The Safety and Efficacy of Upadacitinib in Refractory Autoimmune Related Cholangitis and Atopic Dermatitis With Moderate to Severe Itching

Evaluation of the Safety and Efficacy of Upadacitinib in the Treatment of Atopic Dermatitis With Moderate to Severe Itching and Refractory Autoimmune Related Cholangitis: a Single Arm, Exploratory Clinical Study

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.

Inclusion Criteria

Patients must meet all of the following criteria to be eligible for enrollment:

1. Aged ≥18 and ≤70 years, of either sex.

2. Criteria for Atopic Dermatitis (AD)

   Diagnosis of AD according to the Chinese diagnostic criteria for adult AD, defined as meeting the primary criterion (a) plus either criterion (b) or (c) below:

   1. Presence of symmetrical eczema with a disease duration of more than 6 months.
   2. Personal and/or first-degree family history of atopic diseases (e.g., eczema, allergic rhinitis, asthma, allergic conjunctivitis, etc.).
   3. At least one of the following laboratory findings: elevated serum total immunoglobulin E (IgE), elevated peripheral blood eosinophil count, or positive allergen-specific IgE.

   Presence of moderate-to-severe pruritus, defined as a Visual Analogue Scale (VAS) score ≥4.

3. Criteria for Primary Biliary Cholangitis (PBC)

   Diagnosis of PBC according to practice guideline criteria, defined as meeting at least two of the following three criteria:

   1. Biochemical evidence of cholestasis, primarily elevated alkaline phosphatase (ALP) and/or gamma-glutamyl transferase (GGT).
   2. Positivity for anti-mitochondrial antibody (AMA) or AMA-M2, or positivity for other disease-specific autoantibodies (anti-gp210 or anti-sp100 antibodies).
   3. Histological evidence of non-suppurative destructive cholangitis and small bile duct destruction.

   Patients must have received a standard regimen of ursodeoxycholic acid (UDCA) for ≥12 months (at a dose of no less than 13-15 mg/kg/day) in combination with at least two subsequent-line therapies (including Farnesoid X receptor agonists, peroxisome proliferator-activated receptor agonists, budesonide, or other immunosuppressants) for ≥3 months.

   At screening, ALP ≥1.5 × upper limit of normal (ULN) or GGT ≥5 × ULN.

4. Criteria for Primary Sclerosing Cholangitis (PSC)

For large-duct PSC, diagnosis must meet the following criteria:

1. Biliary imaging showing characteristic multifocal, short-segmental, or annular strictures involving both intra- and extrahepatic bile ducts.
2. At least one of the following clinical manifestations: biochemical evidence of cholestasis (primarily elevated ALP and/or GGT); clinical or histological evidence of coexisting inflammatory bowel disease (IBD); or liver histology showing periductal inflammation with fibrosis (i.e., periductal "onion-skin" appearance).
3. Exclusion of secondary sclerosing cholangitis due to other etiologies.

For small-duct PSC, diagnosis must meet the following criteria:

1. Biochemical evidence of cholestasis with no significant abnormalities on recent biliary imaging.
2. Liver histology showing typical PSC changes as described above (periductal inflammation with fibrosis / "onion-skin" appearance).
3. Exclusion of other causes of cholestasis. Patients must have received a standard regimen of UDCA for ≥3 months (at a dose of no less than 13-15 mg/kg/day). At screening, ALP ≥1.5 × ULN or GGT ≥5 × ULN.

Exclusion Criteria

Patients who meet any of the following criteria will be excluded from enrollment:

1. 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.
2. 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).
3. Total bilirubin >10 × upper limit of normal (ULN).
4. Serum creatinine ≥1.5 × ULN and creatinine clearance <60 mL/min.
5. Platelet count <50 × 10⁹/L.
6. International normalized ratio (INR) >1.5.
7. Serum albumin <3.0 g/dL.
8. Use of moderate or strong inhibitors or inducers of cytochrome P450 3A4 (CYP3A4) within 14 days prior to the first dose of study drug or planned use throughout the study period.
9. Presence of diseases that may cause non-hepatic elevation of ALP (e.g., Paget's disease of bone) or any condition with an anticipated life expectancy of less than 2 years.
10. Known drug abuse or alcohol abuse within 6 months prior to the first dose of study drug, defined as weekly alcohol consumption exceeding 14 standard drinks (1 standard drink equivalent to 360 mL beer, 45 mL of 40% distilled spirits, or 150 mL wine).
11. Unstable concomitant diseases or use of concomitant medications that cannot be maintained on a stable regimen throughout the clinical study period.
12. Pregnant women, women planning to become pregnant, breastfeeding women, or fertile patients (male or female) who are unwilling to use at least one effective method of contraception from the time of signing informed consent until 30 days after the last dose of study drug.
13. Participation in any other interventional clinical trial and receipt of any investigational product within 3 months prior to the first dose of study drug.
14. Positive results for human immunodeficiency virus antibodies (HIV Ab) or Treponema pallidum antibodies (TP Ab).
15. Any other condition that, in the investigator's judgment, would preclude the patient's participation in this study.