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Vol. 45. Núm. S1.
Casos Clínicos en Gastroenterología y Hepatología
Páginas 32-36 (Abril 2022)
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Vol. 45. Núm. S1.
Casos Clínicos en Gastroenterología y Hepatología
Páginas 32-36 (Abril 2022)
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Mycophenolate mofetil as a treatment of severe steroid-resistant immune-related hepatitis
Utilidad del Micofenolato Mofetilo como tratamiento de las hepatitis inmunomediadas secundarias a inmunoterapia resistentes a corticoides
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Cristina Macía-Rodrígueza,
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, Lucia Santomé Coutob, Alberto Fernández Villaverdec, Carlos Romero Reinosob, Javier de la Fuente Aguadoa
a Internal Medicine Department. POVISA Hospital-Ribera Salud Group, Rúa Salamanca 5, 36211 Vigo, USA
b Oncology Department, POVISA Hospital-Ribera Salud Group, Rúa Salamanca 5, 36211 Vigo, USA
c Gastroenterology Department, POVISA Hospital- Ribera Salud Group, Rúa Salamanca 5, 36211 Vigo, USA
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Table 1. Characteristics of patients treated with MMF.
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Vol. 45. Núm S1

Casos Clínicos en Gastroenterología y Hepatología

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Immune checkpoint inhibitors (ICPIs) are a novel class of oncological therapy that improves survival in patients with advanced-stage tumors.1 ICPIs inhibit the T-lymphocyte receptors that downregulate T-cell immunity. ICPIs activate immune population that reacts against tumors but also against non-tumor host cells1 and they can cause immune-related adverse events including hepatotoxicity.2,3 Usually, the interruption of the treatment is sufficient to solve a mild case of hepatotoxicity, but in severe cases it is necessary to start treatment with corticosteroids.3,4 Only a few cases are steroid-resistant and need to be treated with another immunosuppressant as mycophenolate mofetil (MMF).2,4 We present a case of severe steroid-resistant immune-related hepatitis treatment with MMF and review previous cases described.

A 70-year-old woman with a stage-IV melanoma started with itching, jaundice and choluria twelve days after the first doses of nivolumab. Liver analysis found ALT of 141U/l, AST of 123U/l, gamma glutamyl transferase (GGT) of 103U/l, alkaline phosphatase (AP) of 231U/l and Total Bilirubin of 0.4mg/dl. Ultrasound and abdominal tomography were normal. Antinuclear antibodies, anti-liver-kidney microsomal antibody and anti-smooth muscle actine antibodies were negative and hepatitis A, B and C virus serologies were also negative.

After diagnosis of grade-1 CTCAE (Common Terminology Criteria of Adverse Events) immune-related hepatitis, nivolumab was interrupted. Following a control analysis an increase of ALT, AST, TB with normal clotting was found (grade 3 CTCAE), so methylprednisolone (MP) at dose of 1mg/kg was started. Due to a persistent increase of ALT, AST and TB during the following 48h the dose of MP was increased to 2mg/kg without improvement within the following 5 days, so we decided to start MMF at a dose of 2g/day. After that, a progressive improvement of liver function tests was observed (Supplementary Image 1). During the next two months the patient presented a Coxiella Burnetti respiratory infection and a left hip fracture.

We searched using PubMed the cases of immune checkpoint inhibitors hepatitis or hepatotoxicity. We included every study wherein patients received treatment with MMF: 16 studies were found. We excluded four articles because they showed no description of the characteristics of the patients. A total of 12 studies were included in the analysis. We found a total of 30 previous cases of patients treated with MMF (Table 1). If we include our patient in the analysis, 60.0% were female with a mean age of 58.7 years. The more frequent tumor was melanoma in 20 of cases and 16 patients received combined ICPI therapy. The mean time between ICPIs and hepatotoxicity was 80 days. All patients received corticosteroids. MMF was used in doses of 1 or 2g per day, in five cases associated with other treatments (Plasma exchange, Ursodeoxycholic acid, Antithymocyte globulin or Infliximab). Only four patients did not present an improvement of liver analysis. Ten patients presented complications due to immunosuppression therapy, four of them due to steroid use (hyperglycemia, fractures, steroid-induced psychosis).

