Transcript
Tratamiento de la enfermedad de Crohn
Ylse Gutiérrez Grobe R2GE
Evolución de la enfermedad
• 50% de los pacientes tendrán alguna complicación en 20 años
• 10% remisión clínica• Incidencia anual de readmisión hospitalaria 20%• 50% requerirá cirugía a los 10 años de Dx• 55% recurrencia postoperatoria en 10 años
Objetivos
Inducir remisión
Mantenerla
Objetivos del tx
Aminorar síntomas
Mejorar la calidad de vida del paciente
Otras metas individuales:
Curación de fístulas
Niños crecimiento normal
Recomendaciones terapéuticas:
Localización de la enfermedad
Severidad de la enfermedad
Complicaciones asociadas
Defin
icion
es•CDAI <150, paciente sintomático, sin secuelas sintomáticas de la
inflamación
Remisión sintomática
•Requieren del uso de dosis convencionales de esteroides para mantener la sensación de bienestar
Dependientes de esteroides
•CDAI 150-220, pacientes ambulatorios, sin deshidratación ni datos de toxicidad sistémica, dolor, obstrucción y masas abdominales, pérdida de peso <10%
Enfermedad leve-moderada
•CDAI 220-450, no responden al tratamiento para leve-moderada, síntomas mas prominentes , náusea y vómito (sin obstrucción), anemia y pérdida significativa de peso
Enfermedad moderada a severa
•CDAI >450, síntomas a pesar de esteroides y biológicos, fiebre, vómito con evidencia de obstrucción intestinal, irritación peritoneal, caquexia, presencia de absceso
Enfermedad severa/ fulminante
El abordaje terapéutico es individualizado
Respuesta sintomática
Tolerancia a la intervención médica
Tratar enfermedad aguda
Inducción a la remisión
Mantenimiento de la remisión
Medidas generales
La duración del tratamiento para enfermedad activa se deberá continuar hasta la remisión sintomática o falla
Inicia 2-4 semanas
Mejoría máxima 12-16 semanas
Con remisión clínica considerar Tx mantenimiento
Lichtenstein G, Management of Crohn´s disease In adults. Am J Gastroenterol. 2009; 104:465-483
Síntomas
AlternativoLeve a
moderada
AvanzadoModerado a
severo
Terapia secuencial
La terapia se progresa de acuerdo a la severidad al inicio o falla al paso previo
Aminosalicilatos
Corticosteroides
Anti-TNFCiclosporina
Severidad al momento del diagnóstico
Severa
Moderada
Leve
AminosalicilatosTiopurinas
Aminosalicilatos
Anti-TNFTiopurinas
Inducción
Mantenimiento
Colectomía
Generalidades
Inducción
Sulfasalazina
Mesalazina
Esteroides
Azatioprina/6-MP
Metotrexato
Biológicos
Mantenimiento
Sulfasalazina
Mesalazina
Azatioprina/6-MP
Metotrexato
Biológicos
Tx farmacológico
5-ASA
La evidencia no es suficiente
Mesalazina 4g/d efectivo en leve a moderada
Sulfasalazina 4-6 g/día mejor para actividad colónica
Mesalazina no es superior que placebo para mantener la remisión
Mowat C, Cole A. Guidelines for the management of inflammatory bowel disease in adults. Gut 2011;60:571-607
5-ASA
Sulfasalazina 3-6 g/día
Mejor que placebo~43% tasa de remisión vs placebo 30%
No efectivo en enfermedad de ID
Mesalazina ECA 40-55% remisión
Meta-analisisMesalamine 4g/day
Estadísticamente significativo pero no clínicamente
Akobeng et al Cochrane Database of Systematic Reviews 2009
Aminosalicylates for induction of remission or response in
Crohn’sdisease (Review)
Lim WC, Hanauer S
Thisisareprint of aCochranereview, prepared and maintained byTheCochraneCollaboration and published in TheCochraneLibrary
2010, Issue12
http://www.thecochranelibrary.com
Aminosalicylatesfor induction of remission or response in Crohn’s disease (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John W iley & Sons, Ltd.
Aminosalicylates for induction of remission or response in
Crohn’s disease (Review)
Lim WC, Hanauer S
Thisisareprint of aCochranereview, prepared and maintained byTheCochraneCollaboration and published in TheCochraneLibrary
2010, Issue12
http://www.thecochranelibrary.com
Aminosalicylatesfor induction of remission or response in Crohn’s disease (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John W iley & Sons, Ltd.
Cochrane Database of Systematic Reviews 2010, Issue 12
D I S C U S S I O N
Thefocusof thisreviewwasbroad, and all information pertaining
to the efficacy of sulfasalazine or 5-ASA alone for the treatment
of mildly to moderately activeCrohn’sdiseasewhen compared to
placebo, corticosteroids, and other aminosalicylates (alone or in
combination with corticosteroids) wassought. To ensure that ef-
fect estimateswereinterpretableand clinically meaningful in this
review where trials were anticipated to be diverse with different
aminosalicylateformulations, dosages, comparatorsand outcome,
each combination wasconsidered separatelyand only resultsfrom
similar trialsweresynthesized. A random effectsmodel wasused
for pooling data as it allowed between-trial variability to be ac-
counted for in theoverall estimate, producing moreconservative
resultswith wider 95% confidenceintervals. Resultsbased on the
fixed effectsmodel and duration of therapy werealso presented in
sensitivity analysesplanned apriori and thesedid not significantly
alter theresultsobtained with therandom effectsmodel or when
trialswith different duration of treatment wereincluded.
The results showed that sulfasalazine at 3 to 6 g/day had only
modest efficacy over placebo. A pooled RR of 1.38 wasobtained,
that is, patientstreated with sulfasalazinehada38%higher chance
of achieving remission than placebo-treated patients. Thisbenefit
was limited to patients with Crohn’s colitis. Patients with small
bowel diseaseor thosewhocontinued tohaveactivediseasedespite
previouscorticosteroid and sulfasalazinetreatment werenot likely
tobenefit. Sulfasalazinewaslesseffectivethan corticosteroidswith
pooled RR of 0.66, that is, sulfasalazine-treated patientshad 34%
lesschanceof achieving remission than corticosteroid-treated pa-
tients. In addition, sulfasalazine monotherapy was less effective
than combination therapy with corticosteroids. The question of
whether sulfasalazineisauseful adjunct to corticosteroid therapy,
while not the primary focus of this review, was addressed in the
TAS (Trial of adjunctive sulfasalazine in Crohn’s disease) study
(Singleton 1979) and ECCDS: 74% (34/56) and 83% (39/47)
in thecorticosteroid group versus58% (25/43) and 79% (44/56)
in the combination group achieved remission (CDAI < 150) at
theend of 8 weeksand 18 weeksrespectively (P = 0.12 and 0.57
respectively) with a pooled RR of 1.12 (95% CI 0.94 to 1.33)
(See Figure 2), demonstrating that sulfasalazine was not a use-
ful adjunct to corticosteroid therapy. Thesedatasuggest that sul-
fasalazinemay beused asfirst linetherapy for patientswith mildly
to moderately active Crohn’s colitis, reserving the more potent
corticosteroids for patients failing sulfasalazine therapy. This is
consistent with thepharmacology of sulfasalazine, an azo-bonded
prodrug that requires colonic bacteria azo-reductases for the re-
leaseand targeted deliveryof active5-ASA moiety to thecolon. In
contrast, olsalazine, anew azo-bonded 5-ASA dimer, wasshown
to lack therapeuticeffect, with asignificant proportion developing
worseningdiarrhea(Wright 1995). Thisisacommon and unique
dose-related complication of olsalazinetherapy, aconsequenceof
increased ileal secretion and gastrointestinal transit (Rao 1987;
Wadworth 1991; Sandborn 2002a).
Figure 2.
While mesalamine has similar efficacy to sulfasalazine when
equimolar doses are used in ulcerative colitis (3 to 6 g of sul-
fasalazine isequivalent to 1.2 to 2.4 g of mesalamine), low dose
controlled-release mesalamine (Pentasa at 1 to 2 g/day) was not
moreeffectivethanplaceboat inducingremission inactiveCrohn’s
disease (Comparison 04, Outcome 02). Predictably, delayed-re-
lease mesalamine (Salofalk at 2 g/day) was less efficacious than
corticosteroids(Scholmerich 1990).
