamm MA, et al. Once-daily, high-concentration MMX mesalamine in active ulcerative colitis. Gastroenterology. 2007;132:66-75. 2. Tenjarla S, et al. Release of 5-aminosalicylate from na MMX meslaminr tablet during transit throught a simulated
gastrointestinal tract system. Adv Ther. 2007;24(4):826-40. 3. Brunner M, et al. Gastrointestinal transit and 5-ASA release from a new mesalazine extended release formulation. Aliment Pharmacol Ther 2003;17:395402. 4. Mezavant UK Summary of Product Characteristics. Shire
Pharmaceuticals Limited. 5. Hu MY, Peppercorn MA. MMX mesalamine: a novel high-dose, once-daily 5-aminosalicylate formulation for the treatment of ulcerative colitis. Expert Opin Pharmacother. 2008;9(6):1049-58. 6.Kane S, et al. Medication nonadherence and the outcomes of patients
with quiescent ulcerative colitis. Am J Med. 2003;114(1):39-43. 7. Osterman MT, Lichtenstein GR. Reformulation of an aminosalicylate: an example of the importance of pill burden on medical compliance rates. Methods Find Exp Clin Pharmacol. 2009;31(1):41-6. 8. Moraes AC, Pepe C,
Teich V. Anlise de custo-utilidade da mesalazina MMX em comparao mesalazina convencional notratamento da retocolite ulcerativa leve ou moderada sob a perspectiva do Sistema Pblico de Sade Brasileiro. JBES.2012;4(3):436-43.
Data de impresso do anncio: junho/2014.
Material destinado exclusivamente classe mdica.

SE PERSISTIREM OS SINTOMAS, O MDICO DEVER SER CONSULTADO.

Takeda Pharma Ltda. Rua do Estilo Barroco, 721 04709-011 So Paulo SP.
Mais informaes podero ser obtidas diretamente com o nosso
Departamento de Assuntos Cientficos ou por meio de nossos representantes.
 International Journal of Inflammatory Bowel Disease
ISSN: 2339-9627 ISSN: 2339-9961 on line IJI Bowel Disease Volume 1 Number 1 May-August 2014

Official Publication of the Brazilian Study Group of Inflammatory Bowel Disease

Editors
Sender J. Miszputen (SP)
Cyrla Zaltman (RJ)

Editorial Board

Basic Science Selected Summaries, Thesis Marcelo de Souza Cury (MS)

Aytan Miranda Sipahi (SP)
Eduardo Garcia Vilela (MG)
Heitor Siffert Pereira de Souza (RJ)
Henrique Fillmam (RS)
Clinical
Adrson Omar Mouro Cintra Damio (SP)
Andrea Vieira (SP)
Carlos F. Magalhes Francesconi (RS)
Genoile Oliveira Santana (BA)
Jlio Maria Fonseca Chebli (MG)
Marco Antonio Zerncio (RN)
Surgery
Andr da Luz Moreira (RJ)
Antnio Lacerda Filho (MG)
Cludio Saddy Rodrigues Coy (SP)
Harry Kleinubing Junior (SC)
Magaly Gmio Teixeira (SP)
Paulo Gustavo Kotze (PR)
Pediatrics
Maraci Rodrigues (SP)
Vera Sdepanian (SP)
Pathology
Heinrich Seidler (DF)
Kalil Madi (RJ)
Roberto El Ibrahin (SP)
Clinical Challenges/Images in Gl
Eloa Marussi Morsoletto (PR)
Fbio Vieira Teixeira (SP)
Flvio Antnio Quilici (SP)
Maria de Lourdes de Abreu Ferrari (MG)
Advisory Board
Angelita Habr Gama (SP)
Carlos A. Antunes de Brito (PE)
Carlos Walter Sobrado Junior (SP)
Claudio Fiocchi (USA)
Columbano Junqueira Neto (DF)
Cristina Flores (RS)
Cyrla Zaltman (RJ)
Ddia Hermnia Bismara Cury (MS)
Eduardo Lopes Pontes (RJ)
Eloa Marussi Morsoletto (PR)
Fbio Guilherme C. M. de Campos (SP)
Flvio Steinwurtz (SP)
Heda M. Barska dos Santos Amarante (PR)
Helio Rzetelna (RJ)
Idblan Carvalho de Albuquerque (SP)
Joo Gomes Netinho (SP)
Joffre Rezende Filho (GO)
Jos Carlos Borges de Rezende (ES)
Jos Cesar Junqueira (RJ)
Jos Eduardo Vasconcelos Fernandes (SP)
Jos Galvo Alves (RJ)
Jos Miguel Luz Parente (PI)
Juliano Coelho Ludvig (SC)
Ligia Yukie Sassaki (SP)
Lorete Maria da Silva Kotze (PR)
Lucia Libanez Campelo Braga (CE)
Luiz Ernesto de Almeida Troncon (SP)
Marcellus Henrique Loiola P. de Souza (CE)
Maria de Lourdes Setsuko Ayrizono (SP)
Maria Ligia Lyra Pereira (SP)
Marta Brenner Machado (RS)
Mauro Bafutto (GO)
Raquel Franco Leal (SP)
Raul Cutait (SP)
Roberto Luiz Kaiser Junior (SP)
Rogerio Saad Hossne (SP)
Sender Jankiel Miszputen (SP)
Thiago Nunes Santos (SP)
Wilson Roberto Catapani (SP)
Wilton Schmidt Cardozo (SP)
Yu Kar Ling Koda (SP)
Brief Reports
Neogelia Pereira de Almeida (BA)
Orlando Ambrogini Junior (SP)
Case Reports
Antnio Carlos Moraes (RJ)
Marcia Henriques de Magalhes Costa (RJ)
Viewpoints
Fernando Magro (Portugal)
Editorial Assistant
Ftima Lombardi (SP)
contato@gediib.org.br

PERMANYER BRASIL
www.permanyer.com

1
 GEDIIB
Grupo de Estudos da Doena Inflamatria Intestinal do Brasil
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10 andar - conj. 102 CEP 01452-000
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2
Contents

Introduction
Challenges Have Been the Hallmark of Our Group . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
Sender J. Miszputen

Editorial . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
Marco Antnio Zerncio

Original Article
Clinical and Epidemiological Characteristics of Ulcerative Colitis Patients
from Salvador, Bahia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
Sonyara Raudys Oliveira Lisboa, Bruno Csar da Silva, Fernanda Gondim Dias, Valdiana Cristina Surlo
and Genoile Oliveira Santana

Dairy Food Intake by Inflammatory Bowel Disease Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15

Mirella Brasil Lopes, Raquel Rocha, Vanessa Rosa Oliveira, Fernanda Gomes Coqueiro, Naiade Silveira Almeida,
Patrcia Nunes, Andr Castro Lyra and Genoile Oliveira Santana

Proctocolectomy in Crohns disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20

Claudio Coy, Maria de Lourdes Setsuko Ayrizono, Raquel Franco Leal, Priscilla de Sene Portel Oliveira, Debora Gonalves Rossi,
Nielce Paiva, Natalia Panzetti Vieira, Miquelline Almeida and Joo Jos Fagundes

Review Article
Differential Diagnosis between Crohns Disease and Intestinal Tuberculosis in Brazil
and Other Regions with High Incidence of Tuberculosis: A Chronic and Current Dilemma . . . 23
Fernando Marques Moreira de Castro, Guilherme Seixas Barros, Cyrla Zaltman, Kalil Madi, Eduardo Kanaan,
Emmanuel Salgueiro and Antnio Carlos Moraes

Extraintestinal Manifestations of Inflammatory Bowel Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . 32

Mauro Bafutto, Ricardo Duarte Marciano, Alexandre Augusto Ferreira Bafutto, Enio Chaves de Oliveira and
Joffre Rezende Filho

Point of View
The Future of Inflammatory Bowel Disease: Integrating Knowledge to Advance
Understanding and Reach a Cure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44
Claudio Fiocchi

Commented Article
Tacrolimus Salvage in Anti-Tumor Necrosis Factor Antibody Treatment-Refractory
Crohns Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
Sender J. Miszputen

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IJI Bowel Disease Volume 1 Number 1 May-August 2014

Brief Reports
The Anti-Inflammatory Potential of Phenolic Compounds in Grape Juice Concentrate (G8000 tm)
on 2,4,6-Trinitrobenzene Sulfonic Acid-Induced Colitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49
Ana Paula Ribeiro Paiotti, Ricardo Artigiani Neto, Patrcia Marchi, Roseane Mendes Silva, Vanessa Lima Pazine,
Juliana Noguti, Mauricio Mercaldi Pastrelo, Andra Pittelli Boiago Gollcke, Sender Jankiel Miszputen and Daniel Araki Ribeiro,

Concentrated Grape Juice (G8000) Reduces Immunoexpression of Inducible Nitric Oxide

Synthase, Tumor Necrosis Factor-Alpha, COX-2 and DNA damage on 2,4,6-Trinitrobenzene
Sulfonic Acid-Induced Colitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50
Patricia Marchi, Daniel Araki Ribeiro, Ana Paula Ribeiro Paiotti, Ricardo Artigiani Neto and Celina Tizuco Fujiiyama Oshima

Quantitative Assessment of CD30-PositiveLymphocytes and Eosinophils for the

Histopathologic Diagnosis of Inflammatory Bowel Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51
Cristina Flores, Carlos Fernando de Magalhes Francesconi and Lude Meurer

Case Report
Tuberculosis and Biological Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52
Marjorie Argollo, Orlando Ambrogini Junior and Sender J. Miszputen

Clinical Case with Commented Image . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53

Eloa Marussi Morsoletto

4
IJI Bowel Disease Volume 1 Number 1 May-August 2014

Introduction
Challenges Have Been the Hallmark of Our Group

The contribution of each of us, in our individual roles, has enabled us to overcome the challenges we have faced,
further solidifying the team spirit and respect among members, which you only find in great societies.

Editing a magazine is a complex task of laborious logistics and winding steps that do not end with its first publication,
but its birth deserves celebration.

The GEDIIB, and all the staff who have contributed tirelessly to produce this edition, I believe, have found the way
to expand their scientific presence among Brazilian and perhaps international health professionals. This is a realistic goal,
which is based on the qualities already demonstrated by you all experts in the field of inflammatory bowel disease.

Various sections have been created so that everyone can participate, and Im completely sure that this medium will
be used to gain exposure for their work. The Editorial Board is able to receive and give you all the attention you deserve,
according to the standards established by the most prestigious medical publications.

Make your suggestions, send your articles, and let us go forward together towards the journalistic excellence that
our group aspires to.

I salute all of you for this achievement.

Best regards,

Sender J. Miszputen
Professor Associado de Gastroenterologia e Chefe do Setor de Intestino
Departamento de Medicina
Escola Paulista de Medicina
Universidade Federal de So Paulo
So Paulo SP

5
IJI Bowel Disease Volume 1 Number 1 May-August 2014

Instructions to Authors

6
IJI Bowel Disease Volume 1 Number 1 May-August 2014
Editorial
The Brazilian Inflammatory Bowel Disease Study
Group (GEDIIB), a department of the Brazilian Federation
of Gastroenterology (FBG), is honored to present to the
scientific community the first edition of the Internation-
al Journal of Inflammatory Bowel Disease. This is the first
Latin American medical publication to specifically address
inflammatory bowel disease-related topics. The comple-
tion of this endeavor since its conception to printing has
taken great effort, dedication, and respect in order to en-
sure quality and acceptance. This is indeed a historical
moment for all members of GEDIIB, created in 2002 to
bring together health professionals with a particular inter-
est in Crohns disease and ulcerative colitis, with special
emphasis in disseminating scientific knowledge in this
field and providing pathways to acceptable standards of
care for our patients with inflammatory bowel disease.
An individual perception of a significant impact of
inflammatory bowel disease in our population is general-
ly observed among healthcare professionals. However, the
true dimension of this burden across vast regions of our
territory is not fully appreciated. While much has been
done with respect to public policies, which allow patient
access to high-cost medications such as immunosuppres-
sants and biologics, very little has been done to character-
ize the epidemiology of inflammatory bowel diseases in
Brazil. We lack studies on the incidence and prevalence of
these diseases, we do not know their actual impact on
patients quality of life, job absenteeism, and professional
impairment, and we do not measure how much this rep-
resents as an economic issue for our society. Moreover,
there are no clear-cut programs from governmental au-
thorities that directly address the urgent need to compre-
hend all the consequences of inflammatory bowel disease
in our country.
A recent large Canadian study on the global epidemi-
ology of inflammatory bowel disease clearly showed the
paucity of data on these diseases in Latin America1. The
main purpose of this systematic review was to determine
the worldwide incidence and prevalence of ulcerative coli-
tis and Crohns disease in different regions of the world
and with time. The authors analyzed data from 167 stud-
ies from Europe (1930-2008), 52 studies from Asia and the
Middle East (1950-2008), 27 studies from North America
(1920-2004), and just three studies from Latin America.
As expected, while significant information could be ob-
tained for the majority of countries in Europe and North
America, very few or no conclusions could be drawn for
Latin America, Africa, and Eastern countries. The devel-
oping nations appeared to have rare incidence and prev-
alence of inflammatory bowel disease according to this
study, although the authors do recognize a rise in inci-
dence in the last few years. However, this apparent rarity
has frequently been questioned by those who deal with
these diseases in their practices in our country. As the
Authors also pointed out, knowledge about the geograph-
ical distribution of inflammatory bowel disease can give
important clues for characterizing environmental determi-
nants of its intricate immunological puzzle. How import-
ant are industrialization, lifestyle, diet, endemic diseases,
or even sun exposure in its immunopathogenesis? These
and many other questions remain to be elucidated.
Another formidable review on geographical variability
and environmental risk factors for inflammatory bowel
disease was published by Ng, et al.2 from the Epidemiology
and Natural History Task Force of the International Orga-
nization of Inflammatory Bowel Disease (IOIBD). Besides
exploring in detail the variations of inflammatory bowel
disease incidence and prevalence between and within
countries, the paper also brings important insights about
the general perceived increase in incidence over time in
many parts of the world, especially for Crohns disease. The
Authors lay stress upon the fact that smoking and appen-
dectomy, the two most well-established risk factors for
inflammatory bowel disease, cannot fully account for all
its variations in incidence and prevalence. In this regard,
other possible causes such as diet (including its complex
interaction with host genetics and microbiome), antibiotic
use in early life, population density, educational level, vi-
tamin D, oral contraceptives, and vaccinations are dis-
cussed in detail. There is a general understanding in this
paper that the methodology behind epidemiological studies
designed to identify environmental risk factors for inflam-
matory bowel disease is prone to a great number of con-
founders and much work still needs to be done in this area.
Victoria, et al. provided the best data to date on the
incidence and prevalence of Crohns disease and ulcerative
7
colitis in a specific region of So Paulo State in Brazil 3.
Data was collected from 115 inflammatory bowel disease
patients from a reference hospital in a 20-year period
(1986-2005). The majority of individuals with inflamma-
tory bowel disease were white and from urban centers,
with a mean age of 38 years. Females were more affected
by Crohns disease than males. Incidence and prevalence
of both ulcerative colitis and Crohns disease tended to
increase over the study period. During the last observa-
tional period, the prevalence of ulcerative colitis was
14.8/100,000 and that of Crohns disease was 5.6/100,000.
The authors recognize the limitations of the study due to
the small geographical area where it was conducted and
highlight the need for further research in other regions.
This first issue of the International Journal of Inflam-
matory Bowel Disease brings an article entitled Clinical
and epidemiological characteristics of ulcerative colitis
patients in Salvador, Bahia. Lisboa, et al. performed a
cross-sectional study in 151 patients from two inflamma-
tory bowel disease referral centers in the State of Bahia,
Brazil. Prevalence of ulcerative colitis was three-times
greater in females, which is in accordance with other small
studies conducted in Brazil. The mean interval to diagno-
sis was 18.7 months, much higher than reported by some
developed countries, exposing the weakness of the Brazilian
health system in making an efficient diagnostic work-up and
possibly contributing to aggravation of the patients health
status before the initiation of an appropriate treatment. The
8 IJI Bowel Disease Volume 1 Number 1 May-August 2014
authors recognize methodological flaws related to sample
bias of a referral center, but urge the fundamental need to
better characterize the countrys aspects of inflammatory
bowel disease in order to provide regionally tailored care
for our patients. It is truly expected that epidemiological
data will emerge soon from other investigators so that we
will be able to discuss this matter in a much broader view
than what we have today.
I sincerely hope that this first issue of our journal as
well as many others to come will enhance your knowledge
related to the exciting world of inflammatory bowel disease.
Enjoy the reading!
REFERENCES
1. Molodecky NA, Soon IS, Rabi DM, et al. Increasing incidence and prevalence of
the inflammatory bowel diseases with time, based on systematic review. Gas-
troenterology. 2012;142:46-54.
2. Ng SC, Bernstein CN, Vatn MH, et al.; Epidemiology and Natural History Task
Force of the International Organization of Inflammatory Bowel Disease (IOIBD).
Geographical variability and environmental risk factors in inflammatory bowel
disease. Gut. 2013;62:630-49.
3. Victoria CR, Sassaki LY, Nunes HRC. Incidence and prevalence rates of inflam-
matory bowel disease in Midwestern So Paulo State, Brazil. Arq Gastroenterol.
2009;46:20-5.
Marco Antnio Zerncio
Ambulatrio de Doenas Inflamatrias
Intestinais
Faculdade de Medicina
Universidade Potiguar
Natal RN
IJI Bowel Disease Volume 1 Number 1 May-August 2014
Original Article
Clinical and Epidemiological Characteristics of Ulcerative
Colitis Patients from Salvador, Bahia
Sonyara Raudys Oliveira Lisboa1, Bruno Csar da Silva2, Fernanda Gondim Dias2, Valdiana Cristina Surlo2
and Genoile Oliveira Santana2
Abstract
Ulcerative colitis (UC) is part of the group of disorders known
as inflammatory bowel disease (IBD). The etiology of UC is
uncertain, with chronic and progressive characteristics, caus-
ing significant social, psychological, and financial burdens to
patients and public health. Materials and methods: A
cross-sectional study was conducted in a referral service for
IBD patients with UC in the state of Bahia. Data collection
was conducted through interviews with patients and hospital
records. For statistical analysis we used SPSS 17.0 (SPSS,
Chicago, IL). Results: We interviewed 151 patients, 72.2%
were women. Most patients identified themselves as mixed-
race (49.6%). The mean age at diagnosis was 39.6 12.7 years.
The average time between onset of symptoms and determina-
tion of diagnosis was 1.6 years. Current smoking was present
in 2.6% of the interviewees. There was low incidence of fam-
ily history of IBD (92% of the patients denied it). Initial
symptoms most commonly reported were bleeding (68.9%)
and diarrhea (49%). Regarding the extent of UC, 47.5% had
left colitis, 33.6% extensive colitis, and 18.9% proctitis. Of the
patients surveyed, 40.4% reported previous hospitalizations
and only 3.3% required surgical treatment. In respect to pre-
vious and current drug therapy, the use of salicylates was
predominant (79.5 and 77.5%, respectively), with an increase
in the use of immunosuppressive drugs from 2.6% to the
current 7.3%. Steroid therapy was reported in 60.2% of cases.
Extra-intestinal manifestations were reported by 49% of pa-
tients. Conclusion: Most patients interviewed were young
females. There is still a delay in the diagnosis of UC in our
environment, as can be seen by the time elapsed between the
onset of first symptoms and the final diagnosis.
Corresponding author: Genoile Oliveira Santana, genoile@uol.com.br
Key words: Inflammatory bowel disease. Ulcerative colitis.
Epidemiology. Treatment.
1Escola Bahiana de Medicina e Sade Pblica, Salvador, Bahia, Brasil; 2Gastroenterology Unit, University Hospital Professor Edgard Santos, Federal University of Bahia,
Salvador, Bahia, Brazill
Correspondence to: Genoile Oliveira Santana, Av. St. Dumont, Km 05, LTG 31, Cond. PQ. Encontro Itinga, CEP 42700-000 Lauro de Freitas Salvador BA, Brasil.
E-mail: genoile@uol.com.br
Resumo
A colite ulcerativa (UC) parte do grupo de desordens co-
nhecido como doena inflamatria intestinal (DII). A etiolo-
gia da UC incerta, com caractersticas crnica e progressiva,
causando significativos danos sociais, psicolgicos e financei-
ros para os pacientes e danos de sade pblica. Materiais e
mtodos: um estudo transversal foi realizado em um servio
de referncia para pacientes com DII com UC no estado da
Bahia. A coleta de dados foi realizada atravs de entrevistas
com os pacientes e registros hospitalares. Para anlise esta-
tstica, foi utilizado SPSS 17.0 (SPSS, Chicago, IL). Resultados:
foram entrevistados 151 pacientes, 72,2 % eram mulheres. A
maioria dos pacientes se identificou como mestia (49,6%).
A mdia de idade no momento do diagnstico foi de 39,6
12,7 anos. O tempo mdio entre incio dos sintomas e a de-
terminao do diagnstico foi de 1,6 ano. O tabagismo atual
esteve presente em 2,6% dos entrevistados. Houve baixa in-
cidncia de histria familiar de DII (92% dos pacientes nega-
ram). Os sintomas iniciais mais comumente relatados foram
hemorragia (68,9%) e diarreia (49%). Em relao extenso
da UC, 47,5% marcou colite; 33,6% colite extensa, e 18,9%
proctite. Dos pacientes entrevistados, 40,4 % relataram inter-
naes anteriores e apenas 3,3 % exigiram tratamento cirr-
gico. Em relao terapia medicamentosa anterior e atual, o
uso de salicilatos foi predominante (79,5 e 77,5 %, respecti-
vamente), com um aumento da utilizao de frmacos imu-
nossupressores, de 2,6 % para a atual de 7,3 %. A corticote-
rapia foi relatada em 60,2 % dos casos. Manifestaes
extraintestinais foram reportadas em 49% dos pacientes.
Concluso: a maioria dos pacientes entrevistados era de mul-
heres jovens. Ainda existe um atraso no diagnstico da UC
no nosso meio, tal como pode ser visto pelo tempo decorrido
entre o incio dos primeiros sintomas e o diagnstico final.
Palavras-chave: Doena inflamatria intestinal. Colite ulcer-
ativa. Epidemiologia. Tratamento.
9
INTRODUCTION
Ulcerative colitis (UC) is part of a group of diseases
called inflammatory bowel disease (IBD), characterized by
its idiopathic, chronic, inflammatory profile. The etiology
and pathophysiology of UC have not been elucidated, but
genetic and environmental factors are possible contribu-
tors to its development. In this disease, there is an aber-
rant immune response, whose distorted modulation leads
to amplification of the inflammatory signs and increased
levels of proinflammatory cytokines in the intestinal mu-
cosa1. Moreover, etiologic factors intrinsic to the patients
also play an important role in the context of IBD, as can
be seen by the existence of ethnic and family aggregations
and racial variations (highest incidence in Jews and white
individuals than in nonwhites)2.
Inflammatory lesions in UC are reserved to the intes-
tinal mucosa and submucosa, which may present edema,
hyperemia, friability, bleeding, erosions, and ulcerations,
depending on the disease severity. It has an ascending and
homogeneous nature, affecting the rectum and large intes-
tine, but saving the small intestine. The peak incidence is
between the second and third decades of life and there is a
second peak occurring at 55 years, affecting the sexes in
a variable manner3. The symptoms are insidious and can
be present for many years before diagnosis.
The IBDs are reported with a greater prevalence in
northern Europe and western North America, and recent
studies show a gradual increase in the developing regions
such as Africa, Asia, and South America4. The UC has high-
er prevalence in the USA and UK, with 38-229 cases per
100,000 persons/year and 269 per 100,000 persons/year,
respectively, followed by Sweden. However, the increase in
prevalence of UC is seen worldwide. Such increase was
accompanied by changes in the clinical presentation, as well
as the course, treatment and prognosis of the disease5.
In Brazil, there are few studies that discuss the epide-
miological aspects of UC. For the most part, only the clin-
ical features are presented, with no advance in the incidence
and prevalence of this pathology in the Brazilian popula-
tion6. A recent research points to an increase in cases and
hospital admissions due to IBD in southeast Brazil1. It is
possible that the difficulty in differential diagnosis with
other diseases such as schistosomiasis and intestinal tuber-
culosis7, and even with other IBD, plays an important role
in the underestimation of the prevalence in Brazil.
Currently, UC is considered an important public
health problem in regard to the prevalence in young indi-
viduals, clinical course with frequent recurrences and
their impact on the patients quality of life6. In Bahia there
is still a lack of scientific data to help determine a better
profile of this disease in our environment. The following
study aims to clarify and provide relevant data for the
population with UC treated at a referral center for IBD in
Salvador, Bahia, and thus provide support to public health
for better management of these patients.
10
MATERIALS AND METHODS
This is a descriptive cross-sectional study with a con-
venience sample, which targets patients with UC treated
in the outpatient IBD Unit of the University Hospital Pro-
fessor Edgard Santos. The study included all patients treat-
ed between November 2011 and July 2012 with a definite
diagnosis of UC. Those whose diagnosis was changed to
another type of IBD were excluded from the study.
The questionnaire administered to patients contained
the following variables: age at diagnosis, gender, race/
ethnicity (through self-identification as determined by the
Brazilian Institute of Statistical and Geography IBGE8),
education, family income, residence area, smoking, family
history of IBD, time of diagnosis, opening symptoms, dis-
ease extent, previous surgery, number of hospitalizations,
corticosteroid therapy, current and previous drug therapy,
and extra-intestinal manifestations. We applied the Montre-
al classification9. Data were analyzed using SPSS version 17.
The project was approved by the research ethics com-
mittee of the University Hospital Professor Edgard Santos
under number 67/10. For all patients we applied the con-
sent form, as required by resolution 196/96 of the Nation-
al Health Council.
RESULTS
During the study period we interviewed a total of
151 patients, 27.8% were males and 72.2% females, with
a female:male ratio of 2.6:1. The mean age at diagnosis was
39.6 12.7 years. The minimum age was 11 years and
maximum 74 years. There was a predominate number of
patients that self-identified as mixed-race (49.6%), fol-
lowed by black (29.8%).
Regarding smoking habits, there was a majority of
nonsmokers (60.3%). In the smokers group, current and
former, we found an average usage of 8.9 cigarettes/day
and 11.5 years of smoking. The majority of patients had
no family history of IBD (92%). Of those who answered
yes, 5.9% (9 patients), the brother (sister) was the most
frequent family member (3.3%).
Family income was asked in terms of minimum wag-
es where a total of 96.7% (146 respondents) answered this
question. We found that patients incomes between 2 and
5 times the minimum wages were more frequent (62.9%).
Only 4.7% of the interviewees had an income greater than
10 minimum wages.
When asked about their level of education (variable
measured in years), 13.2% of the patients chose not to
respond to the question. Of the 86.8% who answered
(131 patients in total), the majority (57.3%) claimed to
have between 4-7 years of study (Table 1).
On the clinical characteristics of patients, we found
that the average gap between onset of symptoms and the
final diagnosis was 1.6 years, the minimum did not
reach a whole month, and the maximum was 28 years.
IJI Bowel Disease Volume 1 Number 1 May-August 2014
Table 1. Socioeconomic characteristics of 151 patients The median time of diagnosis was 7.8 6.2 years. The
with ulcerative colitis in Salvador-BA, 2011-2012 most frequently reported opening symptoms were bleed-
ing (68.9%), diarrhea (49.0%) and abdominal pain (30.5%).
Gender Among the patients, 59.6% (90 patients) reported no hos-
Male 27.8% pitalizations due to UC so far. Of those who reported
previous hospitalizations, 26.5% declared approximately
Female 72.2%
1-2 episodes and only one patient could not remember the
Age at diagnosis (years) exact number. For previous surgeries, there was a predom-
inance of patients who had never needed to undergo sur-
Mean SD 39.7 12.7
gical procedures due to UC (96.7%).
Median 40.0 Patients were also asked about the need for cortico-
Range 11-74 steroid therapy in the treatment of their disease. Most said
they had used steroids at some point (60.7%). The most
Race/Color prevalent frequency of use of the drug was 1-2 times
White 15.9% (33.8%), while 0.7% did not know an exact number and
one patient chose not to respond.
Black 29.8%
Extra-intestinal manifestations related to UC were
Mixed-race 49.6% reported by 51% of patients, with a predominance of joint
involvement (92.2%) (Table 2).
Asian 4.0%
To determine the degree of extent of the disease, we
Brazilian indian 0.7% used the Montreal classification of 2005. In 5.3% of the
interviewees (eight patients) it was not possible to obtain
Family history
this information. Among the available data (143 patients),
First degree relative 3.3% we found a higher frequency of patients with left colitis
Second degree relative 1.3% (47.5%) at the time of the interview (Table 3).
In regard to previous drug therapy, there was a high-
Other 1.3% er frequency in use of salicylates (79.5%) among the pa-
Smoking tients, with sulfazalazine being the elected drug (21.2%).
About the current therapy, 94.7% of the patients reported
Current smokers 2.6%
using some kind of medication, with new predominance
Ex-smokers 37.1% in the use of salicylates (77.5%), but taking mesalazine as
drug of choice (52.3%). The use of combined therapy with
Nonsmokers 60.3%
immunosuppressives and salicylates increased by 5.9% in
Education (years of study) the current therapy (Table 4).
No education or < 1 year 2.3%

