Comparative analysis of immunotherapy responses in small cell lung cancer patients with dermatomyositis

Abstract

Cancer‐associated dermatomyositis (CAD), a paraneoplastic syndrome characterized by dermatomyositis (DM), frequently presents in association with small cell lung cancer (SCLC). Although the advent of immune checkpoint inhibitors (ICIs) has revolutionized cancer treatment, their efficacy and safety in patients with concurrent autoimmune diseases (AD) and malignancies remains uncertain. Several studies have suggested the safe administration of ICIs in patients with AD, indicating that successful cancer therapy can alleviate CAD symptoms. Conversely, other studies have raised concerns about the potential for ICIs to exacerbate AD flares or immune‐related adverse events (irAEs). A comparative analysis of two cases from our institution emphasizes the variability in ICI responses among SCLC patients with CAD. One patient, previously reported as a case study, exhibited significant clinical improvement in DM symptoms after ICI administration, whereas the other developed severe exfoliative skin changes and experienced an unfavorable prognosis. This variability emphasizes the need for careful patient selection and close monitoring during ICI treatment. We hypothesized that overweight or obese individuals and those with severe initial skin lesions and elevated lactate dehydrogenase levels are more susceptible to developing irAEs following ICI therapy. Therefore, caution is advised when considering immunotherapy in these patients.

When considering the use of immune checkpoint inhibitors in Small Cell Lung Cancer (SCLC) with accompanying Dermatomyositis (DM), it's essential to evaluate the anticancer effect, the risk of immune‐related adverse effects (irAEs), and the potential for worsening of DM. Additionally, factors such as the patient's overweight status, the severity of the initial skin lesions, and the Lactate Dehydrogenase (LDH) levels should be taken into account.

INTRODUCTION

Dermatomyositis (DM), a rare autoimmune inflammatory myopathy, is characterized by muscle weakness and distinctive cutaneous manifestations, including heliotrope rash, Gottron's sign, and facial erythema. ¹ , ² It is frequently associated with malignancy and small cell lung cancer (SCLC) is the most common cancer often associated with DM. ³

Patients with cancer‐associated dermatomyositis (CAD) exhibit antitranscription intermediary factor 1‐γ (anti‐TIF1‐γ) antibodies. ⁴ Mutations or elevated expression of TIF1‐γ, a tumor suppressor that regulates the transforming growth factor‐beta (TGF‐β) signaling pathway, can trigger the production of anti‐TIF1γ antibodies, leading to CAD. Although CAD treatment resembles other DM forms, using steroids and immunosuppressants, evidence suggests that CAD often improves alongside cancer treatment. Therefore, prioritizing cancer treatment is essential. ⁵ , ⁶

Although the advent of immune checkpoint inhibitors (ICIs) has revolutionized cancer treatment, their use in patients with concurrent autoimmune diseases (AD) and malignancies remains uncertain. ICI administration can exacerbate the activation of autoreactive T cells in AD patients, potentially leading to AD flares, severe immune‐related adverse events (irAEs), and therapeutic setbacks. ⁷ , ⁸ , ⁹ , ¹⁰ However, several studies have suggested the safe administration of ICIs in AD patients, with irAEs being generally manageable. ¹¹ , ¹² , ¹³

Here, we present two cases of SCLC and CAD patients who received ICI therapy. One patient, previously reported as a case study, exhibited significant clinical improvement and resolution of skin lesions, ¹⁴ whereas the other developed severe exfoliative skin changes and experienced an unfavorable prognosis. We compared and analyzed these cases to identify potential factors contributing to their distinct outcomes.

CASE REPORT

Two patients, a 78‐year‐old man of normal weight (patient A) and a 57‐year‐old overweight man (patient B), presented with dyspnea and generalized weakness. They were former smokers, and both had a smoking history of over 50 pack‐years. Computed tomography (CT) of the chest revealed a lung mass and enlarged lymph nodes, and a biopsy confirmed SCLC. Both patients were classified as extensive‐stage (ES) disease.