On the other hand, trials assessing higher doses of mesalamine
produced conflicting results. Thepositiveeffect of controlled-re-
lease mesalamine (Pentasa) at 4 g/day in one study (Singleton
1993) was in contrast to the lack of effect in similarly designed
trials (Singleton 1994; Crohn III 1997). Moderate heterogene-
ity and rather largeplacebo effectscould havereduced thepower
to detect astatistically significant differencebetween placebo and
18Aminosalicylatesfor induction of remission or response in Crohn’s disease (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John W iley & Sons, Ltd.
D A T A A N D A N A L Y S E S
Comparison 1. Sulfasalazineversusplacebo
Outcomeor subgroup titleNo. of
studies
No. of
participants Statistical method Effect size
1 Induction of remission (CDAI
<150), therapeutic response
(VHI decrease>=25%) or
clinical improvement
3 289 Risk Ratio (M-H, Random, 95% CI) 1.51 [0.97, 2.35]
2 Induction of remission (CDAI
<150)
2 263 Risk Ratio (M-H, Random, 95% CI) 1.38 [1.02, 1.87]
Comparison 2. Sulfasalazineversuscorticosteroids
Outcomeor subgroup titleNo. of
studies
No. of
participants Statistical method Effect size
1 Induction of remission (CDAI
<150)
2 260 Risk Ratio (M-H, Random, 95% CI) 0.66 [0.53, 0.81]
Comparison 3. Sulfasalazineversussulfasalazineand corticosteroids
Outcomeor subgroup titleNo. of
studies
No. of
participants Statistical method Effect size
1 Induction of remission 1 110 Risk Ratio (M-H, Random, 95% CI) 0.64 [0.47, 0.86]
Comparison 4. Controlled-releasemesalamine(1-2 g/day) versusplacebo
Outcomeor subgroup titleNo. of
studies
No. of
participants Statistical method Effect size
1 Decrease in CDAI >=50, HBI
>=2 or improvement/remission
(asdefined by Tvedeet al)
3 342 Risk Ratio (M-H, Random, 95% CI) 1.07 [0.80, 1.42]
1.1 1 g/day 1 120 Risk Ratio (M-H, Random, 95% CI) 0.91 [0.56, 1.46]
1.2 1.5 g/day 2 107 Risk Ratio (M-H, Random, 95% CI) 1.47 [0.87, 2.49]
1.3 2 g/day 1 115 Risk Ratio (M-H, Random, 95% CI) 0.97 [0.60, 1.55]
43Aminosalicylatesfor induction of remission or response in Crohn’s disease (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John W iley & Sons, Ltd.
D A T A A N D A N A L Y S E S
Comparison 1. Sulfasalazineversusplacebo
Outcomeor subgroup titleNo. of
studies
No. of
participants Statistical method Effect size
1 Induction of remission (CDAI
<150), therapeutic response
(VHI decrease >=25%) or
clinical improvement
3 289 Risk Ratio (M-H, Random, 95% CI) 1.51 [0.97, 2.35]
2 Induction of remission (CDAI
<150)
2 263 Risk Ratio (M-H, Random, 95% CI) 1.38 [1.02, 1.87]
Comparison 2. Sulfasalazineversuscorticosteroids
Outcomeor subgroup titleNo. of
studies
No. of
participants Statistical method Effect size
1 Induction of remission (CDAI
<150)
2 260 Risk Ratio (M-H, Random, 95% CI) 0.66 [0.53, 0.81]
Comparison 3. Sulfasalazineversussulfasalazineand corticosteroids
Outcomeor subgroup titleNo. of
studies
No. of
participants Statistical method Effect size
1 Induction of remission 1 110 Risk Ratio (M-H, Random, 95% CI) 0.64 [0.47, 0.86]
Comparison 4. Controlled-release mesalamine(1-2 g/day) versusplacebo
Outcomeor subgroup titleNo. of
studies
No. of
participants Statistical method Effect size
1 Decrease in CDAI >=50, HBI
>=2 or improvement/remission
(asdefined by Tvedeet al)
3 342 Risk Ratio (M-H, Random, 95% CI) 1.07 [0.80, 1.42]
1.1 1 g/day 1 120 Risk Ratio (M-H, Random, 95% CI) 0.91 [0.56, 1.46]
1.2 1.5 g/day 2 107 Risk Ratio (M-H, Random, 95% CI) 1.47 [0.87, 2.49]
1.3 2 g/day 1 115 Risk Ratio (M-H, Random, 95% CI) 0.97 [0.60, 1.55]
43Aminosalicylatesfor induction of remission or response in Crohn’s disease (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John W iley & Sons, Ltd.
5-ASA efectos adversos
Sulfasalazina Cefalea
Náusea/vómito
Rash
Malabsorción de folatos
Oligospermia reversible
Pancreatitis
Supresión de la médulaósea
Exacerbación paradójica
Nefritis intersticial
Mesalazina
Cefalea
Náusea
Rash
Pancreatitis
Exacerbación paradójica
Nefritis intersticial
Esteroides
Eficacia superior a placebo, antibióticos y mesalazina
Inhiben la activación de Linf T y la producción de citocinas proinflamatorias
Munkholm et al 36% dependientes; 20% resistentes a 1 años
Mowat C, Cole A. Guidelines for the management of inflammatory bowel disease in adults. Gut 2011;60:571-607
Esteroides
Remisión sintomática pero no curación de la mucosa
La mayoría no mantienen remisión a un año después del primer ciclo de esteroide
36% dependientes, 20% resistentes
Prednisona 40 mg a dosis de reducción a 8 semanas
Budesonida9mg/día
Mowat C, Cole A. Guidelines for the management of inflammatory bowel disease in adults. Gut 2011;60:571-607
No mantenimiento de la remisión
Traditional corticosteroids for induction of remission in
Crohn’sdisease (Review)
Benchimol EI, Seow CH, Steinhart AH, GriffithsAM
Thisisareprint of aCochranereview, prepared and maintained byTheCochraneCollaboration and published in TheCochraneLibrary
2010, Issue4
http://www.thecochranelibrary.com
Traditional corticosteroidsfor induction of remission in Crohn’sdisease (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John W iley & Sons, Ltd.
Traditional corticosteroids for induction of remission in
Crohn’s disease (Review)
Benchimol EI, Seow CH, Steinhart AH, GriffithsAM
Thisisareprint of aCochranereview, prepared and maintained by TheCochraneCollaboration and published in TheCochraneLibrary
2010, Issue4
http://www.thecochranelibrary.com
Traditional corticosteroidsfor induction of remission in Crohn’s disease (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John W iley & Sons, Ltd.
D A T A A N D A N A L Y S E S
Comparison 1. Corticosteroidsvs. placebo
Outcomeor subgroup titleNo. of
studies
No. of
participants Statistical method Effect size
1 Remission rate(Late, 15+ weeks) 2 267 Risk Ratio (M-H, Fixed, 95% CI) 1.99 [1.51, 2.64]
2 Development of Any Adverse
Event
1 Risk Ratio (M-H, Fixed, 95% CI) Totalsnot selected
3 Withdrawal From Study DueTo
AdverseEvent
2 267 Risk Ratio (M-H, Fixed, 95% CI) 4.57 [0.75, 27.83]
4 Responseto Treatment 1 Risk Ratio (M-H, Fixed, 95% CI) Totalsnot selected
Comparison 2. Corticosteroidsvs. 5-ASA
Outcomeor subgroup titleNo. of
studies
No. of
participants Statistical method Effect size
1 Remission Rate (Late, 15+
weeks) (Max Pred 60 mg/day +
5-ASA 1.2-2 g/day)
3 322 Risk Ratio (M-H, Fixed, 95% CI) 1.65 [1.33, 2.03]
2 Remission Rate (Late, 15+
weeks) (Sensitivity Analysis-
Sulfasalazinestudiesonly)
2 260 Risk Ratio (M-H, Fixed, 95% CI) 1.53 [1.23, 1.91]
3 Development of Any Adverse
Event
5 396 Risk Ratio (M-H, Random, 95% CI) 3.13 [0.99, 9.90]
4 Development of Any Adverse
Event (Sensitivity Analysis-
Removed high-dose 5-ASA
studies)
2 221 Risk Ratio (M-H, Fixed, 95% CI) 2.38 [1.34, 4.25]
5 Withdrawal from Study Dueto
AdverseEvent
6 478 Risk Ratio (M-H, Fixed, 95% CI) 1.18 [0.61, 2.29]
6 Responseto Treatment 2 Risk Ratio (M-H, Fixed, 95% CI) Totalsnot selected
22Traditional corticosteroidsfor induction of remission in Crohn’s disease (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John W iley & Sons, Ltd.
