Management of Severe Steroid-resistant and Steroid-refractory Hepatotoxicity in Patients Treated with Checkpoint Inhibitor Immunotherapy

Szeremeta Krystyna^*
*Correspondence: Szeremeta Krystyna, Department of Rheumatology and Rehabilitation, Specialty Hospital No. 1, Żeromskiego 7, 41-902 Bytom, Poland, Email:

Introduction

Immune checkpoint inhibitors have revolutionized cancer treatment, offering new hope for patients with various malignancies. These therapies, including PD-1/PD-L1 and CTLA-4 inhibitors, unleash the immune system to attack cancer cells. However, they also carry the risk of immune-related adverse events with hepatotoxicity being a notable concern. Management of steroid-resistant and steroid-refractory hepatotoxicity presents a significant clinical challenge. The first-line treatment for ICI-induced hepatotoxicity is corticosteroids. Guidelines recommend initiating high-dose corticosteroids, such as prednisone or methylprednisolone at 1-2 mg/kg/day, for patients with grade 2 or higher liver enzyme elevations. The goal is to reduce inflammation and prevent further liver damage. For many patients, this approach is effective, and liver enzyme levels return to normal within weeks. A subset of patients, however, do not respond to corticosteroid therapy. Steroid-resistant hepatotoxicity refers to the condition where there is no improvement or worsening of liver enzyme levels despite adequate steroid treatment. Steroid-refractory hepatotoxicity occurs when liver enzymes initially respond to steroids but then elevate again upon tapering or discontinuation of steroids. For patients who do not respond to steroids, alternative immunosuppressive therapies must be considered. The management strategy often involves a multidisciplinary approach, including oncologists, hepatologists, and immunologists [1].

Mycophenolate mofetil is often the next line of treatment for steroid-resistant or refractory hepatotoxicity. It inhibits lymphocyte proliferation, thereby reducing immune-mediated liver damage. MMF is typically started at a dose of 500-1000 mg twice daily. Studies have shown its efficacy in reducing liver enzyme levels in patients unresponsive to corticosteroids. Tacrolimus, a calcineurin inhibitor, is another option. It suppresses T-cell activation and cytokine production, thereby mitigating immune-mediated liver damage. Tacrolimus is usually started at 0.1 mg/kg/day, with dose adjustments based on trough levels and clinical response. Infliximab, an anti-TNF alpha monoclonal antibody, is sometimes used off-label for severe cases. It has shown efficacy in managing other steroid-refractory irAEs, such as colitis. However, its use in hepatotoxicity is limited and carries a risk of exacerbating liver damage, so it is generally considered when other options fail. Agents such as tocilizumab and rituximab have been used in refractory cases, though evidence is limited. These biologics target specific immune pathways and may be effective when standard immunosuppression fails [2].

In extreme cases of fulminant liver failure, liver transplantation may be considered. This is a last resort due to the significant risks and the need for lifelong immunosuppression. Patients with severe hepatotoxicity require close monitoring. Liver function tests should be performed frequently to assess response to treatment. Imaging studies and liver biopsies may be necessary to evaluate the extent of liver damage and rule out other causes of liver dysfunction. Supportive care, including maintaining hydration, nutritional support, and managing symptoms of liver failure, is critical. Patients should avoid hepatotoxic medications and alcohol.

Severe steroid-resistant and steroid-refractory hepatotoxicity in patients treated with checkpoint inhibitors presents a complex clinical challenge. A stepwise approach involving alternative immunosuppressive agents such as MMF and tacrolimus is essential. Early recognition, prompt intervention, and multidisciplinary management are key to improving outcomes in these patients. As our understanding of the mechanisms underlying irAEs grows, personalized and targeted therapies may offer new avenues for effective management. The management of steroid-resistant and steroid-refractory hepatotoxicity remains an evolving field. Continued research is critical to better understand the pathophysiology of ICI-induced hepatotoxicity and to develop more effective treatment strategies. Greater insights into the mechanisms of immune-mediated liver injury will help identify novel therapeutic targets. For example, understanding the role of specific cytokines and immune cells in the development of hepatotoxicity can lead to targeted interventions. Research into genetic predispositions and the role of the gut microbiome in modulating immune responses may also provide valuable information [3].

Description

Identifying biomarkers that predict the onset and severity of hepatotoxicity could enable early intervention and personalized treatment approaches. Potential biomarkers include specific cytokine profiles, immune cell populations, and genetic markers. Research into these biomarkers is ongoing, and their validation could transform the management of ICI-induced hepatotoxicity. The development of new immunosuppressive agents with more favorable safety profiles is another important area of research. Agents that selectively target the pathways involved in hepatotoxicity without broadly suppressing the immune system could offer significant advantages. Trials of novel biologics and small molecules are needed to assess their efficacy and safety in this patient population. Exploring the use of combination therapies may enhance treatment efficacy while minimizing side effects. For instance, combining lower doses of multiple immunosuppressive agents might reduce the risk of infections and other complications associated with high-dose corticosteroids. Clinical trials are necessary to determine the optimal combinations and dosing regimens [4].

For patients who have experienced severe hepatotoxicity, rechallenging with ICIs is a complex decision. Developing standardized protocols for rechallenge and desensitization could help safely reintroduce these potentially life-saving therapies. Research into the timing, dosing, and adjunctive therapies for rechallenge is crucial. Studying the long-term outcomes of patients who have experienced ICI-induced hepatotoxicity is important to understand the full impact of these adverse events. This includes not only liver function and cancer outcomes but also quality of life and psychological well-being. Longitudinal studies will provide valuable data to inform clinical practice. Developing and updating clinical guidelines based on the latest evidence is essential to ensure consistent and effective management of hepatotoxicity. Guidelines should incorporate new research findings, expert consensus, and real-world experience. Key components of comprehensive guidelines include:

Implementing routine screening protocols for liver function tests in patients receiving ICIs can facilitate early detection of hepatotoxicity. Risk assessment tools that incorporate clinical, genetic, and biomarker data can help identify high-risk patients. Clear algorithms for escalating treatment in cases of steroid-resistant or refractory hepatotoxicity can guide clinicians. These algorithms should outline when to initiate alternative immunosuppressive agents, how to monitor response, and when to consider more aggressive interventions such as biologics or liver transplantation. Effective management of hepatotoxicity requires a team-based approach. Oncologists, hepatologists, immunologists, and other specialists should collaborate to develop and implement individualized treatment plans. Regular case discussions and consultations can enhance patient care. Educating patients about the signs and symptoms of hepatotoxicity and the importance of reporting them promptly can lead to earlier intervention and better outcomes. Providing psychological support and resources to help patients cope with the challenges of managing irAEs is also important [5].

Conclusion

Management of severe steroid-resistant and steroid-refractory hepatotoxicity in patients treated with checkpoint inhibitor immunotherapy is a challenging but critical aspect of modern oncology care. Advances in our understanding of immune-mediated liver injury, the development of new therapeutic agents, and the implementation of comprehensive clinical guidelines are essential to improving patient outcomes. Continued research, multidisciplinary collaboration, and a commitment to patient-centered care will ensure that the benefits of checkpoint inhibitors can be maximized while minimizing the risks of serious adverse events.

Acknowledgement

None.

Conflict of Interest

None.

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