High dose UDCA inHigh dose UDCA inthe Treatment of Primary the Treatment of Primary SclerosingSclerosing CholangitisCholangitis
Falk Meeting,Freiberg2006Falk Meeting,Freiberg2006Dr RW ChapmanDr RW Chapman
John Radcliffe HospitalJohn Radcliffe HospitalOxford,UKOxford,UK
Specific Medical Therapy for PSCSpecific Medical Therapy for PSCImmunosuppressantsImmunosuppressants
--prednisoloneprednisolone--budesonidebudesonide--azathioprineazathioprine--ciclosporineciclosporine--tacrolimustacrolimus--methotrexatemethotrexate
AntifibroticsAntifibrotics--colchicinecolchicine
MiscellaneousMiscellaneous--nicotinenicotine--pentoxyphyllinepentoxyphylline
UrsodeoxycholicUrsodeoxycholic acid acid conventional dose 10conventional dose 10--15mg/kg15mg/kg
Summary: results of trials disappointing!Summary: results of trials disappointing!
Novel Approaches to TreatmentNovel Approaches to Treatment
High dose High dose UrsoUrso
Novel drugs Novel drugs egeg silymarinsilymarin; ; perfenidone;enteraceptperfenidone;enteracept
EndoscopicEndoscopic therapy therapy egeg balloon dilatationballoon dilatation
Combination therapyCombination therapyendoscopicendoscopic & drug therapy& drug therapydrug combinationsdrug combinations
The Optimum dose of The Optimum dose of UrsoUrso in in CholestaticCholestaticLiver Diseases (PBC/PSC)?Liver Diseases (PBC/PSC)?
Original dosages in PBC derived from gallstone dissolution data viz10mg/kg body wt
DB controlled trials of low dose UDCA (10DB controlled trials of low dose UDCA (10--15mg/kg) in PSC15mg/kg) in PSC
nonononoimpimp3636momo
105105LindorLindor19971997
n/an/anonoimpimp24 24 momo
4848Van Van HooHoo19981998
impimpnonoimpimp24 24 momo
2020StiehlStiehl19941994
impimpnonoimpimp12 12 momo
1414BeuersBeuers19921992
LiverLiverhistolhistol
SymptSymptimprovimprov
AlkAlkphosphos
Study Study duratdurat
Pt NoPt NoAuthorAuthor
Rationale for High Dose UDCA Rationale for High Dose UDCA in treatment of PSCin treatment of PSC
Low dose doesnLow dose doesn’’t work!t work!
In advanced In advanced cholestasischolestasis in PSC the enrichment of in PSC the enrichment of the bile acid pool is diminished cp cystic fibrosisthe bile acid pool is diminished cp cystic fibrosisStiehlStiehl et al,J et al,J HepatolHepatol 1995,1995,RostRost et et al,Hepatolal,Hepatol 20042004
BiliaryBiliary enrichment with UDCA is proportional to enrichment with UDCA is proportional to administered doseadministered doseRodaRoda et et al,Europal,Europ J Gastro 2002J Gastro 2002RostRost et et al,Hepatolal,Hepatol 20042004
HighHigh--dose UDCA on dose UDCA on biliarybiliaryenrichment in PSCenrichment in PSC
RostRost D,et al; D,et al; HepatologyHepatology 2004;40:6932004;40:693--698698
Biliary enrichment of UDCA
2 doses 10-13 mg/kg;<22mg/kg
Higher dose increased enrichment
Biliary enrichment at various doses ;plateau effect at 22-25mg/kg
High dose UDCA in PSC*High dose UDCA in PSC*
DBCT 26 PSC ptsDBCT 26 PSC ptsRandomised to placebo or UDCA(20 Randomised to placebo or UDCA(20 ––25mg /day) 25mg /day) Repeat liver biopsy/ERCP at 2 yrsRepeat liver biopsy/ERCP at 2 yrs22/26 completed the trial22/26 completed the trialSerum bile acids (HPLC) 0,1,2 yrsSerum bile acids (HPLC) 0,1,2 yrs
