Amyopathic dermatomyositis associated with immune checkpoint inhibitor therapy in lung adenocarcinoma: a case report

Introduction

Immunotherapy checkpoint inhibitors have been extensively employed in the immunotherapy of non-small cell lung cancer (NSCLC) (1). However, the treatment with these inhibitors may also precipitate immune-related adverse events (irAEs), leading to autoimmune diseases (2). We report a case of a patient with stage IV lung adenocarcinoma who developed amyopathic dermatomyositis (ADM) concomitant with rapidly progressive interstitial lung disease (RP-ILD) following treatment with pembrolizumab, an inhibitor of the programmed cell death 1 (PD-1) receptor. To our knowledge, this is the first report on such a case in the literature and may thus expand the clinical knowledge related to irAEs associated with checkpoint inhibitors. We present this case in accordance with the CARE reporting checklist (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2024-2364/rc).

Case presentation

A 67-year-old male patient underwent a computed tomography (CT)-guided lung biopsy, which indicated lung adenocarcinoma, positivity for programmed death-ligand 1 (PD-L1), tumor proportion score (TPS) of 40%, and stage IV T2aN0M1a tumor without EGFR/ALK mutations. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Declaration of Helsinki (as revised in 2013). Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

The pretreatment CT scan did not reveal ILD (Figure 1A). According to the updated 5-year follow-up results from the KEYNOTE-189 study, a phase III clinical trial in patients with untreated metastatic nonsquamous NSCLC without EGFR/ALK mutations, the combination of pembrolizumab, pemetrexed, and platinum chemotherapy may significantly prolong overall survival (OS) and progression-free survival (PFS) compared to chemotherapy alone and provide manageable toxicity regardless of PD-1 expression levels (3,4). Based on this study, it was decided upon to treat the patient with a combination of pembrolizumab, pemetrexed, and carboplatin. Three days after the initiation of systemic therapy, the patient developed symptoms of fever, slight chest tightness, and shortness of breath. Physical examination revealed extensive erythema, papules, flushing, and pruritus on the back, with diffuse brown macules, scaling, and erosive exudative lesions on the buttocks. Allergic dermatitis was suspected, and antiallergic treatment was administered.

Figure 1 Chest CT images during hospitalization showed significant and progressive interstitial lung changes. (A) Chest CT scan images obtained one week prior to anti-tumor therapy; (B) chest CT scan on anti-tumor therapy day 6 revealed interstitial and obstructive pneumonia, suggesting immune-related lung injury; (C) chest CT scan imaging on day 14 post-treatment demonstrated progression of pulmonary injury; (D) chest CT scan imaging on day 39 post-treatment revealed marked interstitial changes in the lungs. CT, computed tomography.

Six days after the initiation of treatment, the patient’s chest tightness and dyspnea worsened. A follow-up, chest CT scan suggested interstitial pneumonia and obstructive pneumonia, leading to a consideration of immune-related lung injury (Figure 1B). The patient was treated with intravenous methylprednisolone 40 mg/day for 21 days, followed by an increased dose of 80 mg/day for 7 days. Additionally, anti-infection and other symptomatic treatments. During this period, the patient also received antibiotic therapy for infection and other symptomatic treatments. However, the patient continued to experience recurrent symptoms of fever, chest tightness, and shortness of breath.

On the 14th day after treatment, a chest CT scan indicated worsening interstitial pneumonia (Figure 1C). The patient was treated with intravenous methylprednisolone (160 mg/day) to modulate immunity, intravenous infliximab (350 mg for once) to inhibit cytokines, and combined anti-infection and supportive treatment On the 39th day after treatment, a chest CT scan showed increased interstitial pneumonic lesions in both lungs (Figure 1D), with multiple areas of gas in the subcutaneous tissue of the mediastinum and neck-back region, suggesting a high probability of immune pneumonia complicated by bacterial infection. Autoantibody spectrum testing indicated positivity for antinuclear antibodies (1:100). No abnormalities were found in the remainder of the autoantibody spectrum, including Sjögren’s syndrome antigen A, Sjögren’s syndrome antigen B, Smith antigen D1, double-stranded DNA, ribonucleoprotein, reticulin antigen, lupus antigen La, histidyl-tRNA synthetase, anti-topoisomerase I antibody, polymyositis-scleroderma antibody, centromere protein B, proliferating cell nuclear antigen, nucleosome, histone, 52-kDa Ro antigen, Ku, antimitochondrial antibody, mitochondrial, and signal recognition particle (SRP)-related autoantibodies. Treatment continued with methylprednisolone (80 mg q12h), combined with mycophenolate mofetil capsules (0.75 g bid) and γ-immunoglobulin (27.5 g for 5 days) for immunomodulatory therapy.

