Prezentare de caz: hepatită indusă de ICI şi miozită cu aspergiloză

Introduction

Immune checkpoint inhibitors (ICIs) targeting PD-1 and CTLA-4 have transformed the treatment landscape of metastatic melanoma. However, their efficacy is accompanied by the risk of immune-related adverse events (irAEs), which may affect nearly any organ system, with emerging biomarkers offering further insight into their pathogenesis^(1,2). Hepatotoxicity can be severe and potentially life-threatening, while immune-mediated myositis, though less common, is a recognized complication^(5,7-11). Opportunistic infections, although rare, may occur in the setting of prolonged or multi-agent im­mu­no­sup­pression^(12-16). This case illustrates a complex, multifaceted irAE with hepatic and muscular involvement secondary to immunotherapy, followed by a secondary pulmonary fungal infection resulting from escalated immunosuppressive therapy for steroid-refractory toxicity. The management required a multidisciplinary approach to irAE care, with vigilant attention to the risk and treatment of opportunistic infections.

Case report

A 41-year-old female with right upper extremity melanoma diagnosed in 2020 after the excision of a right forearm lesion with right axillary sentinel lymph node biopsy (negative at the time) was lost to follow-up until June 2022, when she was found to have biopsy-proven right axillary lymph node metastasis.

She was initiated on nivolumab monotherapy, which was well tolerated and not associated with any adverse events.

Subsequently, she developed brain metastases and underwent a craniotomy in August 2022.

Postoperatively, she received radiation therapy to the surgical bed (27 Gy total dose) and a brief course of corticosteroids for approximately 3-4 weeks.

After completion of steroids, she was initiated on combination therapy with ipilimumab and nivolumab.

Baseline laboratory testing, performed one day prior to initiating ICI therapy, showed normal liver function: total bilirubin 0.2 mg/dL, AST 16 U/L, ALT 27 U/L, alkaline phosphatase 73 U/L, LDH 185 U/L.

Approximately three weeks later, she presented with right upper quadrant abdominal pain, fever, rash and scleral icterus. On admission, laboratory studies revealed: total bilirubin 11.7 mg/dL, AST 1965 U/L, ALT 1828 U/L, alkaline phosphatase 162 U/L, lipase >1400 U/L.

MRCP showed gallbladder wall thickening with sludge, but no biliary obstruction. Viral and autoimmune panels, including hepatitis A/B/C, EBV and CMV, were negative.

A transjugular liver biopsy revealed: “Moderate to severe active hepatitis with bridging necrosis and cholestasis. Per clinical input provided viral serology are negative as are markers of autoimmune hepatitis. The patient is on checkpoint inhibitor therapy for melanoma since September 2022 and the findings are compatible with checkpoint inhibitor induced liver injury”^(1,4,18).

Her diagnosis was established as grade 4 immune-related hepatitis^(1,3). She was initiated on intravenous methylprednisolone at 1 mg/kg/day in divided doses, which was increased to 1.5 mg/kg/day. As liver function tests did not improve after three days, the hepatitis was considered refractory to steroids, and the treatment was escalated to include mycophenolate mofetil 1000 mg b.id.^(1,19) Mycophenolate mofetil was reduced to 500 mg b.i.d. and later discontinued due to leukopenia. Tacrolimus was started at 2-4 mg b.i.d., with dose adjustments based on serum levels (target trough 5-15 ng/ml). This was well tolerated, and it was continued on discharge⁽²⁰⁾.

During steroid taper, she developed bilateral ankle pain and progressive lower extremity weakness. EMG/NCS was normal, though limited. MRI of the pelvis and thighs revealed muscle signal abnormalities and fascial involvement, consistent with mild myositis and fasciitis^(7,9,10,11). The symptoms improved with immunosuppressive therapy, and muscle biopsy was not pursued as the clinical and MRI imaging supported the diagnosis of immunotherapy-induced myositis^(5,7,9).

Approximately six weeks from the initial admission and initiation of immunosuppressive therapy, she developed fever and cough. She had no prior history of exposure or colonization with Aspergillus. Chest CT revealed new left upper lobe nodules. Bronchoscopy with biopsy confirmed pulmonary tissue with septated fungal hyphae consistent with Aspergillus, without malignant cells. She was treated with i.v. amphotericin B and transitioned to oral isavuconazonium (Cresemba®)^(12-16). She was also maintained on prophylactic antimicrobials.