*Mitchell S et al,Gastro 2001
High Dose High Dose UrsoUrso in PSCin PSCHistological Disease stage over 2 yrsHistological Disease stage over 2 yrs
Histological stage worsened in placebo group cp UDCA
High Dose High Dose UrsoUrso in PSCin PSCERCP changes over 2yearsERCP changes over 2years
ERCP worsened in placebo group cp UDCA
High Dose High Dose UrsoUrso in PSCin PSCSerum bile acids (by HPLCSerum bile acids (by HPLC))
73%73%78%78%6%6%High doseHigh doseUDCAUDCA
7.3%7.3%7.8%7.8%3%3%Placebo Placebo groupgroup
atat2years2years
atat1 years1 years
atat0 year0 year
% of % of UDCA UDCA fraction fraction of bile of bile acid poolacid pool
High Dose High Dose UrsoUrso in PSCin PSCSummary of resultsSummary of results
Well toleratedWell toleratedNo effect on colitis activityNo effect on colitis activitySignificant improvements in alkaline Significant improvements in alkaline phosphos/GGT/GGTNo improvements in symptomsNo improvements in symptomsMajority of treated group had improved Majority of treated group had improved inflaminflam/fibrosis scores/fibrosis scores4/10 had regression disease stage 4/10 had regression disease stage –– not not
seen in placebo groupseen in placebo group
High dose High dose UrsoUrso as a therapy for as a therapy for patients with PSC*patients with PSC*
patients / methodspatients / methods
30 PSC pts30 PSC ptstreated with 25treated with 25--30 mg/kg/daily for one 30 mg/kg/daily for one year year ––open studyopen studycompared with historical PSC controlscompared with historical PSC controlsvizviz placebo (52 pts) and mod doseplacebo (52 pts) and mod doseursourso 1313--15mg/kg/daily (53 pts15mg/kg/daily (53 pts))
*Harnois et al;Am J Gastro 2001
High dose UDCA as a therapy for High dose UDCA as a therapy for patients with PSC*patients with PSC*Results at one yearResults at one year
Marked improvement in Marked improvement in LFTLFT’’ssChanges in Mayo Risk Score wereChanges in Mayo Risk Score weresignificantly different at one year significantly different at one year between 3 groupsbetween 3 groupsExpected survival at 4 yearsExpected survival at 4 years-- High dose High dose improvedimproved vsvs placeboplacebo
(p=0.04)(p=0.04)-- Mod dose Mod dose vsvs placeboplacebo-- no differenceno difference
(p=0.4)(p=0.4)Harnois et al;Am J Gastro 2001
97 pts high dose UDCA (1797 pts high dose UDCA (17--23 23 mg/kg) for 5 yearsmg/kg) for 5 years101 pts placebo101 pts placebo
ScandanavianScandanavian trial high dose UDCAtrial high dose UDCA::changes in serum biochemistrychanges in serum biochemistry
Alk phos
ALT
bilirubin
Red =placebo
High dose High dose ScandanavianScandanavian TrialTrial
Death /Transplantation:
7.2% UDCA vs 10.9% placebo(ns)
High dose UDCA High dose UDCA ScandanavianScandanavian study:study:
potential problemspotential problems
Study underpowered Study underpowered (only 10% placebo pts (only 10% placebo pts reached endpoint)reached endpoint)
High dropout rateHigh dropout rate
Dose too low ! (15 Dose too low ! (15 --20mg/kg)20mg/kg)
Study period too short Study period too short (even at 5 yrs!)(even at 5 yrs!)
