Treatment of Overlap Syndromes in Autoimmune Liver Disease: A Systematic Review and Meta-Analysis

Abstract

The treatment of overlap syndromes is guided by small observational studies whose data have never been synthesized in a rigorous, quantitative manner. We conducted a systematic review and meta-analysis to evaluate the efficacy of available treatments for these rare and morbid conditions. We searched the literature for studies comparing ≥2 therapies for autoimmune hepatitis (AIH)-primary biliary cholangitis (PBC), AIH-primary sclerosing cholangitis (PSC), PBC-PSC, AIH-PBC-PSC, autoimmune cholangitis (AIC), or autoimmune sclerosing cholangitis (ASC) with respect to various clinical outcomes, including biochemical improvement and transplant-free survival. A total of 28 studies met the inclusion criteria for AIH-PBC, AIH-PSC, AIC, and ASC. AIH-PBC patients tended to experience more biochemical improvement with ursodeoxycholic acid (UDCA) + [corticosteroids and/or antimetabolites], i.e., "combination therapy", than with corticosteroids ± azathioprine (RR = 4.00, 95% CI 0.93-17.18). AIH-PBC patients had higher transplant-free survival with combination therapy than with UDCA, but only when studies with follow-up periods ≤90 months were excluded (RR = 6.50, 95% CI 1.47-28.83). Combination therapy may therefore be superior to both UDCA and corticosteroids ± azathioprine for the treatment of AIH-PBC, but additional studies are needed to show this definitively and to elucidate optimal treatments for other overlap syndromes.

Keywords: autoimmune liver disease; corticosteroid; immunosuppression; overlap syndrome; ursodeoxycholic acid.

Figure A1

Study selection flow diagram.

Figure A2

Biochemical improvement in AIH-PBC patients treated with combination therapy vs. UDCA alone, including only those studies in which combination therapy consisted of UDCA + corticosteroids ± AZA (i.e., no patients were treated with MMF, or with a combination of UDCA and antimetabolite therapy without corticosteroids). UDCA = ursodeoxycholic acid, AZA = azathioprine, MMF = mycophenolate mofetil.

Figure A3

Biochemical improvement in AIH-PBC patients treated with combination therapy vs. UDCA alone, including only those studies in which AIH-PBC was defined by the Paris criteria. UDCA = ursodeoxycholic acid, Combination = UDCA + [corticosteroids and/or antimetabolites].

Figure A4

Biochemical improvement in AIH-PBC patients treated with combination therapy vs. UDCA alone, including only those studies in which biochemical improvement was defined by both hepatocellular and cholestatic markers. UDCA = ursodeoxycholic acid, Combination = UDCA + [corticosteroids and/or antimetabolites].

Figure A5

Transplant-free survival in AIH-PBC patients treated with combination therapy vs. UDCA alone, including only those studies in which mean or median follow-up time exceeded 90 months. UDCA = ursodeoxycholic acid, Combination = UDCA + corticosteroids ± AZA.

Figure 1

Symptomatic improvement in AIH-PBC patients treated with combination therapy vs. UDCA. UDCA = ursodeoxycholic acid, Combination = UDCA + [corticosteroids and/or antimetabolites].

Figure 2

Biochemical improvement in AIH-PBC patients treated with combination therapy vs. UDCA alone. UDCA = ursodeoxycholic acid, Combination = UDCA + [corticosteroids and/or antimetabolites].

Figure 3

Non-progression of liver fibrosis in AIH-PBC patients treated with combination therapy vs. UDCA alone. UDCA = ursodeoxycholic acid, Combination = UDCA + corticosteroids ± AZA.

Figure 4

Transplant-free survival in AIH-PBC patients treated with combination therapy vs. UDCA alone. UDCA = ursodeoxycholic acid, Combination = UDCA + [corticosteroids and/or antimetabolites].

Figure 5

Biochemical improvement in AIH-PBC patients treated with immunosuppression vs. UDCA. UDCA = ursodeoxycholic acid, steroid = corticosteroids, AZA = azathioprine.

Figure 6

Transplant-free survival in AIH-PBC patients treated with immunosuppression vs. UDCA. UDCA = ursodeoxycholic acid, steroid = corticosteroids, AZA = azathioprine.

Figure 7

Biochemical improvement in AIH-PBC patients treated with combination therapy vs. immunosuppression. Steroid = corticosteroids, AZA = azathioprine, Combination = UDCA + corticosteroids ± AZA.

Figure 8

Transplant-free survival in AIH-PBC patients treated with combination therapy vs. immunosuppression. Steroid = corticosteroids, AZA = azathioprine, Combination = UDCA + corticosteroids ± AZA.

Figure 9

Biochemical improvement in AIC patients treated with immunosuppression vs. UDCA. Steroid = corticosteroids, AZA = azathioprine, and UDCA = ursodeoxycholic acid.

Figure 10

Biochemical improvement in ASC patients treated with combination therapy vs. UDCA. UDCA = ursodeoxycholic acid and Combination = UDCA + prednisone ± AZA.

Figure 11

Transplant-free survival in ASC patients treated with combination therapy vs. UDCA. UDCA = ursodeoxycholic acid and Combination = UDCA + prednisone ± AZA.

Figure 12

Funnel plots of AIH-PBC studies meta-analyzed to compare (a) biochemical improvement and (b) transplant-free survival among patients treated with UDCA vs. combination therapy. UDCA = ursodeoxycholic acid and combination therapy = UDCA + [corticosteroids and/or antimetabolites].