1-3 years 1.5% DISCUSSION

4-7 years 57.3% The results of this study were obtained by sponta-
neous request of patients with UC, treated at a major re-
8-10 years 29.0% ferral center for IBD treatment in the State. Patients are
>11 years 9.9% regularly monitored by gastroenterology specialists,
through assessments every three months. Treatment is
Family income (minimumwages)
provided by the High Cost Drug Program of the Health
No income 1.3% Department of the State of Bahia, which contributed to the
relevance of the study.
2 14.6%
The prevalence of UC in females found in this study
> 2 and 5 62.9% follows the results of researches conducted in So Paulo
> 5 and 10 13.2% and Mato Grosso, Brazil, where the percentage of females
reached 58.9%3,6. Countries like Canada2, Iran4, Malay-
> 10 and 20 4.0% sia10 and Korea11 also showed similar results. However,
> 20 0.7% Edouard, et al. showed a male predominance in France7,
and Oliveira, et al. observed similarity between genders in
Residence Minas Gerais, Brazil1.
Urban area 90.7% Recent studies indicate two peaks of occurrence:
one between 20-39 years and another one between 55-
Rural area 9.3%
70 years5,9,12,13. Some authors also describe similar mean

Sonyara Raudys Oliveira Lisboa, et al.: Clinical and Epidemiological Characteristics of Ulcerative Colitis Patients from Salvador, Bahia 11
Table 2. Clinical characteristics of 151 patients with ulcerative Table 3. Montreal classification of 151 patients with ulcerative
colitis in Salvador-BA, 2011-2012 colitis in Salvador-BA, 2011-2012
Duration of symptoms before diagnosis (years) Disease extension
Mean SD 1.6 2.9 Proctitis 18.9%

Median 1.0 Left colitis 47.5%

Range 0-28 Extensive colitis 33.6%

Duration of diagnosis at time of inclusion in the study

(years)
Table 4. Maintenance drug therapy characteristics
Mean SD 7.8 6.2 of 151 patients with ulcerative colitis in Salvador-BA,
2011-2012
Median 6.0
Previous therapy
Range 0.2-3.4
Salicylates(topical and/or oral) 79.5%
Number of symptoms at presentation
Salicylates + immunosuppressants 4.0%
Only 1 symptom 51.6%
Immunosuppressants 2.6%
2 or more symptoms 48.4%
No medication 13.9%
Initial symptoms
Current therapy
Bleeding 68.9%
Salicylates (topical and/or oral) 77.5%
Diarrhea 49.0%
Salicylates + immunosuppressants 9.9%
Abdominal pain 30.5%
Immunosuppressants 7.3%
Mucus 19.2%
No medication 5.3%
Weight loss 5.3%

Tenesmus 4.6%

Constipation 0.7%

Vomiting 0.7% ages at diagnosis: Cohen, et al. found a mean age of

48.5 years in Porto Alegre, Brazil14; Wiercinska-Drapalo,
Flatulence 0.7% et al. mention prevalence in the 40s in Poland 5. Our pa-
Incontinence 0.7% tients aged preferably between 36-45 and 45-55 years at
the diagnosis, with a mean age of 39.7 years. However, it
Cutaneous manifestation 0.7%
is necessary to emphasize that in all presented studies,
Extra-intestinal manifestations there was no participation of pediatric patients in a con-
Joint involvement 92.2%
siderable amount, which leads to a general increase in the
average age at diagnosis.
Cutaneous 7.8% The initial symptoms of UC have insidious and non-
Number of internments specific characteristics, leading to a delay by the patients
in seeking medical care. Difficulties in the definitive di-
1-2 26.5% agnosis (due to the similar clinical course with other dis-
3-5 8.6% eases, such as parasites) and delay in referring to a spe-
cialized physician delay treatment initiation. Bernstein, et
>5 4.6%
al. report in the study conducted in Canada that about
Number of corticosteroid therapies 10-23% of cases are incorrectly diagnosed, leading to in-
1-2 times 33.8%
appropriate treatments and unnecessary procedures2.
Consequently, the gap between manifestation of the first
3-4 times 14.6% symptoms and the diagnosis has an important variability,
> 5 times 11.3% depending both on the patients and the available medical
resources. In our study, the average interval was greater
Previous surgeries than 1.5 years (18.7 months), which demonstrates the need
Yes 3.3% for better disclosure and recognition of UC in our state.
International researches obtained results that clearly
No 96.7%
demonstrate all the discrepancies that come from scarce

12 IJI Bowel Disease Volume 1 Number 1 May-August 2014

medical resources between the richest countries and the
developing ones. In Iran, Vahedi, et al. reported a mean
interval time that reached 22 months4, while in France
this interval was only two months7.
A study conducted by Tan, et al. found that the most
common symptoms in Malaysia were bloody diarrhea,
mucus, and abdominal pain10. Park, et al. observed an
increased report of rectal bleeding, tenesmus, diarrhea,
and abdominal pain by South Koreans11. We noted that
despite regional differences between these countries and
our study area, the initial symptomatology is still very
similar.
The Montreal classification used in our service was
set at the World Congress of 2005 and involves extent
criteria and degree of clinical activity of UC. In our
study, we only address the extent criteria of the disease.
However, there were cases where this information was
unknown. Among the complete data, there was a pre-
dominance of left colitis, while proctitis had the lowest
frequency. Wiercinska-Drapalo, et al. showed similar ex-
tension frequency in northwestern Poland, where 80% of
patients had left colitis and 5% extensive colitis5. How-
ever, in South Korea, Sri Lanka and in Mato Grosso,
Brazil, there were higher frequencies of proctitis among
the patients, followed by extensive and left colitis3,11,12.
These results demonstrate differences in the variability
of this pathology and reinforce the importance of epide-
miological studies.
Bhat, et al. published a study in 2009 reporting that
French Canadians had a greater propensity to develop UC
after quitting smoking and patients who have never
smoked or are former smokers have higher risk of devel-
oping the disease15. The relation between smoking and UC
has been known for quite some time, with several studies
indicating the protective effect of cigarettes.
The explanation for this lies in the regulation of the
inflammatory cascade by smoking, which modulates cel-
lular and humoral immunity, and interferes with micro-
circulation and smooth muscle contraction15. Souza, et al.,
Edouard, et al. and Vahedi, et al. published results that
corroborate this theory, where approximately 60% of pa-
tients in all three studies were nonsmokers, which is also
near to our data 3,4,7.
The importance of genetic factors in the individual
susceptibility to IBD is undeniable. However, there is a
small incidence of family history of UC. Vahedi, et al.,
Wiercinska-Drapalo, et al. and Niriella, et al. found a pos-
itive family history in proportions ranging from 2.2 to
9.6%4,5,12. Even with the inclusion of second-degree rela-
tives, we found that the final proportions remain similar
to those shown in other studies.
Drug therapy is the most appropriate treatment for
UC. Tan, et al. reported that approximately 88% of South
Korean patients with this pathology were handled solely
by this method10. We also noted that most of our patients
were being treated with oral and/or topical medications.
Sonyara Raudys Oliveira Lisboa, et al.: Clinical and Epidemiological Characteristics of Ulcerative Colitis Patients from Salvador, Bahia
There was, however, an increase of 40.4% among patients
who reported such treatment and 12.6% increase in the use
of immunosuppressants, which can be interpreted as a re-
flection of the continuous and progressive characteristics
of UC through the years. About previous drug use, recent-
ly published studies corroborate our findings, where we
observed that salicylates were the first choice of drugs. Jess,
et al. reported a frequency in the use of salicylates in Den-
mark of 50%, immunosuppressants in 1% of cases, and
topical therapy in 14%16. Vahedi, et al., however, demon-
strated small differences between use of salicylates (22.3%)
and immunosuppressants (12.4%) in Iran4, pointing yet
again to the divergent epidemiologic aspects of this disease.
Due to the effectiveness of drug treatment, few patients
needed surgical treatment17. In agreement with our study,
Wiercinska-Drapalo, et al., Niriella, et al. and Souza, et al.
showed percentages of surgeries ranging from 2-6%3,5,12.
Corticosteroids also have an important role in the
treatment of UC. They are more often reserved for relaps-
ing cases and those of difficult symptomatic control9. The
literature differs in respect to the frequency of their use,
with rates ranging from 7.0 to 16.6% (in studies developed
by Heriksen, et al. and Vahedi, et al., respectively)4,17, and
30.9-56.0% (Park, et al. and Jess, et al., respectively)11,16.
Our research presented similar data to those found in
Korea and Denmark.
The extra-intestinal manifestations are part of the UC
course and can either be caused by direct effect of the
disease, or by intrinsic side effects to certain medications.
Niriella, et al. published results which agree with our
study, where 40.4% of patients of two districts of Sri Lan-
ka had some type of extra-intestinal manifestation, and
among those who reported, arthralgia/arthritis were the
most prevalent (28.3%)12. However, the frequency reported
in our study needs to be further evaluated, since it was
not the main goal, which requires further investigation
with specific methodology for confirmation.
Since it was a clinical epidemiological study, some
flaws of this study should be considered in the final anal-
ysis. The fact, for example, that it was a convenience
sample, automatically excludes patients with UC treated
in other services such as private clinics and public health
facilities for primary and secondary care. Because our
service merely deals with adult patients, only one inter-
viewed patient was under 18 years of age. This fact may
have been responsible for the elevated average age of the
study population, which does not necessarily represent
the reality of patients in our state. The difficulty in ob-
taining data reveals the scarce knowledge of the patients
about their disease.
CONCLUSIONS
The profile of UC patients in this sample is of a young
female, with low education level and family income, whose
disease initially presents with a typical case of diarrhea
13
and bleeding, without family history of IBD. The most
common location is left colitis and there is still a large gap
between the first symptoms and the diagnosis. Treatment
with oral or topical salicylic derivatives was the main
therapy. These data are generally similar to most published
studies in other centers, with the predominance of females
being the bigger disagreement between them. A reliable
knowledge of the clinical and epidemiological character-
istics of UC in our country has great relevance in order to
improve the healthcare for this group of patients.
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IJI Bowel Disease Volume 1 Number 1 May-August 2014
IJI Bowel Disease Volume 1 Number 1 May-August 2014
Original Article
Dairy Food Intake by Inflammatory Bowel
Disease Patients
Mirella Brasil Lopes1, Raquel Rocha1, Vanessa Rosa Oliveira1, Fernanda Gomes Coqueiro1, Naiade Silveira Almeida1, Patrcia Nunes1,
Andr Castro Lyra2 and Genoile Oliveira Santana2
Abstract
Aim: To assess dietary intake of dairy products by inflamma-
tory bowel disease (IBD) patients. Material and methods:
Cross-sectional study. The IBD patients were included be-
tween September 2011 and March 2012. and were attending
an IBD reference center in the city of Salvador, Bahia. The
semi-structured questionnaire and quantitative food frequen-
cy (FFQ) were applied. The FFQ was used to assess the av-
erage daily intake of dairy products, comparing it with the
reference standard. A self-reported change on consumption
of dairy products was answered. Results: The study included
51 IBD patients, 66.7% with ulcerative colitis (UC) and 33.3%
Crohns disease (CD). The mean daily consumption of dairy
products by IBD patients was 1.3 1.3 servings. Most patients
(63.4%) reported food restriction of dairy products. Among
these, UC patients who reported restriction of dairy products
intake presented a statistically significant lower intake of
these products than those who reported not to make such
restriction (p = 0.00). However, in CD patients there was no
statistically significant difference between the two groups,
according to this restriction. Conclusion: The dairy
products intake is inadequate, especially among UC
patients who reported restriction of dairy products.
These results are relevant, considering that IBD patients
have a higher risk for developing osteoporosis and dairy
products are rich in bioavailable calcium.
Corresponding author: Genoile Oliveira Santana, genoile@uol.com.br
Key words: Crohns disease. Ulcerative colitis. Dairy products.
1Department of Sciences of Nutrition, School of Nutrition, Federal University of Bahia, Salvador, Bahia, Brazil; 2Gastroenterology Unit, University Hospital Professor Edgard
Santos, Federal University of Bahia, Salvador, Bahia, Brazil
Correspondence to: Genoile Oliveira Santana, Av. St. Dumont, Km 05, LTG 31, Cond. PQ. Encontro Itinga, CEP 42700-000 Lauro de Freitas Salvador BA, Brasil.
E-mail: genoile@uol.com.br
Resumo
Objetivo: Avaliar o consumo alimentar de laticnios por paci-
entes com doena inflamatria intestinal (DII).
Mtodos: Estudo transversal desenvolvido entre setembro de
2011 e maro de 2012. Pacientes com DII, acompanhados em
um centro de referncia da cidade de Salvador, responderam
um questionrio semiestruturado e outro quantitativo de fre-
quncia alimentar (QFA). O QFA foi utilizado para a avaliao
da ingesto mdia diria de laticnios, comparando-o com o
padro de referncia. Modificaes autorrelatadas sobre o
consumo de laticnios foram respondidas. Resultados: O es-
tudo incluiu 51 pacientes com DII, desses, 66,7% possuam
retocolite ulcerativa (RCU) e 33,3% doena de Crohn (DC).
O consumo mdio dirio de laticnios pelos pacientes com
DII foi de 1,3 pores. A maioria dos pacientes (63,4%)
referiu restrio alimentar aos laticnios. Dentre esses, os
pacientes com RCU que afirmaram restrio de laticnios
apresentaram um consumo estatisticamente menor de latic-
nios em relao aos que afirmaram no realizar tal restrio
(p = 0,00). Contudo, nos pacientes com DC, no houve dif-
erena estatisticamente significante entre os dois grupos,
quanto referida restrio alimentar. Concluso: O consumo
de laticnios inadequado, principalmente entre os indivdu-
os com RCU que referiram restrio de laticnios. Estes resul-
tados so relevantes, considerando que os pacientes com DII
tm um risco maior para o desenvolvimento de osteoporose
e que os laticnios so fontes alimentares ricas em clcio
biodisponvel.
Palavras-chaves: Doena de Crohn. Retocolite ulcerativa. La-
ticnios.
15
INTRODUCTION
Inflammatory bowel disease (IBD), mainly represent-
ed by Crohns disease (CD) and ulcerative colitis (UC), is
characterized by chronic and idiopathic inflammatory dis-
orders. IBD is associated with gastrointestinal and system-
ic complications1 and is one of the great gastrointestinal
problems in the western world. Although rates of preva-
lence, incidence, and mortality are unknown in Brazil,
some regional studies have shown an increase in the fre-
quency of this disease in our country2-5.
Calcium deficiency, mainly associated to the use of
corticosteroids, has been reported in both CD patients and
UC patients6,7. Furthermore, extra-intestinal complica-
tions are reported, like the development of osteoporosis or
osteopenia, as well as fracture risk8.
Between the 1960s and 1970s, some studies reported
an improvement in symptoms and a decreased probability
of disease activity in UC patients who had a dairy products
exclusion diet9,10. These studies reported that milk could
be an important factor in the onset or exacerbation of UC,
despite having several methodological limitations11.
The available data on food consumption of dairy
products by IBD patients are scarce in Brazil. Considering
the importance of the impact of deficiency of calcium in
bone health and quality of life of these patients, the ob-
jective of this study was to evaluate the relationship be-
tween changes in self-reported dietary intake of dairy
products and dietary intake of dairy products for IBD
patients.
MATERIAL AND METHODS
Study design
Observational, cross-sectional, and descriptive study.
Patients
Patients were included in the study according to in-
clusion criteria: age over 18 years and diagnosed according
to clinical, endoscopic, radiological and/or pathological
findings for UC or CD12. Exclusion criteria were: pregnant
women, intestinal resection, patients with other diseases
(malignant disease, celiac disease, and lactose intoler-
ance).
The sample selection was done by convenience and
consecutively in the outpatient Gastroenterology and Nu-
trition Unit of the University Hospital Complex Professor
Edgard Santos, Federal University of Bahia (UFBA), Salva-
dor, Bahia, Brazil. The Gastroenterology Outpatient Unit
is a referral center for specialized care in IBD, with a
contingent of around 500 patients.
After signing the informed consent, the patients were
given anthropometric measurement. The semi-structured
questionnaire had demographic, socioeconomic, clinical
and dietary data, which together with the quantitative
16
food frequency questionnaire (FFQ) were applied. Of the
58 patients who agreed to participate in this study, seven
were excluded because of incomplete information, so the
final sample was 51 patients.
Data evaluation
Data collection was conducted from September 2011
to March 2012. The demographic and socioeconomic data
included: gender, age, education, and monthly income.
Among the clinical data were evaluated: time and location
of disease, disease activity, and gastrointestinal symp-
toms (abdominal pain, bloating, nausea, vomiting, diar-
rhea, bloody stools, and flatulence). Regarding dietary
data, the most current information was analyzed from the
modifications on self-reported consumption of dairy
products (cows milk and derivatives), as well as the jus-
tifications.
In the evaluation of disease activity, the specific dis-
ease activity index (IAD) was applied by using the patient
information on the general state in the last 24 hours pre-
vious to the medical care. The index of Harvey and Brad-
shaw was used in CD patients, and disease activity was
defined when the score was 5 points13. The Lichtiger
Index was used in UC patients and disease activity was
defined when the index was 10 points14. We used the
Montreal classification for UC and CD patients15.
Body mass index (BMI) was considered for classifica-
tion of the anthropometric nutritional status. The cutoff
points for this classification were different for adults and
the elderly17. Anthropometric measurements were per-
formed by a nutritionist. The BMI calculation included
body weight (kg), measured with light clothes and without
shoes, and height (centimeters), using a digital scale with
stadiometer attached. The resolution was 100 g and 0.5 cm
for weight and height, respectively (WHO, 1995).
Evaluation of dietary data
The FFQ was used in combination with a photograph-
ic album of portions to assess the mean daily intake of
dairy products18. The amount of dairy products consumed
per day was transformed into portions and adequate in-
gestion was defined when it was greater than three por-
tions of dairy products per day19.
The restriction of dairy product was defined when the
patient reported a reduction or exclusion of cows milk and
derivatives or replacing them by soybean milk.
Statistical analysis
For descriptive analyses of continuous data, the
mean with standard deviation were calculated. For cate-
gorical data, absolute and relative frequencies were re-
ported. Continuous variables were tested for normality
using the Kolmogorov-Sminorv. We used the Student t
IJI Bowel Disease Volume 1 Number 1 May-August 2014
Table 1. Description of the demographic, socioeconomic, Table 2. Comparison between mean daily in take of dairy
anthro-pometric nutritional and clinical characteristics of the products by inflammatory bowel disease patients and
inflammatory bowel disease patients (n = 51) Salvador-BA, established recommendation (n = 51) Salvador-BA, 2011-2012
2011-2012
Variables Recommendation Daily intake by p*
Variables n % of daily intake IBD patients
Gender Mean SD
Male 23 45.1 Dairy products, 3.0 1.3 1.3 0.00
Female 28 54.9 servings

Schooling IBD: inflammatory bowel disease; SD: standard deviation.

