autoimmune liver diseases treatment updates...autoimmune hepatitis (aih) •unresolving inflammation...
TRANSCRIPT
AUTOIMMUNE LIVER DISEASE: PROGRESS IN PBC & PSC
Maria A. Lagarde, MD
Gastroenterology and Transplant Hepatology
2019
DISCLOSURES
•none
OBJECTIVES
Treatment options for autoimmune hepatitis
Drugs in the pipeline for AIH
New treatment options for PBC beyond Ursodiol
New therapeutic targets for PBC
Treatment strategies for PSC
WHAT IS NEW FOR 2020: GENERAL PATHOPHYSIOLOGY AND
DEMOGRAPHICSOf all autoimmune liver diseases
CHANGES IN DEMOGRAPHICS
• Element exposure as possible pathogenesis mechanism
• Racial disparities in AIH
• PBC is on the rise!
Oral abs. #48 Dyson et Al.
BLACK PATIENTS AND AIH
Younger age median 38 vs 45 years(P < .007)
Higher IgG levels (mean 31.0 vs 27.5 mg/dL) (P <
.04)
Higher proportion of SLE (10%) > whites(2%) (P <
.001)
No difference in response to treatment (P.20) or
rate of relapse (P=0.3), yet
Increased risk of LT and liver-related death
(HR 2.4, 95% CI, 1.4–4.0; P < .001)
DeBoer YS, et Al. Clin.GastroHep 2019.
England and Netherlands
from 1971-2016
88 blacks vs 897 whites with AIH
PBC
Retrospective data from National (Nationwide) InpatientSample (NIS) 2005 to 2014. Total of 22,665 PBC discharges.
Trends in PBC‐related discharges, total charges, length of stay (LoS), and in‐hospital mortality
RESULTS
• PBC-related discharges ↑ from 3.24 (in 2005) to 3.68 per 100k (in 2014)
• Avg. annual ↑↑ of 1.4% (95% CI 0.4%-2.4%)
• ↑ severity of illness and risk of death
• Drop by 5.4% in-hospital mortality rate
Shahab et Al. Hepatol Commun 2019
Incidence/Prevalence
Environmental exposure
Better in-Hospital survival
Early diagnosis, longer survival
Failure of effective 1st line therapy
AUTOIMMUNE HEPATITIS IN
2020
AUTOIMMUNE HEPATITIS (AIH)
• Unresolving inflammation of the liver
• Unknown cause
• 1-2 cases per 100K PPY
• W:M 3.6:1
• All ages, but peak in the young (13-30)
• Variable presentation: commonly slow progression (acute/severe liver failure)
• Diagnosis: clinical, laboratory (abnormal globulins/autoantibodies) and histologic features
• First liver disease found to be manageable with Rx
AIH PREDNISONE + AZA 70 YRS OF EXPERIENCE
• Goal: Normal ALT/AST, GG and IgG
• Cont. treatment for 2 years after normalization
• Histological remission confirmation:
• ~45% of patients in biochemical remission, have positive Bx
• Failure:
• medication intolerance (10%)
• incomplete response (15%) treatment failure (9%)
Verling JM. Clin Gastro Hep 2015
Lammert Current Gast Rep 2016
Unmet needs
Tolerable steroid-free induction regimens
2nd line Rx in refractory or intolerant patients
Management of recurrent AIH (rAIH) post‐liver transplantation (LT)
MYCOPHENOLATE MMF
• Biochemical remission from 31%-73% (discontinuation 13% to 34%)
• Cirrhotics ↑ risk of infections, sepsis, death
• SE: diarrhea, abdominal pain
• Teratogenic!
Zachou. Aliment Pharmacol Ther. 2016
MMF AS A 1ST LINE AGENT?
Real-world observation prospective study (Zachou, 2016)
• 109 pts on Pred+MMF vs 22 pts on Pred+AZA
• 72% in MMF group achieved complete response on Rx w/higher prob of remission (P=0.03)
• Treatment withdrawal was feasible in 40/109 patients and 30 (75%) were still in remission after 24 (2-129) months.
