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Journal of Peking University (Health Sciences) ›› 2022, Vol. 54 ›› Issue (4): 644-651. doi: 10.19723/j.issn.1671-167X.2022.04.010

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Clinical features of immune checkpoint inhibitor-related myositis in patients with urological cancer

Yi-cen YING,Qi TANG*(),Kai-wei YANG,Yue MI,Yu FAN,Wei YU,Yi SONG,Zhi-song HE,Li-qun ZHOU,Xue-song LI*()   

  1. Department of Urology, Peking University First Hospital; Institute of Urology, Peking University; National Urological Cancer Center, Beijing 100034, China
  • Received:2022-04-01 Online:2022-08-18 Published:2022-08-11
  • Contact: Qi TANG,Xue-song LI E-mail:drtangq@bjmu.edu.cn;pineneedle@sina.com

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Abstract:

Objective: Immune checkpoint inhibitors (ICI) have significantly improved the treatment efficacy of a variety of malignant tumors. However, patients may experience a series of special side effects during treatments with ICI. Immune-related myositis after ICI treatment is characterized by autoimmune rheumatic and musculoskeletal damage, which is relatively rare. To analyze the clinical characteristics and outcomes of ICI-associated myositis in urological tumors, we summarized the clinical manifestations, electrophysiological and pathological characteristics, treatments and outcomes in 8 patients. Methods: The clinical data of the 8 patients with immune-related myositis after ICI treatment for urological tumors treated in the Department of Urology, Peking University First Hospital from March 2018 to March 2022 were retrospectively analyzed for demographic characteristics, drug regimen, clinical symptoms, laboratory indices, electromyography examination, pathological manifestations and outcomes. Results: The eight patients included 2 females and 6 males with a median age of 68 years, all treated with ICI for urological neoplasms, including 2 upper tract urothelial carcinoma (UTUC), 3 renal cell carcinoma (RCC), and 3 bladder cancer (BCa). The median time between the first ICI treatment and the detection of immune-related myositis was 39.5 days, and the median duration of treatment was 2 sessions. The main symptoms were muscle pain and weakness, 5 cases with ptosis, 3 cases with secondary rhabdomyolysis, 5 cases with myocarditis, 1 case with myasthenia gravis, and 1 case with enterocolitis. Among them, patients with immune-related myocarditis had a shorter interval from the first anti-programmed cell death protein-1 (PD-1) therapy to the onset of immune-related myositis (P=0.042) compared with patients without myocarditis. The 8 patients had significant elevation of transaminases and muscle enzyme profile indexes, and 5 patients showed positive auto-antibodies. 3 patients had perfected muscle biopsies and showed typical skeletal muscle inflammatory myopathy-like pathological changes with CD3+, CD4+, CD8+, CD20+ lymphocytes and CD68+ macrophage infiltration. After the diagnosis of immune-related myositis, all the 8 patients immediately discontinued ICI therapy and improved after intravenous administration of methylprednisolone alone or in combination with gamma-globulin. Conclusion: Immune-related myositis after ICI treatment is an immune-related adverse reactions (irAEs) with unique clinical and pathological features, commonly combined with cardiovascular adverse reactions. Immediate discontinuation of ICI and initiation of glucocorticoid therapy may improve the patient's condition in a timely manner.

Key words: Immune checkpoint inhibitors, Urological cancer, Myositis, Myocarditis

CLC Number: 

  • R737

Table 1

General characteristics of patients with immune-related myositis after ICI treatment"

Case Gender Age/years Tumor Complications Surgical procedure pTNM stage Grade Post-operative treatment Recurrence/Metastasis
1 F 67 UTUC HBP CHD RNU pT3N0 G3 None None
2 M 72 RCC ILD RN pT3aN0 G2-G3 None Retroperitoneal recurrence with peritoneal metastasis
3* F 66 RCC DM RN NA NA None Pancreas metastases
4 M 73 UTUC HBP RNU pT1N0 G2-G3 None Bladder recurrence
5* M 72 BCa DM TUR-Bt NA G3 GC regimen and intravesical chemotherapy Liver metastases
6 M 69 BCa DM TUR-Bt pT1 G2 None Bladder recurrence
7 M 61 RCC DM NSS pT1bN0 G2 Radiotherapy Mediastinal and liver metastases
8 M 38 BCa HBP TUR-Bt PT1 G1-G2 Intravesical chemotherapy Bladder recurrence

Table 2

Characteristics of immunotherapy in patients with immune-related myositis after ICI treatment"

Case ICI Dosage/mg Combined chemotherapy Treatment period Duration of immunotherapy/d
1 Nivolumab 240 None 2 25
2 Pembrolizumab 200 None 1 15
3 Pembrolizumab 200 None 2 37
4 Tislelizumab 200 Gemcitabine and carboplatin 2 54
5 Toripalimab 240 None 2 29
6 Tislelizumab 200 Gemcitabine and cisplatin 2 47
7 Pembrolizumab 200 None 3 58
8 Sintilimab 200 None 2 42

Table 3

Laboratory findings in patients with immune-related myositis after ICI treatment"