*Student t test; Recommendation for the consumption of dairy products: Philippi,
1st grade 16 31.4 et al., 199919.
2nd grade 31 60.8
Higher education 4 7.8
Incomes*
test to compare means. We adopted a significance level of
1 MW 14 27.4
p 0.05. The statistical program used for construction of
1-3.5 MW 26 51.0 the database and the data analysis was the Statistical Pack-
> 3.5 MW 10 19.6 age for the Social Sciences (SPSS) version 17.0.
Type of IBD
Ulcerative colitis 35 68.6 Ethical considerations
Crohns disease 16 31.4 This study was approved by the ethics committee of
Anthropometric nutritional status the University Hospital Complex Professor Edgar Santos/
Underweight 6 11.8 UFBA under No. 50/2011. All patients who agreed to par-
ticipate signed a consent form.
Normal 31 60.8
Overweight 14 27.4
RESULTS
Extension of ulcerative colitis
Proctitis 17 48.6 In this study, IBD patients presented a mean age of
45.4 13.6 years. The mean disease duration was 7.1
Left-sided ulcerative colitis 9 25.7
4.5 years. The majority (54.9%) was female, 68.6% of pa-
Extensive ulcerative colitis 9 25.7 tients reported education level between high school and
Location of Crohns disease higher education, 51.0% with incomes between 1.0 and
Terminal ileum 4 25.0 3.5 minimum wages, 60.8% presented anthropometric nu-
tritional status appropriate (eutrophic) and 86.3% were
Colon 5 31.2
clinically in remission. The demographic, socioeconomic
Ileocolon 7 43.7 and medical characteristics are shown in table 1.
Upper GI 0 0.0 Proctitis was the most frequent extension, reaching
Behavior of Crohns disease 48.6% (17/35) in UC patients. The ileocolic was the most
frequent location, reaching 43.7% (7/16) in CD patients.
No stricturing, no penetrating 11 68.7
Stricturing and penetrating behavior were present in
Stricturing 2 12.5 12.5% (2/16) and 18.7 (3/16) of DC patients respectively
Penetrating 3 18.7 (Table 1).
Stricturing + perianal 0 0.0 It was observed that 45.1% of IBD patients reported
symptoms (Table 1). Bloating and bleeding were the main
Penetrating + perianal 0 0.0
symptoms reported by UC patients, 22.9% (8/35) and
Disease activity index 20.0% (7/35), respectively. The most common symptoms
Remission 44 86.3 in CD patients were abdominal distension, reaching
Activity 7 13.7 68.7% (11/16), and abdominal pain, reaching 43.7%
(7/16).
Gastrointestinal symptoms
No 28 54.9
Yes 23 45.1
Intake of dairy products

MW: minimum wage; IBD: inflammatory bowel disease; GI: gastrointestinal. In table 2, it can be observed that the mean daily
*50 patients; 35 patients; 16 patients. intake of dairy products by IBD patients is less than that

Mirella Brasil Lopes, et al.: Dairy Food Intake by Inflammatory Bowel Disease Patients 17
Table 3. Frequency of the modifications of dairy products intake
by inflammatory bowel disease patients (n = 51) Salvador-BA,
2011-2012
Variables
Modifying the consumption of dairy products
No
Yes
Types of modifications
Exclusion/reduction
Substitution for nonfat milk
Substitution for soy milk
Increased ingestion
Justifications for restrictions*
Advice from healthcare professionals
Exacerbation or onset of symptoms
Fear of eating
Magazines/brochures /books
Others
*The justifications for restrictions considered the report of reduction/exclusion
and substitution by soy milk (n = 19).
recommended and this difference was statistically signif-
icant (p = 0.00). Compared with the recommended values,
it is emphasized that inadequate consumption of dairy
products in the patients studied was 92.2%, and thus 47
IBD patients had inadequate consumption of dairy
products. Only two patients reported ingestion of a calci-
um supplement.
Change in intake of dairy products
Regarding dietary characteristics, 58.8% (30/51) of
IBD patients reported change in intake of dairy prod-
ucts, among them the majority, 63.3% (19/30), report-
ed restriction of cows milk and derivatives. The more
frequent justification was exacerbation or onset of
symptoms, reaching 47.4% (9/19), and also 36.8%
(7/19) reported orientation by health professionals (Ta-
ble 3).
18
Change in intake of dairy products versus dairy
products intake
It was found that the mean consumption of dairy
n % products was significantly lower in IBD patients who
reported restriction of dairy products than those who re-
ported no restriction (p = 0.01) (Table 4). When the sam-
ple was stratified, this same result was observed among
21 41.2 UC patients (p = 0.00). However, there was no statistical-
ly significant difference in CD patients for this analysis
30 58.8 (p = 0.53) (Table 4).
DISCUSSION
14 46.7
In this study, the majority of the IBD patients who
8 26.7 reported modification of the daily food intake also re-
ported dairy products restriction. Among the main jus-
5 16.7 tifications for this restriction were exacerbation or on-
set of the gastrointestinal symptoms and dietary
3 10.0 counseling.
The occurrence of dairy product restriction has also
been observed in other studies20,21. In a recent study it
was found that of 244 IBD patients interviewed, 27.5%
7 36.8 believed that dairy products should be avoided 22. As a
result of this restriction, some patients replaced dairy
9 47.4
products by soy milk. However, it is known that soy milk
is not a good source of calcium, and this milk, even
1 5.3
though enriched by tricalcium phosphate, has a low cal-
1 5.3
cium bioavailability, making it nutritionally inferior to
cows milk 23,24.
1 5.3 It is reported that one of the main reasons given by
IBD patients for dairy products restriction has been exac-
erbation or onset of the gastrointestinal symptoms20-22.
Interestingly, in some prospective studies, no association
was found between dairy consumption and a higher fre-
quency of recurrence20,25.
Another factor of great relevance to clinical practice,
that has lead these individuals to believe in a worsening
of symptoms after eating dairy products, is the nutrition-
al orientation made by health professionals. The fact that
some patients with IBD, most commonly CD, develop lac-
tose intolerance, frequently contributes to professional
counseling of reduction or exclusion of dairy products,
which in most cases is unnecessary. Studies, particularly
in CD patients, have shown that the symptoms are influ-
enced by the fat present in the milk product instead of the
amount of lactose in foods26,27.
Other factors for the onset of symptoms should also
be considered before the patient needs to make some kind
of restriction, such as eating foods together with lactose
sources, amount of lactose ingested, the residual intestinal
lactase activity, the capacity of the flora from the colon to
ferment lactose, and individual sensitivity of fermentation
products of lactose28.
As in other studies, it was observed that dietary coun-
seling has an important role in the decision of the IBD
IJI Bowel Disease Volume 1 Number 1 May-August 2014
Table 4. Self-reported restriction of dairy products and mean daily dairy products intake by inflammatory bowel disease patients
(n = 51) Salvador-BA, 2011-2012
Variables
IBD patients
Restriction (n = 19)
No restriction (n = 32)
UC patients
Restriction (n = 12)
No restriction (n = 23)
CD patients
Restriction (n = 7)
No restriction (n = 9)
IBD: inflammatory bowel disease; UC: ulcerative colitis; CD: Crohns disease; SD: standard deviation.
*Student t test.
patients to begin a food restriction. Santos, et al., (2003)
had already observed in a previous study with this popu-
lation that the nutritional orientation from health profes-
sionals was the main reason reported by the patients to
assume a dietary restriction.
Jowett, et al.20 found that UC patients who reported
restriction of dairy products showed a lower calcium in-
take than those who did not restrict. The same was found
for consumption of dairy products. In this study, for CD
patients no difference was found for the intake of dairy
products, possibly by having a lower CD sample than the
UC sample. No studies were found in CD patients for this
association. However, the fact of not having been a signif-
icant data does not rule out the importance of these find-
ings from the clinical standpoint.
Thus, the results found in this study are relevant to
clinical practice considering that cows milk and its deriv-
atives are the main sources of bioavailable calcium 29,30. A
low calcium intake is already a common feature in the
Brazilian population. According to the Consumer Expen-
diture Survey31 it was found that the mean daily intake of
calcium in the Northeast was the lowest among the re-
gions of the country. However, the low calcium intake by
IBD patients is a further aggravating factor because the
risk of osteoporosis is greater in these patients compared
to the general population 32.
It is noted that this study has some limitations. The
sample size makes it difficult to extrapolate the data.
Mirella Brasil Lopes, et al.: Dairy Food Intake by Inflammatory Bowel Disease Patients
Dairy products intake (servings) p*
Mean SD
0.7 1.2 0.01
1.6 1.2
0.4 0.5 0.00
1.6 1.2
1.1 1.8 0.53
1.6 1.1
Similarly, a convenience sample precludes generalization
of the results and may be associated with a potential se-
lection bias. Despite this, some of the results were similar
to other studies.
CONCLUSION
The restriction of dairy products is evident in IBD
patients, especially in UC patients. This fact is mainly
influenced by the association with the development of the
gastrointestinal symptoms and dietary restrictive pre-
scriptions. The low consumption of dairy products can
result in a low intake of dietary calcium, which is partic-
ularly relevant in IBD patients, which have higher risk to
develop osteoporosis, increased by deficient calcium sup-
plementation.
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IJI Bowel Disease Volume 1 Number 1 May-August 2014
IJI Bowel Disease Volume 1 Number 1 May-August 2014
Original Article
Proctocolectomy in Crohns disease
Claudio Coy, Maria de Lourdes Setsuko Ayrizono, Raquel Franco Leal, Priscilla de Sene Portel Oliveira, Debora Gonalves Rossi,
Nielce Paiva, Natalia Panzetti Vieira, Miquelline Almeida and Joo Jos Fagundes
Abstract
Introduction: Total proctocolectomy is rare in benign diseas-
es. Its indication in Crohns disease might be understood as
a drastic alternative to a severe disease, non-responsive to
conventional treatments. It implies performing a definite in-
testinal anastomosis, which means a difficult decision for the
patient and the medical team; however, there is a prospect of
prolonged remission and less use of medication. Objective:
Reporting on the indications and on the evolution of Crohns
disease patients who underwent this procedure. Method and
Cases (casuistry): Among the 505 patients with Crohns dis-
ease treated at the Amb de DII Prof. Dr. Ricardo Ges, 12
(2.4%) underwent a total proctocolectomy and ileostomy be-
tween 1980 and 2011, with an average follow-up period of
13.5 years. Results: Average age at the time of the surgery was
39.5 years, and 66.6% of the patients were female. Indications
resulted from perineal onset manifestation in 11 patients
(91.6%); there was an association with a colocutaneous fistu-
la in one patient. Time elapsed between the onset of the
disease and the surgery was 7.4 years, and by the time the
surgery took place, onset manifestation was restricted to col-
orectal segments in nine of the patients (75%). Immediate
post-surgery morbidity was 16.8% (pneumonia and surgical
wound infection). Regarding late evolution, morbidity related
to ileostomy was 66.9%, with paraileostomy hernia being the
most frequent. Recidivism of Crohns disease was 58.3%;
66.7% occurred in the small intestine and 16.8% in the
perineum. Two patients (16.6%) ended up dying due to com-
plications deriving from Crohns disease and among those
patients alive, five have been under drug therapy. Conclu-
sions: Total proctocolectomy in patients with Crohns disease
presents high morbidity related to the ileostomy, high recid-
ivism incidence in the small intestine, and the need for on-
going drug therapy.
Corresponding author: Claudio Coy, claudiocoy@gmail.com
Key words: Crohns disease. Proctocolectomy. Ileostomy. In-
testinal inflammatory disease.
Ambulatrio de Doenas Inflamatrias Intestinais Prof. Dr. Ricardo Ges Coloproctology Group DMAD-FCM-UNICAMP
Correspondence to: Claudio Coy, Rua Belmira Rodrigues, 1290, Sousas, CEP 13105-680, Campinas SP, Brasil. E-mail: claudiocoy@gmail.com
Resumo
Introduo: a proctocoletomia total rara em doenas benig-
nas. Sua indicao na doena de Crohn (DC) pode ser enten-
dida como doena grave no responsiva aos tratamentos
usuais. Implica na confeco de derivao intestinal defini-
tiva, o que acarreta em deciso difcil para o paciente e a
equipe mdica, porm com perspectiva de remisso prolon-
gada e menor emprego de medicamentos. Objetivo: relatar as
indicaes e a evoluo em portadores de DC submetidos a
este procedimento. Mtodo e casustica: entre os 505 porta-
dores de DC atendidos no ambulatrio de doenas inflama-
trias intestinais (DIIs) Prof. Dr. Ricardo Ges, 12 (2,4%)
foram submetidos proctocolectomia total e ileostomia
entre 1980 e 2011, com tempo mdio de acompanhamento
de 13,5 anos. Resultados: a idade mdia, por ocasio da ci-
rurgia, foi de 39,5 anos, sendo 66,6% do sexo feminino. A
indicao foi acometimento perineal em 11 pacientes (91,6%),
sendo que em 1 paciente havia associao com fstula colo-
cutnea. O tempo entre o incio da doena e a cirurgia foi de
7,4 anos, e, por ocasio dessa, o acometimento estava restri-
to aos segmentos colorretais em 9 pacientes (75%). A morbi-
dade ps-operatria imediata foi de 16,8% (pneumonia e
infeo de ferida operatria). Com relao evoluo tardia,
a morbidade relacionada ileostomia foi de 66,9%, sendo a
mais frequente hrnia paraileostomica. A recidiva da DC foi
de 58,3%, sendo que em 66,7% ocorreu no intestino delgado
e em 16,8% no perneo, 2 pacientes (16,6%), evoluram a
bito por complicaes decorrentes da DC e, entre os pacien-
tes vivos, 5 encontram-se em uso de terapia medicamentosa.
Concluso: a proctocolectomia total na DC apresenta alta
morbidade relacionada ileostomia, elevada incidncia de
recidiva em intestino delgado e de manuteno de terapia
medicamentosa.
Palavras-chave: Doena de Crohn. Proctocolectomia. Ileosto-
mia. Doena inflamatria intestinal.
21
INTRODUCTION
Crohns disease (CD) treatment aims at keeping the
patient in clinical remission, avoiding complications and
surgeries. In spite of the fact that currently available ther-
apeutic options are more efficient, the incidence of in-
tra-abdominal resection and intestinal anastomosis is still
80% and fecal diversion reaches 10%1, showing that clin-
ical control is far from expected. The perianal manifesta-
tion of CD corresponds in most cases to a more aggressive
phenotype2,3 and is frequently associated to a colorectal
onset manifestation. Clinical instability and severe peri-
anal onset manifestation may lead to the need for surgery
to perform an intestinal anastomosis.
Total proctocolectomy is rare in benign diseases. Its
indication in Crohns disease might be understood as a
drastic alternative to a severe disease, non-responsive to
conventional treatments. It implies performing a definite
intestinal anastomosis, which means a difficult decision
for the patient and the medical team; however, there is a
prospect of prolonged remission and less frequent use of
medication due to smaller post-surgical recidivism4-6..
This study aims at analyzing the indications and the
results of proctocolectomy with ileostomy (PC-I) in CD.
PATIENTS AND METHODS
This is a retrospective analysis using data from CD
patients treated at the Ambulatrio de Doenas In-
flamatrias Intestinais Prof. Dr. Ricardo Ges - Gastrocen-
tro - UNICAMP, who underwent a total proctocolectomy
and ileostomy between 1980 and 2011. Cases of undeter-
mined colitis, patients who underwent a total colectomy
with ileostomy or ileal reservoir, were excluded. Early
post-surgical complications were considered within 30
days after the surgery. The incidence of late complications
connected with the ileostomy or deriving from mechanical
intestinal obstruction was evaluated. For the diagnosis of
the post-surgical recidivism of CD, clinical, radiologic,
and endoscopic criteria requiring the use of specific drug
therapy were applied.
RESULTS
Among the 505 patients with CD treated at the Am-
bulatrio de Doenas Inflamatrias Intestinais Prof. Dr.
Ricardo Ges - Gastrocentro - UNICAMP 12 (2.4%) un-
derwent a PC-I between 1980 and 2011, with an average
follow-up period of 13.5 years. Average age at the time of
the surgery was 39.5 years, and 66.6% of the patients were
female. Time elapse between onset of the disease and the
surgery was 7.5 years, and by the time the surgery took
place, onset manifestation was restricted to colorectal seg-
ments and to the perineum in nine of the patients (75%).
All patients had undergone some type of previous surgical
procedure, among which perineal abscess drainage or
22
fistulotomies were the most common. Indications result-
ed from perineal onset manifestation in 11 patients
(91.6%); there was an association with a colocutaneous
fistula in one patient. Immediate post-surgery morbidity
was 16.8% (pneumonia and surgical wound infection).
Regarding late evolution, the incidence of complications
related to the ileostomy was 66.9%, with paraileostomy
hernia being the most frequent.
Recidivism of CD was 58.3%; 66.7% of the cases oc-
curred in the small intestine and 16.8% in the perineum.
Five patients (41.6%) have had no symptoms and have not
been under any drug therapy since surgery. Among those
patients who experienced recidivism, three have been un-
der Azathioprine and two have been under a combination
of biological therapy and Azathioprine. Two patients
(16.6%) ended up dying due to late complications deriving
from CD.
DISCUSSIONS
The patients expectation when diagnosed with CD,
which is a chronic and incurable disease, is control of the
symptoms and maintenance of physiological functions
such as anal continence. The perspective of intestinal
anastomosis is a frequent preoccupation in patients with
CD7,8 with implications in quality of life.
The identification of prognostic factors might prove
useful to guide the best conduct, as well as to design the
clinical follow-up strategy, in order to avoid complications.
Smoking9, the presence of intestinal resection, and peri-
anal disease2,10 are considered bad prognostic factors.
PC-I corresponds to an extreme condition in CD and
is indicated in most cases because of perineal sequelae,
which cause anal sphincter dysfunction. In spite of the
need to perform a definite ileostomy, the surgery may
improve the overall quality of life in comparison to that
prior to the surgery, after a period of adaptation to the
intestinal stoma11. In the present study (case-based study),
considering it is a long-term retrospective analysis, during
which therapy practices have changed significantly, time
elapsed until the performance of the procedure was longer
than 13 years, which shows that sequelae, mainly in the
perineum, occurred slowly. Another datum that must be
taken into consideration is the high rate of perineal pro-
cedures prior to the PC-I. Currently, the perspective is that
endoscopic, laboratory and clinical follow-up, if conducted
systematically, may also prevent bigger damages to the
perineum and also provide better clinical control by means
of therapeutic adequacy. A population-based study con-
ducted in Norway showed that mucosa healing was asso-
ciated to a lower rate of colectomies12 and the use of bio-
logical therapy showed full healing of perianal fistulae of
33-36%13,14 and these results remained stable after three
years15.
Surgical treatment in CD is based on economic re-
sections, once it is not a healing procedure. However,
IJI Bowel Disease Volume 1 Number 1 May-August 2014
segmented colectomy may be accompanied by high recid-
ivism rates in the remaining colon segments16 and with
higher recidivism rates in relation to the proctocolecto-
my17. ORiordan, et al.18 have shown that total colectomy
with an ileorectal anastomosis might be accompanied lat-
er by a proctocolectomy in up to 30% of cases. However,
the perspective of a definite ileostomy is not accepted by
most patients, which causes surgeons to opt for the ileo-
rectal anastomosis.
Performing an intestinal stoma allows, in theory, for
regression of the inflammatory process in the distal seg-
ments after the resection by decreasing the antigenic stim-
ulus in the intestinal lumen. However, morbidity associat-
ed thereto must be taken into consideration, mainly when
it is a definite one. Re-operations due to complications
deriving from the ileostomy are reported between 5 and
29%19-21. In the present case-based study, a high incidence
of complications related to ileostomies not associated to
CD, associated to peristomal dermatitis and mainly to her-
nia, was observed. Therefore, preoperative markings and
the performance of an ileostomy (dislocated forward) mit-
igate such occurrences; however, the presence of scars
resulting from prior procedures may make it difficult to
position it adequately.
Recidivism of CD was higher than that described in the
literature after a PC-I, reported between 11 and 40%5,22-24.
In the present case-based study, seven patients presented
post-surgical recidivism, three of which had CD in the
small intestine. Therefore, five patients remain free from
recidivism evidence and five out of ten patients alive have
been under drug therapy. Data obtained contradict anec-
dotal information that PC-I is a procedure that presents
lower incidence of recidivism.
One can conclude that PC-I is performed in patients
with more aggressive forms of the disease, with high re-
cidivism and morbidity rates associated to the ileostomy,
which compromise the post-surgical results. Concurrent
colorectal and perianal onset manifestations because of
CD justify the deployment of more efficient therapeutic
measures and frequent clinical follow-up in order to iden-
tify evolutionary signals that might end up leading to
surgical treatment.
Claudio Coy, et al.: Proctocolectomy in Crohns disease
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history of inflammatory bowel diseases. Gastroenterology. 2011;140:1785-94.
2. Beaugerie L, Seksik P, Nion-LarmurierI, Gendre JP, Cosnes J. Predictors of
Crohns disease. Gastroenterology. 2006;130:650-6.
3. Loly C, Belaiche J, Louis E. Predictors of severe Crohns disease. Scand J Gas-
troenterol. 2008;43:948-54.
4. Fichera A, McCormack R, Rubin MA, Hurst RD, Michelassi F. Long-term out-
come of surgically treated Crohns colitis: a prospective study. Dis Colon Rec-
tum. 2005;48:963-9.
5. Bernell O, Lapidus A, Hellers G. Recurrence after colectomy in Crohns colitis.
Dis Colon Rectum. 2001;44:647-54.
6. Yamamoto T, Keighley MR. Proctocolectomy is associated with a higher com-
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orectal anastomosis in Crohn colitis. Scand J Gastroenterol. 1999;34:1212-5.
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11. Kasparek MS, Glatzle J, Temeltcheva T, Mueller MH, Koenigsrainer A, Kreis ME.
Long-term quality of life in patients with Crohns disease and perianal fistulas:
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13. Sands BE, Blank MA, Patel K, van Deventer SJ. Long-term treatment of recto-
vaginal fistulas in Crohns disease: response to infliximab in the ACCENT II
Study. Clin Gastroenterol Hepatol. 2004;2:912-20.
14. Feagan BG, Panaccione R, Sandborn WJ, et al. Effects of adalimumab therapy
on incidence of hospitalization and surgery in Crohns disease: results from the
CHARM study. Gastroenterology. 2008;135:1493-9.
15. Panaccione R, Colombel JF, Sandborn WJ, et al. Adalimumab sustains clinical
remission and overall clinical benefit after 2 years of therapy for Crohns disease.
Aliment Pharmacol Ther. 2010;31:1296-309.
16. de Buck van Overstraeten A, Wolthuis AM, et al. Intersphincteric proctectomy
with end-colostomy for anorectal Crohns disease results in early and severe
proximal colonic recurrence. J Crohns Colitis. 2013;7:e227-31.
17. Andersson P, Olaison G, Hallbk O, Sjdahl R. Segmental resection or subto-
tal colectomy in Crohns colitis? Dis Colon Rectum. 2002;45:47-53.
18. ORiordan JM, OConnor BI, Huang H, et al. Long-term outcome of colectomy and
ileorectal anastomosis for Crohns colitis. Dis Colon Rectum. 2011;54:1347-54.
19. Ecker KW, Gierend M, Kreissler-Haag D, Feifel G. Reoperations at the ileostomy
in Crohns disease reflect inflammatory activity rather than surgical stoma
complications alone. Int J Colorectal Dis. 2001;16:76-80.
20. Steinberg DM, Allan RN, Thompson H, Brooke BN, Alexander-Williams J, Cooke
WT. Excisional surgery with ileostomy for Crohns colitis with particular refer-
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Surg Engl. 1990 May;72(3):155-7
23. Scammell BE, Andrews H, Allan RN, Alexander-Williams J, Keighley MR. Re-
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23
IJI Bowel Disease Volume 1 Number 1 May-August 2014

