Slides - GI and Liver Association of the Americas

Management of PBC, PSC and
Autoimmune Hepatitis (AIH)
Fred Poordad, MD
Clinical Professor of Medicine
University of Texas Health Science Center, San Antonio
Vice President, Academic and Clinical Affairs
The Texas Liver Institute
San Antonio, Texas
Disclosures
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Consultant/Advisor: AbbVie Inc., Achillion Pharmaceuticals, Anadys Pharmaceuticals,
Inc., Biolex Therapeutics, Inc., Boehringer Ingelheim GmbH, Bristol-Myers Squibb
Company, Gilead, GlaxoSmithKline, Globelmmune Inc., Idenix Pharmaceuticals, Merck &
Co., Inc., Novartis, Tibotec Therapeutics/Janssen Therapeutics, Theravance Biopharma,
Vertex Pharmaceuticals Incorporated
Grants/Research Support: AbbVie Inc., Achillion Pharmaceuticals, Anadys
Pharmaceuticals, Inc., Biolex Therapeutics, Inc., Boehringer Ingelheim GmbH, BristolMyers Squibb Company, Genentech, Inc., Gilead, GlaxoSmithKline, Globelmmune Inc.,
Idenix Pharmaceuticals, Idera Pharmaceuticals, Inc., Intercept Pharmaceuticals, Inc.,
Janssen Pharmaceuticals, Inc., Medarex, Inc., Medtronic, Merck & Co., Inc., Novartis,
Santaris Pharma A/S, Scynexis, Vertex Pharmaceuticals Incorporated,ZymoGenetics
Speaker Bureau: Gilead, Kadmon Corporation, LLC, Merck & Co., Inc., Onyx
Pharmaceuticals Inc./Bayer AG, Genentech, Inc., GlaxoSmithKline, Salix
Pharmaceuticals, Inc., Vertex Pharmaceuticals Incorporated
Outline
• PBC
• PSC
• AIH
PBC: Primary Biliary Cholangitis
•
•
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•
•
Approved name change to “Primary Biliary Cholangitis”
Chronic cholestatic disease with a progressive course which may
extend over many decades
Variable rate of progression
Fatigue, pruritus and Sicca syndrome (dry eyes and/or dry mouth)
1/1000 women age >40 years and is a common indication for
liver transplantation in that population
Kumagi T, Heathcote EJ. Orphanet J Rare Dis. 2008;3:1.
Forms of PBC1
Typical PBC
Preductopenic Variant
PBC With AIH Features
Interlobular
bile ducts
Fibrosis
0
5
10
Years
15 0
5
10
Years
15 0
5
10
Years
• Up to 30% may have a severe, progressive form of PBC resulting
in early development of liver fibrosis and liver failure1
• Some patients progress through histological stages in less than a
decade2
1. Poupon R. J Hepatol. 2010;52(5):745-758; 2. Al-Harthy N, Kumagi T. Hepat Med. 2012;4:61-71.
15
Higher APRI and Elastrography
Associated with Poor Survival
Trivedi PJ, Bruns T, Cheung A, et al. Optimising risk stratification in primary biliary cirrhosis: AST/platelet ratio index predicts
outcome independent of ursodeoxycholic acid response. J Hepatol. 2014;60(6):1249-58;
Corpechot C, Carrat F, Poujol-Robert A, et al. Hepatology. 2012;56(1):198-208.
Natural History Model for PBC
AASLD Suggested Diagnostic Algorithm
for Patients with Suspected PBC
Elevated serum alkaline phosphatase (ALP) activity
Exclude other causes of liver disease including
alcohol and drugs
Cross sectional imaging of liver to exclude biliary obstruction
AMA (Antimitochondrial antibody), ANA (antinuclear antibody), ASMA
(anti-smooth muscle antibody)