Analysis 1.1. Comparison 1 Corticosteroids vs. placebo, Outcome 1 Remission rate (Late, 15+ weeks).
Review: Traditional corticosteroids for induction of remission in Crohn’sdisease
Comparison: 1 Corticosteroidsvs. placebo
Outcome: 1 Remission rate (Late, 15+ weeks)
Study or subgroup Corticosteroids Placebo Risk Ratio Weight Risk Ratio
n/N n/N M-H,Fixed,95%CI M-H,Fixed,95%CI
Malchow 1984 39/47 22/58 48.4 % 2.19 [ 1.54, 3.12 ]
Summers 1979 40/85 20/77 51.6 % 1.81 [ 1.17, 2.81 ]
Total (95% CI) 132 135 100.0 % 1.99 [ 1.51, 2.64 ]
Total events: 79 (Corticosteroids), 42 (Placebo)
Heterogeneity: Chi2 = 0.45, df = 1 (P= 0.50); I2 =0.0%
Test for overall effect: Z = 4.82 (P < 0.00001)
0.1 0.2 0.5 1 2 5 10
Favours placebo Favours steroids
Analysis 1.2. Comparison 1 Corticosteroids vs. placebo, Outcome 2 Development of Any Adverse Event.
Review: Traditional corticosteroids for induction of remission in Crohn’sdisease
Comparison: 1 Corticosteroidsvs. placebo
Outcome: 2 Development of Any Adverse Event
Study or subgroup Corticosteroids Placebo Risk Ratio Risk Ratio
n/N n/N M-H,Fixed,95%CI M-H,Fixed,95%CI
Summers 1979 27/85 5/77 4.89 [ 1.98, 12.07 ]
0.01 0.1 1 10 100
Placebo Events Steroid Events
23Traditional corticosteroidsfor induction of remission in Crohn’s disease (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John W iley & Sons, Ltd.
Analysis 2.1. Comparison 2 Corticosteroids vs. 5-ASA, Outcome 1 Remission Rate (Late, 15+ weeks) (Max
Pred 60 mg/day + 5-ASA 1.2-2 g/day).
Review: Traditional corticosteroids for induction of remission in Crohn’sdisease
Comparison: 2 Corticosteroidsvs. 5-ASA
Outcome: 1 Remission Rate (Late, 15+ weeks) (Max Pred 60 mg/day + 5-ASA 1.2-2 g/day)
Study or subgroup Corticosteroids 5-ASA Risk Ratio Weight Risk Ratio
n/N n/N M-H,Fixed,95%CI M-H,Fixed,95%CI
Malchow 1984 39/47 27/54 37.8 % 1.66 [ 1.23, 2.23 ]
Scholmerich 1990 21/32 8/30 12.4 % 2.46 [ 1.29, 4.69 ]
Summers 1979 51/85 31/74 49.8 % 1.43 [ 1.04, 1.97 ]
Total (95% CI) 164 158 100.0 % 1.65 [ 1.33, 2.03 ]
Total events: 111 (Corticosteroids), 66 (5-ASA)
Heterogeneity: Chi2 = 2.23, df = 2 (P= 0.33); I2 =10%
Test for overall effect: Z = 4.64 (P < 0.00001)
0.1 0.2 0.5 1 2 5 10
Favours 5-ASA Favours steroids
Analysis 2.2. Comparison 2 Corticosteroids vs. 5-ASA, Outcome 2 Remission Rate (Late, 15+ weeks)
(Sensitivity Analysis - Sulfasalazine studies only).
Review: Traditional corticosteroids for induction of remission in Crohn’sdisease
Comparison: 2 Corticosteroidsvs. 5-ASA
Outcome: 2 Remission Rate (Late, 15+ weeks) (Sensitivity Analysis - Sulfasalazine studiesonly)
Study or subgroup Corticosteroids Sulfasalazine Risk Ratio Weight Risk Ratio
n/N n/N M-H,Fixed,95%CI M-H,Fixed,95%CI
Malchow 1984 39/47 27/54 43.1 % 1.66 [ 1.23, 2.23 ]
Summers 1979 51/85 31/74 56.9 % 1.43 [ 1.04, 1.97 ]
Total (95% CI) 132 128 100.0 % 1.53 [ 1.23, 1.91 ]
Total events: 90 (Corticosteroids), 58 (Sulfasalazine)
Heterogeneity: Chi2 = 0.45, df = 1 (P= 0.50); I2 =0.0%
Test for overall effect: Z = 3.78 (P = 0.00016)
0.1 0.2 0.5 1 2 5 10
Favours sulfasalazin Favours steroids
25Traditional corticosteroidsfor induction of remission in Crohn’s disease (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John W iley & Sons, Ltd.
Budesonide for maintenance of remission in Crohn’sdisease
(Review)
Benchimol EI, Seow CH, Otley AR, Steinhart AH
Thisisareprint of aCochranereview, preparedand maintained byTheCochraneCollaboration and published in TheCochraneLibrary
2009, Issue1
http://www.thecochranelibrary.com
Budesonide for maintenance of remission in Crohn’sdisease (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John W iley & Sons, Ltd.
Traditional corticosteroids for induction of remission in
Crohn’s disease (Review)
Benchimol EI, Seow CH, Steinhart AH, GriffithsAM
Thisisareprint of aCochranereview, prepared and maintained by TheCochraneCollaboration and published in TheCochraneLibrary
2010, Issue4
http://www.thecochranelibrary.com
Traditional corticosteroidsfor induction of remission in Crohn’s disease (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John W iley & Sons, Ltd.
Analysis 4.1. Comparison 4 Budesonide 9 mg vs 6 mg, Outcome 1 Maintenance of Clinical Remission.
Review: Budesonide for maintenance of remission in Crohn’s disease
Comparison: 4 Budesonide 9 mg vs6 mg
Outcome: 1 Maintenance of Clinical Remission
Study or subgroup 9 mg 6 mg Risk Ratio Risk Ratio
n/N n/N M-H,Fixed,95%CI M-H,Fixed,95%CI
de Jong 2007 66/81 58/76 1.07 [ 0.91, 1.26 ]
0.1 0.2 0.5 1 2 5 10
Favours 6 mg Favours 9 mg
Analysis 4.2. Comparison 4 Budesonide 9 mg vs 6 mg, Outcome 2 Change in CDAI from baseline.
Review: Budesonide for maintenance of remission in Crohn’s disease
Comparison: 4 Budesonide 9 mg vs6 mg
Outcome: 2 Change in CDAI from baseline
Study or subgroup Budesonide 9 mg Budesonide 6 mgMean
DifferenceMean
Difference
N Mean(SD) N Mean(SD) IV,Fixed,95%CI IV,Fixed,95%CI
1 12 months
de Jong 2007 81 15 (72.81) 76 33 (74.5) -18.00 [ -41.06, 5.06 ]
-100 -50 0 50 100
Favours 6 mg Favours 9 mg
48Budesonide for maintenance of remission in Crohn’sdisease (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John W iley & Sons, Ltd.
Analysis 4.1. Comparison 4 Budesonide 9 mg vs 6 mg, Outcome 1 Maintenance of Clinical Remission.
Review: Budesonide for maintenance of remission in Crohn’s disease
Comparison: 4 Budesonide 9 mg vs6 mg
Outcome: 1 Maintenance of Clinical Remission
Study or subgroup 9 mg 6 mg Risk Ratio Risk Ratio
n/N n/N M-H,Fixed,95%CI M-H,Fixed,95%CI
de Jong 2007 66/81 58/76 1.07 [ 0.91, 1.26 ]
0.1 0.2 0.5 1 2 5 10
Favours 6 mg Favours 9 mg
Analysis 4.2. Comparison 4 Budesonide 9 mg vs 6 mg, Outcome 2 Change in CDAI from baseline.