Review Article
Differential Diagnosis between Crohns Disease and
Intestinal Tuberculosis in Brazil and Other Regions with High
Incidence of Tuberculosis: A Chronic and Current Dilemma
Fernando Marques Moreira de Castro1, Guilherme Seixas Barros2, Cyrla Zaltman3, Kalil Madi4, Eduardo Kanaan5, Emmanuel Salgueiro6
and Antnio Carlos Moraes7

Abstract Resumo

In poor and developing countries, due to clinical, radiologic,
endoscopic, and histopathologic similarities, the differential
diagnosis between Crohns disease and intestinal tuberculosis
has not been an easy task. The interface between both diseas-
es is particularly important in countries with a high incidence
of tuberculosis. In Brazil, for example, the bacillus of tuber-
culosis had once been considered the probable cause of
Crohns disease. In this article, the authors aim to compare
and highlight the key factors and the difficulties for the diag-
nosis and the treatment of Crohns disease in areas with high
occurrence of tuberculosis, which is the case of our country.
Corresponding author: Fernando Marques Moreira de Castro,
fernandommcastro@gmail.com
Nos pases pobres ou em desenvolvimento, devido seme-
lhanas clnica, radiolgica, endoscpicos e histopatolgicos,
o diagnstico diferencial entre a doena de Crohn (DC) e a
tuberculose intestinal (TBi) no foi uma tarefa fcil. A inter-
face entre as duas doenas particularmente importante em
pases com alta incidncia de tuberculose (TB). No Brasil, por
exemplo, o bacilo da TB j foi considerado a causa provvel
da DC. Neste artigo, os autores pretendem comparar e desta-
car os principais fatores e as dificuldades para o diagnstico
e o tratamento da DC em reas com alta ocorrncia de TB,
que o caso do nosso pas.

Key words: Inflammatory bowel disease. Tuberculosis. Palavras-chave: Doena inflamatria intestinal. Tuberculose.

1
Member of Medical Clinical Services at Copa DOr Hospital. Associate Member at GEDIIB; 2Member of Medical Clinical Services at Copa DOr Hospital; 3Member of Medical
Clinical Services and Gastroenterology Services at HUCFF/UFRJ. Affiliate Member at GEDIIB; 4Member of Anatomopathology Services at The Brazilian Circle of Pathology
(CBP); 5Assistant Surgeon General at Copa DOr Hospital; 6Coordinator at Medical Clinical Services at Copa DOr Hospital; 7Chief of Medical Clinical Services at Copa DOr
Hospital. Affiliate Member at GEDIIB. Rio de Janeiro, Brazill
Correspondence to: Fernando Marques Moreira de Castro, Rua Lagoa das Garas, 40/504, Barra da Tijuca, CEP 22793-400, Rio de Janeiro RJ, Brasil.
E-mail: fernandommcastro@gmail.com

24
INTRODUCTION 11-16%7,8. Tuberculosis of the gastrointestinal tract is the
sixth most frequent extrapulmonary onset. The others are
The diagnosis of inflammatory bowel diseases (IBD)
in the lymphatic system, genitourinary system and osteo-
in developing countries does not generally have much
myelitis, military and TB meningitis9.
attention due to enteric infections and also limited aware-
The concomitant presence of TB can be seen in up to
ness of such diseases by both the doctor and the patient1.
46% of patients as an active pulmonary type who have had
In the past decades, there has been observed in such
gastrointestinal tests10. The abdominal symptom of TB
countries, a break in paradigm over the prevalence of in-
might be either a primary consequence due to reactivation
fection and contagious diseases with clinical expression
of a non-active focus acquired in the past or can even be
in the gastrointestinal tract, with their reduction to the
considered secondary after the spread of the disease due
detriment of immunologic diseases (neoplasm and auto-
to sputum, hematogenic causes, being close to an infected
immune disorders). However, pulmonary tuberculosis and
adjoining organ, or intake of unpasteurized milk7,11. The
its extrapulmonary manifestations have sustained preva-
abdominal TB might be enteric, peritoneal, nodal (lymph
lence and incidence due to more aggressive pharmacolog-
nodes) or even involve solid organs (such as liver, spleen,
ical treatment such as immunosuppressive drugs, steroids,
kidneys, pancreas or any combination of the described
and biological drugs1.
organs)12,13. The most frequent in the ileocecal fold, pos-
In countries where the average income is either me-
sibly related to the presence of physiological stasis, high
dium or low, even though epidemiologic studies about the
fluid and electrolyte absorption, minimum digesting ac-
prevalence and incidence of IDB are limited, the epidemi-
tivities, and abundance of lymphoid tissue. There are pre-
ology of IDB is changing, with diagnosis being more fre-
vious events described in medical literature of phagocytes
quent and earlier1.
activities of BCG M cells present in Peyers patches9.
The differential diagnosis between Crohns disease
Previously considered rare in developing countries,
and intestinal tuberculosis has not been an easy task in
the epidemiology of IBD has been changing and the inci-
poor or developing countries due to clinical and radiologic,
dence of Crohns disease as well as ulcerative colitis have
endoscopic, and histopathologic similarities. The bacillus
been increasing in Asian Pacific, India, Eastern Europe,
of the tuberculosis has already been considered the prob-
and South Africa14-16. Such changes have been announced
able cause of Crohns disease. Back in 1932, Crohn, Ginz-
based on the higher incidence of ulcerative colitis and
burg and Oppenheimer2 suggested that the surgery for
followed by Crohns disease 15 or 20 years later17.
regional enteric cases could only be considered after all
acceptable methods for the treatment of tuberculosis (TB)
had been tried and proven ineffective. Recently, with the IMMUNOPATHOGENESIS
biological therapy for Crohns disease, there was an in-
Crohns disease and TB are granulomatous diseases
crease in the complexity of the relationship between the
that affect the digestive system in a similar way. M. tuber-
diseases. The interface between both diseases is particu-
culosis is the causal agent of TB infection, whereas Crohns
larly important in countries with a high incidence of TB
disease has multiple causes including genetic, immuno-
like Brazil. The present review of the literature aims to
logic, environmental and microbial factors. Because of the
compare and highlight the key factors and the difficulties
striking similarities, it is not surprising that both diseas-
for the treatment of Crohns disease in areas with high
es share similar immunopathogenic paths and that corti-
occurrence of TB, which is the case of our country.
coids show efficacy in the control of harmful inflamma-
tory reactions18-20. Both are characterized by potent
adaptive response to Th1 type, whose characteristic is the
EPIDEMIOLOGY
intense production of interferon-gamma (IFN-), IL-12 and
According to WHO, in 2010, 6.2 million cases of TB IL-2321 with the consequent formation of granulomas.
were diagnosed and notified around the world; 5.4 million Despite the intense immunologic response acquired,
new cases are equivalent to 65% of the estimated cases for both illnesses are also associated to disorders related to
the same year. Brazil is one of the 22 countries that con- natural immunity22,23. As for TB, only 5-10% of the pa-
centrate 82% of TB cases in the world 3 (Fig. 1). The rate tients infected by M. tuberculosis develop the active type
in Brazil in 2010 was 42.8 cases out of 100,000 inhabitants of the disease. Like with Crohns disease, the proteases
in 2011. Even though the Brazilian southeast concentrates onsets in TB infections present variations in the interac-
the highest number of cases of TB, the north of the coun- tion of bacteria and the host that possibly contribute to
try presented the highest rates in every year studied. In the phenotype of the disease and the energetic load of the
2011, the northern state of Amazonas (62.6) and Rio de host might have a determining role to guide the efficacy of
Janeiro (57.6), that is located in the southeast, had the his or her natural immunity. Since both are characterized
highest occurrences in the country4. by a vast clinical heterogeneity, probably the polymor-
Approximately 12.5% of all TB cases have extrapul- phism is the predictor of both phenotypes24,25. Different
monary location5,6, where abdominal TB corresponds with from what was written about pulmonary TB cases, the

Fernando Marques Moreira de Castro, et al.: Crohns Disease and Intestinal Tuberculosis in Brazil and Other Regions 25

Figure 1. Estimated TB incidence rates, 2010 (adapted from Global tuberculosis control: WHO report 2011).
genetic contribution for TB infections has not been prop-
erly studied.
A review on Crohns disease or TB infections would
not be complete without approaching Mycobacterium avi-
um paratuberculosis (MAP) in the etiology of Crohns dis-
ease. A long time ago it became evident that Crohns dis-
ease does not exist without MAP and that the intraluminal
concentration of the bacteria might be necessary for the
development of the inflammation in animal models of
IDB26,27.
The recognition of the participation of NOD2 gene
mutations in the increase of susceptibility for the devel-
opment of Crohns disease emphasizes the participation of
intestinal microbiota in the etiopathogenesis of such dis-
order28-30. However the successful usage of biological ther-
apies with anti-factor antibodies (TNF-) for Crohns
disease contributes to the hypotheses of non-infectious
etiology for Crohns disease, since such therapeutic mea-
sures would possibly make the existing infections become
worse. Therefore, if MAP is part of the etiopathogenesis of
the disease, this is probably more complex and not totally
understood. A possible explanation approaches the con-
cept of molecular mimicry, with a crossed reaction be-
tween the intestinal components and the antibodies di-
rected are directed towards the mycobacterial antigens31,32.
26
Estimated new TB
cases (all forms) per
100,000 population
0-24
25-49
50-99
100-299
300
No estimate
DIFFERENTIAL DIAGNOSIS BETWEEN BOWEL
TUBERCULOSIS AND CROHNS DISEASE
Clinical and laboratory approaches
If the natural history of these diseases is considered,
we can observe that TB infections are associated to signif-
icant morbidity and mortality33-35, and they can be cured
after six months of chemotherapy, where RIPE is the first
therapeutic choice in Brazil. However, Crohns disease is
characterized by a chronic inflammatory process that
tends to temporarily evolve and, in most cases, requires
therapies in order to maintain the remission of the disease.
The difficulty to differentiate both diseases is widely
known due to the fact that the existing criteria for both
of them are not exclusive34,36. Both have similar clinical,
radiologic, and endoscopic characteristics and the avail-
able methods used for the diagnosis are still limited. In
places where TB is highly prevalent, the therapeutic test
with active pharmaceutical ingredients for the disease can
still be used whenever the diagnosis is not clear37. How-
ever, such procedure might slow the diagnosis of Crohns
disease as well as make it more difficult to confirm or to
exclude the possibility of TB. Besides, it is important
to point out that this therapy might present serious side
effects. Likewise, the treatment for Crohns disease can
be harmful for the patient whenever the diagnosis of TB
IJI Bowel Disease Volume 1 Number 1 May-August 2014
infection is not considered. 100 years ago, Walsh already
said it was impossible to clearly diagnose bowel TB with
accuracy since the disease was similar to several other
abdominal conditions. Therefore, its histological confir-
mation could be ambiguous38. Based on intuition, the
length of the symptoms could be similar to some charac-
teristics that could differentiate the diseases, but both
have an early insidious symptom that might remain with-
out a diagnosis for several years5.
The presence of anorexia, weight loss, abdominal
pain, change in intestinal rhythm, rectal bleeding, or
presence of abdominal mass can be seen in both diseas-
es7,39-41. There are also complicating factors as intestinal
perforation or obstruction, or formation of intraabdomi-
nal abscess33,42,43. The TB infections rarely have poor in-
testinal absorption and protein-losing enteropathy44,45.
Even though both can harm the gastrointestinal tract
from the mouth to the anus, the prevalent site is the ile-
ocecal fold. Fever can be a common symptom in both
diseases, but in the absence of abdominal abscesses, high-
er temperatures (> 38.5C) are more common in TB in-
fections1.
Taking into account the predicting factors for the
development of Crohns disease, smoking can be an envi-
ronmental associated factor, and it also occurs in pulmo-
nary TB. This association with TB might be justified by
the harmful effect of the smoke in macrophages and also
in the function of pulmonary dendritic cells46. However,
there is no evidence of cause and effect between smoking
and TB infections.
The records of pulmonary TB must be a warning sign
about the possibility of TB infections; however, it occurs
in the minority of the cases5,42,47. Likewise, the presence
of TB in the family background is not frequent 35.
Extra-intestinal symptoms of IDB can be used as
characteristics to distinguish Crohns disease from TB 48,
however, it is not always possible in endemic countries for
TB due to the presence of multiple extra pulmonary and
immunologic complications associated to the infection.
Symptoms in the skin, liver, eyes, and joints can be pres-
ent in both diseases49. Reactive polyarthritis immunolog-
ically mediated (Poncets disease)49, erythema nodosum,
erythema induratum50 and uveitis51 can also be interpret-
ed as Crohns disease manifestations, justifying caution in
the interpretation of such signs and symptoms belonging
to Crohns disease.
Special attention is needed for the association be-
tween inflammation and the state of hypercoagullability.
The IDB patients present 3.6-times higher risk of throm-
boembolic diseases52 and in a similar way, active TB pa-
tients are at risk for deep vein thrombosis (DVT)53,54.
Specifically in relation to TB infections, mesenteric
vasculitis seems to be present in the natural history of the
disease. Shah, et al.55 correlated the findings of barium
studies and mesenteric angiographies in 20 patients. All
the angiographic examinations were abnormal with the
Fernando Marques Moreira de Castro, et al.: Crohns Disease and Intestinal Tuberculosis in Brazil and Other Regions
presence of arterial coating, elongation, and agglomeration
of vessels as well as hypervascularity. Stenotic areas asso-
ciated to the obstruction of Vasa recta, whereas ulcerations
associated to hypervascularity. In another study, Dasgrupta,
et al.56 prospectively analyzed 56 patients with abdominal
TB submitted to surgical intervention, aiming to correlate
both macroscopic and microscopic findings of TB infec-
tions, especially the changes in mesenteric vasculature
with cases of intestinal perforation. The authors observed
that the involvement of mesenteric vasculature by granu-
lomas was commonly associated to the perforation, con-
cluding that vasculitis represented a turning point in the
natural history of TB.
If the penetrating presentation of Crohns disease is
considered, this might be mistaken as enteroenteral, en-
terocutaneous and perianal fistulas also described for TB
cases45,57,58.
Surprisingly, extra-pulmonary TB is normally associ-
ated to the absence of abnormalities in the chest x-ray
(CHR)49. Studies have already demonstrated that pulmo-
nary TB occurs in CXR in less than 50% of TB pa-
tients42,47,59-61. Rarely, is there pulmonary involvement in
Crohns disease and its characteristics are similar to those
in pulmonary TB, being presented as a miliary pattern
with granulomatous inflammation that can be detected by
transbronchial biopsy62. So, ordinary CXR does not ex-
clude the diagnosis of TB.
Mantoux test (also called PPD test), used as a diag-
nostic tool in patients with ileocolonic inflammation, also
has limitations. The crossed reactions with BCG, high
prevalence of mycobacterium in the environment, and gen-
eralized latent infection by M. tuberculosis make the diag-
nosis become more difficult. In Brazil, the tuberculine
used is PPD-RT 23 that must be intradermally injected in
the anterior middle third of the left forearm with a dosage
of 0.1 ml that contains 2 tuberculine units, and has bio-
logical equivalence to 5 tuberculine units of PPD-S, used
in other countries63.
The absence of reaction in HIV patients, primary TB
and spread TB, has already been verified as well as the
anergy of untreated patients with Crohns disease64.
Anemia, leukocytosis, enhanced blood sedimentation
test and an increase of C-reactive protein are seen in the
acute phase of both diseases65,66. The presence of throm-
bocytosis increases the suspicion of Crohns disease, es-
pecially if active, due to reversible hyposplenism. As for
the usage of ASCA by ELISA method to differentiate both
diseases, this was described in a study composed of a
small sample of TB patients of whom only 7% had positive
ASCA, compared to 49% of Crohns disease patients67,
justifying the recommendation of the test for differential
diagnosis. However, this result is controversial since it was
not confirmed in later studies with more samples where
roughly half of the TB patients tested ASCA-positive,
considering the frequency comparable to Crohns disease
patients68,69.
27
ENDOSCOPIC
High digestive endoscopy, ileocolonoscopy and dou-
bleballoon enteroscopy have key roles in the differentia-
tion between TB and Crohns disease170, since they allow
the visualization and performance of biopsies of detected
lesions with posterior histopathological study of the col-
lected material71,72.
Since the ileocecal area is the most affected by both
diseases, ERCP is the initial procedure chosen. In pa-
tients where Crohns disease is suspected or already pos-
itively tested, ileocolonoscopy offers similar sensitivity
(67 vs. 83%) but the specificity is meaningfully higher
(100 vs. 53%) if compared to video capsule endoscopic73.
Even with low increment in the diagnosis through ileos-
copy (up to 3.7%), this procedure can be important for
isolated cases74. The likelihood of histopathologic diagno-
sis is higher when the number of biopsies is up to four
colonic segments75. Endoscopic biopsies of segments close
to stenosis after their dilatation, and also the ileo terminal
even if the macroscopic aspect is normal, increasing the
possibility to confirm the TB diagnosis76,77.
In cases where the colon is not damaged, high diges-
tive endoscopy and enteroscopy might be appropriate1,70,72.
Nowadays, double-balloon enteroscopy is the preferred
choice to evaluate the small intestine due to its capacity
of diagnosis and therapeutics71. To collect fragments
through biopsies of small intestine lesions is fundamental
because the endoscopic aspect does not differentiate both
affections71. Colonic and gastroduodenal biopsies of the
mucosa that is apparently normal might offer clues for
the cases where Crohns disease is suspected75,78.
However, specific endoscopic characteristics have al-
ready been described for both Crohns disease and TB1,70,72.
Transversely disposed ulcers, nodular lesions, and hyper-
trophic lesions similar to masses are TB characteristics.
Longitudinal or aphthous ulcers, when deep, with fistulas
and cobblestone aspects are considered more typical of
Crohns disease. There are not many published reviews
comparing such characteristics or about the impact on the
differential diagnosis. A comparative study of few samples
has shown that anorectal lesions, longitudinal ulcers, aph-
thous ulcers, and the cobblestone pattern have been
significantly more frequent in Crohns disease cases. On
the other hand, fewer than four segments involved, the
distension of ileocecal valve, transverse ulcers, and pseu-
dopolyps have been more frequently associated to TB.
Another study has shown that the diagnosis based on
endoscopic aspects, more frequent in a certain patient,
proved to be accurate in 77 out of 88 patients (87.5%)79. A
more recent prospective study detected random colonic
lesions that were significantly more frequent in Crohns
disease (66 vs. 17%)80 as well as aphthous ulcers (54 vs.
13%), linear ulcers (30 vs. 7%) and superficial ulcers (51
vs. 17%). The cobblestone aspect of the colonic mucosa
only occurred in Crohns disease (17 vs. 0%). The nodular
28
Table 1. Endoscopic characteristics of tuberculosis and Crohns
disease
Intestinal tuberculosis Crohns Disease
Ulcers Ulcers
Circumference orientation Longitudinal orientation
Inflamed/nodular adjoining Normal adjoining mucosa
mucosa
Uncommon aphthous Common aphthous
ulcerations ulcerations
Hyperemic nodules isolated or Cobblestone aspect lesions
agglomerated
Pseudopolyps Random multiple lesions
Hypertrophic mucosa Anorectal lesions
Stenosis Stenosis
Destruction of ileocecal and/or Preserved ileocecal valve
cecal valve
Adapted from Epstein D, et al. Alimentary Pharmacology & Therapeutics, 2007.
lesions of the colonic mucosa were more common in TB
(49 vs. 24.5%). Table 1 summarizes the main endoscopic
characteristics of both TB and Crohns disease.
The endoscopic video capsule was proven to be a
noninvasive and safe method for the diagnosis of Crohns
disease81,82. In a meta-analysis comparing this procedure
with other techniques to visualize the small intestine in
order to obtain IDB diagnosis, it was shown that video
capsule presented 25-40% more diagnostic accuracy than
all the others83.
Endoscopic video capsule has the unique capacity to
detect small ulcers and early inflammatory lesions. Fidder,
et al.84 defined as a positive test for Crohns disease the
presence of four or more ulcers, erosions, or the presence of
a clear exudated area, hyperemic mucosa and edema. There
is not much literature available about the usage of such a
method for TB diagnosis, probably due to the fact that there
is little availability of video capsule imaging in countries
where TB is endemic and also for the difficulty to perform
biopsies. Disperse mucosa ulcers, short, oblique or trans-
verse with necrotic base both in the jejunum and ileum,
were described in TB85. However, it is extremely difficult to
differentiate these diseases based only in these findings.
RADIOLOGIC
Imaging for examination plays an important role in
the differential diagnosis in gastrointestinal patholo-
gies40,86,87. Barium studies are the radiologic base for the
evaluation of the gastrointestinal tract. Abdominal CT
scan is a complementary exam to the barium, especially
for the evaluation of extra-intestinal lesions in such dis-
eases and CT scan with enterography, a hybrid technique
IJI Bowel Disease Volume 1 Number 1 May-August 2014
Table 2. Tomographic characteristics of tuberculosis and Crohns
disease
Intestinal tuberculosis Crohns disease
Mural thickening without Mural thickening with
stratification stratification in the active
inflammation
Concentric stenosis Eccentric stenosis
Rare mesenteric fiber fat Mesenteric fiber fat proliferation
proliferation
Mesenteric inflammation Hypervascular mesentery
without vascular engorgement (the comb sign)
Hypodense lymph nodes with Mild lymphadenopathy
peripheral enhancement
High density ascites Abscesses
Adapted from Pulimood AB, et al. World J Gastroenterol, 2011.
that associates the advantages of both exams described
above88. Table 2 shows the differential characteristics in
CT scan between Crohns disease and TB.
The association of radiologic results with clinical
manifestations among patients, histopathologic changes
and response to the treatment usually enable the diag-
nosis58,89,90.
HYSTOPATHOLOGIC
Macroscopically, TB causes ulcerations, short steno-
sis, important thickening of the intestine wall through
inflammatory process, fibrosis, adherences, or a combi-
nation of all these factors. The ulcers are transverse; gen-
erally a circumference and the extremities are not well
defined, inclined, or protuberant. The adjoining mucosa
might present a flat shape in the villis, ulcers, erosions,
and pseudopolyps. In transverse cut, the intestinal walls
show a cicatrization process and necrosis, frequently with
loss of different layers. Serosa might present 2-5 mm
nodules and adherences. The regional lymph nodes are,
invariably, large and with caseous necrosis91.
The histologic traits in TB are confluent caseous gran-
ulomas containing acid-fast bacilli and surrounded by
lymphoid sheaths, occurring in all layers of the intestinal
wall and regional lymph nodes. At times, they are present
solely in the lymph nodes91. Initial granulomas are found,
generally inside the lymphoid tissue92. There might also
be extensive pylori metaplasia. The healing process occurs
through fibrosis and epithelial regeneration starts in the
ulcer extremities. Cicatrization granulomas are surround-
ed by fibrous tissue of lymph nodes and do not occur in
the intestinal wall91. Sometimes, the cicatrization process
results in stenosis. The changes of mesenteric vascularity,
especially the arterial occlusions, that might produce isch-
emia and contribute to the development of stenosis37.
Fernando Marques Moreira de Castro, et al.: Crohns Disease and Intestinal Tuberculosis in Brazil and Other Regions
In the macroscopy of Crohns disease, the thickening
of the abdominal wall, lesions without continuity and ste-
nosis are visualized. The stenosis lesions are normally larg-
er than the ones seen in TB. The act of involving the fat
tissue is common, just like the adherences, fistulas, and
extra-intestinal abscesses93. Aphthous ulcers are seen in
early stages and coalesce to form stellate ulcers. Profound
ulcerations, when longitudinal with the presence of fissure,
are characteristic of Crohns disease. It also has character-
istics such as smaller longitudinal ulcers separated by ede-
ma or normal mucosa, having the cobblestone aspect94.
In microscopic aspects, aphthous ulcers in lymphoid
follicles, fissures with extension as far as its proper muscle
or even more profound, destruction of the mucosa archi-
tecture, pylori metaplasia, presence of cryptitis and forma-
tion of abscesses with mild to severe chronic inflamma-
tion are commonly detected. Such changes are frequently
segmented or uneven and with transmural extension.
Pro-eminent lymphoid follicles in the submucosa and
serosa are also characteristics of this disease. Granulomas
are small and visualized in 50-60% of the dried pieces and
they might be found approximately in 25% of the lymph
nodes in the site94. Table 3 presents some of the principal
histopathologic characteristics of Crohns disease and TB
described in three studies.
SPECIFIC METHODS
The presence of Kochs bacillus in smearing or cul-
tures might be considered the most reliable method in the
differential diagnosis between both diseases, despite
the low sensitivity in the diagnosis of the techniques.
Besides, mycobacteria take 4-6 weeks to grow in culture,
and this amount of time can be reduced to 2 or 3 weeks
when automated systems of culture are used such as BAC-
TEC, Mycobacteria growth indicator tube (MGIT), sys-
tem for mycobacterial detection MB/BacT and the system
of culture II ESP96. However, BACTEC has shown low
sensitivity for TB diagnosis47,66.
The other three mentioned methods have not been eval-
uated yet for the diagnosis of this intestinal infection type.
The diagnosis for TB by polymerase chain reaction (PCR)
is based on the magnification of chromosomal oligonucle-
otides in M. tuberculosis being highly specific. The analy-
sis of intestinal fragments obtained either through endos-
copy or surgery by using PCR can be swiftly performed
with results in 48 hours97. However, this exam might oc-
casionally be positive in Crohns disease patients98,99. The
sensitivity of the test is low, with no relation between
positivity and the histologic characteristics such as caseous
necrosis or granulomas98,99. A TB diagnosis through intes-
tinal fragments by PCR has high predictive value even
though they have very low negative predictive value.
The Quantiferon-TB Gold (QFT-G, Cellestis Limited,
Carnegie, Victoria, Australia) consists of the perfor-
mance of ELISA in vitro for the detection of liberation of
29
Table 3. Prevalence of specific histologic changes in tuberculosis and Crohns disease: comparative analysis 13,75,95

