Download Pediatric PSC Medical Issues

Pediatric Primary Sclerosing
Cholangitis:
Medical issues
06.24.2016
Udeme D. Ekong MD MPH
Associate Professor of Pediatrics
Yale University School of Medicine
Medical Director
Pediatric Hepatology and Pediatric Liver Transplantation
Yale New Haven Transplantation Center.
SLIDE 0
Objectives of this session
• Highlight the subtle differences between
Childhood PSC vs. Adult PSC
– autoimmune liver disease commonly seen
in childhood PSC
– therapies used in childhood PSC
• Discuss clinical studies in childhood PSC
• Discuss treatment trials in childhood PSC
SLIDE 1
Background
• PSC does affect children
– but at a lower prevalence of 1/4th to 1/5th that of
adults
• The mean age at diagnosis of PSC in children
is ~13-years
• Male predominance
SLIDE 2
Background
• The majority of children with PSC have
inflammatory bowel disease (IBD), most
commonly ulcerative colitis
• In contrast to adults, the blood test levels
of ALP is generally not helpful because of
the wide range of normal values induced
by growing bones in children
SLIDE 3
Background
• The outcome of PSC in children may be
somewhat better than that of adults:
– dominant strictures
– recurrent infection of the liver (cholangitis)
– cancer of the bile ducts (cholangiocarcinoma)
All relatively uncommon in children
SLIDE 4
Background
• ~1/3rd of pediatric PSC patients require
transplantation by adulthood
• Other than liver transplantation, there are no
conclusive proven therapies to improve longterm disease outcomes.
SLIDE 5
Pediatric PSC vs. Adult PSC
• Childhood PSC is different from the adult
disease in several ways:
– there is a greater association with
autoimmune blood tests
– higher incidence of PSC overlapping with
autoimmune hepatitis (AIH) – this is seen
in ~25% to 28% of pediatric patients vs.
~6% of adult patients.
SLIDE 6
Pediatric PSC vs. Adult PSC
• There is also an entity in children termed
“autoimmune cholangitis” that may be a
unique subset of PSC/AIH overlap which
may have a better response to
steroids/azathioprine and a better
outcome.
SLIDE 7
Pediatric PSC vs. Adult PSC
• Limited pediatric studies have suggested
that children with AIH/PSC overlap may
require more immunosuppressive therapy
(steroids & azathioprine) to achieve
complete normalization of liver blood
tests.
SLIDE 8
Pediatric PSC vs. Adult PSC
–a trend towards higher liver blood test
levels at diagnosis as compared to
adults
–on intermediate-dose ursodiol therapy,
there is a more striking and prompt
improvement in liver blood tests as
compared to adults
SLIDE 9
Pediatric PSC vs. Adult PSC
• These features suggest that childhood PSC
may either be a different disease than
adult PSC or an earlier stage of the same
disease process.
S L I D E 10
Pediatric PSC vs. Adult PSC
• More importantly, the higher prevalence
of autoimmune features in pediatric PSC
compared to the adult disease may have
important implications for treatment and
outcome, and results of drug trials in
adults are not necessarily applicable to
children with PSC.
(children are not small adults).
S L I D E 11
Pediatric PSC trials
• More studies are needed to correlate liver
biopsy findings in childhood PSC and
PSC/AIH overlap with outcomes and
response to treatment.
S L I D E 12
Pediatric
PSC
PI: Mark Deneau MD, MS
University of Utah
Currently 586 children from 26
Consortium
centers in: Canada
Ireland
Finland
France
Greece
Korea
Italy
Israel
Poland
Saudi Arabia
Slovenia
United Kingdom
United States
Far and away the largest collection of pediatric
data to date, larger than most adult series.
And still growing!
Pediatric
PSC
Consortium
Aims:
Pediatric • Define PSC outcomes in children
• how do they do at 1, 5 or 10
years after diagnosis? (we
Consortium
know very well)
PSC
• Determine objective predictors of
outcome
• can simple bloodwork at
diagnosis tell us something
about how a patient’s disease
will progress? (yes, it
probably can)
Pediatric
PSC
Aims contd:
• Comparative effectiveness of
Consortium
medications on survival
outcomes
• does ursodiol work? (some
say ay others say nay)
We are also exploring:
Pediatric
PSC
Consortium
• PSC recurrence after
transplant
• Autoimmune hepatitis / PSC
“overlap”
• A prognostic model of pediatric
PSC (enter age, sex, labs and get
projected 5 and 10-yr outcome,
probability of response to
ursodiol or vancomycin, etc)
Pediatric
PSC
Consortium
We are also exploring:
• Co-occurring autoimmune
diseases in PSC:
• celiac disease,
• hypothyroidism (under
acting thyroid gland),
• vasculitis (inflammation
involving blood vessels in
the body).