Review: Budesonide for maintenance of remission in Crohn’s disease
Comparison: 4 Budesonide 9 mg vs6 mg
Outcome: 2 Change in CDAI from baseline
Study or subgroup Budesonide 9 mg Budesonide 6 mgMean
DifferenceMean
Difference
N Mean(SD) N Mean(SD) IV,Fixed,95%CI IV,Fixed,95%CI
1 12 months
de Jong 2007 81 15 (72.81) 76 33 (74.5) -18.00 [ -41.06, 5.06 ]
-100 -50 0 50 100
Favours 6 mg Favours 9 mg
48Budesonide for maintenance of remission in Crohn’sdisease (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John W iley & Sons, Ltd.
Analysis 4.5. Comparison 4 Budesonide 9 mg vs 6 mg, Outcome 5 W ithdrawals Due to Adverse Events.
Review: Budesonide for maintenance of remission in Crohn’s disease
Comparison: 4 Budesonide 9 mg vs6 mg
Outcome: 5 WithdrawalsDue to Adverse Events
Study or subgroup Budesonide 9 mg Budesonide 6 mg Risk Ratio Risk Ratio
n/N n/N M-H,Fixed,95%CI M-H,Fixed,95%CI
de Jong 2007 1/81 3/76 0.31 [ 0.03, 2.94 ]
0.01 0.1 1 10 100
6 mg withdrawals 9 mg withdrawals
Analysis 5.1. Comparison 5 Budesonide 9 mg/day vs prednisolone 40 mg/day (weaning), Outcome 1
Maintenance of Clinical Remission.
Review: Budesonide for maintenance of remission in Crohn’s disease
Comparison: 5 Budesonide 9 mg/day vsprednisolone 40 mg/day (weaning)
Outcome: 1 Maintenance of Clinical Remission
Study or subgroup Budesonide Prednisolone Risk Ratio Risk Ratio
n/N n/N M-H,Fixed,95%CI M-H,Fixed,95%CI
1 3 months
Schoon 2005 27/46 32/44 0.81 [ 0.60, 1.09 ]
2 6 months
Schoon 2005 24/46 29/44 0.79 [ 0.56, 1.12 ]
3 12 months
Schoon 2005 23/46 28/44 0.79 [ 0.55, 1.13 ]
0.1 0.2 0.5 1 2 5 10
Favours prednisolone Favours budesonide
50Budesonide for maintenance of remission in Crohn’sdisease (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John W iley & Sons, Ltd.
Analysis 5.4. Comparison 5 Budesonide 9 mg/day vs prednisolone 40 mg/day (weaning), Outcome 4
Abnormal ACTH Stimulation Test.
Review: Budesonide for maintenance of remission in Crohn’s disease
Comparison: 5 Budesonide 9 mg/day vsprednisolone 40 mg/day (weaning)
Outcome: 4 Abnormal ACTH Stimulation Test
Study or subgroup Budesonide Prednisolone Risk Ratio Weight Risk Ratio
n/N n/N M-H,Fixed,95%CI M-H,Fixed,95%CI
Schoon 2005 13/36 20/33 100.0 % 0.60 [ 0.36, 1.00 ]
Total (95% CI) 36 33 100.0 % 0.60 [ 0.36, 1.00 ]
Total events: 13 (Budesonide), 20 (Prednisolone)
Heterogeneity: not applicable
Test for overall effect: Z = 1.97 (P= 0.048)
0.1 0.2 0.5 1 2 5 10
Pred Group Abnorm Bud Group Abnorm
Analysis 6.1. Comparison 6 Budesonide 6 mg vs mesalamine 3 g/day, Outcome 1 Maintenance of clinical
remission.
Review: Budesonide for maintenance of remission in Crohn’s disease
Comparison: 6 Budesonide 6 mg vsmesalamine 3 g/day
Outcome: 1 Maintenance of clinical remission
Study or subgroup Budesonide Mesalamine Risk Ratio Risk Ratio
n/N n/N M-H,Fixed,95%CI M-H,Fixed,95%CI
Mantzaris2003 13/29 5/28 2.51 [ 1.03, 6.12 ]
0.1 0.2 0.5 1 2 5 10
Favours 5-ASA Favours budesonide
52Budesonide for maintenance of remission in Crohn’sdisease (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John W iley & Sons, Ltd.
Antibióticos
Se ha usado de manera empírica, y hacen falta estudios para demostrar su eficacia
Las bacterias entéricas juegan un papel en algunas complicaciones de la EC
Los más comunes son metronidazol y ciprofloxacino
Antibióticos
Metronidazol
Tratamiento para enfermedad perianal
20 mg/kg/día x 3 meses reduce el riesgo de recurrencia post a la resección ileocecal
Ciprofloxacino
Eficacia similar que el metronidazol para enfermedad perianal
Mowat C, Cole A. Guidelines for the management of inflammatory bowel disease in adults. Gut 2011;60:571-607
Antibiotics and Inflammatory Bowel Diseases
Dig Dis 2013;31:379–384DOI: 10.1159/000354704
381
Gut mucosa is separated from the intestinal lumen by a mucous layer. After mucous layer removal, aerobic cul-ture of colonic biopsies in CD patients shows a high con-centration of bacteria, primarily Escherichia coli , while in healthy individuals it is sterile [25] . An increased pres-ence of E. coli , particularly the adherent-invasive E. coli (AIEC) pathovar, has been reported by several studies in CD tissue [3, 26, 27] . Pathogenic AIEC are able to colo-nize the intestinal mucosa by adhering to epithelial cells, to invade these cells, and to survive and replicate within macrophages, inducing the secretion of large amounts of tumor necrosis factor-α [28] . Nowadays, AIEC are per-haps the most likely candidate organisms in promoting the CD inflammatory process. In addition, a decreased number of protective bifidobacteria, lactobacilli and the more recently studied Faecalibacterium prausnitzii, Bac-teroide fragilis and Firmicutes , has been reported in CD patients [25, 29] .
Genetic susceptibly in some subjects with CD is related to polymorphisms in the NOD2/CARD15 gene, suggest-ing that individuals with mutations in NOD2 present de-fective intestinal immune responses to gut microbiota. About 20% of CD patients are homozygous for NOD2 variants and they may have an increased susceptibility to CD localized at the ileum [30] . Moreover, a loss of immu-nologic tolerance to the commensal flora has been ob-served in patients with active IBD [31] . On the assump-tion of these and other data, antibiotics are employed as primary therapy for treatment of acute flares, and for postoperative recurrence prevention [32–34] .
Antibiotics as Primary Therapy in Active Crohn’s Disease The data supporting the role of AIEC in the pathogen-
esis of CD provide the rationale for a therapeutic manipu-lation of the intestinal flora through the use of antibiotics active against these bacteria. Some antibiotics, such as clarithromycin and ciprofloxacin, are able to penetrate macrophages and may therefore be effective in eradicating the bacteria. However, a randomized, placebo-controlled trial performed with clarithromycin, at a dose of 1 g for 3 months, in 41 patients with active CD, was stopped because no difference in the remission or response rate between the antibiotic and placebo was observed [35] .
Metronidazole and ciprofloxacin are the most fre-quent studied and employed antibiotics, even though their role as primary therapy in active CD remains con-troversial. Metronidazole, active against some parasites and most anaerobic bacteria, including Bacteroides and Clostridium species, was first reported to be effective in CD in an open study in 1975 [36] . Ciprofloxacin is a qui-nolone derivative with a selective suppressive effect on the intestinal microflora. Not only E. coli , but also other Enterobacteriaceae are especially sensitive to this antibi-otic, which, on the contrary, does not particularly affect anaerobic bacteria.
Several randomized clinical trials have evaluated the efficacy of these antibiotics, used alone or in combina-tion, at inducing remission in CD ( table 2 ) [35, 37–42] . The results of these studies have shown that patients with colonic localization get more benefit from antibiotics, probably because of the higher bacterial concentration in the colon than in the small bowel. In addition, the asso-
Table 2. Antibiotic trials as primary therapy in acute flares
Reference (first author) Antibiotic (dose) Patients, n Time, weeks
Control Remission, %
act ive control
Ursing, 1982 [37] metronidazole (800 mg/day) 78 16 sulfasalazine NSSutherland, 1991 [38] metronidazole (10 or 20 mg/kg) 99 16 placebo 27 25
36Colombel, 1999 [39] ciprofloxacin (500 mg bid) 40 6 mesalamine 56 55Arnold, 2002 [40] ciprofloxacin (500 mg bid) 47 26 placebo p < 0.001Prantera, 1996 [41] ciprofloxacin (500 mg bid) +
metronidazole (500 mg bid)41 12 methylprednisolone
0.7–1 mg/kg45.5 63
Greenbloom, 1998 [42] ciprofloxacin (500 mg bid) +metronidazole (250 mg tid)
72 10 – 68 –
Leiper, 2008 [35] clarithromycin (1,000 mg/day) 41 12 placebo 26 27
NS = Not significant.
