Rapid ILD in Amyopathic Dermatomyositis with Anti-MDA5 After Nivolumab: A Hidden Threat

Abstract

A positive anti-MDA5 antibody titer; clinicians' amyopathic dermatomyositis is an extremely rare autoimmune condition often associated with life-threatening rapidly progressive interstitial lung disease. We report a rare case of the development of RP-ILD in a 68-year-old male with malignant mesothelioma after treatment with the immune checkpoint inhibitor nivolumab. The patient initially did not present with dermatomyositis but developed characteristic skin manifestations and severe respiratory symptoms two months after initiating ICI therapy. Even with aggressive immunosuppressive treatment, the patient's condition worsened to respiratory failure and death. Analysis post-mortem showed that she harbored pre-existing anti-MDA5 antibodies that were significantly increased after nivolumab administration, suggesting that ICI may play a role in the exacerbation of underlying autoimmune processes. This case underscores the need for screening for autoimmune markers in patients with cancer before receiving ICI therapy and taking careful surveillance for potential immune-related adverse events like RP-ILD.

Introduction

This is another less common subtype known as clinically amyopathic dermatomyositis, characterized by typical skin manifestations without significant muscle involvement. There is a subset of patients with RP-ILD and CADM positive for anti-melanoma differentiation-associated gene 5 (anti-MDA5) antibodies with a very high mortality rate. The correlation of CADM, anti-MDA5 antibodies, and RP-ILD makes it a major clinical challenge, especially in the context of immune modulation.

Among the ICIs, nivolumab was demonstrated to inhibit the programmed death-1 pathway and improve the host immune response against tumor cells. The entire scenario of anticancer therapy has been significantly changed by this drug. However, ICIs can also cause several immune-related adverse events that range from inflammatory conditions in the skin, lungs, and other organs. The incidence of inflammatory myopathies resulting from ICIs has also been described in isolated cases; but the evidence is still scarce in linking CADM with ICIs, especially in those patients with pre-existing anti-MDA5 antibodies.

Here, a case report is described of a patient with malignant mesothelioma who, during the course of nivolumab treatment, subsequently developed RP-ILD. Postmortem analysis showed baseline anti-MDA5 antibodies that became higher during ICI therapy, raising a possible mechanistic association between the increased antibody levels and RP-ILD onset.

Case Presentation

A 68-year-old male with a history of malignant pleural mesothelioma, whose disease had progressed despite the usual chemotherapy, received nivolumab. He had neither respiratory symptoms nor signs of dermatomyositis before starting ICI. Routine laboratory tests, including autoantibody screening, were not checked before the commencement of nivolumab because he had no clinical indicators for autoimmune disease.

Only two months into his treatment, he started showing manifestations over the skin, including erythematous patches over the dorsal hands and heliotrope rash over the eyelids, classic signs of dermatomyositis. He complained at the same time of worsening shortness of breath that had rapidly progressed in the span of a few weeks. Pulmonary function tests revealed a considerable decline in lung capacity, whereas high-resolution computed tomography revealed diffuse ground-glass opacities, culminating in the diagnosis of interstitial lung disease.

This patient received immunosuppressive therapy with high doses of corticosteroids and cyclophosphamide, but this did not improve his status at all; he went on to experience acute respiratory failure and died three months after the onset of respiratory symptoms.

Postmortem Findings

To understand the rapid progression of the patient's condition, a postmortem analysis was conducted, and serum samples collected before and after starting nivolumab were tested for myositis-specific autoantibodies. Results revealed that the patient had a positive titer for anti-MDA5 antibodies before ICI therapy, which had not been noted previously due to a lack of autoimmune screening. Subsequent increases in levels after commencing nivolumab therapy suggested further immune amplification with nivolumab therapy.

Histopathological examination of lung tissue revealed extensive fibrosis and inflammation, as in rapidly progressive ILD. The characteristic skin lesions on her hands and face were examined and features compatible with dermatomyositis were present. These findings, taken together with the positivity for the anti-MDA5 antibody, confirmed the diagnosis of CADM with RP-ILD as a lethal complication of ICI therapy.