Consider liver biopsy, especially if AST>5x ULN or AMA negative
Clinical Features Vary Greatly
Between Patients
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•
•
•
•
•
Fatigue1,2
Pruritus1,2
Concurrent autoimmune diseases1,2
Reduced bone density1,2
Hypercholesterolemia1,2
Xanthoma and Xanthelasma2,3
PBC can range from asymptomatic and slowly
progressive to symptomatic and rapidly evolving.1
1. Selmi C, et al. Lancet. 2011;377(9777):1600-1609; 2. Carey EJ, et al. Lancet. 2015;386(10003):1565-1575;
3. Lindor KD, et al. Hepatology. 2009;50(1):291-308.
Assessing and Managing Fatigue
•
Though fatigue caused by PBC may not be reversible, associated causes of
fatigue should be actively excluded—or identified and managed1,2
Rule Out:
Consider Fatigue Management Strategies:
Associated causes of fatigue
(disease or medication):
Fatigue may be improved by:
• Anemia2
• Modafinil (100-200 mg)6,7
• Depression2
• Methotrexate for patients with severe fatigue8
• Maintaining regular physical activity4,5
• Sleep disorder2
• Hypothyroidism1-3
• Medications that can cause or contribute to fatigue
(eg, excessive antihypertensive medication)1
1. European Association for the Study of the Liver. J Hepatol. 2009;51(2):237-267; 2. Lindor KD, et al. Hepatology. 2009;50(1):291-308;
3. Elta GH, et al. Dig Dis Sci. 1983;28(11):971-975; 4. Cook NF, et al. Br J Nurs. 1997;6(14):811-815;
5. Graydon JE, et al. Cancer Nurs. 1995;18(1):23-28; 6. Jones DEJ, et al. Aliment Pharmacol Ther. 2007;25(4):471-476;
7. Ian Gan S, et al. Dig Dis Sci. 2009;54(10):2242-2246; 8. Babatin MA, et al. Aliment Pharmacol Ther. 2006;24(5):813-820.
Pruritus Is Common Among PBC Patients
•
•
Prevalence reported as high as 69%1
Unknown etiology1,2
– Bile salts, endogenous opioids, histamine,
serotonin, progesterone/ estrogen, and
autotaxin/lysophosphatidic acid are suspected
pruritogens2
•
•
•
Diurnal variation – most intense itch in the
late evening2
Localization reported at limbs – soles of feet,
palms of hands2
Exacerbated by contact with wool, heat,
or pregnancy3
1. Imam MH, et al. J Gastroenterol Hepatol. 2012;27(7):1150-1158;
2. Beuers U, et al. Hepatology. 2014;60(1):399-407;
3. Lindor KD, et al. Hepatology. 2009;50(1):291-308.
Pinheiro NC, et al. BMJ Case Rep. 2013.
https://thebileflow.wordpress.com/2011/10/
19/ pathology-pruritus/.
Numerous Treatment Options Exist to Help
Patients Manage Their Pruritus
General Recommendations1
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•
•
•
•
First-line2-4
Bile acid sequestrants:
• Cholestyramine
• Colestipol, colesevelam
Skin moisturizer
Wet, cooling, or moist wraps
Topical agents with symptomatic relief (eg, camphor, menthol)
Relaxation techniques
Training to stop the cycle of itch, scratch, itch
The following agents may be used for pruritus that is refractory to bile acid sequestrants:
Second-line2-4
Rifampicin
Third-line2-4
Oral opioid antagonists:
• Naltrexone
• Nalmefene
Fourth-line2-4
Selective serotonin reuptake inhibitors:
• Sertraline
1. Weisshaar E, et al. Acta Derm Venereol. 2012;92(5):563-581; 2. European Association for the Study of the Liver. J Hepatol. 2009;51(2):237-267;
3. Lindor KD, et al. Hepatology. 2009;50(1):291-308. 4. Hohenester S, et al. Semin Immunopathol. 2009;31(3):283-307.
Many Patients with PBC Also Suffer from
Cholestasis and/or Cirrhosis
% of Patients Affected
Complications of chronic cholestasis1
Osteoporosis
20%-44%
Hyperlipidemia
75%-95%
Vitamin deficiency
8%-33%
Complications related to cirrhosis
6%
(with early-stage disease)1
Varices associated with portal hypertension
Hepatocellular carcinoma
~31%
(with late-stage disease)2
1%-6% of patients per year1
1. Carey EJ, et al. Lancet. 2015;386(10003):1565-1575; 2. Lindor KD, et al. Hepatology. 2009;50(1):291-308.
Long Term Management
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•
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•
Liver chemistry tests every 3-6 months
Thyroid status (TSH) annually
Bone mineral densitometry every 2-4 years
Vitamins A, D, K annually if bilirubin >2.0
Upper endoscopy every 1-3 years if cirrhotic or
Mayo risk score >4.1
• Ultrasound ± AFP every 6 months in patients with
known or suspected cirrhosis
Ursodeoxycholic Acid (UDCA)
• Orally administered nontoxic bile acid
• Replaces the bile acids normally produced by the liver, which
are more toxic and can harm the liver
• UDCA in a dose of 13-15 mg/kg/day is the only currently FDA
approved therapy for PBC
• UDCA is initiated gradually and given BID
• Improvement in liver tests will be seen within a few weeks and
90% of the improvement usually occurs within 6-9 months
AASLD Guidance Document
ALP <1.67 X ULN and Normal Bilirubin after
1 Year of UDCA Is Highly Predictive of Outcome
Global PBC Study Group
(N=4845)
Lammers. EASL, AASLD. 2013.