Do
wnlo
ad
ed b
y:
HIN
AR
I N
epal
15
8.2
32
.240
.78 -
9/3
/2014
5:1
3:4
7 A
M
Dig Dis 2013;31:379–384
Probiotics for induction of remission in Crohn’sdisease
(Review)
Butterworth AD, ThomasAG, AkobengAK
Thisisareprint of aCochranereview, prepared and maintained byTheCochraneCollaboration and published in TheCochraneLibrary
2009, Issue1
http://www.thecochranelibrary.com
Probioticsfor induction of remission in Crohn’sdisease (Review)
Copyright © 2009 The Cochrane Collaboration. Published by John W iley & Sons, Ltd.
Probiotics for induction of remission in Crohn’s disease
(Review)
Butterworth AD, ThomasAG, Akobeng AK
Thisisareprint of aCochranereview, prepared and maintained byTheCochraneCollaboration and published in TheCochraneLibrary
2009, Issue1
http://www.thecochranelibrary.com
Probiotics for induction of remission in Crohn’s disease (Review)
Copyright © 2009 The Cochrane Collaboration. Published by John W iley & Sons, Ltd.
D A T A A N D A N A L Y S E S
Comparison 1. Probioticsversusplacebo
Outcomeor subgroup titleNo. of
studies
No. of
participants Statistical method Effect size
1 Induction of remission 1 11 OddsRatio (M-H, Fixed, 95% CI) 0.09 [0.04, 17.20]
Analysis 1.1. Comparison 1 Probiotics versus placebo, Outcome 1 Induction of remission.
Review: Probiotics for induction of remission in Crohn’sdisease
Comparison: 1 Probioticsversusplacebo
Outcome: 1 Induction of remission
Study or subgroup Treatment Control OddsRatio Weight OddsRatio
n/N n/N M-H,Fixed,95%CI M-H,Fixed,95%CI
Schultz 2004 4/5 5/6 100.0 % 0.80 [ 0.04, 17.20 ]
Total (95% CI) 5 6 100.0 % 0.80 [ 0.04, 17.20 ]
Total events: 4 (Treatment), 5 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 0.14 (P= 0.89)
0.1 0.2 0.5 1.0 2.0 5.0 10.0
Favours L. GG Favours placebo
W H A T ’ S N E W
Last assessed asup-to-date: 20 April 2008.
12 May 2008 Amended Converted to new review format.
10Probiotics for induction of remission in Crohn’s disease (Review)
Copyright © 2009 The Cochrane Collaboration. Published by John W iley & Sons, Ltd.
.
Cochrane Database of Systematic Reviews 2008, Issue 3.
Tiopurinas
Efectivas para inducir remisión y mantenimiento
AZA/MP
AZA 2-2.5 mg/kg/día y MP 0.75-1.5 mg/kg/día
INICIAR
2 o mas cursos de esteroide en 12 meses
Recaída a dosis menores de 15 mg/día
Recaída 6 semanas después de haber suspendido esteroide
Mowat C, Cole A. Guidelines for the management of inflammatory bowel disease in adults. Gut 2011;60:571-607
Gut1995;37:674-678
Gastroenterology 2013;145:1464–1478
Azathioprine or 6-mercaptopurine for maintenance of
remission in Crohn’s disease (Review)
PrefontaineE, Sutherland LR, MacDonald JK, Cepoiu M
Thisisareprint of aCochranereview, prepared and maintained byTheCochraneCollaboration and published in TheCochraneLibrary
2009, Issue1
http://www.thecochranelibrary.com
Azathioprine or 6-mercaptopurine for maintenance of remission in Crohn’s disease (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John W iley & Sons, Ltd.
Azathioprine or 6-mercaptopurine for maintenance of
remission in Crohn’s disease (Review)
PrefontaineE, Sutherland LR, MacDonald JK, Cepoiu M
Thisisareprint of aCochranereview, prepared and maintained byTheCochraneCollaboration and published in TheCochraneLibrary
2009, Issue1
http://www.thecochranelibrary.com
Azathioprine or 6-mercaptopurine for maintenance of remission in Crohn’s disease (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John W iley & Sons, Ltd.
D A T A A N D A N A L Y S E S
Comparison 1. Maintenanceof remission
Outcomeor subgroup titleNo. of
studies
No. of
participants Statistical method Effect size
1 Maintenance of remission
(Azathioprine)
7 463 Peto OddsRatio (Peto, Fixed, 95% CI) 2.32 [1.55, 3.49]
1.1 Azathioprine dose 2.5
mg/kg/day
2 84 Peto OddsRatio (Peto, Fixed, 95% CI) 4.13 [1.59, 10.71]
1.2 Azathioprine dose 2.0
mg/kg/day
5 224 Peto OddsRatio (Peto, Fixed, 95% CI) 3.01 [1.66, 5.45]
1.3 Azathioprine dose 1.0
mg/kg/day
1 155 Peto OddsRatio (Peto, Fixed, 95% CI) 1.20 [0.60, 2.41]
2 Maintenance of remission
(6-MP, 50 mg/day)
1 87 Peto OddsRatio (Peto, Fixed, 95% CI) 3.32 [1.40, 7.87]
Comparison 2. Steroid SparingEffect
Outcomeor subgroup titleNo. of
studies
No. of
participants Statistical method Effect size
1 Final prednisone dose < 10
mg/day
2 30 Peto OddsRatio (Peto, Fixed, 95% CI) 5.22 [1.06, 25.67]
1.1 Steroid sparing effect 2 30 Peto OddsRatio (Peto, Fixed, 95% CI) 5.22 [1.06, 25.67]
Comparison 3. AdverseEvents(Toxicity)
Outcomeor subgroup titleNo. of
studies
No. of
participants Statistical method Effect size
1 Withdrawalsdue to adverse
events(Azathioprine)
6 530 Peto OddsRatio (Peto, Fixed, 95% CI) 3.74 [1.48, 9.45]
2 Withdrawalsdue to adverse
events(6-MP)
1 87 Peto OddsRatio (Peto, Fixed, 95% CI) 2.04 [0.63, 6.60]
14Azathioprine or 6-mercaptopurine for maintenance of remission in Crohn’s disease (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John W iley & Sons, Ltd.
Analysis1.1. Comparison 1 Maintenance of remission, Outcome 1 Maintenance of remission (Azathioprine).
Review: Azathioprine or 6-mercaptopurine for maintenance of remission in Crohn’sdisease
Comparison: 1 Maintenance of remission
Outcome: 1 Maintenance of remission (Azathioprine)
Study or subgroup Treatment ControlPeto
OddsRatio WeightPeto
OddsRatio
n/N n/N Peto,Fixed,95%CI Peto,Fixed,95%CI
1 Azathioprine dose 2.5 mg/kg/day
Candy 1995 14/25 2/20 11.3 % 7.12 [ 2.11, 23.99 ]
Summers 1979 16/19 15/20 7.1 % 1.73 [ 0.37, 8.05 ]
Subtotal (95% CI) 44 40 18.3 % 4.13 [ 1.59, 10.71 ]
Total events: 30 (Treatment), 17 (Control)
Heterogeneity: Chi2 = 2.00, df = 1 (P = 0.16); I2 =50%
Test for overall effect: Z = 2.92 (P = 0.0035)
2 Azathioprine dose 2.0 mg/kg/day
D’Haens 2007 18/32 9/29 16.5 % 2.73 [ 1.00, 7.45 ]
Lemann 2005 38/40 36/43 8.8 % 3.17 [ 0.80, 12.54 ]
O’Donoghue 1978 13/23 8/27 13.4 % 2.95 [ 0.97, 9.00 ]
Rosenberg 1975 7/10 4/10 5.6 % 3.16 [ 0.57, 17.62 ]
Willoughby 1971 4/5 2/5 2.9 % 4.48 [ 0.41, 49.42 ]
Subtotal (95% CI) 110 114 47.2 % 3.01 [ 1.66, 5.45 ]
Total events: 80 (Treatment), 59 (Control)
Heterogeneity: Chi2 = 0.15, df = 4 (P = 1.00); I2 =0.0%
Test for overall effect: Z = 3.64 (P = 0.00027)
3 Azathioprine dose 1.0 mg/kg/day
Summers 1979 37/54 65/101 34.5 % 1.20 [ 0.60, 2.41 ]
Subtotal (95% CI) 54 101 34.5 % 1.20 [ 0.60, 2.41 ]
Total events: 37 (Treatment), 65 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 0.52 (P = 0.60)
Total (95% CI) 208 255 100.0 % 2.32 [ 1.55, 3.49 ]
Total events: 147 (Treatment), 141 (Control)
Heterogeneity: Chi2 = 7.75, df = 7 (P = 0.36); I2 =10%
Test for overall effect: Z = 4.05 (P = 0.000050)
Test for subgroup differences: Chi2 = 5.60, df = 2 (P= 0.06), I2 =64%
0.1 0.2 0.5 1 2 5 10
Favours placebo Favours azathioprine
15Azathioprine or 6-mercaptopurine for maintenance of remission in Crohn’s disease (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John W iley & Sons, Ltd.