StongStong possibility of type II errorpossibility of type II error
*Lindor et al:N Engl J Med 1997
Olsson et al:J Hepatol2004
Low dose UDCA High dose UDCA
5 yr Survival
What about even Higher Dose What about even Higher Dose UDCA in PSC?*UDCA in PSC?*
2 year DBRCT pilot study in 33 PSC 2 year DBRCT pilot study in 33 PSC pts pts Munich & OxfordMunich & OxfordPts randomised to UDCA either Pts randomised to UDCA either 10mg/kg; 20 or 30 mg/10mg/kg; 20 or 30 mg/kgmkgmLiver biopsy 0 and 2 years assessed Liver biopsy 0 and 2 years assessed using Ludwig Scoreusing Ludwig Score
*Cullen S. Rust C, Fleming K, Beuers U, Chapman RW: EASL 2006
High dose UDCA High dose UDCA Improvement in liver function TestsImprovement in liver function Tests
T-test (within treatment group)
10mg 20mg 30 mg
Bilirubin p=0.77 p=0.71 p=0.57
Alk Phos p=0.01 p=0.01 p=0.03
AST p=0.08 p=0.03 p=0.09
ALT p=0.05 p=0.02 p=0.06
GGT p=0.01 p=0.01 p=0.01
High Dose UDCA in PSCHigh Dose UDCA in PSCMayo Risk Scores;Mayo Risk Scores;
difference in survival probabilities from difference in survival probabilities from baseline to end of the studybaseline to end of the studyM ayo scor es - Di f f er ence i n sur vi val pr obabi l i t i es f r om basel i ne t o end of st udy
0
0.5
1
1.5
2
2.5
3
3.5
1 year 2 year s 3 year s 4 year s
T i me ( y e a r s )
A l l
10mg/ kg
20mg/ kg
30mg/ kg
Time in yrs1 yr 4yrs
Survival probabilities
High dose UDCA in PSCHigh dose UDCA in PSCChange in Ludwig score
All patientsn=31
Low dose UDCA (10mg/kg)n=11
Standard dose UDCA (20mg/kg)n=11
High dose UDCA (30mg/kg)n=9
Improved 6 19% 1 9% 2 18% 3 33%
No change 17 55% 7 64% 8 73% 2 22%
Worsening 3 10% 2 18% 0 0% 1 11%
No biopsy 5 16% 1 9% 1 9% 3 33%
High Dose UDCA in PSC*High Dose UDCA in PSC*
Very high dose (Very high dose (ieie 30mg/kgm) well 30mg/kgm) well toleratedtoleratedCholestaticCholestatic LFTLFT’’ss -- improved in all groupsimproved in all groupsTrend towards improvement in the Trend towards improvement in the Ludwig score in standard and high dose Ludwig score in standard and high dose groupsgroupsSignificantly increased survival ( using Significantly increased survival ( using Mayo Risk score) in 30mg/kg groupMayo Risk score) in 30mg/kg groupHowever SMALL pilot study!However SMALL pilot study!
*Cullen S et al; EASL 2006*Cullen S et al; EASL 2006
UDCA treatment for PSCUDCA treatment for PSCUDCA anticancer roleUDCA anticancer role
Evidence in favour of reduction of Evidence in favour of reduction of colon cancer risk in PSC/IBDcolon cancer risk in PSC/IBD
Tentative evidence for reduction in Tentative evidence for reduction in risk of risk of cholangiocacholangioca : not proven: not proven
Effect of UDCA dose is unknown inEffect of UDCA dose is unknown inchemoprotectionchemoprotection
High dose UDCA in PSCHigh dose UDCA in PSC
Data still suggestive that UDCA Data still suggestive that UDCA indicated in high doseindicated in high dose
Large US study in progressLarge US study in progress
New studies are unlikely to occur New studies are unlikely to occur vizviz cancer protective effectcancer protective effect
on colon & ? bile ductson colon & ? bile ducts
High Dose High Dose UrsoUrso in PSCin PSC--combination combination therapy: the future?therapy: the future?
