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.
Highlights
The term “overlap syndromes” is used to describe a family of rare, morbid conditions characterized by biochemical, immunologic, histologic, or cholangiographic features of more than one of the well-recognized autoimmune liver diseases: Autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC) [1]
Of the three studies pertaining to autoimmune cholangitis (AIC), two compared ursodeoxycholic acid (UDCA) to corticosteroids ± AZA [22,24], while the third compared combination therapy to a complex personalized regimen consisting of UDCA, prednisolone, AZA, mycophenolate mofetil (MMF), budesonide, rifampicin, and several other agents [23]
Among the 21 AIH-PBC studies in our systematic review, four were ineligible for meta-analysis: One because it was the only study comparing UDCA to placebo [13], one because of an ambiguous overlap between treatment groups [22], and two because no clinical outcomes occurred during follow-up [69,72]
Summary
The term “overlap syndromes” is used to describe a family of rare, morbid conditions characterized by biochemical, immunologic, histologic, or cholangiographic features of more than one of the well-recognized autoimmune liver diseases: Autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC) [1]. These overlap syndromes include AIH-PBC, AIH-PSC, PBC-PSC, AIH-PBC-PSC, autoimmune cholangitis (AIC), and autoimmune sclerosing cholangitis (ASC). In some studies patients appeared to benefit from UDCA alone [7,10,13], or from just corticosteroids with or without AZA [3,14]. At 10 years, progression to cirrhosis among patients with AIH-PBC is approximately 44–48% [18,19], and transplant-free survival is 52–92% [19,20,21]
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