Pulimood, et al. (1999) Pulimood, et al. (2005) Kirsch, et al. (2006)

Southern India13 Southern India75 South Africa95
TBi (n = 20) DC (n = 20) TBi (n = 33) DC (n = 31) TBi (n = 18) DC (n = 25)
Caseous necrosis 40 0 36 0 22 0

Confluent granulomas 60 0 42 3 50 0

5 granulomas / biopsy field 40 0 45 0 44 24

10 granulomas / biopsy field 33 0

Large granulomas Diameter > 200 m Diameter > 400 m Area > 0.05 mm2

90 5 51 0 67 8

Submucosa granulomas 45 5 39 6 44 12

Ulcers coated by epithelioid histiocytes 45 5 61 0 61 8

Disproportional inflammation of the 65 5 67 10

submucosa

Architect distortion distant from 0 62

inflammatory granulomas

Data in percentage

Adapted from Epstein D, et al. Alimentary Pharmacology & Therapeutics, 2007.

interferon-gamma after the stimulus by antigens of M.
tuberculosis.
The test is approved by FDA (Food and Drug Admin-
istration) to assist in the diagnosis of latent and active
forms of infection by bacillus. The synthetic peptides used
in this test are absent in all BCG types and almost all
mycobacteria that are not TB, except for M. Kansasii, M.
Szulgai and M. Mainum. Its main advantages are: absence
of cross-reaction with BCG and with most non-TB myco-
bacteria, avoiding the measurement trend; and the possi-
ble usage to control the response in anti-TB therapy. The
limitations of this method include the necessity of up to
12 hours of incubation and the lack of capacity of differ-
entiation of active and latent forms of infection88. However
the role of this exam for TB diagnosis is not clear so far,
and it might be used in the future as a follow-up method
of patients under anti-TB therapy, also as an answer to
intriguing cases and previously to be used as a biological
therapy for Crohns disease patients88.
THE ROLE OF SURGERY
The surgical indications for TB patients aim the diag-
nosis and the resolution of obstructive intestinal process-
es. In previous studies66,88, symptoms like fever, changes
in the intestinal rhythm, recurrent intestinal occlusions,
such as the diffuse compromising state of the whole small
intestine with multiple stenosis and the presence of pro-
found linear ulcers with cobblestone aspect in the intes-
tinal mucosa, the abdominal distension, ascitis, peritone-
al nodes and the compromising of the illeus/ileocolonic
valve without multiple stenosis were more present in TB.
GENERAL CONSIDERATIONS
In endemic countries with TB, like Brazil, even if the
patient presents a previous diagnosis of Crohns disease,
it becomes fundamental to consider the differential diag-
nosis of TB. An early investigation must be performed with
thorough anamnesis associated to imaging methods, colo-
noscopy with biopsies and further performance of culture
for M. tuberculosis. The association of such measures al-
lows the diagnosis in most cases1,88. In endemic countries
for TB, the clinical differentiation between both diseases
is an important dilemma for clinical doctors and gastro-
enterologists as well.
The present review highlights the most important
differential diagnosis between TB and Crohns disease,
including new techniques for diagnosis such as endo-
scopic capsule, abdominal CT scan with enterography,
PCR and the immunologic tests for M. tuberculosis.
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95. Kirsch R, Pentecost M, Hall Pde M, et al. Role of colonoscopic biopsy in distin-
guishing between Crohns disease and intestinal tuberculosis. J Clin Pathol.
2006;59:840-4.
96. Morgan MA, Horstmeier CD, DeYoung DR, Roberts GD. Comparison of a radio-
metric method (BACTEC) and conventional culture media for recovery of my-
cobacteria from smear-negative specimens. J Clin Microbiol. 1983;18:384-8.
97. Gan H, Ouyang Q, Bu H, et al. Value of polymerase chain reaction assay in
diagnosis of intestinal tuberculosis and differentiation from Crohns disease.
Chin Med J (Engl). 1995;108:215-20.
98. Amarapurkar DN, Patel ND, Amarapurkar AD, Agal S, Baigal R, Gupte P. Tissue
polymerase chain reaction in diagnosis of intestinal tuberculosis and Crohns
disease. J Assoc Physicians India. 2004;52:863-7.
99. Li JY, Lo ST, Ng CS. Molecular detection of Mycobacterium tuberculosis in
tissues showing granulomatous inflammation without demonstrable acid-fast
bacilli. Diagn Mol Pathol. 2000;9:67-74.
IJI Bowel Disease Volume 1 Number 1 May-August 2014
IJI Bowel Disease Volume 1 Number 1 May-August 2014

Review Article
Extraintestinal Manifestations of Inflammatory Bowel
Disease
Mauro Bafutto1, Ricardo Duarte Marciano2, Alexandre Augusto Ferreira Bafutto2, Enio Chaves de Oliveira3 and Joffre Rezende Filho1

Abstract Resumo

Extraintestinal manifestations of inflammatory bowel disease
are prevalent in both ulcerative colitis and Crohns disease.
The most common manifestations involve the musculoskele-
tal and dermatological systems. Other manifestations involve
the hepatobiliary system as well as the hematologic, ocular,
neurologic, pancreatic, renal, cardiac, and pulmonary sys-
tems. It is important to know how to recognize extraintesti-
nal manifestations and distinguish them from secondary
complications or even other pathologies not related to inflam-
matory bowel disease. A multidisciplinary team approach is
often needed for effective management, and emergency situ-
ations require prompt evaluation. This paper reviews the di-
agnosis, therapy, and management of the more common ex-
traintestinal manifestations of inflammatory bowel disease.
Corresponding author: Mauro Bafutto, maurobafutto@yahoo.com.br
As manifestaes extraintestinais das doena inflamatrias
intestinais (DIIs) so predominantes na colite ulcerativa (CU)
e na doena de Crohn (DC). As manifestaes mais comuns
envolvem os sistemas msculo-esquelticos e dermatolgicos.
Outras manifestaes envolvem o sistema hepatobiliar, bem
como o hematolgico, o ocular e o neurolgico, o pncreas e
o sistema renal, o cardaco e o pulmonar. importante saber
reconhecer as manifestaes extraintestinais e distingui-las
de uma complicao secundria ou mesmo a partir de outras
patologias no relacionadas DII. Muitas vezes, abordagem
multidisciplinar necessria para uma gesto eficaz, e situa-
es de emergncia necessitam de avaliao rpida. Este tra-
balho revisa o diagnstico, o tratamento e a gesto das ma-
nifestaes extraintestinais mais comuns de DII.

Key words: Inflammatory bowel disease. Extraintestinal man- Palavras-chave: Doena inflamatria intestinal. Manifesta-
ifestation. Arthritis. Primary sclerosing cholangitis. Derma- es extraintestinais. Artrite. Colangite esclerosante prim-
tology. ria. Dermatologia.

1MedicalClinic Department, Clinical Gastroenterology Discipline, Faculty of Medicine, Federal University of Gois; 2Faculty of Medicine, Catholic University of Gois;
3
Department of Surgery, Faculty of Medicine, Federal University of Gois; Brazil
Correspondence to: Mauro Bafutto, Rua T 62, 625 Ed. Atntida Apto. 600; Setor bueno, Goinia, Gois GO, CEP 74223-180 Brasil. E-mail: maurobafutto@yahoo.com.br

33
INTRODUCTION
Inflammatory bowel disease (IBD) may affect several
organ systems other than the digestive tract, with more
prevalent manifestations in the musculoskeletal, ocular,
and dermatological systems (Table 1). In the most recent
scientific literature, the frequency of extraintestinal man-
ifestations (EIM) of IBD varies between 21-47%1-4,75. The
manifestation frequency is similar or slightly higher in
Crohns disease (CD). The most common EIM are joints,
followed by dermatological ones. The occurrence of mul-
tiple EIMs varies between 4.5-14.6%, being more frequent
in CD. The most common association is joint with oph-
thalmologic3-4.
The distinction between a true EIM, that is a primary
IBD pathology, and a secondary complication of the base
disease (e.g. malnutrition or secondary effects of medica-
tion) or a pathology, that even of autoimmune character-
istic, may not be causally related to IBD, which is not al-
ways easy, and demands from the physician a great
knowledge of EIM and an accurate degree of clinical sus-
picion during the follow-up of patients with IBD (Table 2
and 3).
The last Brazilian Consensus on treatment of IBD
does refer to EIM and its relation to the activity of IBD.
However, it does not separate or differentiate the compli-
cated or associated pathologies from the manifestations of
IBD itself65 (Table 4).
Inflammatory bowel disease pathogenesis, and possi-
bly their EIM, are based on the relationship of genetics,
immune deregulation, microbial flora, and intestinal bar-
rier dysfunction5.
The role of genetic factors has been implicated in the
pathogenesis of IBD and their EIM. Familial occurrence of
IBD is approximately four-times higher in CD than in
ulcerative colitis (UC)4. Results of several studies revealed
Table 1. Main extraintestinal manifestations of inflammatory
bowel disease
Musculoskeletal: peripheral arthritis, sacroiliitis, ankylosing
spondylitis
Ophthalmologic: uveitis, episcleritis, scleritis
Mucus-cutaneous: erythema nodosum, pyoderma gangrenosum,
Sweets syndrome, aphthous stomatitis
Hepatobiliary: primary sclerosing cholangitis
Pancreatic: acute pancreatitis, chronic pancreatitis
Hematologic: thromboembolism
Renal: glomerulonephritis, nephropathy, interstitial nephritis
Neurological: multiple sclerosis, optic neuritis
Lung: bronchiectasis, asthma, bronchiolitis obliterans with
organizing pneumonia (BOOP)
Cardiac: pericarditis
a total of nine loci associated with IBD, designated DII1-
9, which possibly influence the presentation and manifes-
tations of inflammatory disease5. Several studies have
demonstrated a possible association between HLA poly-
morphisms and IBD.
There is an increase in the susceptibility of presenting
an EIM in individuals with UC associated with certain
alleles: HLA-DRB*0103 allele correlates with articular and
ophthalmologic manifestations; HLAB8/DR3 allele is as-
sociated with primary sclerosing cholangitis (PSC)6.
Uveitis might be associated to HLA-B*27, B*58 and
DRB1*0103, whereas erythema nodosum may be associ-
ated with B*15 and TNF-1031C7. Recently, a new gene
(TRAF3IP2) has been associated to an increased risk of
cutaneous extraintestinal manifestations in IBS pa-
tients69. The HLA-B*27 allele is strongly associated with

Table 2. Main complications secondary to inflammatory bowel disease

System Complication
Musculoskeletal Septic arthritis, metabolic osteopathy

Ophthalmologic Cataract, opportunistic infections

Dermatologic Infections, stretch marks, acne (corticosteroid), glossitis (vitamin B or zinc deficiency), acrodermatitis enteropathica
(zinc deficiency), skin rashes or drug-induced eruptions, anal fissures

Hepatobiliary Gallstones (Crohns disease), hepatic steatosis

Pancreatic Drug-induced pancreatitis (azathioprine, mesalazine)

Hematologic Anemia (iron, folate, or vitamin B12 deficiencies)

Renal Kidney stones (oxalate calculations), acute interstitial nephritis (mesalamine)

Neurologic Peripheral neuropathy (lack of vitamin B12), drug-induced leukoencephalopathy (infliximab)

Respiratory Opportunistic infections, hypersensitivity pneumonia

Cardiac Drug-induced pericarditis (mesalazine)

34 IJI Bowel Disease Volume 1 Number 1 May-August 2014

Table 3. Autoimmune diseases associated with inflammatory enteropathic arthropathies, mainly axial arthropathy, be-
bowel disease68 ing present in about 56% of patients with IBD and axial
disease. However, whereas HLA-B*27 is present in 90% of
Alopecia areata classical ankylosing spondylitis, its prevalence is 30%
Ankylosing spondylitis among patients with spondylitis associated to CD9. Type I
Bronchiiolitis obliterans peripheric arthritis is associated preferentially to HLA-B35,
Cold urticria whereas type II is mainly associated to HLA-B448.
Hemolytic anemia Protein NOD2 seems to play an important role as an
Henoch-Schoenlein intracellular sensor of bacterial components. NOD2
Insulin dependent diabetes mellitus CARD15-involved polymorphisms appears to be a genetic
Pancreatitis
target to be exploited: 78% of CD patients with symptom-
atic or asymptomatic sacroiliitis had at least one mutation
Primary biliary cirrhosis
compared to 48% of the control group with CD. The NOD2
Primary Sclerosing Cholangitis
mutations may consist in a loss of surveillance activity,
Polymiositis
resulting in loss of the control of intestinal mucosa re-
Raynauds phenomenon sponse to bacterial agents. A possible consequence may be
HIV-positive rheumatoid arthritis the beginning of systemic responses that lead to uncon-
Sjogrens syndrome trolled inflammation1,9.
Thyroid diseases The role of immune deregulation is supported,
Vitiligo among others, by the fact that several immune-mediated
Wegeners granulomatosis diseases have a higher frequency in patients with IBD,
Takayasu arteritis suggesting some common element or immune process.
Several EIMs, including arthritis, ankylosing spondylitis,

Table 4. Manifestations of IBD and their relation with activity of disease65

Manifestaes UC CD Related to disease activity

Rheumatologic

Arthralgia/arthritis 6-30% 15-35% +

Sacroiliitis 5-15%

Ankylosing Spondylitis 1-6%

Dermatologic

Aphthous stomatitis 4-25% 10-30% +

Erythema nodosum 2-5% 15% +

Pyoderma gangrenosum 1-5% 1-2% + or

Ophthalmologic

Episcleritis 2-4% +

Uveitis 0.5-3.5%% + or

Hepatobiliary

PSC 2-8% 1-2% + or

Gallstones 15-30%

Renal

Kidney stones 2-5% 5-20%

Amyloidosis Rare (1%)

UC: ulcerative colitis; CD: Crohns disease; PSC: primary sclerosing cholangitis.

Mauro Bafutto, et al.: Extra-intestinal Manifestations of Inflammatory Bowel Disease 35