Studies of combination therapy Studies of combination therapy with with UDCA (low dose)UDCA (low dose)
--antibioticsantibiotics((metronidazolemetronidazole) ) --PosPos [DBCT] [DBCT]
--immunomodulatoryimmunomodulatory((mycophenolatemycophenolate mofetilmofetil) ) --Neg (DBCT)Neg (DBCT)
--immunosuppressant immunosuppressant ( ( predpred 1mg/kg;Azathioprine 1mg daily)1mg/kg;Azathioprine 1mg daily)
-- PosPos (Uncont)(Uncont)--rifampicin (no trial)rifampicin (no trial)
High Dose High Dose UrsoUrso in PSCin PSC--combination therapycombination therapy
Studies of combination therapy Studies of combination therapy with UDCAwith UDCA
--antibioticsantibiotics((metronidazolemetronidazole) ) --
Positive [DBCT]Positive [DBCT]
--immunomodulatoryimmunomodulatory((mycophenolatemycophenolate mofetilmofetil) ) --
Negative[DBCTNegative[DBCT]]
--immunosuppressant immunosuppressant (( dd 1 /k A thi i1 /k A thi i
High dose UDCA in PSCHigh dose UDCA in PSC
Data still suggestive that UDCA Data still suggestive that UDCA indicated in high doseindicated in high dose
Large US study in progressLarge US study in progress
New studies are unlikely to occur New studies are unlikely to occur vizviz cancer protective effectcancer protective effect
on colon & ? bile ductson colon & ? bile ducts
Potential Benefits of Potential Benefits of UrsodeoxycholicUrsodeoxycholicacid in Colon Cancer*acid in Colon Cancer*
Toxic bile acids Toxic bile acids vizviz deoxycholicdeoxycholic acid induce cell acid induce cell proliferation proliferation --induces induces dysplasiadysplasia and colon cancer and colon cancer [in vitro model] NB Effects reversed by UDCA[in vitro model] NB Effects reversed by UDCA
In vivo In vivo –– reduced prevalence of Colon reduced prevalence of Colon Polyps/cancer in PBC treated with UDCAPolyps/cancer in PBC treated with UDCA
Colonic Colonic dysplasiadysplasia / cancer increased in PSC/UC / cancer increased in PSC/UC compared with UC alonecompared with UC alone
*Martinez et al;Nutr Cancer 1998;31:111-8
Proportion of PSC/UC pts free of colonic Proportion of PSC/UC pts free of colonic cancer / cancer / dysplasiadysplasia**
**PardiPardi et al,Gastro 2003;124:889et al,Gastro 2003;124:889--33
n=29n=29
n=23n=23
NB Similar results in Oxford
Novel treatment for PSCNovel treatment for PSCUDCA anticancer roleUDCA anticancer role
Strong evidence in favour of reduction of Strong evidence in favour of reduction of colon cancer risk in PSC/IBDcolon cancer risk in PSC/IBD
Tentative evidence for reduction in risk of Tentative evidence for reduction in risk of cholangiocacholangioca : not proven: not proven
Effect of UDCA dose is unknownEffect of UDCA dose is unknown
Novel Approaches to TreatmentNovel Approaches to Treatment
Novel drugsNovel drugs
High dose High dose UrsoUrso
EndoscopicEndoscopic therapytherapy
Combination therapyCombination therapyendoscopicendoscopic & drug therapy& drug therapydrug combinationsdrug combinations
High Dose High Dose UrsoUrso in PSCin PSC--combination therapycombination therapy
Studies of combination therapy with UDCAStudies of combination therapy with UDCA
--antibiotics(metronidazole)Positiveantibiotics(metronidazole)Positive [DBCT] [DBCT]
--immunomodulatoryimmunomodulatory((mycophenolatemycophenolate mofetilmofetil) Negative[DBCT]) Negative[DBCT]
--immunosuppressant immunosuppressant ( ( predpred 1mg/kg;Azathioprine 1mg daily)1mg/kg;Azathioprine 1mg daily)
Positive [Positive [UncUnc]]
Novel Treatments of PSCNovel Treatments of PSCConclusionConclusion