CAMARO TRIAL:
• RCT on MMF vs AZA. Enrolling until Dec 2019. NCT02900443
Doycheva. Liver Inter 2019
LOWER STEROID DOSES. SAFE?
Retrospective cohort study with AIH (5 countries/9ctrs-
Europe)1978-2017
Patients divided to:
HD (n=281)
LD (n=170)
Primary outcome: normalization of
AST/ALT @6m
Pape. Clin Gastroenterol Hepatol 2019
AST/ALT AST/ALT
+GG
FUTURE THERAPIES
DRUG Stage Mx of Action outcome
JKB-122
Ph 2
(open
label)
Toll-like r4
(TLR4)
Agonist
Change in
ALT
VAY736
Ianalu-
mab
Ph 2&3
(RDB-
PCT)
MAB→
B-cell
activating
receptor
ALT
normal
IL-2
Ph 2
(open
label)
Treg inducer% of Tregs
@day 8
Treg Cells
(inf)
Ph 1&2
(open
label)
Down-
regulates
pro-inflamm.
state
Biochem.
Immun.
remission
LPS (gut
bacteria)
TLR411
2
2
3 3
3
4
4
Doycheva. Liver Inter 2019Manns. J Hepatol. 2015
PRIMARY BILIARY
CHOLANGITIS IN 2020
PRIMARY BILIARY
CHOLANGITIS
• Chronic cholestasis
• Inflammation and destruction of small interlobular bile ducts
• Mainly affects middle-aged females
• Clinical presentation: pruritus, fatigue and sicca symptoms
• Criteria 2/3:
• Unexplained elevation of ALP > 1.5 x ULN
• Positive AMA
• Non-suppurative destructive cholangitis on histology
UDCA STILL1ST LINE?
- USE in all patients who have elevated ALP
- Improves biochemistries
- Slows progression of fibrosis
- Delays appearance of EVs
- Lowers IgM and cholesterol
- Use of UDCA decreases death or the need for LT
90
78
66
79
59
32
0
10
20
30
40
50
60
70
80
90
100
5-year 10-year 15-year
UDCA-treated Untreated
Transplant-Free Survival
Lammers et Al Gastroenterology 2014
SECOND LINE THERAPY
40% of patients do not respond to UDCA
When to consider?
• Lack of Biochemical response at 1 year
GLOBE-PBC/UK-PBC risk stratification scores
AST to
Platelet
Ratio
Index
(APRI)
Lindor. Hepatology 2019
OBETACHOLIC ACID
• FXR agonist • Inhibits BA uptake/synthesis• TNF-alpha pathway• Increases BA secretion
• FDA Approved based on the NEJM POISE trial (Nevens, 2016)
• 216 pts failed/intolerant to UDCA 1ary EP: Normalization of ALP (<1.67 ULN, and n-Tbili)
• OCA 46/47% vs 10% UDCA
• Worsening PBC and death in CPT B-C
PEROXISOME PROLIFERATOR ACTIVATOR RECEPTOR (PPAR)
• PPAR 𝛂: reg. bile acid homeostasis, PPL secretion and inflammatory path.
• PPAR 𝛅: improves insulin res. and lipid metab. enhanced energy use, anti-inflammatory properties
• PPAR 𝛄: regulates adipogenesis, anti-inflammatory, anti-fibrotic properties
Fibrate In the liver Other
benefits
Fenofibrate-α Cholestasis markers TNF levels
TG
Bezafibrate-
pan
Cholestasis markers and
inflammation
Pruritus
stiffness
Seladelpar-δ Cholestasis markers and
inflammation
LDL
Elafibranor-α/δ fatty deposition and
inflammation
In the US, fenofibrate is approved for treatment of hyperlipidemia and bezafibrate is not available.