erythema nodosum, pyoderma gangrenosum, iritis, uve-
itis, and PSC, have an immune component. Several im-
mune diseases (asthma, bronchitis, arthritis, multiple
sclerosis, etc.) are more prevalent in IBD patients and the
patients with these conditions have shown a higher risk
of IBD than general population, pointing to a common
factor or immunological process2.
The appearance of an EIM increases the chance of
developing another EIM. The coexistence of EIMs is par-
ticularly observed in peripheral arthritis, erythema nodo-
sum, and lesions of the biliary tract and eyes. Because of
these observations, the possibility of an ethiopathogenic
factor in common has been raised. It was demonstrated
that the colonic epithelium and UC extraintestinal affect-
ed organs (especially eyes, skin, gallbladder, and canalic-
uli) shows predominant expression of tropomyosin iso-
form hTM5, which seems to be a self-antigenic target
protein in UC10.
Furthermore, it was observed that CD patients with
colonic involvement have a higher risk of developing joint
EIMs than those with isolated disease in the small intes-
tine, and the incidence of joint EIM greatly reduces after
ileocecal resection, suggesting that bacterial overgrowth
proximal to the ileocecal valve may be related to EIMs4.
MUSCULOSKELETAL MANIFESTATIONS
Joint involvement is the most common EIM in IBD
patients, showing a frequency of 10-35%, and is most com-
monly found in CD, without significant difference between
males and females3,4,8. Symptoms may vary from arthralgia
to acute arthritis with joint swelling and erythema.
Recognition of its connection to IBD dates from 1930
after Bargens publication11 and was called colitic arthri-
tis in 1958 by Bywaters and Ansell. It was later described
as enteropathic arthritis12, a classification that is used
nowadays, generally designating a group of seronegative
spondyloarthropathies.
Peripheral arthritis
Enteropathic arthritis may present as two major enti-
ties: peripheral arthritis and axial arthritis. Oxfords
study13 classified peripheral arthritis in two types: type I,
a pauci-articular, acute and self-limited arthritis, that usu-
ally occurs during exacerbation periods of IBD and that is
not associated to HLA-B27 antigen; and type II, a symmet-
ric polyarthritis whose symptoms persist for months to
years, with an independent course of IBD.
In the most recent studies, the prevalence of periph-
eral arthritis varies from 7.4-30%, with predominance of
arthritis type I. Regarding peripheral arthritis in UC and
DC, some studies show no differences, and others reveal
a higher frequency in CD (10-20%) than in UC (5-10%). It
seems to be prevalent in women and may be associated to
enthesitis, tenosynovitis, and dactylitis3,8.
36
Arthritis type I (or asymmetric oligoarthritis) affects
less than five joints (pauci-articular), is manifested by
arthralgia, edema, and/or increased temperature of the
affected joints, usually acute and often self-limited. The
lower limb joints are the most affected, reaching large or
small joints, and may present an asymmetrical and migra-
tory characteristic. They may also be associated to ery-
thema nodosum and to uveitis. It is related to the activi-
ty of IBD, the average duration is 5-10 weeks, and 25-40%
of patients show recurrence. Arthritis type I might precede
the onset of IBD81.
In cases of monoarthritis or oligoarthritis in IBD pa-
tients, which, in addition to carrying a chronic and debil-
itating disease, are frequently seen in the use of anti-in-
flammatory and immunosuppressive drugs, one should
always be aware of the possibility of infection. In these
cases, septic arthritis is usually a result of fistulization or
bacteremia81.
Arthritis type 2 (polyarticular) is a symmetrical poly-
arthritis, often involving five or more joints, and the meta-
carpophalangeal joints are the most commonly affected. Its
course is independent from the activity of IBD and it may
last for several months. The coexistence with other EIMs
is rare, except for uveitis. In general, the intestinal symp-
toms of IBD precede or coexist with arthritis type 284.
Axial involvement
Axial arthritis progresses independently of IBD and
can behave as sacroiliitis or ankylosing spondylitis, refer-
ring to an inflammatory involvement of sacroiliac and spine
joints, respectively. It affects any age and equal proportions
of men and women, unlike idiopathic ankylosing spondyli-
tis, which prevails in men, with onset before age 4077.
Axial arthritis presents clinical and radiological char-
acteristics similar to the idiopathic forms, without any
extra-joint manifestations, with inflammatory and noctur-
nal nature back pain, with lumbar pain and morning stiff-
ness that improves with ambulation. It is accompanied by
progressive limitation of the spine axis movement. How-
ever, sacroiliitis usually courses in an asymptomatic form,
being diagnosed by imaging methods84.
The axial involvement tends to precede the intestinal
manifestations, has a chronic course independent of the
activity of IBD, and HLA B 27 can be found in up to 50%
of cases81.
Diagnosis can be made by the modified New York
criteria14 or the European group criteria for the study of
spondyloarthropathy15.
Radiographs of the spine are usually normal in early
stages of axial arthropathy, with possible further develop-
ment of bamboo spine. Computerized axial tomography
scan of the spine and bone scintigraphy are the most
sensitive in detecting axial arthropathy, but currently the
gold-standard is magnetic resonance imaging (MRI)16. In
order to evaluate its frequency, the methodology used in its
IJI Bowel Disease Volume 1 Number 1 May-August 2014
diagnosis is determining. Even so, studies differ on ob-
tained values of the prevalence of axial arthritis in IBD,
varying from 17-35%1, without significant statistic differ-
ences between CD and UC.
In the study by Lanna, et al.17, the pattern and fre-
quency of joint manifestations were analyzed in 130 Bra-
zilian patients with IBD (71 with CD and 59 with UC),
with or without signs of active inflammation. X-rays of
the lumbar spine, sacroiliac joints, and the calcaneus
were performed, as well as typing of HLA-B27. Joint man-
ifestations occurred in 31.5% of patients: 38% with CD
and 23.7% with UC. Peripheral involvement occurred in
22 patients, five axial, and mixed in 14 patients.
The most frequently involved joints were the knees
(56.1%), ankles, and hips, in a predominantly oligoarticu-
lar and asymmetric pattern, with the prevalence of pattern
type I being therefore verified. Eight patients were positive
for all the ankylosing spondylitis diagnosis criteria. Ra-
diographic sacroiliitis occurred in 12 patients. Enthesitis
was detected in seven patients, most with CD, and located
mainly in the Achilles tendon. Enthesitis is a specific
manifestation of spondyloarthropathies and can be a pre-
senting sign of pathology of this group, especially in
younger people3,8.
The treatment for arthritis type 1 is related to the
treatment of IBD. When the use of 5-ASA is indicated,
sulfazalazine is preferable to mesalazine, due to the anti-
arthritic effects of the first one. Nonsteroidal anti-inflam-
matory drugs should be avoided because of the risk of
reactivation of IBD. In severe cases, the symptoms can be
relieved with intra-articular injection of corticosteroids.
Arthritis type 2 generally requires long-term treatment. It
can be initiated with sulfazalazine at a maximum dose of
4,500 mg/day. If not effective, systemic corticosteroids or
methotrexate can be used84.
In the treatment of axial arthritis, sulfazalazine may
be used, although it is less effective than in peripheral
arthritis. Corticosteroid injections in the sacroiliac joint,
guided by MRI, may be an option in patients with intense
lumbar pain. The immunosuppressive agent of choice is
methotrexate84.
The use of anti-tumor necrosis factor (anti-TNF) ther-
apy may be indicated in severe or resistant cases. It pres-
ents good results in patients with articular manifestations
and IBD, particularly infliximab, adalimumab, and more
recently, certolizumab in patients with CD. Currently, in-
fliximab is the first-choice drug for patients with spondy-
litis associated with IBD84.
Changes in skeleton
Osteoporosis and osteopenia associated to IBD have a
prevalence of 2-30% and 40-50%, respectively18. Therefore,
metabolic bone disease in IBD is a reality, but it is ques-
tionable whether it represents an EIM or a secondary com-
plication of intestinal disease. The loss of bone density and
Mauro Bafutto, et al.: Extra-intestinal Manifestations of Inflammatory Bowel Disease
Table 5. Ophthalmic manifestations of inflammatory bowel
disease
Uveitis (iridocyclitis, choroiditis)
Episcleritis
Scleritis
Retinal pigment epitheliopathy
Optic neuritis
Serous retinal detachment
Retinal vascular occlusion
Retinal vasculitis
consequent fractures has a multifactorial etiology. The
main causal factors are treatment with corticosteroids and
the systemic inflammation of the disease itself19,20. Al-
though the inflammatory condition of the systemic intes-
tinal disease, characterized by an increase in circulation
cytokines, leads to an increased osteoclast activity through
the osteoclast receptor (RANK), the secondary effect of
treatment seems very important, given patients with os-
teopenia have a higher probability of current or previous
treatment with corticosteroids20. More than 27% loss of
bone mass after one year of therapy with prednisone has
been demonstrated21.
It is important that the treatment of metabolic bone
disease (calcium, vitamin D, alendronate, hormone re-
placement therapy) also passes through the treatment of
base inflammatory disease and, where possible adapting
to each case, using alternative drugs to corticosteroids
such as mesalazine and azathioprine, which may play a
positive role in maintaining bone mass and consequent
prevention of osteoporosis associated to IBD81.
Ophthalmic manifestations
Ophthalmic complications of IBD have been known
since the first description of two patients with conjuncti-
vitis and corneal infiltrates by Crohn in 1925. Several
ophthalmologic conditions have been reported in IBD pa-
tients, with incidences ranging from 2-29%, more frequent
in CD, with uveitis being the most prevalent, followed by
episcleritis (Table 5)23,67,68.
In a Brazilian study17 the frequency of EIMs was 6.2%,
with prevalence of anterior uveitis followed by scleritis
and episcleritis. The frequency of ocular involvement was
similar in patients with CD (6.8%) and UC (5.4%), and
there was no statistical association with the activity of
bowel disease or arthritis.
In another study24, the prevalence of ophthalmic man-
ifestations in IBD was 22.92% in patients with UC and
60% in patients with CD, and there was no significant
difference regarding age and sex between patients with or
without eye involvement. The high rate obtained may be
because of the small number of patients (96) in this study.
37
The most detected eye diseases were, in decreasing order,
conjunctivitis, blepharitis, uveitis, cataracts, and episcleri-
tis. There is no significant difference between groups with
and without ocular involvement related to intestinal dis-
ease activity. Nor does it establish any link between the
bowel segment involved and ocular involvement. The high
prevalence of conjunctivitis and blepharitis obtained are
due to the fact that these diseases are frequent in the
general population and, therefore, coincident in patients
with IBD.
The occurrence of cataracts associated with IBD in
this and other studies has been found after long-term
therapy with steroids. Therefore, such ocular disease is a
complication of therapy and not a true EIM. Extraintesti-
nal involvement (with the exception of the eye) was noted
in 28 of 116 patients, predominantly arthritis, with a
12.7% incidence in these patients. This result corroborates
previous data that ocular involvement is frequently asso-
ciated with other EIM complications, usually of a joint 25.
In the study of Felekis, et al.23, the most frequent
EIMs were anterior uveitis (iridocyclitis: 11.5%) and
posterior uveitis (choroiditis: 3.8%) followed by epis-
cleritis (7.7%). Also reported were cases of optic neuritis,
vasculitis, changes in the retinal pigment epithelium, and
serous retinal detachment, among others79,82. The high
frequency of EIMs (43%) distributed almost evenly be-
tween CD and UC indicates that many ocular manifesta-
tions are relatively quiet and should be screened early in
these patients in order to reduce visual morbidity in IBD
patients.
Uveitis can be accompanied by potentially severe con-
sequences. When associated with UC, it is frequently bi-
lateral, with insidious onset and long duration. Its clinical
presentations are eye pain, blurred vision, photophobia,
and headaches. The progression to visual loss is a threat
that requires urgent reference to an ophthalmologist. Top-
ical and systemic treatment is done with steroids. Inflix-
imab has good efficiency25.
Episcleritis may be painless, presenting hyperemic
conjunctiva and sclera, accompanied or not by itching and
burning sensation. Episcleritis usually does not require
specific treatment besides the treatment of the underlying
bowel disease26. Recent literature has reported a rare case
of a syndrome with sub-retinal fibrosis and panuveitis as
an EIM of UC27. This is a rare syndrome that presents
unilateral posterior uveitis progressing to sub-retinal fi-
brosis.
MUCOCUTANEOUS MANIFESTATIONS
The prevalence of skin manifestations associated with
IBD assumes values between 2-34%28,29,83. The association
of these events with IBD is unknown. Some authors sug-
gest that there may be an antigenic response of the bowel
disease, since dermatological manifestations usually coin-
cide with exacerbation of the base intestinal disease. There
38
Table 6. Mucocutaneous manifestations of inflammatory bowel
disease
Erythema nodosum
Pyoderma gangrenosum
Sweets syndrome
Oral ulcerations
Psoriasis
Lichen planus
Erythema multiform
Vegetative pyostomatitis
is a wide spectrum of these manifestations (Table 6), but
the most common are erythema nodosum and pyoderma
gangrenosum28. The diagnosis is made clinically. About
9.3% of patients with IBD had a major dermatological
manifestation, including erythema nodosum and pyoder-
ma gangrenosum 30.
Erythema nodosum
The prevalence of erythema nodosum in patients with
IBD is 2-20%30,67,68,83. Erythema nodosum is the most com-
mon cutaneous manifestation in CD, affecting more than
15% of patients, and with women being more affected than
men28. The dermatological manifestation rarely precedes
the diagnosis of IBD, and the severity of erythema nodo-
sum does not necessarily correlate with the severity of
bowel disease31.
Erythema nodosum affects the subcutaneous fat (sep-
tal panniculitis) and is clinically characterized by subcu-
taneous nodules, violet or red, sensitive and elevated. It
usually affects the extensor surfaces of the extremities,
particularly the anterior tibia area, and it tends to occur
in periods of IBD activity. In general, it evolves without
ulceration or sequelae. Erythema nodosum appears to re-
sult from a delayed-type hypersensitivity reaction. Biopsy
is not necessary, but histologically the lesion reveals a
nonspecific focal panniculitis29. The disease is self-limit-
ing and the prognosis is good. Remission has an average
duration of five weeks. The treatment of IBD usually re-
sults in improvement of erythema nodosum. Supportive
treatment with compression stockings, leg elevation, and
bed rest may be sufficient. In more severe cases, systemic
steroids may be necessary28. In refractory cases, the use of
dapsone or infliximab has shown good results67.
Pyoderma gangrenosum
Pyoderma gangrenosum is a rare manifestation, with
incidence values of 0.5-2.0%, and it can occur in both CD
and UC. Together with Sweets syndrome, it belongs to
the group of neutrophilic dermatoses. Clinically, pyoder-
ma gangrenosum can be presented in four types: classic,
IJI Bowel Disease Volume 1 Number 1 May-August 2014
pustular, bullous, and vegetative. Classic pyoderma gan- Table 7. Hepatobiliary changes associated with inflammatory
grenosum is characterized by a deep and painful ulcer, bowel disease
with a violet edge and a purulent necrotic center. It tends
EIM UC CD
to affect the legs, but it can occur anywhere in the body
including the head, neck, and genitals. It occurs in multi- PSC
ple locations in 70% of cases32. Patients tend to develop PSC large channel + +
an ulcer in response to a traumatic injury, a phenomenon
called pathergy67. PSC small channel (pericholangitis) + +
Treatment includes treating the underlying bowel Cirrhosis + +
disease and wound care, sometimes including the need
Hepatoma + +
for debridement of necrotic material. Steroids are consid-
ered the most effective treatment for pyoderma gangre- Cholangiocarcinoma + +
nosum. In mild cases, corticosteroids may be associated
Others
with dapsone. In more severe cases, initially high doses
of prednisolone may be used, with pulse therapy for Hepatic steatosis + +
three days being very effective. The immunosuppressant Granuloma +
azathioprine/6-mercaptopurine may be used in cases of
addiction to steroids33,67,68. Cyclosporine, tacrolimus, pi- Amyloidosis +
mecrolimus, cromolyn sodium acid, 5-amino salicylic Biliary stones +
acid, and growth factors derived from platelets have been
Autoimmune hepatitis +
reported in the literature as treatment options for pyoder-
ma gangrenosum, with varying rates of success34. Recent- EIM: extraintestinal manifestations; UC: ulcerative colitis; CD: Crohns disease;
ly, good results with anti-TNF treatment have been re- PSC: primary sclerosing cholangitis.

ported76.

Sweets syndrome
Sweets syndrome, or acute febrile neutrophilic der-
matosis, has only recently been recognized as an EIM of
IBD. It predominantly affects women between 30-50 years
of age and it is clinically characterized by erythematous
nodules, wheals, or inflammatory plaques, usually locat-
ed on the face, neck and limbs, the external auditory
canal, and oral cavity. The eruption is characterized by
pain or burning, and it may be associated with general
symptoms such as fatigue, headaches, and fever. The
pathogenesis is unknown. Sweets syndrome tends to oc-
cur in the active phase of the underlying bowel disease.
The rashes respond well to treatment with topical or
systemic steroids35.
Oral ulcerations
Oral aphthous ulcers are one of the most common
mucosal membrane manifestations in IBD. They may oc-
cur in 10% of patients with UC and 20-30% of patients
with CD. Clinically, lesions appear as painful ulcers,
round or oval, with pseudomembranous base and enan-
thematous edges. They may be located in the buccal or
labial mucosa, palate, or oropharynx. The manifestation
may occur, recur, or be exacerbated by activity of the
underlying intestinal disease. Differential diagnoses are
oral herpes simplex, Behets disease, and coxsackie virus
infection4,67.
In general, they are quickly resolved with remission
of the disease28.
HEPATOBILIARY MANIFESTATIONS
Several hepatobiliary changes are associated IBD.
However, most of them are, actually, complications of
IBD. The primary hepatobiliary pathology that is actually
associated with IBD, while an EIM of the primary disease,
is PSC36 (Table 7).
Primary sclerosing cholangitis is a chronic and pro-
gressive disease, of unknown etiology, characterized by
inflammation, fibrosis and stenosis of the biliary tree in-
tra- and/or extrahepatic. It is considered a premalignant
development of cholangiocarcinoma. While PSC is rare in
the general population, it is strongly associated with IBD
in such a way that more than 90% of patients with IBD have
also PSC, and the diagnosis of IBD usually precedes the
diagnosis of PSC for several years. This disorder affects
3-7% of patients with UC and less frequently patients with
CD. It seems to be prevalent in young men, with some
studies referring to a 2:1 ratio relative to females67.
In patients with PSC, IBD often presents some typical
characteristics: pan-colonic extension, low intestinal ac-
tivity, ileitis, and high incidence of pouchitis after col-
ectomy. These data suggest the existence of a specific
clinical phenotype IBD-PSC37. It has high positivity for
autoantibodies to neutrophils (p-ANCA). Most (70%) pa-
tients have the HLA-DR3,B8 haplotype. Endoscopic retro-
grade cholangiopancreatography (ERCP) and MR cholan-
giography are diagnosis methods, showing the typical
pattern of irregularity of the bile ducts, with some areas
of narrowing and some of dilatation 38.

Mauro Bafutto, et al.: Extra-intestinal Manifestations of Inflammatory Bowel Disease 39

 Ursodeoxycholic acid is the most-used drug in thera-
py. It has demonstrated to have a positive effect, since
some studies report an improvement in liver biochemistry
and histology, in doses of 20-30 mg/kg/day. However, the
improvement of symptoms is questioned and does not
reduce mortality rates. It can also improve the prognosis
of disease and reduce the risk of colon cancer as well as
cholangiocarcinoma of these patients36,67. For the treat-
ment of itching, cholestyramine, rifampicin and naltrex-
one are used.
Liver transplantation is the most effective treatment,
with 85-90% survival at five years. However, recurrence
of the disease can be observed in up to 20% of patients
after transplantation67.
Patients with IBD are also at increased risk for auto-
immune hepatitis (AIH). In one study, UC was present in
16% of patients with AIH 36.
Gallstones are more prevalent in CD patients, with a
frequency of 13-34% of cases. They usually occur due to
malabsorption of bile salts in the ileum. Liver biochemis-
try abnormalities (aminotransferases and alkaline phos-
phatase) are commonly observed in patients with sepsis
and malnutrition in severe cases of IBD. They usually
correlate with disease activity and return to normal after
remission. Hepatic steatosis is also frequently found in
critically ill patients, malnourished and under use of cor-
ticosteroids4,67.
Less common liver disorders in IBD are: portal vein
thrombosis, Budd Chiari syndrome, fatty liver, and gran-
ulomatous hepatitis70.
PANCREATIC MANIFESTATIONS
The cases of pancreatitis associated with IBD are
mostly complications secondary to drug therapy of IBD
(mesalamine, azathioprine, 6-MP). Therefore, as an EIM
of IBD, pancreatitis is an infrequent disease or weakly
recognized. However, even with weak epidemiologic ex-
pression, its existence cannot be ignored.
A literature review showed 33 cases of chronic pan-
creatitis associated with IBD, 20 patients with CD and
13 with UC. Of these, only four cases (three of UC and
one DC) were identified as EIM, given the absence of al-
ternative causes for the pancreatitis39. The prevalence of
pancreatitis in 1,057 patients with IBD was determined
from the database of two hospitals in Madrid 39. The value
obtained was 2.74% (29 cases); of these, only four patients
(0.38%) were considered idiopathic, and therefore likely
to constitute an EIM. Three of these four patients had
chronic pancreatitis. These data indicate that pancreati-
tis in patients with IBD is most often due to a cause not
related to the intestinal pathology, and that cases of pan-
creatitis as EIMs are comparatively rare.
Studies show the presence of pancreatic autoantibod-
ies in 40% of patients with CD. In a series of 64 patients
with CD, the proportion of antibody-positive individuals
40
with exocrine insufficiency was 27% compared with 8%
in the antibody-negative group 4.
Inque, et al.40 have shown that acute pancreatitis is
not frequent, but it could be an occasional EIM in UC.
However, Bermejo, et al.41 considered that acute pancreati-
tis as an EIM of IBD could be classified in more cases than
expected, since the frequency of idiopathic pancreatitis
obtained in the study reached 20% of all patients with
pancreatitis.
HEMATOLOGIC MANIFESTATIONS
Inflammatory bowel disease is associated with an
increased risk of hematological disorders42. The most com-
mon thrombotic manifestations are deep vein thrombosis
(usually in the lower limbs) and pulmonary thromboem-
bolism. Thromboembolic events (TE) are recognized as
the most important because they can be fatal. Patients
with IBD are at increased risk (about threefold) of TE and
the incidence varies between 1.0-7.7% in clinical studies
and 39-41% in postmortem studies, and they are an im-
portant cause of morbidity and mortality43,46. It has been
demonstrated that in young patients, TE is more aggres-
sive, causing significant morbidity (stroke, retinal vascular
occlusive thrombus deposition in cerebral, retinal and
mesenteric vessels, massive pulmonary embolism)71,80.
Multivariate analysis showed that patients with both UC
(OR: 1.85) and CD (OR: 1.48) have higher rates of TE than
those without IBD. The active fistulizing CD is a risk fac-
tor for TE67.
Thromboembolism is an EIM of IBD, which results
from the interaction between genetic and acquired risk
factors. Studies have demonstrated an imbalance of pro-
coagulant factors, anticoagulants and fibrinolytic agents,
predisposing patients with IBD to thrombosis44,45. In ad-
dition, the study by Miehsler, et al. was instructive on how
IBD itself is a risk factor for TE43. This study compared
patients with IBD, rheumatoid arthritis, and celiac disease
with controls matched for age and sex, showing that pa-
tients with IBD have a risk of TE increased 3.6-times in
contrast to other inflammatory diseases that showed no
increased risk.
The cause of this strong association between IBD
and TE remains unclear. However it is known that ve-
nous thromboembolism is more common than arterial
thromboembolism, and that the majority of TE occurs in
patients with active disease. Risk factors are hospitaliza-
tion, prolonged immobilization, sepsis, surgeries, and
invasive procedures. Some studies describe mortality of
1.0-1.2% after restorative proctocolectomy due to throm-
boembolic tendency complications71. Moreover, in severe
disease, thrombocytosis associated with increased con-
centrations of various clotting factors lead to a pro-clot-
ting condition44,45.
Hyperhomocysteinemia is associated with thromboem-
bolism in IBD patients. It is not clear whether the mutation
IJI Bowel Disease Volume 1 Number 1 May-August 2014
of the gene for methylenetetrahydrofolate reductase (MTHFR),
which leads to hyperhomocysteinemia, is more common
in patients with IBD. However, it has been shown that the
combined deficit of MTHFR, B12 vitamin, and folate is
observed in IBD patients with TE71. Besides, the use of
inhibited folate drugs (methotrexate, sulfazalazine) could
contribute to acquired hyperhomocysteinemia46.
Several studies have investigated the relation between
genetic risk factors for thrombosis and IBD. Factor V
Leiden, factor II and factor XIII, among others, as well as
vasoactive and thrombophilic genes have been investigat-
ed. Literature data show that these genetic factors are not
usually more common in patients with IBD than in others.
Nevertheless, when these factors occur in patients with
IBD, they are more susceptible to the development of TE.
Therefore, the study of genetic defects of clotting in pa-
tients with IBD with previous TE or family history of TE
seems justifiable46. Likewise, the use of low doses of hep-
arin is also advisable in hospitalized patients with IBD,
unless there is presence of severe bleeding4.
Anemia is relatively common, and may be present in
9-74% depending on the subpopulation studied. It can
occur not only from blood loss, but from iron, folate or
vitamin B12 deficiencies in patients with IBD4,67.
RENAL MANIFESTATIONS
It remains unclear whether certain kidney diseases
and urinary tract infections that affect patients with IBD
are, effectively, EIMs of the underlying inflammatory dis-
ease.
In patients with CD, oxalate and uric acid stones are
relatively common. Due to poor absorption of fats, calcium
binds to the luminal fatty acids. The absence of free cal-
cium results in increased absorption of oxalate, hyperox-
aluria, and formation of oxalate urolithiasis. Hyperoxal-
uria may also cause tubulointerstitial nephritis. Preventive
treatment for this consists of a low oxalate diet and oral
calcium supplementation (1-2 g/day)4.
The formation of uric acid stones happens in cases
when there is volume depletion (diarrhea, ileostomy) and
when there is a hyper-metabolic state, usually in severely
ill patients4.
Amyloidosis can occur due to the presence of chron-
ic inflammation. It is caused by extracellular deposition
of an acute-phase plasma protein (serum amyloid A pro-
tein, SAA). It affects more patients with CD than UC,
usually with more than 15 years of evolution4.
In patients with IBD, there are reported cases of glo-
merulonephritis causing nephrotic syndrome and renal
failure. These renal pathologies of various histologies ap-
pear to be related to the activity of intestinal disease and
respond favorably to treatment of IBD47. Although rare,
there are also cases of IgA nephropathy associated with
IBD48. In these cases, treatment of the underlying IBD also
tends to improve the nephropathy.
Mauro Bafutto, et al.: Extra-intestinal Manifestations of Inflammatory Bowel Disease
In some cases, a drug etiology is hypothesized, rela-
tively to those used treat IBD, to treat drug monitoring
DII. The UKs drug surveillance recorded a low incidence
of renal damage associated with therapeutic salicylates49.
A recent epidemiological study demonstrated that the ap-
pearance of kidney damage is related to the severity of
underlying IBD more than the treatment with 5-ASA50.
NEUROLOGIC MANIFESTATIONS
There is increasing evidence that EIMs also occur in
the peripheral and central nervous system. The establish-
ment of a causal relationship between IBD and neurolog-
ical manifestations is based on cases of neurological dam-
age in patients with IBD, reported in literature. The most
common clinical entity is multiple sclerosis. Less fre-
quently, there is: optic neuritis, progressive multifocal
leukoencephalopathy (PML), peripheral neuropathies, and
even rare, subclinical sensorineural hearing loss58. A re-
view of scientific literature and a cohort study on the oc-
currence of demyelinating diseases in IBD revealed a four-
fold increased risk of demyelinating diseases in patients
with IBD, regardless of medical treatment 51. Demyelinat-
ing disease is characterized by inflammation and focal
destruction of myelin sheaths in the white matter of the
central nervous system (CNS).
In some studies, cases of patients with CD under
infliximab therapy are reported, diagnosed with multiple
sclerosis52-54 or optic neuritis55,56. It is not known exactly
if the neurological symptoms were due to treatment with
infliximab, or if the demyelinating processes represent
manifestations of a subclinical state of neurological dis-
ease exacerbated by biological treatment in a population
at increased risk of demyelinating disease. The develop-
ment of progressive leukoencephalopathy was related to
the use of natalizumab and anti-TNF therapy. Two recent
studies have shown an increased risk of demyelinating
disease in patients with IBD that were not treated with
infliximab or other biological therapy. The use of metro-
nidazole and vitamin B12 deficiency are potential causes
of peripheral neuropathy4,72,74.
The cohort population study by Bernstein, et al. re-
ported a significant increase in the risk of multiple scle-
rosis patients with UC, but not in patients with CD2. In a
retrospective study of Gupta, et al., optic neuritis and
other demyelinating diseases in patients with UC and DC
were diagnosed57.
PULMONARY MANIFESTATIONS
Several pulmonary manifestations have been report-
ed in patients with IBD and the spectrum of pulmonary
involvement may cover the whole respiratory system,
from larynx to pleura. The majority of cases occurs after
the diagnosis of IBD, but may occasionally precede diag-
nosis59.
41
Table 8. Level of evidence in favor of infliximab and/or adalimumab in the treatment of various extraintestinal manifestations of
inflammatory bowel disease66
Extraintestinal manifestations Data from retrospective cases Data from prospective cases Data from randomized controls
Ankylosing spondylitis Yes Yes Yes