Discussion

This case particularly underscores that ICIs might potentially flare or induce related autoimmune diseases. In addition to myositis and ILD, beyond the side effects of irAEs induced by ICIs, the literature has been very diverse; however, this seems to be the first recorded case of nivolumab-associated RP-ILD in a patient who presented with pre-existing anti-MDA5 antibodies. The absence of muscle involvement and the presence of typical skin manifestations are quite compatible with the diagnosis of CADM and may be easily missed in cancer patients.

Pathophysiology of Anti-MDA5 Antibodies and RP-ILD

Anti-MDA5 antibodies are strongly associated with CADM and are a risk factor for the development of RP-ILD, which has a more dismal prognosis. These antibodies bind MDA5, a cytosolic RNA sensor critical for the antiviral immune response. The mechanism by which anti-MDA5 antibodies cause lung injury is incomplete but thought to represent aberrant immune activation resulting in inflammation and fibrosis within lung parenchyma.

This probably triggered an underlying autoimmune process in the patient. ICI drugs inhibit the function of PD-1, a receptor that operates as a brake on T-cell activity; thus, they enhance the immune response to cancer cells. However, it has been shown that this heightened immune activity can result in a breakdown in tolerance for self-antigens, such as MDA5, resulting in or exacerbating autoimmune conditions. The rise of anti-MDA5 antibodies post-nivolumab may suggest that the treatment may have induced an already dormant autoimmune process which manifests into RP-ILD.

Screening and Monitoring for Autoimmune Risk in ICI Therapy

The development of RP-ILD in this patient raises important questions about the role of autoimmune screening in patients scheduled to receive ICIs. While autoimmune diseases have traditionally been considered a contraindication to ICI therapy, many patients with subclinical autoimmunity may go undiagnosed until they develop irAEs. This case suggests that screening for specific autoantibodies, such as anti-MDA5, may help identify patients at risk for developing severe autoimmune complications like RP-ILD.

In patients with positive anti-MDA5 antibodies, close monitoring of pulmonary function and early intervention with immunosuppressive therapy may improve outcomes. This case also highlights the need for a multidisciplinary approach to managing patients on ICIs, involving oncologists, pulmonologists, and rheumatologists to mitigate the risk of severe irAEs.

Treatment Considerations for RP-ILD in CADM

The treatment of RP-ILD in CADM is challenging, particularly in the setting of ICI-induced immune dysregulation. Immunosuppressive therapies, including corticosteroids, calcineurin inhibitors, and cyclophosphamide, are commonly used to manage RP-ILD. However, these therapies may be insufficient in rapidly progressing cases, as seen in this patient. In some cases, plasma exchange or intravenous immunoglobulin (IVIG) may be considered, although their efficacy remains uncertain.

In patients who develop RP-ILD following ICI therapy, discontinuation of the ICI is essential, and aggressive immunosuppression should be initiated as early as possible. Unfortunately, even with prompt treatment, the prognosis for RP-ILD associated with anti-MDA5 antibodies remains poor, with mortality rates as high as 50-90%. This case emphasizes the need for further research into more effective therapies for this lethal complication.

Conclusion

This case report highlights the potential activity of ICIs in the re-activation or manifestation of autoimmune diseases, which may lead to severe complications like RP-ILD in the background of pre-existing anti-MDA5 antibodies. There is a need for the development of RP-ILD following nivolumab treatment in a patient with malignant mesothelioma based on the pre-treatment risk assessment for the autoimmune factors and vigilant follow-up for irAEs. Given the very poor outcomes associated with RP-ILD in patients with CADM, it is crucial to diagnose and manage the disease as quickly as possible to optimize outcomes. This case requires further research in therapies tailored to the specific result of RP-ILD in a patient on ICI therapy, especially in a patient who harbors pre-existing autoimmune markers.

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