Systematic Review and Meta-analysis: Immunosuppressive Agents for the Treatment of Primary Biliary Cholangitis
PDF

Keywords

Primary biliary cholangitis
Immunosuppressive agents
Meta-analysis

DOI

10.26689/jcnr.v5i4.2283

Abstract

Background and aim: There are still no clinically satisfactory therapy for PBC. This study was performed to assess the safety and efficacy of IAs for the therapy of PBC. Methods: Relevant studies were identified and selected by searching PubMed, Web of Science and Cochrane Library databases. The primary outcome was defined as the need for mortality or liver transplantation. Adverse effects and liver biochemical variables were a secondary outcome. Results: Nine randomized controlled trials, involving six different treatment regimens with a total of 996 patients, were included in the analysis. On meta-analysis, IAs was not associated with a reduction in risk of mortality or liver transplantation (risk ratio [RR]: 0.92, 95% confidence interval [CI]: 0.69-1.22, P = 0.57, I2 = 0%), and have resulted in more adverse effects (RR: 1.44, 95% CI: 1.08-1.92, P = 0.01, I2 = 19%). Subgroup analysis showed that IAs monotherapy caused adverse effects such as diarrhea, abdominal pain, and renal insufficiency (RR: 1.36, 95% CI: 1.01-1.82, P = 0.04, I2 = 48%). IAs therapy did not prominently improve markers of liver function except for alkaline phosphatases (weighted mean difference [WMD]: -0.38, 95% CI: -0.62 to -0.14, P = 0.002). Conclusions: IAs cannot reduce the risk of mortality or liver transplantation, whether in IAs monotherapy or combination therapy, and even be associated with more adverse effects.

References

Gulamhusein AF, Hirschfield GM., 2020, PBC: Pathogenesis and Therapeutic Opportunities. Nature Reviews. Gastroenterology & Hepatology, 17(2):93–110.

Selmi C, Lleo A, Pasini S, et al., 2009, Innate Immunity and PBC. Current Molecular Medicine, 9(1):45–51.

Carey EJ, Ali AH, Lindor KD., 2015, PBC. The Lancet, 386(10003):1565–1575.

Silveira MG, Brunt EM, Heathcote J, et al., 2010, American Association for the Study of Liver Diseases Endpoints Conference: Design and Endpoints for Clinical Trials in PBC. Hepatology (Baltimore, Md.), 52(1):349–359.

Poupon RE, Lindor KD, Cauch-Dudek K, et al., 1997, Combined Analysis of Randomized Controlled Trials of UDCA in PBC. Gastroenterology, 113(3):884–890.

Parés A, Caballería L, Rodés J, et al., 2000, Long-Term Effects of UDCA in PBC: Results of a Double-Blind Controlled Multicentric Trial. Journal of Hepatology, 32(4):561–566.

Beuers U, Lindor KD., 2011, A Major Step Towards Effective Treatment Evaluation in PBC. Journal of Hepatology, 55(6):1178–1180.

Azemoto N, Abe M, Murata Y, et al., 2009, Early Biochemical Response to UDCA Predicts Symptom Development in Patients with Asymptomatic PBC. Journal of Gastroenterology, 44(6):630–634.

Pascart T, Richette P., 2018, Colchicine in Gout: An Update. Current Pharmaceutical Design, 24(6):684–689.

Mika A, Stepnowski P., 2016, Current Methods of the Analysis of IAs in Clinical Materials: A Review. Journal of Pharmaceutical and Biomedical Analysis, 127:207–231.

QIAN J-D, et al., 2000, Treatment of PBC with UDCA, Prednisolone and Immunosuppressants in Patients Not Responding to UDCA Alone and the Prognostic Indicators. Clinics and Research in Hepatology and Gastroenterology. DOI: https://doi.org/10.1016/j.clinre.2020.03.026.

Poupon RE, Huet PM, Poupon R, et al., 1996, Randomized Trial Comparing Colchicine and UDCA Combination to UDCA in PBC. Hepatology. 24(5):1098–1103.