Table 1.

Characteristics of patients treated with MMF.

Study  Age (years)  Sex  Tumor  Previous treatment with ICPIs  Treatment  Time I/H (days)/cycles (number)  Corticosteroid  Additional treatments  Normalization of liver analysis  Complications 
PresentStudy  70  Melanoma  No  Nivolumab  12/1  MP  No  Yes  Coxiella Burnetti respiratory infectionLeft hip fracture 
Ahmed et al., 2015BMJ Case Report  50  Melanoma  No  Ipilimumab  ND  MP 2mg/kg  No  Yes  Asymptomatic sinus bradycardiaLymphopenia 
Tanaka et al., 2017Jpn J Clin Oncol  59  Melanoma  Nivolumab  Ipilimumab  36/2  MP pulse 1000mg/d x3 then P 1mg/kg  No  Yes  No 
McGuire et al., 2018Cancer Immunol Immunother.  57  Melanoma  No  Anti-PD-1  189/9  MP 2mg/kg  No  Yes  No 
Hsu et al., 2020Oncologist  67  Hepatocellular carcinoma  No  Nivolumab  183/ND  P 1mg/kg  No  Yes  Steroid-induced Hyperglycemia 
Doherty et al., 2017ESMO Open  49  B-rapidly acceleratd fibrosarcoma  No  Pembrolizumab  8/1  P 1mg/kg  Ursodeoxycholic acid  Yes  NeutropaeniaDMFracture T11 
Doherty et al., 2017ESMO Open  76  Epitheliod mesothelioma  No  Pembrolizumab  1/1  P 1mg/kg    No  Lymphopaenia 
Chmiel et al., 2011J Clin Oncol  60  Melanoma  No  Ipilimumab  31/2  MP pulse 500mg/d x 9 d  Antithymocyte globulin  Yes  Steroid-induce psychosis 
Lomax et al., 2018J Skin Cancer  58  Melanoma  Ipilimumab  Pembrolizumab  30/1  MP 0.5mg/kg x3 d  No  Yes  Pneumocystis jiroveci pneumonia 
Lomax et al., 2018J Skin Cancer  67  Melanoma  Ipilimumab  Pembrolizumab  ND/2  MP 1mg/kg then P  No  Yes  No 
De Martin et al., 2018J Hepatol  63  Melanoma  Pembrolizumab  Ipilimumab  49/ND  2.5mg/kg  No  Yes  No 
Cheung et al., 2019Frontline Gastroenterol  76  Melanoma  Ipilimumab  Pembrolizumab  ND  No  Yes  No 
Cheung et al., 2019Frontline Gastroenterol  42  Melanoma  Pembrolizumab  Ipilimumab  ND  DX then P  No  Yes  No 
Cheung et al., 2019Frontline Gastroenterol  49  Melanoma  No  Ipilimumab+Nivolumab  ND  MP then P  Infliximab  Yes  No 
Cheung et al., 2019Frontline Gastroenterol  45  Melanoma  No  Ipilimumab+Nivolumab  ND  No  Yes  No 
Cheung et al., 2019Frontline Gastroenterol  51  Melanoma  No  Ipilimumab+Nivolumab  ND  MP then P  No  Yes  No 
Cheung et al., 2019Frontline Gastroenterol  21  Melanoma  No  Ipilimumab+Nivolumab  ND  MP then P  No  Yes  No 
Cheung et al., 2019Frontline Gastroenterol  71  Melanoma  Nivolumab  Ipilimumab  ND  No  Yes  No 
Corrigan et al., 2019JHEP Rep.  53  Melanoma  No  Ipilimumab+Nivolumab  39/3  MP 200mg/day  No  No  Severe neutropenia 
Riveiro-Barciel et al.2020Liver Int.  58  Renal Carcinoma  No  Anti-PD-1  28/1  CS 1mg/kg  No  Yes  Pneumonia 
Riveiro-Barciel et al., 2020Liver Int.  58  Esophageal Adenocarcinoma  No  Anti-PD-1  336/4  CS 1mg/kg  No  Yes  No 
Riveiro-Barciel et al., 2020Liver Int.  44  NK/T-cell lymphoma  No  Anti-PD-1  168/2  CS 1mg/kg  No  Yes  No 
Riveiro-Barciel et al., 2020Liver Int.  62  Non-small-cell lung Carcinoma  No  Anti-PD-1  140/5  Cs 1mg/kg  No  Yes  No 
Riveiro-Barciel et al., 2020Liver Int.  38  Cervical Squamous cell Carcinoma  No  Anti-PD-1+Anti-CTLA  56/4  Cs 1mg/kg  No  Yes  No 
Riveiro-Barciel et al., 2020Liver Int.  76  Melanoma  Nivolumab  Anti-CTLA  42/2  Cs 2mg/kg  Plasma exchange  Yes  No 
Riveiro-Barciel et al., 2020Liver Int.  71  Urothelial Carcinoma  No  Anti-PD-L1  49/1  Cs 1mg/kg  No  Yes  No 
Riveiro-Barciel et al., 2020Liver Int.  90  Sigma Adenocarcinoma  No  Anti-PD-1  84/8  Cs 1mg/kg  No  Yes  No 
Riveiro-Barciel et al., 2020Liver Int.  51  Melanoma  No  Anti-PD-1  56/3  Cs 2mg/kg  No  Yes  No 
Riveiro-Barciel et al., 2020Liver Int.  69  Non-small-cell lung Carcinoma  No  Anti-CTLA-4  58/2  Cs 1mg/kg  No  Yes  No 
Ziogas et al., 2020J Immunother Cancer  70  Melanoma  Nivolumab  Ipilimumab  ND/3  MP 2mg/kg  Ursodeoxycholic acid  No  Thrombocytopenia 
Spänkuch et al., 2017Eur J Cancer  49  Melanoma  No  Nivolumab+Ipilimumab  ND/3  MP 2mg/kg  No  No  No 

