Immune Checkpoint Inhibitor‐Induced Myositis, Myocarditis, Myasthenia Gravis, and Autonomic Neuropathy Successfully Treated With Rituximab

Myositis, myocarditis, and myasthenia gravis (MG) can develop as immune-related adverse events (irAEs) associated with immune checkpoint inhibitors (ICIs) and are sometimes associated with high mortality rates [1]. While this triad of neurological irAEs (n-irAEs) is relatively common, autonomic neuropathy is rare [2]. Conventional treatments for n-irAEs include steroids, intravenous immunoglobulin (IVIG), and/or plasma exchange (PE). Rituximab has been reported to be effective in some refractory cases of the n-irAE triad, suggesting the involvement of B cells [3]. Here, we report a patient who developed autonomic neuropathy in addition to myositis, myocarditis, and MG as irAEs. The patient's autonomic neuropathy and respiratory failure were refractory to conventional treatments but responded to rituximab. An 81-year-old female was diagnosed with local recurrences of malignant melanoma on her thumb. Nivolumab was started on Day 1 (Figure 1). Her creatine kinase (CK) level rose to 561 U/L on Day 14, without any symptoms. After the second nivolumab administration on Day 15, she noted lower back pain and found it difficult to get out of bed. On examination, there was tenderness in the lumbar paraspinal muscles and muscle weakness during back extension from the prone position. Her CK level rose to 7225 U/L on Day 24. Magnetic resonance imaging showed high signal intensity on the short-TI inversion recovery in the bilateral lumbar paraspinal and oblique muscles. We diagnosed irAE-myositis and began methylprednisolone pulse therapy, followed by 0.5 mg/kg/day of prednisolone. She began to notice diplopia and ptosis on Day 28. On Day 30, electrocardiography showed a complete right bundle branch block (CRBBB) that was not present on Day 28, and her troponin I level rose to 1359 pg/mL (normal < 26.2 pg/mL). We restarted methylprednisolone pulse therapy and increased prednisolone to 1 mg/kg/day for irAE-myocarditis. Her CK and troponin I levels decreased and her CRBBB improved, but she developed hypercapnic coma on Day 35 (Figure 1). Serum anti-acetylcholine receptor (AChR) antibodies and anti-striated muscle antibodies were positive. We diagnosed irAE myasthenic crisis. Noninvasive ventilation was initiated, followed by tracheostomy and mechanical ventilation on Day 39. Muscle biopsy of the anterior tibialis muscle on Day 39 revealed infiltration of a large number of CD8+ cells and a lesser number of CD4+ cells and CD20+ cells, indicating ongoing active myositis (Figure 2). Six courses of PE were followed by IVIG and oral tacrolimus for her irAE-myositis and MG. Despite these treatments, she could not be weaned off the ventilator. On Day 50, she developed severe transient hypotension. Autonomic testing revealed a decrease in the coefficient of variation of R-R intervals (CVR-R) and an absent sympathetic skin response (SSR). irAE-autonomic neuropathy was diagnosed. Based on B cell infiltration in the muscle tissues and the positive autoantibodies, a pathogenic role of B cells was suggested for her multiple irAEs. As conventional treatments were not effective for the respiratory failure and did not prevent the development of autonomic neuropathy, we administered rituximab after ethical review in our hospital and informed consent. Subsequently, her hypotension, CVR-R, SSR, and respiratory failure gradually improved. She was weaned off the ventilator on Day 117. The irAEs did not rebound during prednisolone tapering. The patient presented with a variety of irAEs including myositis, myocarditis, MG, and autonomic neuropathy. As reported previously [4, 5], several n-irAEs may develop rapidly and sequentially, making early recognition and timely intervention crucial. ICIs activate not only autoreactive T cells, but also autoreactive B cells, which express high levels of PD-1 and contribute to autoimmunity [6], leading to the production of autoantibodies from B cells. B cell infiltration has been observed in the affected muscles of patients with irAE-myositis [7]. Although reports are scarce, the efficacy of rituximab in some patients with the n-irAE triad suggests the involvement of B cells [3]. Based on the possible involvement of B cells in n-irAEs, we administered rituximab, which resulted in dramatic recovery from the respiratory failure and autonomic neuropathy. Our case suggests that rituximab should be a promising therapeutic option for refractory respiratory failure associated with myositis or MG, as well as autonomic neuropathy, which all developed as n-irAEs. Because reports of rituximab in n-irAE are limited [3], further reports are needed to assess the effectiveness of rituximab in this type of clinical situation and guide decisions regarding its use. Daisuke Kawata: conceptualization, data curation, writing – original draft, writing – review and editing. Hisanori Hasegawa: conceptualization, writing – original draft, writing – review and editing, supervision. Naoki Kimura: conceptualization, supervision, writing – review and editing. Yasuhiro Tagawa: conceptualization, data curation. Hirokazu Sasaki: conceptualization, data curation, writing – review and editing. Shinsuke Yasuda: conceptualization, writing – review and editing, writing – original draft, supervision. The authors thank Mrs. Katsuko Yamasaki for her contribution to the pathologic diagnosis of the patient. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. The authors declare the following potential conflicts of interest with the publication of this report: Naoki Kimura and Shinsuke Yasuda have received grants from Chugai pharmaceuticals. Hisanori Hasegawa, Naoki Kimura, and Shinsuke Yasuda have received honoraria for lectures from Chugai pharmaceuticals and Ono pharmaceutical. The remaining authors declare no conflicts of interest. The data that support the findings of this study are available from the corresponding author upon reasonable request.