Pediatric
PSC
Consortium
Looked back at all cases of
pediatric-onset PSC at member
institutions
Patients followed from time of PSC
diagnosis to the development of :
• Portal hypertension
• Liver transplantation
• Death
Pediatric
PSC
Consortium
Analyze factors associated with:
• Development of portal
hypertension
• Liver transplantation/Death
Identify clinical predictors of poor
outcome at the time of diagnosis of
PSC
• Male vs. female
• Large duct vs. small duct disease
• Bilirubin >2 vs <2 at diagnosis
• PSC/AIH overlap vs. PSC
without overlap
• IBD vs. no IBD
Pediatric
PSC
Consortium
Interim results:
First 97 patients (from the first 8
centers) followed for 5-years:
Mean age at diagnosis 13.1-years
~2/3rds male
~1/3rd or 35% also had AIH
81% had inflammatory bowel
disease (IBD)
• In ¼ of patients, the measure
for jaundice was abnormal
(bilirubin level > 2) at time of
diagnosis
•
•
•
•
Pediatric
PSC
Consortium
Interim results:
Outcome 5-years following
diagnosis of PSC:
• 84% of patients still had their
own liver (this is a good thing)
• ~2/3rds or 68% of patients did
not have portal hypertension
(this is also a good thing)
Pediatric
Interim results:
PSC
Factors at diagnosis of PSC
associated
with a higher risk of
Consortium
death or liver
transplantation:
Predictor
Reference
Hazard
Ratio
P
Male
female
8.9
0.04
Large duct
PSC
Small duct
PSC
1.9
ns
Total
bilirubin
>2
Total
bilirubin
<2
4.8
0.008
AIH
No AIH
1.3
ns
IBD
No IBD
3.1
ns
Pediatric
PSC
Consortium
Take home message:
Outcome 5-years following
diagnosis of PSC:
• A little over 1/3rd of pediatric
PSC patients will progress to
portal hypertension within 5years of diagnosis
• Male gender and elevated
bilirubin at time of diagnosis are
risk factors for progressive PSC
Pediatric
PSC
Consortium
Take home message:
Outcome 5-years following
diagnosis of PSC:
• Outcomes were similar whether
or not the larger or smaller bile
ducts (tubes draining the liver)
were involved in the disease
process.
Summary
Pediatric
PSC
Consortium
• Stay tuned!
• 4 scientific abstracts
submitted to the
Liver Meeting 2016
(AASLD)
• Manuscripts and
“final” results late
2016, early 2017
STOPSC
(Studies of Primary
Sclerosing Cholangitis)
Consortium
Sponsored by the Morgan Foundation
Principal Investigators:
Dennis Black, MD (Memphis)
Benjamin Shneider, MD (Houston)
27
Comparison of pediatric and
adult PSC patient baseline
laboratory values
At diagnosis
Adult PSC
Pediatric PSC
ALP (IU/L)
330±83
350±66
ALT (IU/L)
75.4±12.6
123±24
AST (IU/L)
61.4±10.1
92.5±20
GGT (IU/L)
343±106
217±68
T. Bilirubin (mg/dl)
2.32±1.02
0.47±0.13
D. Bilirubin (mg/dl)
1.36±0.98
0.18±0.07
Trend of children with PSC at diagnosis having less
cholestasis and more hepatocellular injury than adults.