Analysis 1.2. Comparison 1 Maintenance of remission, Outcome 2 Maintenance of remission (6-MP, 50
mg/day).
Review: Azathioprine or 6-mercaptopurine for maintenance of remission in Crohn’s disease
Comparison: 1 Maintenance of remission
Outcome: 2 Maintenance of remission (6-MP, 50 mg/day)
Study or subgroup Treatment ControlPeto
OddsRatio WeightPeto
OddsRatio
n/N n/N Peto,Fixed,95%CI Peto,Fixed,95%CI
Hanauer 2004 24/47 9/40 100.0 % 3.32 [ 1.40, 7.87 ]
Total (95% CI) 47 40 100.0 % 3.32 [ 1.40, 7.87 ]
Total events: 24 (Treatment), 9 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 2.72 (P= 0.0065)
Test for subgroup differences: Not applicable
0.1 0.2 0.5 1 2 5 10
Favours placebo Favours 6-MP
Analysis 2.1. Comparison 2 Steroid Sparing Effect, Outcome 1 Final prednisone dose < 10 mg/day.
Review: Azathioprine or 6-mercaptopurine for maintenance of remission in Crohn’s disease
Comparison: 2 Steroid Sparing Effect
Outcome: 1 Final prednisone dose < 10 mg/day
Study or subgroup Treatment ControlPeto
OddsRatio WeightPeto
OddsRatio
n/N n/N Peto,Fixed,95%CI Peto,Fixed,95%CI
1 Steroid sparing effect
Rosenberg 1975 8/10 4/10 83.5 % 4.87 [ 0.85, 27.86 ]
Willoughby 1971 5/5 4/5 16.5 % 7.39 [ 0.15, 372.38 ]
Total (95% CI) 15 15 100.0 % 5.22 [ 1.06, 25.67 ]
Total events: 13 (Treatment), 8 (Control)
Heterogeneity: Chi2 = 0.04, df = 1 (P = 0.85); I2 =0.0%
Test for overall effect: Z = 2.03 (P= 0.042)
Test for subgroup differences: Not applicable
0.02 0.1 1 10 50
Favours placebo Favours azathioprine
16Azathioprine or 6-mercaptopurine for maintenance of remission in Crohn’s disease (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John W iley & Sons, Ltd.
Metotrexate
Efectivo para inducir remisión y para el mantenimiento
Puede inducir curación de la mucosa
25 mg/semana IM mejor que
No recomendación firme respecto a la duración
Uso prolongado asocia a mayor remisión
Methotrexate for maintenance of remission in Crohn’sdisease
(Review)
Patel V, MacDonald JK, McDonald JWD, ChandeN
Thisisareprint of aCochranereview, prepared and maintained byTheCochraneCollaboration and published in TheCochraneLibrary
2009, Issue4
http://www.thecochranelibrary.com
Methotrexate for maintenance of remission in Crohn’sdisease (Review)
Copyright © 2009 The Cochrane Collaboration. Published by John W iley & Sons, Ltd.
Azathioprine or 6-mercaptopurine for maintenance of
remission in Crohn’s disease (Review)
PrefontaineE, Sutherland LR, MacDonald JK, Cepoiu M
Thisisareprint of aCochranereview, prepared and maintained byTheCochraneCollaboration and published in TheCochraneLibrary
2009, Issue1
http://www.thecochranelibrary.com
Azathioprine or 6-mercaptopurine for maintenance of remission in Crohn’s disease (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John W iley & Sons, Ltd.
Maté-Jiménez 2000: Jadad score= 2 (A 1, B 0, C 0, D 0, E 1).
Allocation concealment was unclear and blinding was not used.
Thisstudy wasdetermined to haveahigh risk of bias(SeeFigure
1)
Oren 1997: Jadad score= 4 (A 1 , B 0, C 1, D 1, E 1). Alloca-
tion concealment wasunclear. Although themanuscript doesnot
describemethodsused for randomization and allocation conceal-
ment thesemethodswerelikely to beadequatebased on adequate
methods described in other published studies by these authors.
Theoverall risk of biasishigher than that of theFeagan study but
much lower than theMate-Jiminez study (SeeFigure1).
Effects of interventions
Feagan 2000
After 40 weeksof treatment, relapseoccurred in 14 of 40 (35%)
patientsassigned methotrexateand 22 of 36 (61%) patientsgiven
placebo (OR 0.36; 95% CI 0.15 to 0.87; P=0.02). The NNT
(number needed to treat) to prevent onerelapsewas4. Themean
time to relapse with methotrexate was > 40 weeks, and with
placebo it was 22 weeks. Of the 36 patients who relapsed, 22
were subsequently treated with methotrexate 25 mg IM weekly.
Twelve(55%) of thesepatientsagain werein remission at week 40
compared to 2 of 14 patients (14%) who were not treated with
methotrexateafter relapse. Theoverall incidenceof adverseevents
wassimilar inboth groups. Common adverseeventsincludednau-
seaand vomiting, symptomsof acold, abdominal pain, headache,
joint pain or arthralgia, and fatigue. Noneof thepatients in the
methotrexategroup had aseriousadverseevent compared to two
in theplacebo group (cervical dysplasiaand viral respiratory tract
infection. Onemethotrexatepatient withdrew from thestudy be-
causeof nausea.
Oren 1997
Theproportion of patientsentering first remission was10 of 26
(38%) in the MTX group, 13 of 32 (41%) in the 6-MP group,
and 12 of 26 (46%) in theplacebo group. Thesedifferenceswere
not statistically significant. Nine patients receiving MTX (90%;
95% CI 57% to >99.9%) maintained remission after induction
compared to 8 patients receiving 6-MP (62%; 95% CI 35% to
82%) and 8 patients receiving placebo (67%; 95% CI 39% to
86%). Therewereno statistically significant differencesbetween
the threegroups. The time to first remission and to first relapse
data were similar in all groups (data not available). The MTX
group did show agreater mean total time (months) in remission
and proportion of total study time in remission, but the results
werenot statistically significant (datanot available). Onepatient
in theMTX group withdrew dueto an adverseevent (headache)
comparedtoonepatient in the6-MPgroup(leukopeniaandstom-
atitis) and nonein theplacebo group.
Maté-Jiménez2000
After completing 30 weeks of induction treatment, 28 total pa-
tients with CD had achieved remission, including 15 of 16 pa-
tients(94%) in the6-MP group, 12 of 15 patients (80%) in the
MTX group, and 1 of 7 patients(14%) in the5-ASA group. After
76 weeksof treatment 8 of 12 MTX patientsmaintained remis-
sion compared to 8 of 15 6-MPpatientsand zero5-ASA patients.
Thesedifferenceswerenot statistically significant. Maté-Jiménez
2000 did not report adverse events separately for patients with
ulcerativecolitisand Crohn’sdisease. Adverseeventsexperienced
by patients who received MTX included nausea and dyspepsia,
mild alopecia, mild increasein AST levels, peritoneal abscess, hy-
poalbuminemia, severerash and atypical pneumonia. Threeof 26
patientstreated with MTX withdrew dueto adverseeventscom-
pared to 4 of 30 patientstreated with 6-MP.