They developed skin lesions characterized by erythematous rashes around their eyes and on both cheeks. However, patient B presented with more severe and extensive skin manifestations involving all extremities (Figure 1a–c). Both patients also experienced limb weakness and difficulties walking and swallowing. Positron emission tomography‐computed tomography (PET‐CT) revealed diffuse hypermetabolic lesions in muscle and soft tissues (Figure 2). Notably, serum muscle enzymes, creatine phosphokinase (CPK) and lactate dehydrogenase (LDH), were elevated. Due to the muscle weakness, electromyography (EMG) and muscle biopsy were performed. EMG revealed acute myopathy and biopsy findings were consistent with DM (Figure 3). Further investigations for DM, including anti‐TIF1‐γ and antinuclear antibodies, yielded positive results, leading to the diagnosis of CAD, a paraneoplastic syndrome associated with SCLC.

FIGURE 1.

Changes in skin lesions for both patients. (a) Initial skin lesions of patient A. (b and c) Initial skin lesions of patient B, characterized by an erythematous rash around the eyes, cheeks, and extremities. (d) Improved skin lesions of patient A following atezolizumab administration. (e and f) Exfoliative skin lesions covering the entire body of patient B after atezolizumab administration.

FIGURE 2.

Positron emission tomography‐computed tomography (PET‐CT) of both patients. Both the PET‐CT images (a) and (b) indicate the presence of small cell lung cancer, with diffuse uptake observed in all soft tissues.

FIGURE 3.

Pathological findings of biceps brachii biopsy. (a) Hematoxylin and eosin staining showing scattered atrophic muscle fibers (black arrow) and occasional internal nuclei (100×). (b) Electron microscopy demonstrating tubuloreticular inclusions in endothelial cells, suggestive of dermatomyositis (black arrow) (30 000×). (c) Hematoxylin and eosin staining showing myofiber splitting (yellow arrow) and myofiber atrophy (yellow arrowhead) (20×). (d) Electron microscopy showing tubule‐reticular inclusions in the cytoplasm of endothelial cells, indicative of dermatomyositis (yellow arrows) (10 000×).

Both patients received treatment for SCLC and CAD, including steroids and chemotherapy with carboplatin, etoposide, and atezolizumab. This treatment regimen resulted in a significant reduction in CPK and LDH levels in both patients.

Patient A exhibited a notable improvement in his overall condition, muscle strength and skin manifestation (Figure 1d). Conversely, the LDH levels in patient B suddenly elevated (Figure 4) and he developed severe skin changes that differed from his initial symptoms (Figure 1e,f). His overall condition deteriorated, compared to patient A. Despite administration of antibiotics and close monitoring, patient B passed away 3 weeks after chemotherapy had been initiated (Table 1).

FIGURE 4.

Graph of serum muscle enzymes in both patients. Creatine phosphokinase (CPK) and lactate dehydrogenase (LDH) showed a concurrent decrease in both patients. However, patient B experienced a subsequent sudden increase in LDH levels.

TABLE 1.

Patient characteristics.

	Case A	Case B
Characteristics
Age/sex	78/M	57/M
Comorbidity	COPD, gastric cancer (s/p subtotal gastrectomy)	COPD subclinical hypothyroidism severe fatty liver
Bodyweight	55 kg	87 kg
Height	165 cm	174 cm
BMI	20.20 kg/${\mathrm{m}}^2$	28.73 kg/${\mathrm{m}}^2$
General shape	Cachexia	Overweight, edematous
Smoking history	80‐pack‐year	54‐pack‐year
	Ex‐smoker (quit 15 years ago)	Current smoker
Lung cancer stage	SCLC, ES	SCLC, ES
Dermatomyositis
Skin	Facial rash, thickened skin on the finger joints	Diffuse erythema face, extremities
Muscle weakness	Peripheral muscle weakness	Peripheral muscle weakness
	Bed‐ridden state	Bed‐ridden state
Swallowing	Difficult	Difficult
Antinuclear Antibody	Homogenous with speckled 1:1280	Speckled 1:320
Anti‐TIF1‐γ	+	+
Laboratory results (before ICIs)
WBC	8530/μL	8090/μL
Hb	12.9 g/dL	10.9 g/dL
Platelet	77 000 g/dL	205 000 g/dL
ANC	6660/μL	5600/μL
CRP	3.1 mg/dL	2.1 mg/dL
Procalcitonin	0.22 ng/mL	0.06 ng/mL
LDH	1386 U/L	894 U/L
CPK	1315 U/L	2028 U/L
Course
Changes of CPK, LDH	CPK: 1386 → 572	CPK: 2159 → 1474 → 476
	LDH: 1318 → 28	LDH: 1122 → 626 → 2594
Skin change	Skin improvement	Skin eruption, peeling off exfoliative patch change