Pediatric PSC liver tests at
diagnosis and 1-year into
therapy
All patients (n=47)
Test
Mean at
diagnosis
Mean at
1-yr into
UDCA Rx
ALT
233±327
62±69
AST
236±248
58±48
GGT
553±676
92±32
 Remarkable
biochemical
response
 Response
comparable in
children with
AIH/PSC overlap
and small duct PSC
29
Ursodeoxycholic Acid (UDCA)
Therapy in Pediatric Primary
Sclerosing Cholangitis: A Pilot
Withdrawal/Reinstitution Trial
Sponsor: FDA Office of Orphan Product
Development
ClincalTrials.gov NCT01088607
Grant Principal Investigators:
Dennis Black, MD (Memphis)
Benjamin Shneider, MD (Houston) 30
Pilot UDCA
Withdrawal/Reinstitution
Trial
 Pilot study as a prelude to a prospective,
randomized, placebo-controlled trial in
children with PSC for UDCA or other
therapy off UDCA
 Establish safety of UDCA withdrawal
 Validation of more reasonable surrogate
markers for disease progression and response
to therapy
31
STOPSC
Consortium
Rationale
 Ursodeoxycholic acid (UDCA) therapy
improves biochemical markers of liver
disease, but even in high doses does not
clearly improve the long-term outcome
in adult trials.
32
STOPSC
Consortium
Rationale
 Furthermore, an adult trial of high-dose
UDCA therapy suggested a higher
incidence of serious adverse events and
poor outcomes with UDCA treatment.
 These results have led to an initiative in
many centers to discontinue UDCA
therapy in their adult patients.
33
STOPSC
Consortium
Rationale
 Childhood PSC is different from Adult
PSC in several ways.
 In childhood PSC, in response to
intermediate-dose UDCA therapy, we
see a more striking and prompt
improvement in liver blood tests as
compared to adults .
34
STOPSC
Consortium
Rationale
 In light of the prompt normalization of
liver blood test results and the fact that
UDCA therapy is well tolerated in
children, pediatric hepatologists are
reluctant to generalize the adult UDCA
study results to children and stop UDCA
therapy.
35
STOPSC
Consortium
Dilemma:
 Should UDCA therapy be stopped in
pediatric PSC patients to avoid a
possible adverse influence on long-term
outcomes at the risk of losing a possible
beneficial effect on disease progression
in children?.
36
Current Study Sites
 Study Centers












Le Bonheur Children’s Medical Center, UTHSC, Memphis
Mt. Sinai School of Medicine, New York
University of California, San Francisco
Lurie Children’s Hospital, Northwestern Univ., Chicago
The Children’s Hospital Colorado, Univ. of Colorado
Children’s Hospital of Pittsburgh, Univ. of Pittsburgh
Phoenix Children’s Hospital
Children’s Hospital of Philadelphia
LA Children’s Hospital
Emory University School of Medicine, Atlanta
Yale-New Haven Children’s Hospital
Texas Children’s Hospital, Baylor College of Medicine,
Houston
 DCC
 EMMES Corporation, Rockville, MD
37
STOPSC
Consortium
Study Protocol
38
STOPSC
Consortium
Risk/Benefit Ratio
 Risk of disease flare off UDCA
 PSC is slowly progressive, not generally
marked by acute flares unless acute
obstruction or bacterial cholangitis
 Anecdotally, biochemistries return to pretreatment range when UDCA is stopped
39
STOPSC
Consortium
Risk/Benefit Ratio
 Risk of disease flare off UDCA
 Stepped withdrawal and drug-free for only 8
weeks
 Frequent comprehensive surveillance
 Defined Significant Disease Flare with trigger
to immediately restart UDCA
40
Risk/Benefit Ratio
 Benefit
 Currently not known if UDCA therapy in pediatric
PSC is trading short-term benefit (biochemical
improvement) for long-term harm (accelerated
cirrhosis, portal hypertension, need for
transplant), as may be the case in adults
 AASLD currently does not recommend UDCA in
adult PSC patients
41
STOPSC
Consortium
Risk/Benefit Ratio
 Benefit
 Data will be used in the design of a larger
prospective, randomized, placebo-controlled
UDCA trial in children with PSC
 Data will be useful for informing the removal of
UDCA therapy in future trials of other drugs
42
Summary
STOPSC
Consortium
• 27 patients recruited –
goal is 30 then
enrollment will be closed
• Data analysis will begin
once the last patient
completes the 24 week
protocol
• Stay tuned!!!
Conclusion
• While there are no reliable reports of the
incidence and prevalence of PSC in
children, it is clearly much less common
in this age group
• The natural history of PSC in children is
only partially defined due to the lack of
long-term follow-up studies and
significant referral biases in currently
published case series.