Pooled analyses
MethotrexateversusplaceboA total of 98 patientswere included
in thepooled analysis(Feagan 2000; Oren 1997). After 36 to 40
weeks of treatment 35 of 40 patients treated with methotrexate
maintained remission compared to 22 of 48 patientstreated with
placebo. Thepooled oddsratio for maintenanceof remission was
3.11 (95% CI 1.31 to 7.41; P= 0.01; SeeFigure2). Thenumber
needed to treat to prevent onerelapsewas4.
Figure 2. Forest plot of comparison: 1 Methotrexate versus Placebo, outcome: 1.1 Proportion of patients
maintaining clinical remission.
6Methotrexate for maintenance of remission in Crohn’sdisease (Review)
Copyright © 2009 The Cochrane Collaboration. Published by John W iley & Sons, Ltd.
Methotrexateversus6-mercaptopurine
A total of 50 patientswereincluded in thepooled analysis(Maté-
Jiménez 2000; Oren 1997). More patientswho wereassigned to
methotrexate(17/22) maintained remission compared to patients
who received 6-MP (16/28). However, this difference was not
statistically significant (OR 2.63; 95% CI 0.74 to 9.37; P= 0.14;
SeeFigure3).
Figure 3. Forest plot of comparison: 2 Methotrexate versus 6-MP, outcome: 2.1 Proportion of patients
maintaining clinical remission.
D I S C U S S I O N
Crohn’sdiseaseisachronic inflammatory diseaseof thegut that is
characterized byperiodsof remission and exacerbations. Oncere-
mission isinduced, patientsoften requirelong-term maintenance
therapy in order to prevent relapse and avoid chronic corticos-
teroid use. Thisgenerally requirestheuseof immunosuppressive
agents(assteroid sparing agents).
Methotrexate, an immunosuppressive, isan effectivedrug for the
treatment of activeCrohn’sdisease(Feagan 1995; Alfadhli 2004).
Accordingly, current practice guidelines recommend the use of
methotrexatefor thispurpose(Lichtenstein 2006).
Threerandomized, controlledstudiesthat investigated theefficacy
of methotrexate for maintenance of remission of Crohn’sdisease
wereidentified for thisreview. Thethreestudiesdiffered signifi-
cantly with respect to methodology. Two studiesinvestigated the
efficacy of methotrexate compared to placebo. Feagan 2000 isa
well-designed trial that establishesmethotrexateasan effectiveand
safedrug for maintenancetherapy in Crohn’sdisease. Thisstudy
had thelargest number of patientsand used intramuscular injec-
tionsof methotrexateat adoseof 15 mgweekly. Thetrial showed
that in Crohn’s patients who had been induced into remission
with methotrexate, significantly morepatientsremained in remis-
sion while taking methotrexatecompared to placebo. Theother
study, Oren 1997, alsocomparedmethotrexatetoplacebo. It used
oral methotrexateat a lower dose(12.5 mg weekly). Theresults
showed no differencebetween patientstreated with methotrexate
or placebo. Thelower doseof methotrexate, oral routeof admin-
istration, and small patient population may havebeen factors in
thelack of benefit seen with methotrexate.
Two studies looked at methotrexate compared to 6-MP. Maté-
Jiménez 2000 is a randomized, controlled trial that used oral
methotrexate 10 mg weekly in patients that had achieved remis-
sion on ahigher dose(15 mgorally weekly). When compared to
patients treated with 6-MP, there was no statistically significant
differencewith respect to maintenance of remission. Oren 1997
also did not show astatistically significant differencebetween the
methotrexateand 6-MPgroups. Both of thesestudiesused alow
doseof oral methotrexateand enrolled small numbersof patients.
Neither of thesestudiesusedapower calculation todeterminehow
many patientsneeded to beenrolled to beableto detect clinically
important differencesbetween study groups.
Maté-Jiménez2000 also investigated oral methotrexatecompared
to 5-ASA. Methotrexatepatientsweresignificantly morelikely to
maintain remission than 5-ASA patients. However only 1 patient
in the5-ASA group participated in themaintenancephaseof the
study. No conclusionscan bedrawn from theseresults
Only1studyexaminedtheeffect of methotrexateonqualityof life.
In Oren 1997, therewasanon-significant trend towardsimprove-
ment in the mean Harvey-Bradshaw index in the methotrexate
group during thefinal 3 monthsof thestudy. Theanalysisof the
7Methotrexate for maintenance of remission in Crohn’sdisease (Review)
Copyright © 2009 The Cochrane Collaboration. Published by John W iley & Sons, Ltd.
Analysis 3.1. Comparison 3 Methotrexate versus 5-ASA, Outcome 1 Proportion of patients maintaining
clinical remission.
Review: Methotrexate for maintenance of remission in Crohn’s disease
Comparison: 3 Methotrexate versus5-ASA
Outcome: 1 Proportion of patientsmaintainingclinical remission
Study or subgroup Methotrexate 5-ASA OddsRatio Weight OddsRatio
n/N n/N M-H,Fixed,95%CI M-H,Fixed,95%CI
Mat -Jim nez 2000 8/12 0/1 100.0 % 5.67 [ 0.19, 169.53 ]
Total (95% CI) 12 1 100.0 % 5.67 [ 0.19, 169.53 ]
Total events: 8 (Methotrexate), 0 (5-ASA)
Heterogeneity: not applicable
Test for overall effect: Z = 1.00 (P= 0.32)
0.1 0.2 0.5 1 2 5 10
Favours control Favours treatment
W H A T ’ S N E W
Last assessed asup-to-date: 29 April 2009.
Date Event Description
7 July 2009 New citation required and conclusionshavechanged Substantiveamendment
H I S T O R Y
Protocol first published: Issue1, 2008
Review first published: Issue4, 2009
Date Event Description
15 July 2008 Amended Converted to new review format.
16Methotrexate for maintenance of remission in Crohn’sdisease (Review)
Copyright © 2009 The Cochrane Collaboration. Published by John W iley & Sons, Ltd.
Anti-TNF
Efectiva para mantener la remisión
Únicamente se debe administrar por médicos con experiencia en el manejo de la enfermedad de Crohn con biológicos
Excluir infección previo al inicio del tratamiento
Infliximab
• Enfermedad moderada a severa
• Refractaria a 5-ASA, esteroides e inmunosupresores
Enfermedad inflamatoria
Enfermedad fistulizante
Infliximab
Para enfermedad fistulizante iniciar hasta haberse excluido infección
No se recomienda para enfermedad fibroestenótica
Infusión inicial p/2 hrs, subsecuentes en 1 hr
Reiniciar Tx después de un año de suspensión riesgo de reacciones a la infusión
Infliximab
Dosis de carga 5 mg/kg a la semana 0, 2 y 6
Si no hay respuesta a después de 2 dosis, cambiar a adalimumab o a 10 mg/kg
Si hay respuesta, mantenimiento a intervalos de 8 semanas
Disminución de la eficacia, disminuir los intervalos 6 semanas, a 10 mg/kg
Gastroenterol Clin N Am 43 (2014) 457–478
Inducción a la remisión
Mantenimiento de la remisión
Gastroenterol Clin N Am 43 (2014) 457–478
Adalimumab
Inducción 40/80 mg sc en semanas consecutivas
Mantenimiento 40 mg SC en semanas alternas
Si hay pérdida de respuesta incrementar la administración a semanas consecutivas
Gastroenterol Clin N Am 43 (2014) 457–478
Inducción de la remisión
Mantenimiento de la remisión
Gastroenterol Clin N Am 43 (2014) 457–478
Gastroenterol Clin N Am 43 (2014) 457–478
Inducción de la remisión
Mantenimiento de la remisión
Gastroenterol Clin N Am 43 (2014) 457–478
Nutrición
Enteral nutrition for maintenance of remission in Crohn’s
disease (Review)
AkobengAK, ThomasAG
Thisisareprint of aCochranereview, prepared andmaintained byTheCochraneCollaboration and published in TheCochraneLibrary
2009, Issue3
http://www.thecochranelibrary.com
Enteral nutrition for maintenance of remission in Crohn’sdisease (Review)
Copyright © 2009 The Cochrane Collaboration. Published by John W iley & Sons, Ltd.