Obeticholic Acid (OCA): A Modified Bile Acid
and FXR Agonist
OCA (6E-CDCA)
CDCA
obeticholic acid
chenodeoxycholic acid
6-α ethyl substitution
FXR EC50 = 8.6 µM
~100x increased potency
FXR EC50 = 90 nM
OCA in Patients with PBC:
POISE Study Design
If on UDCA: Continue UDCA
Randomization Strata
Subjects stratified 1:1:1 by:
Placebo (n=73)
Screening
1. ALP >3x ULN and/or AST >2x ULN and/or
total bilirubin >ULN (Paris I)
2. Not receiving UDCA treatment
OCA 10 mg (n=73)
Titrate to OCA 10 mg (n=33)
OCA 5 mg
0
W2
M3
Remain at OCA 5 mg (n=36)
M6
M9
Nevens F, et al. J Hepatol. 2014:60(suppl): Abstract 0168
M12
•
OCA Titration at 6 Months: Subjects in OCA
titration arm titrated from 5 mg to 10 mg at
Month 6 if they met any of the following
criteria at the Month 6 assessment:
1.
The primary endpoint (ALP <1.67x ULN
or bilirubin ≤ULN) was not achieved
2.
No evidence of tolerability issues, e.g. pruritus
ALP ≥1.67 xULN and/or total bilirubin >ULN to <2
xULN; Stable UDCA or unable to tolerate UDCA
OCA Treatment Significantly Reduced ALP
LS Mean (SE) Change in ALP (U/L)
Placebo (n=73)
Titration OCA (n=70)
10 mg OCA (n=73)
0
***
-50
***
-100
***
***
***
***
***
-150
***
***
***
-200
0
6
Time (Months)
12
***p<0.0001 vs. placebo for all post baseline values of Titration OCA and 10 mg OCA groups Baseline values (mean ± SE, U/L):
Placebo 327 ± 13; Titrated OCA: 326 ± 14; 10 mg OCA: 316 ± 12; N=216
Titration OCA group: 5 mg OCA for 6 months then titrated to 10 mg OCA if tolerated & ALP ≥1.67x ULN or bilirubin >ULN
Nevens F, et al. J Hepatol. 2014:60(suppl): Abstract 0168
OCA Treatment Resulted in Significant
Decreases in Markers of Hepatobiliary Damage
LS Mean (SE) Change from Baseline
GGT (U/L)
ALT (U/L)
0
AST (U/L)
0
0
-50
-10
-10
-100
***
***
-20
-150
***
***
***
-30
-200
-250
***
***
Month 6
Month 12
Placebo (n=73)
-40
***
***
-20
***
***
***
Month 6
Month 12
Titration (n=70)
-30
Month 6
10 mg OCA (n=73)
***p<0.001 vs. placebo
Titration OCA group: 5 mg OCA for 6 months then titrated to 10 mg OCA if tolerated & ALP ≥1.67x ULN or bilirubin >ULN
Month 12
Significant Increase in OCA Treated Patients Meeting
Primary Endpoint Compared to Placebo
R e s p o n d e rs (% )
% Responder Criteria:
Percentage of patients
achieving ALP <1.67x ULN
with bilirubin ≤ULN and
≥15% reduction in ALP
O p e n -L a b e l P h a s e
D o u b le -B lin d P h a s e
80
A ll R e c e iv e O C A
5 mg
T it r a t io n
R a n d o m iz e d T r e a t m e n t
60
***
***
******
***
***
40
***
***
3
6
***
20
***
0
0 .5
9
12
LTSE LTSE LTSE LTSE
3
6
9
12
T im e ( M o n t h s )
D B T re a tm e n t G ro u p
P la c e b o  U D C A , n
73
73
73
73
73
64
60
56
24
T itr a tio n O C A  U D C A , n
70
70
70
70
70
63
62
54
25
10 m g O C A  U D C A , n
73
73
73
73
73
64
59
54
25
***p<0.0001; P-values for comparing treatments in the double-blind phase are obtained using CMH General Association test stratified
by randomization strata factor; LTSE study on going.
Overall Findings
•
The effect of OCA was consistent independent of age at diagnosis,
duration of PBC and baseline ALP.