Corpechot NEJM 2018
BEZAFIBRATE
• 24-month DBPCT phase 3
• 100 patients inadequate response to UDCA
• UDCA + bezafibrate vs. UDCA + placebo
FROM THE GUIDANCE 2018
Fibrates can be considered as OFF-label use alternatives for patients with PBC and inadequate response to UDCA
Use of Fibrates is discouraged in patients with decompensated liver disease CPT B or C
FROM BASIC SCIENCE: • Hepatic mast cell (MCs) infiltration and
activation correlates with biliary damage and fibrosis in late stage PBC. • Activated MCs →H2-histamine receptors (H2HR)
signals → disease progression
• biliary HDC (histidine)→ perpetuate injury →autocrine mechanisms.
• Secretin and Secretin receptor: • excretion of bicarb/Cl- (by secretin) appears
protective from BAs
• Promotes cholangiocyte proliferation
Inhibition of MC activation or
biliary HDC/H2HR signaling
Potential therapeutic target
Mice (advanced PBC) treated
with Secretin and UDCA
amelioration of ductopenia
liver damage and fibrosis
vs. controls
PRIMARY SCLEROSING CHOLANGITIS
IN 2020
PSC
• Chronic, immune-mediated cholestasis
• Inflammation and fibrosis of IH/EH bile ducts
• Progressive to cirrhosis/portal HTN
• Median LT-free survival 12 yrs
• Males (70%) > females
• Diagnosis at 20-40 yrs (can present in childhood)
• 60-80% have IBD (occurs in 2-7% pts with IBD)
• Associated with AIH 7-10% (overlap)
• Other outcomes: bacterial cholangitis, bone disease, cholangiocarcinoma, higher risk for colon cancer
DIAGNOSIS
Liver biopsy is not necessary when Cholangiography is characteristic
Exceptions: Small duct PSC, AIH overlap
ERCP may be used 1st in patients who are symptomatic or require interventions
MRCP has replaced ERCP as the diagnostic modality of choice for asymptomatic individuals
May miss early PSCNo radiation, non-
invasive
TREATMENT OPTIONS
There is NO
treatment
UDCA
Maybe, but if at all
LOW dose <15mg/kg
This Year
Statins and AZA
Fecal microbiota transplantation
Cilofexor
STATINS AND AZA
Swedish population cohort PSC+IBD 2005-2014 (n=2914)
Drug exposure PLUS Risk or death, LT, EVB, and cancer
Findings
• Statin and AZA use ↓ Risk of • all-cause mortality (HR 0.68 / 0.66; 95%
CI) • Death or liver transplantation (HR, 0.50 /
0.65; 95%)
• Exposure to UDCA did not affect mortality (HR, 1.04; 95% CI)
FMT10 pts with PSC+IBD (9UC/1CD) and ALP1.5>ULN (mean 489U/L) open label single FMT. LFTs and microbiome up to 24 wks
• 1st outcome: safety
• 2nd outcome drop in ALP levels >50%
• stool microbiota and metabonomic dynamics
Findings
• NO adverse events, 3/10 patients had drop in ALP >50%
• Diversity increased in all patients
• Patients with higher engrafting OTUs (bacterial variety and restitution) had the higher ALP response
CILOFEXOR
Methods:
• DBRPCT comparing 2 doses of Cilofexor and PBO x 12 weeks
• 52 non-cirrhotics with large-duct PSC and ALP > 1.67 x ULN
Main Findings:
• ↓ALP irrespective of UDCA use
• ↓ALT, GGT, TIMP-1, C4 and BA’s
• Grade 2-3 pruritus less frequent with Cilofexor c/w PBO
Conclusion
• significant ↓ in liver biochemistry and markers of cholestasis w/o aggravating pruritus
TAKE HOME POINTS
AIH has effective therapy, but there is an unmet need for steroid spearing therapy
that is safe and effective
In PBC, UDCA and OCA are now first and second line therapy, with new
therapeutic targets rapidly approaching.
PPAR inh-fibrates are the most promising new therapies for PBC
PSC remains a diagnosis without treatment. Potential future therapies
(including Cilofexor) are still in early stages
THANK YOU!