Peripheral arthropathy Yes Yes Yes

Erythema nodosum Yes Yes No

Pyoderma gangrenosum Yes Yes Yes

Uveitis Yes Yes No

Primary sclerosing cholangitis No No No

Table 9. Temporal associations between flares of inflammatory bowel disease and the various extraintestinal manifestations are
seemingly independent of their treatment responses to tumor necrosis factor inhibitors 66
EIM Parallel course to IBD Separate course from IBD Response to anti-TNF
Axial arthropathy X X

Peripheral arthropathy X X

Erythema nodosum X X

Pyoderma gangrenosum X X

Episcleritis X X

Uveitis X X

EIM: extraintestinal manifestation; IBD: inflammatory bowel disease; TNF: tumor necrosis factor.

The increase in disease activity may be associated
with changes in pulmonary function. Airways are the
most common site of pulmonary involvement associated
with IBD, representing about 39% of cases. Within this
location, bronchiectasis is the most common respiratory
disease in these patients67.
Several studies have demonstrated subclinical pulmo-
nary abnormalities in 50-69% of patients with IBD. The
most prevalent are the reduction of gas transfer and in-
creased residual volume67.
The study by Bernstein, et al.2 reported respiratory
airways illness as the most frequent chronic disease asso-
ciated with CD patients, and the second most linked to
UC. The probability of these patients suffering from asth-
ma is 30-40% and 50-70% in UC and DC, respectively, and
compared with controls. A recent study confirms these
data and records an increased prevalence of asthma in
patients with IBD64.
Parenchymal lung disease is not often associated with
some IBD. Its occurrence is mainly in UC and the most
reported disease is bronchiolitis obliterans organizing
pneumonia (BOOP)59. Other manifestations include pleu-
ritis and overlap syndromes73.
Pulmonary involvement by drugs used in IBD, such as
mesalamine, sulfazalazine, and methotrexate, may be asso-
ciated with several complications. Salicylates particularly
can be involved in different types of interstitial lung dis-
ease and pulmonary disease such as granulomatous
BOOP60.
CARDIAC MANIFESTATIONS
There are few reported cases of cardiac manifestations
of IBD78. Pericarditis is a rare EIM of IBD and the diagno-
sis of its association with IBD is usually established by
exclusion of other etiologies1. Despite the small number
of reported cases associating pericarditis with IBD, it is a
condition for which treatment is important because of
potentially severe and chronic complications60,61.
Mesalazine has been implicated in pericarditis as an
acute hypersensitivity reaction, which evolves within
weeks after initiation of therapy62,63. Therefore, it is im-
portant to differentiate between pericarditis as a compli-
cation of IBD, subsequent to therapy with mesalazine, and
pericarditis as an EIM of IBD.
In a Canadian population study, patients both with
CD and UC presented risk of developing pericarditis com-
pared to controls2.
A recent study from Finland identified a higher oc-
currence of coronary disease in patients with IBD. Accord-
ing to the study, the cause is unknown, but the chronic
inflammation could predispose to arteriosclerosis64.

42 IJI Bowel Disease Volume 1 Number 1 May-August 2014

THERAPEUTIC CONSIDERATIONS
The advent of biological response modifiers, for ex-
ample inhibitors of TNF-, has significantly improved the
treatment of IBD and its EIMs. The significant level of
evidence for the therapeutic use of these agents, such as
infliximab and adalimumab, supports the decision of its
clinical introduction in the context of EIMs of IBD (Table
8 and 9)66.
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cutaneous extraintestinal manifestations in Inflammatory Bowel Disease. J
Crohns Colitis. 2013;7:44-52.
70. Uko V,Thangada S, RadhakrishnanK. Liver Disorders in Inflammatory Bowel
Disease. Gastroenterol Res Pract.2012;2012:642923.
71. Canero A, Parmeggiani D, Avenia N, et al. Thromboembolic tendency (TE) in IBD
(Inflammatory bowel disease) patients. Ann Ital Chir. 2011;pii:S0003469X11017519.
72. Singh S, Kumar N, Loftus EV, Kane SV. Neurologic complications in patients
with inflammatory bowel disease: Increasing relevance in the era of biologics.
Inflamm Bowel Dis. 2013;19:864-72.
73. Basseri B, Enayati P, Marchevsky A, Papadakis KA. Pulmonary manifestations
of inflammatory bowel disease: case presentations and review. J Crohns Colitis.
2010;4:390-7.
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74. Zois CD,Katsanos KH,Kosmidou M,Tsianos EV. Neurologic manifestations in
inflammatory bowel diseases: current knowledge and novel insights. J Crohns
Colitis. 2010;4:115-24.
75. Vavricka SR,Brun L,Ballabeni P,et al. Frequency and risk factors for extrain-
testinal manifestations in the Swiss inflammatory bowel disease cohort. Am J
Gastroenterol.2011;106:110-19.
76. Cubero CC, Tudela MMR, Maestrojuan JJS, Venegas JJP. Pyoderma Gangreno-
sum Associated With Inflammatory Bowel Disease. Report of Two Cases With
Good Response to Infliximab. Reumatol Clin. 2012;08:90-2.
77. De Vos M, Hindryckx P, Laukens D. Novel development in extraintestinal
manifestations and spondylarthropathy. Best Pract Res Clin Gastroenter-
ol.2011;25(Suppl 1):S19-26.
78. Yarur AJ, Deshpande AR, Pechman DM, Tamariz L, Abreu MT, Sussman DA.
Inflammatory bowel disease is associated with an increased incidence of car-
diovascular events. Am J Gastroenterol.2011;106:741-7.
79. Vayalambrone D, Ivanova T, Misra A. Nonischemic Central Retinal Vein Oc-
clusion in an Adolescent Patient with Ulcerative Colitis. Case Rep Ophthalmol
Med.2011;2011:963583.
80. Tabibian JH,Streiff MB. Inflammatory bowel disease-associated thromboembo-
lism: a systematic review of outcomes with anticoagulation versus catheter-di-
rected thrombolysis. Inflamm Bowel Dis.2012;18:161-71.
81. Arvikar SL, Fisher MC. Inflammatory bowel disease associated arthropathy.
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82. Barabino AV, Gandullia P, Calvi A, et al. Sudden blindness in a child with
Crohns disease. World J Gastroenterol.2011;17:4344-6.
83. Huang BL, Chandra S, Shih DQ. Skin Manifestations of Inflammatory Bowel
Disease. Front Physiol.2012;3:13.
84. Brakenhoff LKPM, van der Hijde DM, Hommes DW. IBD and arthropathies: a
practical approach to its diagnosis and management. Gut. 2011;60:1426-35.
IJI Bowel Disease Volume 1 Number 1 May-August 2014
IJI Bowel Disease Volume 1 Number 1 May-August 2014

Point of View
The Future of Inflammatory Bowel Disease: Integrating
Knowledge to Advance Understanding and Reach a Cure
Claudio Fiocchi

INTRODUCTION the outcome of biological interactions in IBD is hard even

Most experts agree that the main components of in-
flammatory bowel disease (IBD) have been identified, and
they include the environment, genetic make-up, gut mi-
crobiota and the immune response1. What is still unclear,
however, is whether all these components are necessary
and equally important and how they interact with each
other to cause IBD. By studying each component separate-
ly, considerable progress has undoubtedly been achieved
in our understanding of Crohns disease (CD) and ulcer-
ative colitis (UC), but progress can be further accelerated
by integrating the knowledge derived from each one of
them. Here we will discuss and try to merge two specific
components of the IBD pathogenesis: genes and environ-
mental factors.
GENE-GENE INTERACTIONS
In recent years genome-wide association studies have
uncovered close to 200 genetic associations, some restrict-
ed to CD, others to UC, and others shared between the
two forms of IBD2. However, these associations only ex-
plain about one-fourth of all IBD cases3, and this has lead
to the new notion that, instead of looking for additional
genes, we should start looking at the interaction among
genes identified so far to explain the rest of IBD. The ex-
istence of gene-gene interactions (GXG) in IBD is practi-
cally certain because this is the case in essentially all
complex diseases. To detect GXG (also called epistasis)
mathematical models can be used4, but this approach tests
quantities but not effects, and the detected statistical in-
teractions do not imply biological interactions. Predicting
when assessing well-defined common pathways (such
as the interleukin-23/Th17 pathway), but some are emerg-
ing. A recent report describes the enhanced production
of the cytokines interleukin-1 and interleukin-6 in CD
patients with a wild-type NOD2 gene, but carrying a vari-
ant of the autophagy gene ATG16L15. This is an example
of a functional abnormality, possibly resulting from a
GXG that may initiate or boost inflammation, and more
GXG will almost certainly be discovered in the future,
which will allow to clarify the impact of multiple other
genetic interactions in IBD.
GENE-ENVIRONMENT INTERACTIONS
In addition to numerous GXG, it is unquestionable
that gene-environment interactions (GXE) are also prom-
inent in IBD, and the number of environmental factors
associated with disease development is undoubtedly much
greater than those already recognized, such as smoking,
foods, drugs, etc. So, if we multiply the number of IBD
gene variants with the endless number of natural and
man-made products existing in the environment (the ex-
posome) the possibilities are essentially infinite. In fact,
if we consider the number of genes involved in the recog-
nition and processing of food antigens, gut microbes, po-
tential pathogens or pathobionts, and a whole host of xe-
nobiotics, the result is an enormous number of GXE with
distinct effects determining diverse clinical courses, dis-
ease outcomes, and responses to therapy. Nevertheless, the
discovery of the gene component of GXE can still be high-
ly rewarding. A recent study found the amino acid position

Department of Gastroenterology and Hepatology, Digestive Disease Institute, Department of Pathobiology, Lerner Research Institute, The Cleveland Clinic Foundation,
Cleveland, Ohio, USA
Correspondence to: Claudio Fiocchi, Department of Pathobiology, Lerner Research Institute, Department of Gastroenterology and Hepatology, The Cleveland Clinic Foundation,
Cleveland, Ohio 44195, USA. E-mail: fiocchc@ccf.org

45
11 of HLA-DRB1 to be a major determinant of chromo-
some 6p association with UC6. Since this position is in the
peptide-binding groove of the HLA, its alteration could
affect antigen recognition and results in an anomalous
immune response linked to UC pathogenesis. This exam-
ple illustrates the importance of investigating GXE, and
how the integration of multiple genes with multiple envi-
ronmental factors may explain not only many cases of IBD,
but also the diversity of clinical manifestations.
ENVIRONMENT-GUT MICROBIOTA INTERACTIONS
Health depends on the proper balance of the host
with the microbiome, i.e. the sum of all microbial com-
munities populating the body. This is particularly true for
the intestinal tract because it harbors the largest and most
varied number of microorganisms7. This balance is essen-
tial and it goes through an evolution that starts immedi-
ately after birth, and evolves from early life to early child-
hood, adulthood and old age8. One of the most striking
examples of how the intestinal microbiota is modified is
by the use of antibiotics that can alter both its quantity
and quality. Under normal conditions the microbiota re-
turns to baseline after discontinuation of antibiotics, but
this may not be so under special periods of evolution,
such as the early years of life, which is considered a sen-
sitive period. Changes during this period can have dra-
matic long-term consequences, as shown by a popula-
tion-based study showing that the more and the earlier
the use of antibiotic occurs in infancy, the higher the risk
of developing IBD, and CD in particular 9. Therefore, both
the type and the timing of microbial priming of the gut
mucosal immune system are of paramount importance, as
they induce conditions that either defend against or pre-
dispose to IBD.
FOOD-GUT MICROBIOTA INTERACTIONS
Among many environmental factors, foods have long
been linked to IBD, but supporting evidence has always
been scarce. Dietary interventions early in life can deter-
mine the composition of the gut microbiota with life-long
effects. Children from rural Africa, where IBD is nonexis-
tent, have a dramatically different composition of the gut
biota from that of European children living in urban cen-
ters10. Adults submitted to different types of diets show
variable changes in colonic bacteria11, and adults ingesting
mostly animal protein and fat also have a gut microbiota
different from those on a carbohydrate-rich diet12.
Not only quality but quantity also matters in deter-
mining gut biota composition, as indicated by studies of
obese subjects, who display clear-cut obesity-associated
changes compared to lean controls. Western-style foods
are associated with proinflammatory changes of the gut
microbiome. These abnormalities not only affect the car-
riers, but may be transmitted to their progeny through
46
epigenetic influences that act during the highly sensitive
period of fetal development13.
Common food additives can also have a detrimental
effect on the gut microbiota, as exemplified by maltodex-
trin, a ubiquitous substance found in most sweeteners.
Ongoing studies show that maltodextrin promotes adhe-
sion of bacteria to gut epithelial cells and simultaneously
suppresses autophagy in these cells, resulting in an in-
crease of the intestinal bacteria load, a condition known
to predispose to intestinal inflammation.
INTEGRATING THE ENVIRONMENT, GENES,
AND THE IMMUNE RESPONSE
In view of what has been discussed so far, the exis-
tence of several GXG and GXE interactions relevant to IBD
pathogenesis seems obvious, leading to a pathogenetic
integration of genes, foods, and the gut microbiota. This
integration requires a link between the trigger and the
receptor pathway. For bacteria, the link is well-known and
is represented by TOLL-like and NOD-like receptors,
which are present on practically all cells. In contrast, the
link between other environmental factors and the host is
less clear. One good example is provided the aryl hydro-
carbon receptor (Ahr), a receptor that can bind a wide
range of ligands14. Evidence of the importance of Ahr in
IBD has been recently reported. In both CD and UC pa-
tients, the expression of Ahr is decreased, and activation
of the Ahr improves experimental models of colitis15. This
is important because the Ahr can bind multiple environ-
ment-derived products, and the downstream pathway can
modulate the immune response, resulting in positive or
negative effects, which may be implicated in IBD patho-
genesis. For instance, different immune responses may
result from this interaction, and the Th1/Th17 pattern of
CD and the atypical Th2 pattern of UC could be interpret-
ed as the end result of the sum of multiple GXG and GXE
interactions in each form of IBD.
The overall input of the environment on the host re-
sponse is modulated by epigenetic modifications, a system
of chemical tags that modify chromatin structure and
switch genes on and off during development, health, and
disease, starting immediately after conception and lasting
a lifetime. Thus, epigenetics can be viewed as the ultimate
controller of final gene expression. A huge number of
environmental factors induce epigenetic changes, includ-
ing smoke, particulate air pollution, asbestos, metals, sil-
ica, benzene, etc.16, all of them linking the environment
to ultimate gene expression.
SENSITIVE PERIODS AND INFLAMMATORY BOWEL
DISEASE DEVELOPMENT
During human life there are periods where the environ-
ment and epigenetics have a decisive impact: these are the
so-called sensitive periods when the host is particularly
IJI Bowel Disease Volume 1 Number 1 May-August 2014
susceptible to modulatory effects. The best example of a
sensitive period is life in utero, when both external and
internal influences impose changes that will affect, in a
positive or negative fashion, the future individual for the
rest of his/her life17.
The notion of sensitive period is novel in IBD, but
there is already an increased awareness that early child-
hood IBD may be different from adult IBD18. Another ex-
ample is how maternal obesity results in intestinal inflam-
mation and fibrosis in the offspring13. This is a possible
example of conditioning of IBD during fetal development
through maternal epigenetic influences.
INTEGRATING ALL FACTORS RELEVANT TO
INFLAMMATORY BOWEL DISEASE PATHOGENESIS
TO DEVELOP NEW THERAPIES
Interactomics is the system utilized to understand
how and whether health or disease will result from the
complex integration of all factors relevant to any particular
disease process19. This notion must also be applied to IBD,
but for the time being we need to limit the number of
factors relevant to its pathogenesis as we recognize them
now. We need to learn how to integrate IBD-specific infor-
mation, and perhaps compare it to data from other chron-
ic immune-mediated conditions, to develop new therapeu-
tic approaches. We are nowhere near to this situation, but
at least there is a rapidly expanding awareness that chron-
ic inflammatory diseases like IBD, already defined as com-
plex diseases, are actually more intricate than believed
even less than a decade ago. This newly appreciated com-
plexity is such that no single approach will ever find a
solution for IBD, and broad-scale programmatic and com-
bined approaches are needed. Attempts to develop such
approaches are underway, as indicated by the reports of the
European Science Foundation Forward Look for GXE In-
teractions in Chronic Diseases20, and the recommendations
from a workshop sponsored by the U.S. National Institutes
of Health on GXE Interplay in Common Complex Diseas-
es21. Practical implementations will be slow in coming, but
investigators and clinicians devoted to IBD must at least
Claudio Fiocchi: The Future of Inflammatory Bowel Disease: Integrating Knowledge to Advance Understanding and Reach a Cure
start familiarizing themselves with the reality of the situ-
ation and integrate information accumulating from differ-
ent pathogenic components to solve the IBD puzzle.
REFERENCES
1. Xavier RJ, Podolsky D. Unraveling the pathogenesis of inflammatory bowel
disease. Nature. 2007;448:427-34.
2. Thompson AI, Lees CW. Genetics of ulcerative colitis. Inflamm Bowel Dis.
2011;17:831-48.
3. Zuk O, Hechter E, Sunyaev SR, Lander ES. The mystery of missing heritability:
Genetic interactions create phantom heritability. Proc Natl Acad Sci USA.
2012;109:1193-8.
4. Achkar JP, Fiocchi C. Gene-gene interactions in inflammatory bowel disease:
biological and clinical implications. Am J Gastroenterol. 2009;104:1734-6.
5. Plantinga TS, Crisan TO, Oosting M, et al. Crohns disease-associated ATG16L1
polymorphism modulates proinflammatory cytokine responses selectively upon
activation of NOD2. Gut. 2011;60:1229-35.
6. Achkar JP, Klei L, Bakker PI, et al. Amino acid position 11 of HLA-DRbeta1 is
a major determinant of chromosome 6p association with ulcerative colitis.
Genes Immun. 2012;13:245-52.
7. Ley RE, Peterson DA, Gordon JI. Ecological and evolutionary forces shaping
microbial diversity in the human intestine. Cell. 2006;124:837-48.
8. Dominguez-Bello MG, Blaser MJ, Ley RE, Knight R. Development of the human
gastrointestinal microbiota and insights from high-throughput sequencing. Gas-
troenterology. 2011;140:1713-19.
9. Hviid A, Svanstrom H, Frisch M. Antibiotic use and inflammatory bowel dis-
eases in childhood. Gut. 2011;60:49-54.
10. De Filippo C, Cavalieri D, Di Paola M, et al. Impact of diet in shaping gut mi-
crobiota revealed by a comparative study in children from Europe and rural
Africa. Proc Natl Acad Sci USA. 2010;107:14691-6.
11. Walker AW, Ince J, Duncan SH, et al. Dominant and diet-responsive groups of
bacteria within the human colonic microbiota. ISME J. 2011;5:220-30.
12. Wu GD, Chen J, Hoffmann C, et al. Linking long-term dietary patterns with gut
microbial enterotypes. Science. 2011;334:105-8.
13. Yan X, Huang Y, Wang H, et al. Maternal obesity induces sustained inflamma-
tion in both fetal and offspring large intestine of sheep. Inflamm Bowel Dis.
2011l;17:1513-22.
14. Denison MS, Nagy SR. Activation of the aryl hydrocarbon receptor by structur-
ally diverse exogenous and endogenous chemicals. Annu Rev Pharmacol.
2003;43:309-34.
15. Monteleone I, Rizzo A, Sarra M, et al. Aryl hydrocarbon receptor-induced signals
up-regulate IL-22 production and inhibit inflammation in the gastrointestinal
tract. Gastroenterology. 2011;141:237-48.
16. Feil R, Fraga MF. Epigenetics and the environment: emerging patterns and
implications. Nat Rev Genet. 2011;13:97-109.
17. Bateson P. The return of the whole organism. J Biosci. 2005;30:31-9.
18. Kugathasan S, Cohen S. Searching for new clues in inflammatory bowel dis-
ease: tell tales from pediatric IBD natural history studies. Gastroenterology.
2008;135:1038-41.
19. Lee S, Brown A, Pitt WR, et al. Structural interactomics: informatics approach-
es to aid the interpretation of genetic variation and the development of novel
therapeutics. Mol Biosyst. 2009;5:1456-72.
20. Renz H, Autenrieth IB, Brandtzaeg P, et al. Gene-environment interaction in
chronic disease: a European Science Foundation Forward Look. J Allergy Clin
Immunol. 2011;128(Suppl):S27-49.
21. Bookman EB, McAllister K, Gillanders E, et al. Gene-environment interplay in
common complex diseases: forging an integrative model-recommendations from
an NIH workshop. Genet Epidemiol. 2011. [Epub ahead of print].
47
IJI Bowel Disease Volume 1 Number 1 May-August 2014
Commented Article
Comment: Sender J. Miszputen
Tacrolimus Salvage in Anti-Tumor Necrosis Factor
Antibody Treatment-Refractory Crohns Disease
Gerich ME, Pardi DS, Bruinig DH, Kammer PP, Becker BD, Tremaine WT. Inflamm Bowel Dis. 2013;19:1107-11
Primary nonresponse to anti-TNF agents is not un-
common and among those who respond, at least one-third
fails to maintain a long-term response1.
Material and methods
This retrospective observational study analyzed 17 fe-
male and seven male symptomatic Crohns disease pa-
tients, unresponsive or intolerant of at least one anti-TNF
agent, and treated with tacrolimus. All patients had clin-
ically active disease and, after meeting inclusion criteria,
received doses of this calcineurin inhibitor of between 0.1
and 0.2 mg/kg/day, adjusted according to trough level,
response, and side effects.
Most patients (75%) had ileocolonic disease, and
21% had upper gastrointestinal involvement. Median dis-
ease duration was 9.5 years and 63% of patients had
perianal penetrating lesions. Nearly all the patients
(96%) had failed thiopurine monotherapy and 46% to
methotrexate. All but one had failed to previous treat-
ment with infliximab (intolerant or unresponsive) and
five with adalimumab.
Response was defined as improvement after at least
seven days of treatment of one or more of the following:
bowel movement frequency, fistula output, rectal bleeding,
abdominal pain, extraintestinal manifestations, or overall
well-being. Remission required all of the following: fewer
than three stools/day, no bleeding, no abdominal pain, no
extraintestinal manifestations, increased well-being, and
no ongoing use of steroids. Loss of response was defined
Professor Associado de Gastroenterologia e Chefe do Setor de Intestino Departamento de Medicina, Escola Paulista de Medicina, Universidade Federal de So Paulo,
So Paulo SP, Brasil
Correspondence to: Sender J. Miszputen, Setor de Intestino Departamento de Medicina, Escola Paulista de Medicina, Universidade Federal de So Paulo,
So Paulo SP, Brasil. E-mail: sender.miszputen@unifesp.br
48
as any reason for discontinuation of tacrolimus (included
worsening of symptoms), necessary addition of steroids,
or surgery.
Results
Sixteen patients (67%) were considered as respond-
ers and steroid-free observed in 21%, over a median treat-
ment of 3.8 months. The response rates were similar
between penetrating (n = 12) and non-penetrating dis-
ease (n = 12) and this result identified that tacrolimus
has equivalent efficacy regardless of disease behavior.
The median time to response was 21 days, being the same
for both groups, with a median duration of response of
3.7 months. In five responders the treatment was inter-
rupted because of adverse effects2 (both had acute kidney
injury), insufficient response2 and loss of insurance1. At
least one adverse reaction was observed in 18 patients
(75%) during tacrolimus treatment, requiring dose re-
duction in eight and discontinuation of the drug in six
of them. Acute kidney injury and paresthesia were the
main reasons.
Five patients achieved remission, with a median du-
ration of 3.8 months. One of them was maintained on
methotrexate and one on azathioprine monotherapy. The
third received a combination of azathioprine and tacroli-
mus, but had recurrence of the disease after stopping the
calcineurin inhibitor due to tremor. The fourth was in
clinical remission within four months of treatment, and
the fifth maintained remission for more than 2.5 years
with tacrolimus monotherapy, but recurred after dose re-
duction.
Discussion
Previous studies referred to the efficacy of tacrolimus
for Crohns disease treatment 2-4. A systematic review of
tacrolimus studies reported response and remission rates
in Crohns disease patients of 37 and 44% respectively5.
In this uncontrolled cohort, response occurred within ap-
proximately three weeks and remission in a median of two
months. Only one-third had dose reduction due to adverse
effects and only one-fourth tacrolimus discontinuation. In
part of the patients immunomodulatory monotherapy was
possible and remission maintained after stopping tacroli-
mus. This study provides evidence that this drug shows
its efficacy in some patients with Crohns disease without
response or intolerance to biologic treatment, including
postponed surgery.
Comments
Cyclosporine and tacrolimus are drugs commonly
used in emergency situations in hospitalized patients
Sender J. Miszputen: Tacrolimus Salvage in Anti-Tumor Necrosis Factor Antibody Treatment-Refractory Crohns Disease
with complications of inflammatory bowel disease (severe
forms of inflammatory activity, toxic megacolon etc.)
without initial response to steroids and anti-TNF prod-
ucts. A second alternative relates their possible action as
an anti-inflammatory maintenance drug. In this study,
the combination of tacrolimus with immunomodulatory
agent monotherapy allowed removal of the calcineurin
inhibitor in patients that achieved remission. In summa-
ry, the use of tacrolimus seems to be effective in patients
with severe Crohn disease refractory to steroids and an-
ti-TNF therapy. Postponing surgery in the acute phase
and perhaps avoiding future surgery in a significant num-
ber of these patients are recommendations for attempting
this treatment.
REFERENCES
1. Hanauer SB, Feagan BG, Lichtenstein GR, et al. Maintenance infliximab for
Crohns disease: the ACCENT I randomized trial. Lancet. 2002;359:1541-9.
2. Baumgart DC, Pintoffl JP, Sturm A, et al. Tacrolimus is safe and effective in
patients with severe steroid-refractory or steroid-dependent inflammatory bow-
el disease--a long-term follow-up. Am J Gastroenterol. 2006;101:1048-56.
3. Satsangi J, Silverberg MS, Vermeire S, et al. The Montreal classification of in-
flammatory bowel disease: controversies, consensus, and implications. Gut.
2006;55:749-53.
4. Tamaki H, Nakase H, Matsuura M, et al. The effect of tacrolimus (FK-506) on
Japanese patients with refractory Crohns disease. J Gastroenterol. 2008;43:774-9.
5. McSharry K, Dalzell AM, Leiper K, et al. Systematic review: the role of tacroli-
mus in the management of Crohns disease. Aliment Pharmacol Ther. 2011;34:
1282-94.
49
IJI Bowel Disease Volume 1 Number 1 May-August 2014

