Colangite Biliare Primitiva STRATIFICAZIONE DEL RISCHIO Domenico ALVARO

Colangite Biliare Primitiva STRATIFICAZIONE DEL RISCHIO Domenico ALVARO, MD Sapienza, University of Rome, Italy

PBC what to do after the diagnosis ? - Disease stage ! - Prognosis: risk stratification !

J. Hepatology 2017 Gut 2018 Hepatology 2018 DLD 2017

PBC Phenotype Age Gender Serology Usually > 45 years Immunoglobulin Biliary tree imaging Liver histology Ig. M typically elevated Female > Male (9: 1) AMA in ~95% disease-specific ANA in ~30% -50%; ASMA may be present Normal Lymphocytic infiltrate; inflammatory duct lesion; granuloma may be present Abbreviations AMA antimitochonaddrial antibody; ANA antinuclear antibody; ASMA, anti-smoth-muscle antibody; IBD, inflammotory bowel desease: MRCP, magnetic resonance cholangiography; PBC, primary biliary choalngitis. Trivedy PJ et al. Al. iment Pharmacol Ther 2012; 36: 517 -533.

The Two Sides of PBC Mild Disease Aggressive Disease • In elderly women • Mild itch as the symptom • Responds well to UDCA • Risk very low and unlikely to die of liver disease or need translplant • In young women (men ? ) • Fatigue as a prominent or even lifealtering feauture • gp 210 ANA, interface hepatitis • Minimal response to UDCA • High risk of need for transplant, requires second line therapy 50 -60% of our pts. 10 -15% of our pts. Abbreviations ANA antinuclear antibody; PBC, primary biliary choalngitis; UDCA, ursodeoxycholic acid.

PBC: risk stratification ? ? ? Asymptomatic AMA+ ALP high Silent Slowprogressive Rapidprogressive (elderly women, mild itch, UDCA- (young women, fatigue, UDCA-non- responders) AMA+ ALP normal Interface hepatitis/PBC-AIH overlap (non responder ) Portal hypertension-type progression (ACA-pos. ) Hepatocellular failure-type progression (Anti-gp 210 antibody pos. )

PBC: risk stratification ! UDCA responders VS UDCA non responders

PBC: the way to precision medicine MAIN PRINCIPLES: - More proactive and predictive approach to medicine; - Risk stratification; - Individualization of treatment for each patient; - Prevention rather than the treatment of symptoms; ‘the right treatment, for the right person, at the right time’ !

PBC: staging and prognostic indexes at the diagnosis ! RISK STRATIFICATION ! EASL guidelines 2017

PBC: staging and prognostic indexes at the diagnosis ! -Anti-Sp 100 and anti-gp 210 ANA to be checked since their prognostic significance !? -Cirrhosis should be checked by US (PV doppler) indirect signs ! -Transient elastography to classify PBC patients with or without severe fibrosis ! - Alkaline phosphatase serum levels ! -Category of evidence = II-2 -Grade of evidence = A 1

Non-specific antinuclear antibodies (ANA) are found in at least 30% of PBC cases (85% AMA-neg. PBC) ANA directed against nuclear body or envelope proteins such (anti-Sp 100, anti-gp 210) show a high specificity for PBC (>95%), but with low sensitivity ! EASL practice guidelines, J Hepatol 2009

ANA PBC-specific (30% of PBC, > 95% of AMA-neg): Anti-gp 210 antibody: • PBC-specific anti-nuclear antibody, targets …nuclear pore complex (NPC); • Associated with more aggressive disease, more severe interface and lobular hepatitis, late stage PBC (Wesierska-Gadek 2006); • Marker of hepatocellular failure-type progression in PBC. Anti sp 100 antibody: • Found in many other autoimmune diseases, including systemic lupus erythematosus and systemic sclerosis (SSc); • Prognostic significance of sp 100 antibodies unclear ! Anti-centromere antibodies (ACA): • Characteristic of SSc but also found in PBC patients without coexistent SSc; • Predictive of portal hypertension-type disease progression, without synthetic failure (Gao et al. 2008); EASL practice guidelines, J Hepatol 2009

PBC: UDCA-response + Liver stiffness ? ! C. Corpechot

2015

15, 875 PBC cohort (63. 0± 13. 5 y, 78% female, 46% with cirrhosis); 6083 (38%) had ALP≥ 1. 5×ULN Associated with : --more pruritus --more cirrhosis, + other autoimmune diseases Multivariate analysis: --presence of other autoimmune diseases --compensated or decompensated cirrhosis --being male …. . higher risk of cirrhosis

Asymptomatic primary biliary cirrhosis: a study of its natural history and prognosis. J Springer et al. American Journal of Gastroenterology 1999.

PBC: risk stratification ! UDCA responders VS UDCA non responders

PBC: UDCA response as main prognostic index ! * Dichotomous models, easy to use but: -only two levels of risk; -fail to quantify intermediate levels of risk; -ignore the relationship between risk and time They do not indicate whether the high-risk patient will need a LT tomorrow or fifteen years in the future !

PBC: UDCA response as main prognostic index ! To properly inform treatment decisions, continuous risk index (or score) that quantifies the individual’s risk in relation to time are demanding …

PBC: risk stratification ! UDCA responders VS UDCA non responders

Costo UDCA = 180 -220 euro/anno !

2703 PBC included in the UK-PBC cohort for derivation of the model 460 PBC in the external validation cohort: AUROC= 0. 83 (95% CI 0· 79– 0· 87)

In 20 PBC liver biopsy UDCA response score associated with ductular reaction (r=– 0· 556, p=0· 0130) and intermediate hepatocytes (probability of response was 0· 90 if intermediate hepatocytes were absent vs 0· 51 if present).

Studi prospettici sui predittori istologici di risposta al trattamento e sulla progressione istologica di malattia in pazienti PBC trattati con UDCA+OCA sono indispensabili per stabilire quando cessare il trattamento o cambiare farmaco !