UDCA indicated in PSC/UC ptsUDCA indicated in PSC/UC ptsbecause of reduced risk of colonic because of reduced risk of colonic neoplasianeoplasia
Further trials required of combination studies of Further trials required of combination studies of UDCA with other agentsUDCA with other agents
antibiotics antibiotics egeg metronidazolemetronidazole
endoscopicendoscopic therapies therapies
Novel drug therapies for PSCNovel drug therapies for PSCEtanerceptEtanercept (anti TNF antibody)(anti TNF antibody)
Pilot study :25 mg twice weekly s/c [10 PSC pts]Pilot study :25 mg twice weekly s/c [10 PSC pts]treated for 1 year*treated for 1 year*No improvement in No improvement in LFTLFT’’ss ((bilirubinbilirubin 2x!)2x!)2 /5 pts improved itch2 /5 pts improved itch
NB: PSC pts refractory: all had failed UDCA and /or MTXNB: PSC pts refractory: all had failed UDCA and /or MTXNO trials of NO trials of infiximabinfiximab ((etanerceptetanercept no good in IBD)no good in IBD)
*Epstein MP,Kaplan MM*Epstein MP,Kaplan MMDig Dig DisDis SciSci 20042004
Novel Approaches to TreatmentNovel Approaches to Treatment
Novel drugsNovel drugs
High dose High dose UrsoUrso
EndoscopicEndoscopic therapytherapy
Combination therapyCombination therapyendoscopicendoscopic & drug therapy& drug therapydrug combinationsdrug combinations
Novel drug therapies for PSCNovel drug therapies for PSC
SilymarinSilymarin (antioxidant)(antioxidant) aka milk aka milk thistlethistlePilot study :140 mg Pilot study :140 mg tdstds 1 year [22 PSC pts]1 year [22 PSC pts]No effectNo effect
AnguloAngulo et al,2003et al,2003
PerfenidonePerfenidone ((antifibroticantifibrotic))
Pilot study :2400mg daily 1year [24 Pilot study :2400mg daily 1year [24 PSCptsPSCpts]]No benefit ;adverse effects 23/24No benefit ;adverse effects 23/24
AnguloAngulo et al,Dig et al,Dig DisDis SciSci 2002;47:1572002;47:157
Low Dose UDCA in PSCLow Dose UDCA in PSCSurvival free of treatment failureSurvival free of treatment failure**
*Lindor et al:N Engl J Med 1997
High Dose High Dose UrsoUrso in PSCin PSCAims of the StudyAims of the Study
RandomisedRandomised placebo controlled pilot study placebo controlled pilot study using high dose UDCA(20mg/kg/day)in using high dose UDCA(20mg/kg/day)in order to;order to;Determine effect of high dose UDCA on Determine effect of high dose UDCA on clinical,biochemical,cholangiographicclinical,biochemical,cholangiographichistological features of PSC over 2yrhistological features of PSC over 2yrAssess side effect profile and effect on Assess side effect profile and effect on activity of colitisactivity of colitis
High Dose High Dose UrsoUrso in PSCin PSCPatients / MethodsPatients / Methods
26 pts with PSC 26 pts with PSC randomisedrandomised to UDCA to UDCA or placeboor placeboFull Full assesmentassesment at entry at entry ((clinical;biochem;liverbiopsy;ERCPclinical;biochem;liverbiopsy;ERCP))Repeat liver biopsy/ERCP at 2 yrsRepeat liver biopsy/ERCP at 2 yrsSerum bile acids at 0;1yr;2yrSerum bile acids at 0;1yr;2yr
--measured by HPLCmeasured by HPLC
High Dose High Dose UrsoUrso in PSCin PSCResults Results -- ClinicalClinical
22 of 26 pts completed the trial:22 of 26 pts completed the trial:3 pts withdrawn:3 pts withdrawn:..One pt in UDCA group One pt in UDCA group –– main ductmain duct
stricture/transplantstricture/transplant.One pt in placebo group .One pt in placebo group –– varicealvaricealhaemorrhagehaemorrhage.One pt died unrelated cause.One pt died unrelated cause
High Dose UDCA in PSCHigh Dose UDCA in PSCResults Results -- ClinicalClinical