Brief Reports
The Anti-Inflammatory Potential of Phenolic Compounds in
Grape Juice Concentrate (G8000tm) on 2,4,6-Trinitrobenzene
Sulfonic Acid-Induced Colitis
Ana Paula Ribeiro Paiotti1, Ricardo Artigiani Neto1, Patrcia Marchi1, Roseane Mendes Silva2, Vanessa Lima Pazine2, Juliana Noguti1,
Mauricio Mercaldi Pastrelo3, Andra Pittelli Boiago Gollcke4, Sender Jankiel Miszputen2 and Daniel Araki Ribeiro1,3

Background grape juice on 2,4,6-trinitrobenzene sulfonic acid-in-

Chronic inflammatory bowel disease, mainly ulcerative
colitis and Crohns disease, is a naturally remitting and recur-
ring condition of the digestive tract. Although its precise
etiology is unknown, it is probably related to an abnormal
exacerbated immune response to otherwise innocuous stim-
uli, which is not properly abrogated by the feedback system
that normally downregulates the mucosal response to luminal
factors. As in other inflammatory processes, inflammatory
bowel disease is characterized by an upregulation of the syn-
thesis and release of a variety of proinflammatory mediators,
such as eicosanoids, platelet-activating factor, reactive oxygen,
and nitrogen metabolites and cytokines, thus influencing mu-
cosal integrity and leading to excessive tissue injury.
Flavonoids are able to inhibit enzymes and/or, due to
their antioxidant properties, regulate the immune re-
sponse. Grapes and their derived products are considered
major sources of phenolic compounds, categorized as fla-
vonoids and non-flavonoids. The first group comprises
catechins, epicatechins, epigallocatechin, kaempferol,
quercetin, myricetin, and anthocyanins among others. The
second group includes phenolic acids, hydroxybenzoic and
hydroxycinnamic acids, and stilbenes, the subgroup that
contains the resveratrol molecule. This phytoalexin is syn-
thesized in the skin of the fruit as a response to stress
caused by fungal attack (Botrytis cinerea and Plasmopara
viticola), mechanical damage, or UV light irradiation.
Material and methods
The goal of the present study was to evaluate the
mechanisms of action of phenolic compounds present in
duced colitis. A total of forty-one male Wistar rats
were randomized into seven groups: negative control
group; 2,4,6-trinitrobenzene sulfonic acid non-treated
induced colitis; 2% grape juice control group; 1% grape
juice 24 hours after 2,4,6-trinitrobenzene sulfonic acid
colitis induction; 1% grape juice on day 7 after colitis
induction; 2% grape juice 24 hours after colitis induction;
2% grape juice on day 7 after colitis induction. The ani-
mals were given grape juice (G8000TM), supplied by
Golden Sucos, in their drinking water. All rats were
killed on day 16 following the experiment.
Results
The 1% grape juice-treated induced colitis group
showed marked clinical improvement when compared
with the 2,4,6-trinitrobenzene sulfonic acid-induced coli-
tis group. Rats that received 1% grape juice on day 7 after
colitis induction presented reduced intensity of macro-
scopic and histological scores. Statistically significant dif-
ferences (p < 0.05) of tumor necrosis factor-alpha and
inducible nitric oxide synthase mRNA expression were
detected in the groups treated with grape juice at the 1%
dose after inducing experimental colitis when compared
with the 2,4,6-trinitrobenzene sulfonic acid group.
Conclusion
Grape juice reduced the noxious effects induced by
colitis caused by 2,4,6-trinitrobenzene sulfonic acid, espe-
cially at the 1% dose.

1Department of Pathology, Universidade Federal de So Paulo, Escola Paulista de Medicina UNIFESP, So Paulo, Brazil; 2Division of Gastroenterology, Universidade Federal

de So Paulo, Escola Paulista de Medicina UNIFESP, So Paulo, Brazil; 3Department of Biosciences, Universidade Federal de So Paulo, Escola Paulista de Medicina
UNIFESP, So Paulo, Brazil; 4Food and Nutrition Department, Food Engineering Faculty, Universidade de Campinas UNICAMP, Campinas, So Paulo, Brazil
Correspondence to: Ana Paula Ribeiro Paiotti, Rua Costa Barros, 2050, BL 03 Apto. 1805, CEP 03210-00, So Paulo SP, Brasil. E-mail: anapribeiro@ig.com.br

50
IJI Bowel Disease Volume 1 Number 1 May-August 2014

Brief Reports
Concentrated Grape Juice (G8000) Reduces
Immunoexpression of Inducible Nitric Oxide Synthase,
Tumor Necrosis Factor-Alpha, COX-2 and DNA damage
on 2,4,6-Trinitrobenzene Sulfonic Acid-Induced Colitis
Patricia Marchi, Daniel Araki Ribeiro, Ana Paula Ribeiro Paiotti, Ricardo Artigiani Neto and Celina Tizuco Fujiiyama Oshima

Background
The aim of this research was to evaluate the phenolic
compounds present in grape juice regarding the reduction
of the harmful effects induced by the experimental colitis.
Material and methods
A total of 42 Wistar rats were distributed randomly in
seven groups: G1 group Sham: saline solution control; G2
2,4,6-trinitrobenzene sulfonic acid/ethanol: control
2,4,6-trinitrobenzene sulfonic acid (50 mg/kg); G3 2%
grape juice control; G4 2,4,6-trinitrobenzene sulfonic
acid/ethanol treated with 1% grape juice 24 hours after coli-
tis induction; G5 2,4,6-trinitrobenzene sulfonic acid/etha-
nol treated with 1% grape juice from day 7 after colitis in-
duction; G6 2,4,6-trinitrobenzene sulfonic acid/ethanol
treated with 2% grape juice 24 hours after colitis induction;
G7 2,4,6-trinitrobenzene sulfonic acid/ethanol treated with
2% grape juice from day 7 after colitis induction. All animals
were euthanized 16 days after the start of the experiment.
Results
The immunoexpression of tumor necrosis factor-al-
pha and inducible nitric oxide synthase was lower after
the treatment with concentrated grape juice (G8000)
24 hours or seven days after colitis induction in all treat-
ed doses used. The immunoexpression of COX-2 was low-
er in all groups treated with 1% grape juice. The 1% grape
juice (G8000) in the last seven days of treatment, as well
as 2% grape juice, reduced the genotoxicity in the periph-
eral blood.
Conclusion
Concentrated grape juice (G8000), mainly the 1%
dose, exerted anti-inflammatory effects in the chronic
colitis caused by 2,4,6-trinitrobenzene sulfonic acid as a
result of modulation in the expression of proinflammato-
ry cytokines, and, in addition, reduced the genotoxicity in
cell of the peripheral blood.

Department of Pathology, Universidade Federal de So Paulo, Escola Paulista de Medicina UNIFESP, So Paulo, Brazil
Correspondence to: Patricia Marchi, Universidade Federal de Medicina de So Paulo UNIFESP Departamento de Gastroenterologia Rua Sena Madureira, 1500, 5. andar,
CEP 04021-001, So Paulo SP. Brasil. E-mail: patimarchi@hotmail.com

51
IJI Bowel Disease Volume 1 Number 1 May-August 2014

Brief Reports
Quantitative Assessment of CD30-PositiveLymphocytes
and Eosinophils for the Histopathologic Diagnosis
of Inflammatory Bowel Disease
Cristina Flores, Carlos Fernando de Magalhes Francesconi and Lude Meurer

Objective 78.3% and a specificity of 71% for the diagnosis of ul-

To quantitate CD30+lymphocytes and eosinophils in
biopsies for the histopathologic discrimination of Crohns
disease and ulcerative colitis.
Design
185 patients were diagnosed with inflammatory bow-
el disease by a gastroenterologist and corroborated by five
years of follow-up. Patients were treatment-naive at the
time of biopsy. Samples were taken from diseased areas of
the colon and examined by an experienced gastrointesti-
nal pathologist.
Results
The median number of eosinophils in biopsies taken
from affected segments was 42(25.5-63.5) in Crohns dis-
ease and 107 (67-123) in ulcerative colitis (p < 0.001).
Biopsies containing 70 eosinophils had a sensitivity of
cerative colitis (area under the ROC curve 0.767; 95%
CI: 0.696-0.838). A median ofthree cells (range 2-6) was
found in diseased Crohns disease biopsies and 33 CD30+
cells (range 24-52) in diseased ulcerative colitis biopsies
(p < 0.001).The cutoff determined by the ROC curve was
15 (sensitivity 97.5%, specificity 94.3%, PLR 17.1, NLR 0.03,
AUC: 0.967; 95% CI: 0.941-0.993). After a value was as-
signed to each variable based on their contribution to the
diagnosis, a histopathologic score out of ten was devised
for the diagnosis of Crohns disease. When the score was
5, the specificity was 100% and the sensitivity 86.8%.
Conclusion
Routine histopathologic assessment, along with
quantification of CD30+ cells, is highly accurate for
discriminating between Crohns disease and ulcerative
colitis. All the measured parameters are easy to perform,
low-cost, and available in most pathological laboratories.

Department of Gastroenterology and Pathology, Universidade Federal do Rio Grande do Sul, Faculdade de Medicina and Hospital de Clnicas de Porto Alegre, Porto Alegre RS, Brazil
Correspondence to: Av. Cristovo Calombo, 2424 Apto. 111, Floresta CEP:90560-002, Porto Alegre RS, Brasil. E-mail: cfloresgastro@gmail.com

52
IJI Bowel Disease Volume 1 Number 1 May-August 2014

Case Report
Tuberculosis and Biological Therapy
Marjorie Argollo, Orlando Ambrogini Junior and Sender J. Miszputen

XXXXX
Correspondence to: Marjorie Argollo, Rua Sampaio Viana, 425, Apto. 18 Paraiso, CEP 04004-001, So Paulo SP. Brasil. E-mail: marjorieargollo@hotmail.com

53
IJI Bowel Disease Volume 1 Number 1 May-August 2014

54
IJI Bowel Disease Volume 1 Number 1 May-August 2014
Case Report
Clinical Case with Commented Image
Eloa Marussi Morsoletto
Recent studies describe the importance of the muco-
sa healing after an endoscopy as a key parameter in man-
agement and prognosis of intestinal inflammatory diseas-
es (IID). This fact reinforces the role of endoscopy in
monitoring inflammatory activity in IID, because this
method allows for a direct evaluation of the extension and
severity of the lesions to the mucosa.
The structural basis of the mucosa healing would
be an intact barrier of the intestinal epithelium imped-
ing the movement of commensal bacteria in the mucosa
and sub-mucosa which would activate the immune cells
subsequently. Therefore, the healing of the mucosa must
be considered as a first happening in the suppression of
the inflammation in the deeper layers of the intestine
walls1.
In patients with active IID, the endoscopy my help
select those who really need to receive a more active and
aggressive therapy at an earlier stage for two reasons:
firstly, because severe lesions after an endoscopy may an-
ticipate a bad result with an increase in the risk of colec-
tomy and other complications. Secondly, patients who do
not have lesions after an endoscopy will not benefit from
more aggressive therapy, which carries potential risks.
Therefore, endoscopic evaluation may help to charac-
terize the response to treatment and guide strategic deci-
sions in the management of IID2.
Service of Digestive Endoscopy Saint Vincent Hospital; Curitiba PR, Brazil
Correspondence to: Eloa Marussi Morsoletto, Rua Veronica Szeremeta, 22, So Braz, CEP 82320-410, Curitiba PR. Brasil. E-mail: marmor@onda.com.br
The clinical relevance of the healing of the mucosa in
patients with IID was initially pointed out when it was
proven that therapy with Azathioprine promoted the heal-
ing of the mucosa in patients with Crohns disease3.
At the time there was no clear correlation between
the healing of the mucosa and recidivism rates, so an
approach focused on improving the symptoms arising
from Crohns disease was the mainstream therapy in the
1990s. This point of view changed drastically as a result
of studies using biological therapy (antibody anti-TNF), in
which the induction the healing of the mucosa was quite
remarkable.
CASE REPORT
Female patient, 37 years of age, elementary school
teacher, born and raised in the countryside of the state of
Paran, Brasil. Six-year history with episodes of bloody
evacuations.
There were no laboratory tests, but there was only one
colonoscopy performed in her hometown, with a diagnosis
for ulcerative colitis (with no images).
She had been using 2.4 g/day of mesalazine on a
continuous basis and 20 mg/day of prednisone sporadi-
cally, when there was a worsening in the diarrhea epi-
sodes.
55
Clinical test
Moon face (Cushings syndrome). Wet and reddish
mucosa. Weight: 60 kg. Height: 1.68 m. Vital signs:
normal
A bdomen: with mild distention, diffusely painful to
deep hand pressing. No masses or visceromegaly
were found. Normal abdominal sounds (bowel
sounds).
Other aspects of the clinical test were normal.
Laboratory tests
Hemoglobin: 12.70. Hematocrit: 38.50. Plaques: 328,000.
ASCA: 13.6. ANCA: non-reactive.
PCR: 24 mg/l; reference value < 6. VHS: 81 mm/h; ref-
erence value < 20 mm.
Parasitology stool test (3 samples): negative.
Colonoscopy performed
Numerous ulcerative lesions, some quite deep, con-
fluent, entangled with a congested edematous mucosa, in
the descending colon, the sigmoid and rectum.
Terminal ileum mucosa, transverse colon, and as-
cending colon with no endoscopic alterations.
AP: [N.T. from greekap: based on the foregoing] Chron-
ic inflammatory process, without granulomas, but sugges-
tive of Crohns disease (Fig. 1)
A prednisone 40 mg/day plus mesalazine 4.0 g/day
plus azathioprine 150 mg/day combination was started.
After 1 1/2 months, prednisone was phased out complete-
ly. After 4 months of evolution, there was an absolute
clinical improvement and laboratory tests (hemogram,
VHS, PCR, liver function, pancreas function, and kidney
function) were normal.
56
Mesalazine was phased out and just azathioprine
150 mg/day was kept.
Entero-tomography without alterations.
Clinical follow-ups and laboratory tests were conduct-
ed every three months.
After one year, the colonoscopy was repeated. Healing
scar areas, with several pseudo-polyps and mucosa bridg-
es were observed. There are no ulcerations, congestions
and/or friability of the mucosa (Fig. 2).
COMMENTS
This case shows that in spite of the fact that Crohns
disease has increased significantly throughout the world,
including in Brazil, there is still some carelessness in the
diagnosis and treatment of the disease.
This patient bore an incorrect diagnosis for 6 years,
receiving an insufficient dose of mesalazine and several
rounds of corticosteroids. Besides, no clinical nor labora-
tory periodical controls were conducted. After defining
the correct diagnosis as well as the extension and severity
thereof, we just introduced an immune-suppressor (aza-
thioprine 2.5 mg/kg/day) and were able to obtain an ab-
solute improvement, observed in the clinical and labora-
tory levels and even the healing of the mucosa. Therefore,
we have been able to offer the patient a better prognosis,
with better quality of life and possibly avoiding surgical
resections.
REFERENCES
1. Neurath MF, Travis SPL. Mucosal healing in inflammatory bowel disease: a
system- atic review. Gut. 2012;61:1619-35.
2. Alles M, Lmann M. Role of endoscopy in predicting the disease course in in-
flammatory bowel disease. World J Gastroenterol. 2010;16:2626-32.
3. DHaens G, Geboes K, Ponette E. Healing of severe recurrent ileitis with aza-
thioprine therapy in patients with Crohns disease. Gastroenterology. 1997;112:
1475-81.
IJI Bowel Disease Volume 1 Number 1 May-August 2014
Figure 1. Disease activity: extensive and deep ulcers, some confluent.

Figure 2. After one year of azathioprine: scar lesions with mucosalbridges and pseudo-polyps.

Eloa Marussi Morsoletto: Clinical Case with Commented Image 57

O tratamento da Doena
Inflamatria Intestinal (DII)
precisa ser, alm de ecaz,
1,2

conveniente* para o paciente.

Convenincia e eficcia:
sachs em dose nica. ** 1-3

Pentasa Sach 1x ao dia vs

5
2x ao dia em RCU leve a moderada

61% dos pacientes atingiram a

remisso clnica e endoscpica
5
com Pentasa Sach 4g 1x ao dia

Adaptado de Flouri B. et al, 20135.

*comodidade posolgica: uma vez ao dia3. **no tratamento de manuteno da Retocolite Ulcerativa (RCU)