•
Titration from 5 to 10 mg based on clinical response improved
tolerance, minimized dropouts due to pruritus, and showed
comparable efficacy to 10 mg OCA after 1 year. Thus, starting
patients on OCA 5 mg with titration to 10 mg based on the clinical
response appears to be an appropriate dosing strategy.
•
OCA given to individuals with PBC with an inadequate response to or
unable to tolerate UDCA produced a significant clinically meaningful
improvement in liver biochemistry, which have been shown to
correlate strongly with clinical benefit.
PSC: Primary Sclerosing Cholangitis
Proposed Pathogenesis of PSC
• Bacterial translocation to biliary tree
– Animal model of bacterial overgrowth
– Link with ulcerative colitis
• Immunologically mediated
– CEP in bile
– HLA associations
• Deficient biliary chloride transport
– CFTR mutations
PSC Variant
• Small-duct PSC
– 5% of PSC
– Normal cholangiogram but biopsy showing features
of PSC
– Can progress to classic PSC
Histologic Features of PSC
Eaton JE, Talwalkar JA, Lazaridis KN, et al. Pathogenesis of Primary Sclerosing Cholangitis and Advances in
Diagnosis and Management. Gastroenterology. 2013;145:521-536.
Survival in Small vs. Large Duct PSC
Bjornsson E, Olsson R, Berqquist A, et al. The Natural History of Small-Duct Primary Sclerosing Cholangitis. Gastroenterology.
2008;134(4):975-80
Autoimmune Pancreatitis/
Cholangitis in PSC
• IgG4 elevated in 9% PSC patients
• These patients have more aggressive disease
• These patients may be more steroid responsive
Proportion without OLT
Natural History “PSC” & IgG4
Time (yrs)
Mendes F, Jorgensen R, Keach J, et al. Elevated Serum IgG4 Concentration in Patients with Primary Sclerosing Cholangitis.
Am J Gastroenterol. 2006;101:2070-75.
Colon Cancer Risk with IBD/PSC
PSC/CUC
CUC
Risk %
50%
31%
10%
9%
2%
10 Years
5%
20 Years
25 Years
Broome U, Lofberg R, Veress B, et al. Primary sclerosing cholangitis and ulcerative colitis: Evidence for increased neoplastic potential.
Hepatology. 1995;22(5):1404-8
Ursodiol in PSC
High Dose Ursodiol for PSC
60
UDCA
Placebo
50
40
30
20
10
0
Death
Minimal Listing
Criteria for Transplant
Varices
Total Endpoints
Lindor KD, Kowdley KV, Luketic VA, et al. High-dose ursodeoxycholic acid for the treatment of primary sclerosing cholangitis. Hepatology.
2009;50(3):808-14.
High-Dose Urso in UC & PSC Patients
Led to Higher Cancer Risk
Eaton J, Silveira MG, Pardi DS, et al. High-dose ursodeoxycholic acid is associated with the development of colorectal neoplasia in patients
with ulcerative colitis and primary sclerosing cholangitis. Am J Gastroenterol. 2011;106(9):1638-45.
Future PSC Treatment?
Drug/Class
Company
Phase
Dr. Falk Pharma
(Germany)
Phase 2
Intercept
Phase 2
Simtuzumab (monoclonal antibody)
Gilead
Phase 2
Vedolizumab (integrin receptor antagonist)
Takeda
Case Reports
Biotie Therapies
(UK)
Phase 2
Generic
Small studies
Norursodeoxycholic Acid
Obeticholic Acid (FXR Agonist)
BTT1023 (anti-VAP-1 antibody)
Vancomycin (antibiotic)
Conclusion
PSC
• No established therapy
• Ursodiol role being defined
• High does UDCA (28 – 30 mg/kg/day) to be avoided
• Risk of gallbladder, bile duct, and colon cancer
• ?Screening for cholangiocarcinoma
Autoimmune Hepatitis
• Disease of the hepatic parenchyma
• Break of tolerance against hepatocytes in a susceptible host
• Predominantly in women
• Hypergammaglobulinemia, circulating autoantibodies
• Histopathologically: interface hepatitis with a marked
lymphoplasmocytic inflammatory infiltrate and piecemeal
necrosis of periportal hepatocytes
Environmental Triggers
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•
•
•
Hepatitis C: anti-LKM1 against CYP2D6
Ticrynafen: anti-LKM2 against CYP2C9
Hepatitis D: anti-LKM3 against uridine diphosphate glucuronosyl
transferase 1A
Dyhydralazine: anti-LM against CYP1A2
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•
•
•
•
•
Minocycline
Nitrofurantoin
α-methyldopa
Atorvastatin, simvastatin
Imatinib mesylate
IFNβ
Association of HLA DRB1 Alleles with
AIH-Wide Geographic Variability
HLA Allele
Population
#Path.