Case ALT/(IU/L) AST/(IU/L) CK/(IU/L) LDH/(IU/L) HBDH/(IU/L) CK-MB/(μg/L) cTnI/(g/L) hs-TnI/(g/L) hs-CRP/(mg/L) BNP/(ng/L) FT3/(pmol/L) FT4/(pmol/L) TSH/(mIU/L) IgM/(g/L) Auto-antibodies
1 142 223 4 859 844 759 140.4 2.483 NA 6.63 105 NA NA NA NA AchE.Ab; Titin.Ab; RyR.Ab
2 167 377 5 587 730 605 153.2 NA 1 428.1 45.25 29 4.24 17.66 2.75 NA NA
3 110 81 1 291 601 556 96.7 NA 17.0 1.49 11 5.35 24.3 0.2 0.41TPOAb; TgAb; ANA; SS-A; AMA-M2
4 269 327 7 251 1 389 1 206 276.6 0.118 NA 29.98 NA NA NA NA NA NA
5 147 265 4 295 822 709 107.8 1.010 NA 90.47 98 3.42 16.28 4.52 NA TPOAb; TgAb
6 186 363 7 590 970 851 145.9 NA 2 588.2 15.73 30 4.15 10.69 0.38 0.57ANA; AMA-M2; Titin.Ab; LRP4.Ab
7 96 136 2 622 469 405 58.9 NA 171.6 NA NA 6.80 23.94 0.05 0.35 LRP4.Ab
8 63 40 595 238 190 9.5 NA 27.7 NA NA NA NA NA NA NA

Table 4

Symptoms, diagnosis and outcomes in patients with immune-related myositis after ICI treatment"

Case Symptoms Immune-related complications ECG UCG Electro-myography Initial treatment Outcomes
1 Palpitation, choking, dyspnea, dizziness, blurred vision, edema in both eyes, right lipomatosis ptosis Myocarditis; Myasthenia gravisAtrial premature beats; Ⅲ° atrioventricular block; Complete right bundle branch conduction block; TⅢ, aVF, V3, V4, V5, V6 hypoplasia; QRSⅢ, aVF abnormal Q wavesEF=82.3%; Ventricular septum thickening; Abnormal left ventricular diastolic function (grade Ⅱ); Mildly elevated pulmonary artery systolic pressure (36.3 mmHg) Normal MP 120 mg qd, IVIG 20 g qdImproved; glucocorticoid reduction; Died of tumor progression
2Vomiting, weakness, right lipomatosis ptosis, diplopia, deepening of urine colorMyocarditis; RhabdomyolysisAtrial premature beats; Premature ventricular contractionsEF=78.1%; Mildly elevated pulmonary artery systolic pressure；Stellate hyperechogenicity of the ventricular septum is seenNerve conduction slowed down MP 120 mg qd, IVIG 30 g qd Improved; Glucocorticoid reduction
3Weakness of limbs, lipomatosis ptosis, muscle pain, chest tightness, palpitation, headache, difficulty in chewing and seeingMyocarditisAtrial premature beats; Premature ventricular contractions; ST partial Ⅰ, Ⅱ, Ⅲ, aVF, V4, V5, V6 inferior shift; T partial V3, V4, V5, V6 hypoplasia, inversionEF=62.4% Normal IVIG 25 g qd Improved; Glucocorticoid reduction
4Right lipomatosis ptosis, muscle pain, shortness of breath after activityNone Sinus tachycardia EF=84.9%；Left ventricular wall thickening Nerve conduction slowed down; Neurogenic damage MP 80 mg qd Improved; Complete radical cystectomy
5 General weakness MyocarditisAtrial fibrillation; Premature ventricular contractions; Right bundle branch conduction block; ST most Ⅰ, Ⅱ, aVF, V4, V5, V6 inferiorly displacedBasal thickening of the ventricular septum；EF=76.7% Nerve conduction slowed down; Neurogenic damage MP 80 mg qdImproved; Glucocorticoid reduction; Died of tumor progression
6Generalized myalgia, left lipomatosis ptosis, deepening of urine colorMyocarditis；RhabdomyolysisPremature ventricular contractions; ST partial Ⅲ, aVF downshiftEF=72.9% Nerve conduction slowed down; Myogenic damage MP 120 mg qd IVIG 30 g qd Improved; Complete radical cystectomy
7Generalized myalgia, deepening of urine color, severe abdominal pain and diarrhea with blood in the stoolEnterocolitis；Rhabdomyolysis Episodic premature ventricular contractions EF=61.7%；Ascending aortic widening Nerve conduction slowed down MP 120 mg qd Improved; Glucocorticoid reduction
8 Slight muscle pain and weakness in both lower limbs None Normal NA NA UnusedRestart ICI after symptomatic treatment

Figure 1

Muscle biopsy from pathological changes of patients with immune-related myositis after ICI treatment A and B, pathological changes of inflammatory myopathy: muscle necrosis, regeneration, and focal invasion of inflammatory cells (HE, A, ×200; B, ×100); C to I, immunohistochemical staining results (C, CD3, ×200; D, CD4, ×200; E, CD8, ×200; F, CD20, ×200; G, CD68, ×200; H, MHC-Ⅰ, ×200; I, C5b-9, ×200)."

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