On the 44th day after treatment, due to significant chest tightness and shortness of breath with poor oxygen saturation, the patient was transferred to the intensive care unit and provided noninvasive mechanical ventilation support. Laboratory results indicated positivity for anti-MDA5 antibody (+++), suggesting a diagnosis of dermatomyositis (DM) without muscle involvement secondary to RP-ILD. Immediate treatment was adjusted to include intravenous methylprednisolone (480 mg/day) pulse therapy, three days later, the treatment was changed to intravenous methylprednisolone 80 mg/day, combined with tacrolimus 3 mg/day to suppress the immune system. Regrettably, despite the treatments, the patient’s condition continued to worsen, ultimately leading to respiratory failure and death was pronounced. The patient endured a total of 52 days from the onset of the disease to death.

International multidisciplinary team (iMDT) discussion

Discussion among physicians from Ningbo Yinzhou No. 2 Hospital

IrAEs typically affect the skin, gastrointestinal tract, liver, endocrine organs, and lungs. In skin-related adverse reactions, patients predominantly manifest as mild itching or rash. Gastrointestinal toxicity is primarily characterized by diarrhea. Hepatic toxicity is clinically manifested mainly by elevated transaminase levels and hyperbilirubinemia. Common endocrine irAEs include hypophysitis, thyroid dysfunction, and less frequently, type 1 diabetes mellitus. In addition, systemic and rheumatic irAEs such as arthralgia, myalgia, granulomatous irAEs, vasculitic irAEs, and systemic irAEs have also been reported. Additionally, Arthralgia, muscular, granulomatous, vasculitic, and systemic irAEs are categorized under systemic and rheumatic irAEs. Other organ-specific irAEs include renal toxicity and ocular toxicity (5). Severe adverse events such as pneumonia, myocarditis, neurotoxicity, myositis, nephritis, and hematologic toxicity, although uncommon, can lead to extremely serious consequences when they occur (6).

The estimated mortality rate of immune checkpoint inhibitors (ICIs) ranges from 0.3% to 1.3% (7). One study has found that the individual mortality rate is 0.36% for patients receiving PD-1 inhibitors, 0.38% for those receiving PD-L1 inhibitors, 1.08% for those receiving CTLA-4 inhibitors, and 1.23% for patients undergoing combination therapy (5). A meta-analysis further confirmed that the spectrum of fatal irAEs caused by anti-PD-1 and PD-L1 are usually due to pneumonia (35%), hepatitis (22%), and neurotoxicity (15%) (7).

Adverse events related to PD-1 inhibition in both the lung and skin have been well documented. The immune-related adverse events in the lung are mainly manifested as interstitial change (8). Skin-related adverse events, such as eczema, psoriasis-like and lichenoid phenotypes, maculopapular rash, pruritus, and immunobullous diseases, have been reported in the literature (9). DM has been previously reported as irEA, primarily manifested by dermatological lesions and myopathic symptoms (10). Kudo et al. reported a case of advanced lung adenocarcinoma where the patient developed skin lesions and muscle weakness following anti-PD-1 therapy (11). Yu et al. reported on the concomitant development of Wong-type DM during anti-PD-1 treatment (12). However, there are few reports in the literature regarding DM complicated by anti-MDA5 antibody-positive RP-ILD.

Pan et al. and Kato et al. respectively reported the occurrence of anti-MDA5 antibody-positive RP-ILD in patients with lung adenocarcinoma and malignant pleural mesothelioma following treatment with ICIs (13,14). According to these reports, there may be a certain correlation between immunotherapy and ADM, but more clinical evidence is needed to substantiate this. In our case, the patient developed nonmyopathic DM following anti-PD-1 treatment, accompanied by significant interstitial lung changes, and tested positive for anti-MDA5 antibodies. Therefore, this report is highly significant in enriching the understanding of irAEs associated with PD-1 inhibitors.

