Long-term results of mycophenolate mofetil vs. azathioprine use in individuals with autoimmune hepatitis

George N Dalekos; Pinelopi Arvaniti; Nikolaos K Gatselis; Stella Gabeta; Anna Samakidou; George Giannoulis; Eirini Rigopoulou; George K Koukoulis; Kalliopi Zachou

doi:10.1016/j.jhepr.2022.100601

Long-term results of mycophenolate mofetil vs. azathioprine use in individuals with autoimmune hepatitis

JHEP Rep. 2022 Sep 30;4(12):100601. doi: 10.1016/j.jhepr.2022.100601. eCollection 2022 Dec.

Authors

George N Dalekos^{1

2}, Pinelopi Arvaniti^{1

2}, Nikolaos K Gatselis^{1

2}, Stella Gabeta^{1

2}, Anna Samakidou¹, George Giannoulis¹, Eirini Rigopoulou^{1

2}, George K Koukoulis³, Kalliopi Zachou^{1

2}

Affiliations

¹ Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, Larissa, Greece.
² European Reference Network on Hepatological Diseases (ERN RARE-LIVER), General University Hospital of Larissa, Larissa, Greece.
³ Department of Pathology, Faculty of Medicine, School of Health Sciences, University of Thessaly, Larissa, Greece.

Abstract

Background & aims: We have shown previously that mycophenolate mofetil (MMF) might be used as first-line treatment instead of azathioprine (AZA) in individuals with autoimmune hepatitis (AIH). Herein, we present our long-term prospective data on response and outcome after first-line therapy with MMF in treatment-naïve individuals with AIH, as similar data are missing.

Methods: During the 21 years of the study, 292 individuals with AIH were included (females: 213; median age: 59 [17-85] years). Patients received either prednisolone 0.5-1 mg/kg/day alone (n = 19) or in combination with AZA 1-2 mg/kg/day (n = 64) or MMF (n = 183). The tapering schedule of prednisolone was identical between groups. We assessed the rates of complete biochemical response (CBR) at 6 months, 12 months, and the end of follow-up; non-response (4 weeks of treatment); CBR off prednisolone; adverse effects; CBR off treatment; histological remission; and overall and liver-related mortality between the AZA and MMF groups.

Results: The MMF group had lower non-response (p = 0.02) and higher CBR rates at 12 months (86 vs. 71.8%; p <0.05) and the end of follow-up (96 vs. 87.2%; p = 0.03) than the AZA group. Treatment change was more frequent in the AZA group (43.7 vs. 11%; p <0.001), mostly because of intolerance, whereas MMF was proven safe (serious complications 3.8 vs. 18.8%; p = 0.0003). MMF-treated patients were more frequently eligible to stop immunosuppression according to the guidelines (p <0.05). Cirrhosis at diagnosis, age at diagnosis >60 years, and longer disease duration were independent predictors of liver-related mortality.

Conclusions: MMF seems an efficient alternative first-line treatment option for AIH, bearing lower non-response at 4 weeks and higher CBR rates at 12 months and the end of follow-up than AZA. In addition, MMF was proven to be safe, leading more frequently to the eligibility for stopping immunosuppression according to the guidelines.

Impact and implications: For more than 40 years, azathioprine (AZA) has been considered the standard treatment for induction and maintenance of response in autoimmune hepatitis (AIH). However, treatment usually needs to be maintained for life, as relapses are common after AZA cessation. Therefore, alternative treatment options are needed. Herein, we showed that the use of mycophenolate mofetil (MMF) as an alternative first-line immunosuppressant was much more efficient in the long-term than AZA as attested by the lower non-response rates at 4 weeks and higher response rates at 12 months and the end of follow-up. Moreover, AZA-treated patients were more prone to change treatment because of intolerance, whereas MMF-treated patients were more often eligible to achieve treatment withdrawal.

Keywords: AIH, autoimmune hepatitis; ALT, alanine aminotransferase; ANA, antinuclear antibodies; AZA, azathioprine; Autoimmune hepatitis; Azathioprine; CBR, complete biochemical response; HASL, Hellenic Association for the Study of the Liver; HR, hazard ratio; IAIHG, International AIH Group; LSM, liver stiffness measurement; MMF, mycophenolate mofetil; Mycophenolate mofetil; Outcome; SMA, smooth muscle antibodies; Survival; ULN, upper limit of normal; anti-LC1, anti-liver cytosol type 1 antibodies; anti-LKM1, anti-liver/kidney microsomal type 1 antibodies; anti-SLA/LP, antibodies against soluble liver antigen/liver pancreas; mHAI, modified hepatitis activity index.