Anti-CTLA-4: anticytotoxic T-lymphocyte antigen 4; Cs: corticosteroids; DM: diabetes mellitus; F: female; M: man; ICPIs: Immune checkpoint inhibitors; MMF: mycophenolate mofetil; MP: Methylprednisolone; ND: not described; P: Prednisone; Time I/H: Time between inmunotheraphy/hepatitis.

ICPIs are commonly used in oncological therapy and between 3% and 10% of cases can cause hepatotoxicity.2 Usually, interruption of the treatment and treatment with corticoisteroids are enough to heal the hepatotoxicity.5 However, some cases are steroid-resistant and another immunosuppressant is needed. We found that MMF was effective in the majority of the cases. ICPIs-induced hepatotoxicity in these cases was developed after 8–12 weeks from the start of the treatment.2,3 A strict follow-up of these patients is recommended for an early diagnosis and treatment of hepatotoxicity. MMF is a reversible inhibitor of inosine monophosphate dehydrogenase and it is used in second-line therapy for autoimmune hepatitis. In the cases that we analyzed, we observed that MMF can be safely used on second line in patients with steroid-resistant immune-related hepatitis with a normalization of the liver analysis in the majority of the cases. Some patients presented complications related to the immunosuppression and steroid treatment. As a consequence, it is important to decrease the dose of immunosuppressant treatment as soon as possible.

In conclusion, MMF is an effective and safe therapeutic alternative for the treatment of steroid-resistant immune-related hepatitis.

Ethics statement and consent

The study followed the criteria of the Helsinki Declaration and the patient has given the written informed consent for publication.

Funding statement

This research received no grant from any funding agency in the public, commercial or not-for-profit sectors.

Conflicts of interest

All authors declare no conflicts of interest.

Appendix A
Supplementary data

The following are the supplementary data to this article:

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Immunotherapy-related hepatitis: real-world experience from a tertiary centre.
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Immune-related adverse events associated with immune checkpoint blockade.
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