ADM is a distinct subtype of DM and is characterized by the typical dermatological manifestations of DM without objective signs of myositis and by normal findings in laboratory tests such as serologic enzyme levels, electromyography, and muscle biopsy. In serum muscle enzyme tests, levels of creatine kinase, aldolase, aspartate transaminase (AST), alanine transaminase (ALT), and lactate dehydrogenase (LDH) are significantly elevated in patients with DM but are either normal or only mildly elevated in patients with ADM. Since the patient did not undergo muscle pathology, his condition is referred to as ADM in this report. The patient had a history of a back rash for 2 months, accompanied by itching, which was neither located in common areas nor exposed to direct sunlight, and the characteristic V-sign on the neckline was not prominent, indicating that it was not a characteristic dermatological manifestation of DM. Furthermore, serum muscle enzyme tests were normal at the time of admission, leading to an initial misdiagnosis as eczema. Additionally, ADM is a systemic disease and positive for anti-MDA5 antibody, with the lungs being the most commonly affected organ. ILD is a common manifestation and the main cause of mortality in such cases. In our case, the patient tested positive for anti-MDA5 antibodies and presented with mediastinal emphysema, which suggests a poor prognosis (15). Ikeda et al. found that the prevalence of ILD among patients with ADM is 100%, with 80% of these patients dying from acute ILD within 90 days and all exhibiting positivity for anti-MDA5 antibodies (16). Gan et al. reported that over 80% of the 108 patients with ADM in their retrospective study were diagnosed with ILD (17). In our case, due to the patient’s family’s refusal to have skin and muscle biopsy performed, we did not obtain a pathological report of the skin and muscle. Among the adverse events related to anti-PD-1 therapy, pulmonary interstitial changes are not uncommon. Therefore, when the patient developed ILD, our initial suspicion was ILD induced by anti-PD-1 therapy leading to irAEs (9). However, despite the administration of corresponding treatment and the exclusion of various pathogens, the patient’s ILD worsened. Combined with the positive anti-MDA5 antibodies, based on the experience of rheumatology and immunology specialists, it was ultimately deduced that the patient had ADM-related ILD (although the possibility of anti-PD-1 therapy-related pneumonia could not be completely ruled out). Unfortunately, the high mortality rate of RP-ILD and the late treatment led to the patient’s death.

In this case, the patient developed severe ILD shortly after anti-PD-1 therapy, giving us ample reason to consider a correlation between the two. We speculate that anti-PD-1 therapy triggered ADM-associated ILD, leading to disease progression. However, the underlying mechanism remains unclear. We speculate that pembrolizumab may enhance antigen presentation due to immune activation caused by PD-1 blockade.

Additionally, studies have demonstrated a close association between ADM and DM with malignancies, with findings suggesting that about 12% of patients with ADM may codevelop malignancies. The malignancies commonly associated with ADM include breast cancer, lung cancer, and ovarian cancer (18,19). Hence, there may be a correlation between the patient’s lung malignancy and ADM.

Several further questions regarding the diagnosis and treatment of this patient are as follows

Question 1: Is it necessary to screen for autoimmune diseases before administering ICIs to patients?

Expert opinion: Dr. Takehiro Uemura

It is advisable to conduct screening for autoimmune diseases before initiating ICI therapy if there are any signs suggesting the potential presence of such conditions. Early identification of underlying autoimmune disorders could aid in predicting the risk of irAEs and inform tailored monitoring strategies.

Question 2: Is autoimmune disease an absolute contraindication to ICI therapy?

Expert opinion: Dr. Takehiro Uemura

A retrospective study indicates that preexisting autoimmune diseases do not universally lead to severe exacerbations when treated with ICIs, suggesting that such conditions are not an absolute contraindication (20). However, for patients with preexisting interstitial lung disease, a more cautious approach in case selection is recommended to mitigate the risk of adverse reactions.

Question 3: How should we standardize the treatment for the RP-ILD encountered in this patient?

Expert opinion: Dr. Takehiro Uemura

Early intervention with high-dose corticosteroids is preferred following diagnosis. If ineffective, while no definitive protocol exists, early addition of agents such as infliximab, tacrolimus, cyclophosphamide, or intravenous immunoglobulin could be considered based on individual patient response and clinical experience.

Question 4: Is AMD a result of ICI treatment or does it exacerbate the condition?

Expert opinion: Dr. Takehiro Uemura

There are limited reports addressing this relationship, making it difficult to draw a definitive conclusion. However, in this case, the patient developed respiratory symptoms indicative of ADM-related interstitial lung disease shortly after receiving pembrolizumab, suggesting that the treatment may have triggered the condition in a susceptible patient with a predisposing background.

Conclusions

Both immunotherapy with checkpoint inhibitors and ADM can have dermatological manifestations and concomitant ILD, thereby delaying diagnosis. The case serves as a valuable clinical reference for the future management of irAEs caused by ICIs and emphasizes the necessity of early screening for anti-MDA5 antibodies in patients with checkpoint inhibitor pneumonitis presenting as RP-ILD. In this case, the mechanisms underlying the relationships between checkpoint inhibitors, increased antigen presentation, and tumor progression are not yet clear but may represent a novel research direction in the field of anti-PD-1 therapy.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2024-2364/rc

Peer Review File: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2024-2364/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2024-2364/coif). T.U. receives grants from Amgen, Boehringer Ingelheim, Eli Lilly, Takeda and Ono Pharmaceutical; and personal fees from Amgen, AstraZeneca, Boehringer Ingelheim, Chugai, Daiichi Sankyo, Eli Lilly, Kyowa Kirin, MSD, Novartis Pharma, Ono Pharmaceutical, Taiho, and Takeda. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Declaration of Helsinki (as revised in 2013). Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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