RR
DRB1*0301
North America, UK
297
3.39
India
20
3.79
Argentina
122
3
DRB1*0404
Mexico
30
7.71
DRB1*0405
Argentina
84
10.4
Japan
77
4.97
Argentina
122
16.3
India
20
6.47
DRB1*1301
Neuberger, et al. Liver International. 2006:26; Czaja A. CurrOpinGastro. 2007:23,2006:22; Vergani, et al. CurrOpinGastro. 2001:17.
Circulating Autoantibodies (I)
Antibody
Target antigen
Liver disease
Significance
ANA
?
AIH (60-80%), PBC, PSC
drug-induced hepatitis
HCV, HBV, NASH
15% general population
SMA
actin, tubulin
vimentin, desmin
filamentous actin
AIH (60-80%), HCV
HLA A1-B8-DR3
pANCA
?
AIH (65-95%), PSC
LKM-1
Cytochrome P450 2D6
AIH (4%-AIH-2), HCV
LKM-2
Cytochrome P450 2C9
Ticrynafen-induced hepatitis
LKM-3
UGT1A
AIH-2, HCV, HDV
LM
Cytochrome P450 1A2
Dyhydralazine, HCV
Cytochrome P450 2A6
APECED
Formimino transferase cyclodeaminase
AIH(<5%, 50% AIH-2), HCV
Disease activity
Younger patients
UGA supressor serine- tRNA protein
complex
AIH (10-30%), HCV
More severe course
LC-1
SLA/LP
Clinical Presentations
• 30% present with cirrhosis
• Up to 50% may present with jaundice
• Asymptomatic-abnormal enzymes
– Often discovered during evaluation for other
autoimmune conditions
International AIH Scoring System
(International AIH Group)
J Hepatol. 1999.
Simplified Criteria for Diagnosis of AIH
(International Autoimmune Hepatitis Group)
Hepatology. 2008.
Criteria for Treatment
• Criteria for treatment
– Symptomatic disease and either
• AST>10-fold normal
• AST 5-10 fold normal and >2-fold elevation of IgG
– Presence of fibrosis
Goals for Treatment of AIH
• Primary endpoint: normalization of ALT
• Secondary endpoint: normalization of immunoglobulin
G levels
• Tertiary endpoint: normalization of histological activity
• Quaternary endpoint: resolution of fibrosis
• Final goal: to achieve sustained remission without the
need for drug therapy, maintaining the hepatic reserve
Gershwin, et al. Seminars in Liver Dis. 2007;27.
Combination Therapy
Acute presentation and
severe histological activity
Asymptomatic AIH and
mild-moderate histological activity
Corticosteroids 30-60 mg/day for
1-2 weeks + AZA 50-100 mg/day
Corticosteroids 20 mg/day for
1-2 weeks + AZA 50 mg/day
Gradual reduction
2.5 mg/week+same AZA dose
Prednisone 10 mg/day +
AZA 50-100 mg/d
Gradual taper off
prednisone
Prednisone 5-10 mg/day +
AZA 50 mg/day
Gradual taper off
prednisone
Adjust the AZA dose depending on the biochemical response and tolerance
Modified from Medina, et al. Aliment Pharmacol Ther. 2003.
Can You Stop Therapy?
•
Remission:
–
–
–
–
•
Asymptomatic
Aminotransferase<2xN
Normal IgG
Inactive liver histology
Relapse after D/C of therapy
– 80-90%
•
Risk for relapse:
–
–
–
–
–
Presence of cirrhosis
Time from initial biochemical remission
High baseline IgG
Marked portal plasma cell infiltrate (31% relapse)
A1, B8, DR3 haplotype
Alternatives for AIH Treatment
•
For primary treatment/first line:
– Budesonide
•
For refractory cases
– Cyclosporine
– Tacrolimus
•
For special cases:
– Intolerant to AZA
• MMF:
– start at 500 mg BID, increase to 1 mg BID
– Not effective for AZA refractory cases (even 3 mg/day)
– Category D drug in pregnancy by FDA: NTPR data: 50% miscarriages, 22% malformations
• 6TG
– 0.3 mg/kg QD
Loza, et al. Nature Clinical Practice. 2007.
Summary
• Autoimmune conditions of the liver can be difficult
to diagnose
• Early treatment may improve outcome
• All are chronic conditions and have extra-hepatic
manifestations and increased cancer risk
• Liver transplant is not necessarily curative for any
of the conditions, but can certainly extend life