What are the criteria to start second-line treatment in Primary Biliary Cholangitis (PBC), specifically in terms of lab values and duration of Ursodeoxycholic Acid (UDCA) therapy?

Criteria for Starting Second-Line Treatment in Primary Biliary Cholangitis (PBC)

Second-line therapy should be initiated in PBC patients who have an inadequate response to UDCA after 12 months of treatment at 13-15 mg/kg/day, defined as ALP ≥1.67 times the upper limit of normal (ULN) and/or total bilirubin >ULN, or less than 15% reduction in ALP from baseline. 1

Biochemical Response Criteria

The assessment of response to first-line UDCA therapy is crucial for determining when to initiate second-line treatment. Several validated criteria exist:

Primary Response Criteria (after 12 months of UDCA therapy):

• Paris-II criteria: ALP ≤1.5×ULN, AST ≤1.5×ULN, and normal bilirubin
• Toronto criteria: ALP ≤1.67×ULN
• Rotterdam criteria: Normalization of abnormal bilirubin and/or albumin
• Barcelona criteria: Decrease in ALP >40% or normalization
• Paris-I criteria: ALP ≤3×ULN, AST ≤2×ULN, and bilirubin ≤1 mg/dL

Risk Stratification Tools:

• GLOBE score: Includes age, total bilirubin, ALP, albumin, and platelet count after 12 months of UDCA
• UK-PBC score: Includes baseline albumin and platelet count, and bilirubin, AST/ALT and ALP after 12 months of UDCA

Timing of Assessment

While 12 months is the standard timeframe for evaluating UDCA response 1, recent research suggests earlier assessment may be beneficial:

• The Xi'an criterion proposes evaluation at 1 month after UDCA initiation (ALP ≤2.5×ULN, AST ≤2×ULN, and TBIL ≤1×ULN) 2
• Early identification of non-responders could prevent prolonged ineffective treatment

Specific Laboratory Values Indicating Need for Second-Line Therapy

After 12 months of UDCA therapy at 13-15 mg/kg/day, second-line therapy should be initiated if:

1. ALP ≥1.67×ULN (primary criterion) 1, 3
2. Total bilirubin >ULN 1
3. ALP reduction <15% from baseline 1, 3

Risk Factors for Disease Progression

Patients with these additional factors should be considered for earlier or more aggressive second-line therapy:

• Liver stiffness measurement ≥10 kPa (indicating advanced fibrosis) 4
• Age ≤62 years 4
• Elevated GGT >3.2-fold ULN at 12 months 1
• APRI score >0.54 after 12 months of UDCA therapy 1

Second-Line Treatment Options

When criteria for second-line therapy are met, options include:

1. Obeticholic acid (OCA): FDA and EMA approved

   • Starting dose: 5 mg once daily for 3 months
   • Titration to 10 mg once daily based on tolerability and response 3

2. Bezafibrate: Used off-label in combination with UDCA

   • Has shown efficacy in reducing ALP levels and improving pruritus 1, 5

Monitoring During Second-Line Therapy

• Monitor liver biochemistry (ALP, bilirubin, transaminases) every 3 months
• For patients on bezafibrate: monitor serum creatinine and watch for myalgia 5
• For patients on OCA: monitor for pruritus, which is a common side effect 3

Special Considerations

• Pregnancy: UDCA should be continued during pregnancy, but OCA is not recommended due to lack of safety data 1
• Pruritus: Severe pruritus may require specific management with cholestyramine, rifampicin, or other agents 1, 5
• Clinical trials: Consider referring patients with inadequate UDCA response for clinical trials of emerging therapies 1

Recent Evidence on Treatment Goals

Recent research suggests that even in patients considered "adequate responders" by Paris-II criteria, achieving complete normalization of ALP is associated with significant survival benefits, particularly in patients with advanced fibrosis (liver stiffness ≥10 kPa) and/or age ≤62 years 4. This suggests that treatment goals may need to be more stringent than previously thought.