Almasio LL, Floreani A, Chiaramonte M, et al., 2000, Multicentre Randomized Placebo-Controlled Trial of UDCA With or Without Colchicine in Symptomatic PBC. Aliment Pharmacol Ther. 14(12):1645–1652.

Wolfhagen FH, VAN Hoogstraten HJ, Van Buuren HR, et al., 1998, Triple Therapy with UDCA, Prednisone and Azathioprine in PBC: a 1-Year Randomized, Placebo-Controlled Study. J Hepatol., 29(5):736–742.

Combes B, Emerson SS, Flye NL, et al., 2005, Methotrexate (MTX) Plus UDCA in the Treatment of PBC. Hepatology (Baltimore, Md.), 42(5):1184–1193.

Hendrickse MT, Rigney E, Giaffer MH, et al., 1999, Low-Dose Methotrexate is Ineffective in PBC: Long-Term Results of a Placebo-Controlled Trial. Gastroenterology, 117(2):400–407.

Ikeda T, Tozuka S, Noguchi O, et al., 1996, Effects of Additional Administration of Colchicine in UDCA-Treated Patients with PBC: A Prospective Randomized Study. Journal of Hepatology, 24(1):88–94.

Khanna A, Jopson L, Howel D, et al., 2019, Rituximab Is Ineffective for Treatment of Fatigue in Primary Biliary Cholangitis: A Phase 2 Randomized Controlled Trial. Hepatology, 70(5):1646–1657.

Lombard M, Portmann B, Neuberger J, et al., 1993, Cyclosporin a Treatment in PBC: Results of a Long-Term Placebo-Controlled Trial. Gastroenterology, 104(2):519–526. DOI: 10.1016/0016-5085(93)90422-9.

Wiesner RH, Ludwig J, Lindor KD, et al., 1990, A Controlled Trial of Cyclosporine in the Treatment of Primary Biliary Cirrhosis. N Engl J Med, 322(20):1419-24.

Zhu GQ, Huang S, Huang GQ, et al., 2015, Optimal Drug Regimens for PBC: A Systematic Review and Network Meta-Analysis. Oncotarget, 6(27):24533–24549.

Suraweera D, Rahal H, Jimenez M, et al., 2017, Treatment of PBC UDCA non-responders: A Systematic Review. Liver International: Official Journal of the International Association for the Study of the Liver, 37(12):1877–1886. DOI: 10.1111/liv.13477.

Shah RA, Kowdley KV., 2020, Current and Potential Treatments for PBC. The Lancet Gastroenterology & Hepatology, 5(3):306–315. DOI: 10.1016/S2468-1253(19)30343-7.

Leung J, Bonis PA, Kaplan MM., 2011, Colchicine or Methotrexate, with Ursodiol, are Effective After 20 Years in a Subset of Patients with Primary Biliary Cirrhosis. Clinical Gastroenterology and Hepatology: The Official Clinical Practice Journal of the American Gastroenterological Association, 9(9):776–780.

Rautiainen H, Kärkkäinen P, Karvonen AL, et al., 2005, Budesonide Combined with UDCA to Improve Liver Histology in PBC: A Three-Year Randomized Trial. Hepatology (Baltimore, Md.), 41(4):747–752.

Rautiainen H, Färkkilä M, Neuvonen M, et al., 2006, Pharmacokinetics and Bone Effects of Budesonide in PBC. Alimentary Pharmacology & Therapeutics, 24(11-12):1545–1552.

Treiber G, Malfertheiner P., 2005, Mycophenolate Mofetil for the Treatment of PBC in Patients with an Incomplete Response to Ursodeoxycholic Acid. Journal of Clinical Gastroenterology, 39(9):837-8.

Bowlus CL, Yang GX, Liu CH, et al., 2019, Therapeutic Trials of Biologics in Primary Biliary Cholangitis: An Open Label Study of Abatacept and Review of the Literature. Journal of Autoimmunity, 101:26–34.

Tsuda M, Moritoki Y, Lian ZX, et al., 2012, Biochemical and Immunologic Effects of Rituximab in Patients with Primary Biliary Cirrhosis and an Incomplete Response to Ursodeoxycholic Acid. Hepatology (Baltimore, Md.), 55(2):512–521.