Analysis 2.1. Comparison 2 Elemental formula supplements versus no supplementation, Outcome 1
Relapse.
Review: Enteral nutrition for maintenance of remission in Crohn’sdisease
Comparison: 2 Elemental formula supplementsversusno supplementation
Outcome: 1 Relapse
Study or subgroup Supplements No supplements OddsRatio Weight OddsRatio
n/N n/N M-H,Fixed,95%CI M-H,Fixed,95%CI
Takagi 2006 9/26 16/25 100.0 % 0.30 [ 0.09, 0.94 ]
Total (95% CI) 26 25 100.0 % 0.30 [ 0.09, 0.94 ]
Total events: 9 (Supplements), 16 (No supplements)
Heterogeneity: not applicable
Test for overall effect: Z = 2.07 (P= 0.039)
0.1 0.2 0.5 1 2 5 10
Favours supplements Favours no supplemen
W H A T ’ S N E W
Last assessed asup-to-date: 29 April 2007.
27 May 2008 Amended Converted to new review format.
H I S T O R Y
Protocol first published: Issue2, 2006
Review first published: Issue3, 2007
30 April 2007 New citation required and conclusionshavechanged Substantiveamendment
D E C L A R A T I O N S O F I N T E R E S T
Dr Akobengand Dr Thomashaveboth received financial support from SHSInternational for induction studiesof enteral nutrition in
children with Crohn’sdisease.
12Enteral nutrition for maintenance of remission in Crohn’sdisease (Review)
Copyright © 2009 The Cochrane Collaboration. Published by John W iley & Sons, Ltd.
Azathioprine or 6-mercaptopurine for maintenance of
remission in Crohn’s disease (Review)
PrefontaineE, Sutherland LR, MacDonald JK, Cepoiu M
Thisisareprint of aCochranereview, prepared and maintained byTheCochraneCollaboration and published in TheCochraneLibrary
2009, Issue1
http://www.thecochranelibrary.com
Azathioprine or 6-mercaptopurine for maintenance of remission in Crohn’s disease (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John W iley & Sons, Ltd.
LocalizaciónEnfermedad ileal e ileocólica
En base a la severidad de la enfermedad
Enfermedad moderada
Esteroides orales 20-40 mg prednisona, budesonida9 mg (enfermedad ileocecal)
Anti-TNF enfermedad refractaria (inducción y mantenimiento)
Considerar cirugía temprana
Riesgo acumulado de desarrollar fístula perianal
10% a 1 año
15% a 5 años
20% a 10 años
Presencia de fístula
12 % en enfermedad ileal
15% en ileocólica
41% colónica
92% rectal
LocalizaciónPerianal
Descartar la presencia de sepsis perianal
Tratamiento quirúrgico
Extensión de la enfermedad (IRM, ultrasonido)
Metronidazol 400 mg c/8 hrs, con o sin ciprofloxacino 500 mg C/12 hrs
AZA 2-2.5 mg/kg/dia o MP 0.75-1.5 mg/kg/día
Anti-TNF enfermedad severa perianal, fístula enterocutánea refractaria
LocalizaciónPerianal
LocalizaciónEnfermedad fistulizante no perianal
Fistula entero-cutánea, fístula entero-enteral, fístula entero-visceral (vejiga, vagina)
No existen estudios aleatorizados controlados para la enfermedad fistulizante
Fístulas sintomáticas requieren tratamiento quirúrgico
LocalizaciónOtros sitios
• Esteroides tópicos, tacrolimus tópico, inyección intra-lesional de esteroides, dieta de exclusión, nutrición enteral, infliximab
Enfermedad oral
• Peor pronóstico
• Adición de IBP, reportes de caso Tx con anti-TNF
Enfermedad gastro-duodenal
Enfermedad leve a moderada
Sin tabaquismoPresentación inicial leveNo enfermedad perianal
No manifestaciones gastrointestinales
Cesar tabaquismoSulfasalazina y/o antibióticos
Cesar tabaquismoBudesonida/corticoesteroides
Continuar y observar
Disminuir, suspender y observar
Azatioprina o MTX
Azatioprina o MTX
Agregar anti TNFDetener Aza/MTX
A los 6 meses
Enfermedad colónica Enfermedad en intestino delgado
Respuesta No respuesta
Respuesta No respuesta
Recaída en el 1er año
Recaída
Enfermedad ileal, ileocólonica, colónica:
Mesalazina 3.2 a 4 g/día
Ileocolónica o colónica:
Sulfasalazina 3 – 6 g
Evidencia:
• Mínimamente efectiva vs placebo
• Menos efectiva que esteroides y que budesonida
Colon derecho o ileon Budesonida 9mg/día
Terapia antituberculosa no es efectiva
1/3 logra remisión a las 16 semanas con sulfasalazina
Mesalazina 3.2 – 4 g mostró diferencia significativamente vs placebo, pero sin relevancia clínica (beneficio de CDAI 18 puntos)
¿Antibióticos?
Hipótesis causa o factor exacerbante
Metronidazol 10 – 20mg/kg vs placebo
Metronidazol ileocolitis y colitis
Metronidazol vs sulfasalazina – cruzado pacientes que fallaron a uno, respondieron al otro
Ciprofloxacino vs Mesalazina 50% alcanzaron remisión clínica
Ciprofloxacino +Metronidazol + budesonida (9mg/d) tendencia en enfermedad colónica
Rifaximina 200 c/12hrs no superioridad vs placebo
Budesonida oral 9mg c/24hrs > mesalazina o placebo
Semejante a otros esteroides orales en ileon distal y/o colon derecho
Budesonida ha mostrado ser el mejor tratamiento con eficacia a corto plazo y mejor perfil de seguridad
Budesonida es la opción preferida como terapia primaria en pacientes con
enfermedad leve a moderada que tienen enfermedad localizada en ileon y/o colon
derecho
El manejo en EC en tracto GI superior:
IBP
Costico-esteroides sistémicos
Azatioprina
6 mercaptopurina
Metotrexato
Infliximab
Adalimumab
Certolizumab pegol
Enfermedad moderada a severa
Sin tabaquismoEdad de presentación >18 años
Enfermedad extensaEnfermedad perianal
Manifestaciones extraintestinales
Cesar tabaquismoAzatioprina / MTX y anti TNF
Continuar y observar
¿Cirugía?Drogas experimentales
Prednisona 40-60mg/d hasta resolución de síntomas o reinicio de ganancia de peso (7-28 días)
Azatioprina y 6 MP para mantener la remisión inducida por esteroides
Metotrexato parenteral 25mg/semana para EC dependiente de esteroides o refractaria a esteroides
Anti TNF:
Infliximab, adalimumab, certolizumab pegol
Pacientes que no respondieron a terapia con corticoesteroides o inmunosupresores
Infliximab e Infliximab + azatioprina son más efectivos que la azatioprina en pacientes que fallaron a terapia de primera línea
Infliximab, adalimumab, certolizumab pegolalternativas a la terapia con esteroides en pacientes con contraindicación
Tx con corticoesteroides
50 a 70% alcanzan remisión a las 8 a 17 semanas
Prednisona 0.5 – 0.75 mg/kg (40mg)/ día
80 – 90% alcanzan respuesta
Prednisona 1mg/kg o metilprednisona 1mg/kg
Estrategias
STEP UP VS TOP DOWN
Aloi, M. et al. (2013) Nat. Rev. Gastroenterol. Hepatol
Best Practice & Research Clinical Gastroenterology 28 (2014) 473–483
Lancet 2008; 371: 660–67
Tratamiento quirúrgico
Indicaciones de cirugía
Surgery. 2008: 26(8): 352-356
Indicaciones de cirugía electiva
① Cáncer por E. Crohn
② Incapacidad para superar síntomas
③ Complicaciones relacionadas a medicamentos
④ Mal apego a tratamiento médico
J Korean Soc Coloproctol 2012;28(3):121-131
JAMA. 2013;309(20):2150-2158
Predictores de cirugía
Eur J Gastroenterol Hepatol 2013, 25:129–134
Am J Gastroenterol 2003;98:2712- 2718
Cirugía temprana significativamente más frecuente en pacientes con enfermedad ileal localizada
Dolor abdominal fue el síntoma más frecuente que se presentó previo a la cirugía
Am J Gastroenterol 2012; 107:1693–1701
top related