No improvement in symptomsNo improvement in symptoms ieiefatigue/malaise/fatigue/malaise/pruritispruritis –– despite despite improvement in biochemistryimprovement in biochemistry
No adverse events/side effectsNo adverse events/side effects-- in in particular no particular no diarrhoeadiarrhoea/worsening of /worsening of activity of inflammatory bowel diseaseactivity of inflammatory bowel disease
ScandanavianScandanavian trial high dose UDCA:trial high dose UDCA:changes in serum biochemistrychanges in serum biochemistry
Alk phos
ALT
bilirubin
Red =placebo
High dose High dose UrsoUrso in PSCin PSCSerum BiochemistrySerum Biochemistry
p=.93p=.934343444441414141AlbuminAlbumin
p=.01p=.01178178476476595595560560GgtGgt
p=0.1p=0.14747878780806161AstAst
p=.03p=.03455455834834875875791791AlkAlk phosphos
p=.08p=.081616161624241919bilirubinbilirubin
P P valuevalue
UDCAUDCA2yr2yr
UDCAUDCA0yr0yr
PlacPlac2yr2yr
PlacPlac0 yr0 yr
MeanMean
High Dose High Dose UrsoUrso in PSCin PSCLiver Histology Liver Histology
Portal inflammation scores over 2 yrsPortal inflammation scores over 2 yrs
Comparison of 3 doses of UDCA on Comparison of 3 doses of UDCA on duodenal bile acid enrichment at 1 yrduodenal bile acid enrichment at 1 yr
Low Dose UDCA in PSC*Low Dose UDCA in PSC*Survival Free of Treatment FailureSurvival Free of Treatment Failure
Stage 1 or 2 diseaseStage 1 or 2 disease
*Lindor et al;N Engl J Med 1997
Low dose UDCA* High dose in PSC**Low dose UDCA* High dose in PSC**Survival Free of Liver TransplantationSurvival Free of Liver Transplantation
*Lindor et al;N Engl J Med 1997 **Olsson et al;J Hepatol 2004
Low dose UDCA in PSC*Low dose UDCA in PSC*Survival Free of Liver Survival Free of Liver
TransplantationTransplantation
*Lindor et al;N Engl J Med 1997
Management of PSCManagement of PSCManagement of chronic Management of chronic cholestasischolestasisManagement of end stage liver diseaseManagement of end stage liver diseaseManagement of complications spec to PSC Management of complications spec to PSC -- --dominant stricturedominant stricture
--biliarybiliary sludgesludge--cholangiocarcinomacholangiocarcinoma
Specific Medical Therapy Specific Medical Therapy ––to prevent diseaseto prevent diseaseprogressionprogression
Liver TransplantationLiver Transplantation
Comparison of 3 doses of UDCA inComparison of 3 doses of UDCA inPBC PBC –– randomized trial*randomized trial*
Effect on Mayo Risk ScoreEffect on Mayo Risk Score
Low dose 5-7mg/kg;stand 13-15;high23-25mg/’kg/daily
*Angulo et el;J Hepatol 1999
Low doseLow dose
Mod /high dose
Primary Primary SclerosingSclerosing CholangitisCholangitis
Chronic Chronic cholestaticcholestaticliver diseaseliver diseaseStricturingStricturing and and dilatation of dilatation of biliarybiliarytreetreeProgresses to Progresses to cirrhosis/liver cirrhosis/liver failurefailurePredisposes to Predisposes to cancer (bile cancer (bile duct;colon;pancduct;colon;panc))
Comparison of 3 doses of UDCA inComparison of 3 doses of UDCA inPBC PBC –– randomized trial*randomized trial*
Effect on Alkaline Effect on Alkaline PhosphatasePhosphatase
Low dose 5-7 mg/kg/daily
Mod 13-15mg/kg;high 23-25mg/kg/daily
*Angulo et al;J Hepatol 1999
Comparison of 3 doses of UDCA in Comparison of 3 doses of UDCA in PBC PBC –– ConclusionsConclusions**
UrsodeoxycholicUrsodeoxycholic Acid in doses of 5Acid in doses of 5--25 mg/kg/day is well tolerated25 mg/kg/day is well tolerated
Dose of 13Dose of 13--15 mg/kg/day is the 15 mg/kg/day is the preferred dose in the treatment of preferred dose in the treatment of PBCPBC
*Angulo et al:JHepatol1999