Discussion

This case demonstrates the potential severity and complexity of irAEs associated with checkpoint inhibitors. Grade 4 hepatitis is uncommon but life-threatening, often requiring escalation beyond corticosteroids^(1,3). The histologic confirmation of ICI-induced hepatitis helped justify immunosuppressive intensification^(1,4,18).

Autoimmune hepatitis typically occurs 5-7 weeks after the initiation of immunotherapy in treatment-naive patients⁽¹⁷⁾. However, in patients who are re-challenged with immunotherapy or receive combination regimens, the onset may occur sooner, as seen in our patient. Unique to this case is the coexistence of two serious irAEs – hepatitis and myositis – in the same treatment course^(5,7-11).

The management of steroid-refractory hepatitis remains a clinical challenge. Grade 4 hepatitis occurs in 4-9% of patients on combination ICI therapy⁽³⁾. The American Society of Clinical Oncology guidelines state that liver biopsy should be considered to exclude other etiologies for persistent or refractory hepatitis if blood work or imaging evaluations are not conclusive⁽¹⁾. Liver biopsy can provide histopathological evidence of immune-mediated injury, which is crucial for guiding further immunosuppressive therapy^(1,4,18).

The European Society for Medical Oncology guidelines similarly recommend liver biopsy in cases of severe ICI-induced hepatitis to confirm the diagnosis and exclude other potential causes of liver injury⁽¹⁸⁾. This is particularly important in patients who do not respond to corticosteroids, as histological confirmation can help in deciding whether to escalate immunosuppressive treatment. Liver biopsy confirmed severe acute hepatitis and helped guide management⁽¹⁸⁾.

ASCO and ESMO guidelines recommend corticosteroids as first-line therapy, with escalation to mycophenolate mofetil (MMF) or tacrolimus in steroid-refractory cases^(1,18). This recommendation reflects the need to control severe hepatic inflammation when corticosteroids alone are inadequate.

Mycophenolate mofetil (MMF) inhibits inosine monophosphate dehydrogenase, thereby reducing lymphocyte proliferation. It has demonstrated effectiveness in resolving steroid-refractory ICI hepatitis, with many patients achieving resolution or downgrading of hepatitis severity⁽¹⁹⁾. Tacrolimus, a calcineurin inhibitor that suppresses T-cell activation, has also been successfully employed in corticosteroid-resistant ICI hepatitis⁽²⁰⁾. Both agents are generally well tolerated and offer valuable alternatives for immunosuppressive control^(19,20).

Immune-related myositis was diagnosed clinically and based on MRI findings. No muscle biopsy was pursued, as MRI and clinical presentation were sufficient for diagnosis. While rare (<1%), immune-related myositis may present subtly, and the MRI can provide crucial diagnostic information when EMG is inconclusive^(7-11). Additionally, overlap with myocarditis and myasthenia, as reported in fatal cases, should remain in the differential^(5,6).

The development of pulmonary aspergillosis underlines the importance of infection surveillance in immunosuppressed patients. Notably, the patient had no prior Aspergillus exposure, and she developed symptoms approximately six weeks into immunosuppressive therapy. Physicians should be aware that corticosteroids, while critical for managing irAEs, can increase the risk of opportunistic infections such as aspergillosis and may reactivate latent fungal infections^(12-16).

Conclusions

This case highlights the importance of early recognition and multidisciplinary management of severe immune-related adverse events. Grade 4 checkpoint inhibitor-induced hepatitis may require escalation beyond corticosteroids, including second- and third-line agents, such as mycophenolate mofetil (MMF) and tacrolimus^(1,19,20). Liver biopsy is a useful diagnostic tool in confirming immune-related hepatitis and in guiding the immunosuppressive therapy^(1,4,18). Although immune-related myositis is rare, MRI can play a crucial role in identifying muscle inflammation when EMG findings are inconclusive^(7-11). This case also emphasizes the importance of monitoring for opportunistic infections like aspergillosis in patients receiving prolonged immunosuppression^(12-16). Ultimately, the effective management of complex immune-related adverse events relies on early recognition, timely escalation of therapy, and close multidisciplinary collaboration^(1,2).

Autor corespondent: Cornelia Banciu-Odell E-mail: corneliaodell@gmail.com

CONFLICT OF INTEREST: none declared.

FINANCIAL SUPPORT: none declared.

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