Cholestatic liver diseases are characterized by jaundice, pruritus, and elevated levels of alkaline phosphatase (ALP) and gamma-glutamyl transferase (GGT). Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) represent the major autoimmune-driven entities within this category. Without effective intervention, these conditions may progress to liver failure and even death. Ursodeoxycholic acid (UDCA), the first-line therapy for PBC, has been shown to improve prognosis; however, 20%-40% of patients exhibit an inadequate biochemical response. For PSC, no clearly effective pharmacologic agent is currently available. In refractory patients, pruritus often progressively worsens, severely impairing quality of life and treatment adherence, underscoring an urgent need for novel therapeutic approaches that simultaneously address disease control and itch relief.
Autoimmune-associated cholangitis frequently coexists with atopic dermatitis, and in a subset of patients, pruritus may be compounded by dermatologic factors. The pruritus of atopic dermatitis involves the JAK-STAT signaling pathway, which not only serves as a convergent node for pruritic signals but also constitutes a key downstream hub in the immune dysregulation characteristic of cholangitis. Inhibition of this pathway is therefore hypothesized to alleviate pruritus and modulate aberrant immune responses. Case reports have suggested that upadacitinib, a selective JAK inhibitor, may improve biochemical parameters in refractory PBC and exhibit potential anti-fibrotic effects.
To this end, investigators plan to conduct an exploratory clinical study to systematically evaluate the safety and efficacy of upadacitinib in patients with atopic dermatitis complicated by moderate-to-severe pruritus and refractory autoimmune-associated cholangitis.
Aged ≥18 and ≤70 years, of either sex.
Criteria for Atopic Dermatitis (AD)
Presence of symmetrical eczema with a disease duration of more than 6 months.
Personal and/or first-degree family history of atopic diseases (e.g., eczema, allergic rhinitis, asthma, allergic conjunctivitis, etc.).
Known concurrent or history of other hepatobiliary diseases, including but not limited to: active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection; complete biliary obstruction; acute cholecystitis or symptomatic cholelithiasis; suspected or confirmed hepatocellular carcinoma (HCC) or cholangiocarcinoma.
Child-Pugh Class C cirrhosis; evidence of end-stage liver disease, including: history of liver transplantation or being on the liver transplant waiting list; Model for End-Stage Liver Disease (MELD) score >20; severe portal hypertension complications (including severe gastric or esophageal varices, refractory or diuretic-resistant ascites, history of variceal bleeding); or other serious cirrhosis-related complications (spontaneous bacterial peritonitis, hepatic encephalopathy, hepatorenal syndrome, hepatopulmonary syndrome).
Total bilirubin >10 × upper limit of normal (ULN).
Serum creatinine ≥1.5 × ULN and creatinine clearance <60 mL/min.
Single group
Upadacitinib 15 MG
DrugThis is a single-arm, open-label, fixed-dose exploratory clinical trial. All eligible subjects who meet the inclusion and exclusion criteria will receive a uniform, fixed-dose regimen of upadacitinib in combination with background therapy, without a concurrent control group. The administered dose is 15 mg once daily (QD), which falls within the recommended dose range for atopic dermatitis as approved in the upadacitinib Chinese package insert (product labeling). This study will not investigate alternative dosage regimens, nor will it evaluate the efficacy or safety of off-label dose levels.
Pruritus of atopic dermatitis
Change from baseline in the Visual Analogue Scale (VAS) score for pruritus during the study period.
Biochemical composite endpoint of autoimmune-associated cholangitis
Proportion of patients achieving the biochemical composite endpoint at Week 12 and Week 24, defined as a ≥30% reduction in alkaline phosphatase (ALP) from baseline without elevation in direct bilirubin (DB).
Degree of liver fibrosis
Change from baseline in liver stiffness measurement assessed by transient elastography (FibroTouch/FibroScan).
Blood eosinophil count
Change from baseline in peripheral blood eosinophil count during the study period.
Peripheral blood immune cell subpopulations
Change from baseline in peripheral blood immune cell subpopulations during the study period.
Serum immunoglobulin levels
Change from baseline in serum immunoglobulin levels (IgG, IgM, IgA) during the study period.
Liver function
Percentage change from baseline in serum levels of alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT), total bilirubin (TB), direct bilirubin (DB) , alanine aminotransferase (ALT), aspartate aminotransferase (AST) and albumin (ALB) during the study period.
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