Abbreviations: ANC, absolute neutrophil count; BMI, body mass index; COPD, chronic obstructive pulmonary disease; CPK, creatine phosphokinase; CRP, C‐reactive protein; ES, extensive stage; Hb, hemoglobin; ICIs, immune checkpoint inhibitors; LDH, lactate dehydrogenase; SCLC, small cell lung cancer; WBC, white blood cells.

DISCUSSION

Patient B developed sudden and severe skin exfoliation following the administration of ICIs. Consultations with rheumatology and dermatology specialists revealed that the aggravated skin manifestations were considered unlikely to represent an exacerbation of DM. Also, they suggested that decreased CPK level, a specific marker of muscle inflammation associated with myositis, did not indicate a deterioration of DM. Diagnostic workup, including cardiac enzymes, chest x‐ray, and brain imaging did not reveal any specific findings that could directly account for the death of the patient. Considering the abrupt changes in the skin condition of the patient following ICI administration, it was concluded that the cause of death was a fatal irAE. Although no bacterial strains were identified in blood cultures, it was hypothesized that the extensive and severe skin lesions resulting from the irAE could have led to infection and sepsis, ultimately leading to the patient's demise.

The irAE manifested in patient B was classified as grade 3, according to the common terminology criteria for adverse events, indicating a life‐threatening condition. ¹⁵ , ¹⁶ Although the pathophysiology of irAEs remains unclear, the principles observed in autoimmune and autoinflammatory conditions, such as the loss of regulatory control and overactivation of the immune system, may play a role in their development. ¹⁷ , ¹⁸

Despite the absence of definitive biomarkers for irAEs, several studies suggest that an elevated LDH during the pre‐irAE phase could predict irAE occurrence. ¹⁹ , ²⁰ Multiple studies have reported that patients with pre‐existing AD are more susceptible to AD flares or irAEs when treated with ICIs. ¹¹ , ²¹ , ²² These studies have also demonstrated an increased risk of irAEs or AD flares in obese individuals. ²² , ²³ , ²⁴ , ²⁵ Although no differences were observed in cancer staging or chemotherapy between the two cases, a higher body mass index and more severe and extensive skin lesions in patient B at the initial presentation may have increased his risk of developing irAE. Furthermore, elevated LDH levels in patient B could have served as an early indicator of the impending irAE.

Considering the lack of well‐defined baseline characteristics for predicting favorable outcomes in cancer patients with AD who receive ICIs, it is essential to closely monitor clinical presentations and changes in blood parameters, including LDH, particularly when administering ICIs to patients with higher body mass index and extensive skin lesions.

In conclusion, the use of ICIs in patients with AD, such as DM, remains uncertain. Notably, caution is advised when considering immunotherapy in these patients, particularly in those with risk factors for irAEs, such as being overweight or obesity, severe initial skin lesions, or elevated LDH levels.

AUTHOR CONTRIBUTIONS

SY Kim organized the clinical information of the patients and wrote the manuscript, while DK Kim provided in‐depth analysis of the patient cases. SY Choi took the EM pictures, and CU Chung supervised the case report writing.

FUNDING INFORMATION

This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean Government (MSIT) (no. 2022R1A2C2010148), the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (no. HR20C0025).

CONFLICT OF INTEREST STATEMENT

The authors declare no conflicts of interest.

ETHICS STATEMENT

The study was completed and approved by our local ethics review board in accordance with the declaration of Helsinki.

Kim S, Kim DK, Choi S‐Y, Chung C. Comparative analysis of immunotherapy responses in small cell lung cancer patients with dermatomyositis. Thorac Cancer. 2024;15(8):672–677. 10.1111/1759-7714.15238