Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Current Neurology and Neuroscience Reports
Published in: Current Neurology and Neuroscience Reports 10/2018

01-10-2018 | Nerve and Muscle (L H Weimer, Section Editor)

Neuromuscular Complications of Programmed Cell Death-1 (PD-1) Inhibitors

Authors: Justin C. Kao, Adipong Brickshawana, Teerin Liewluck

Published in: Current Neurology and Neuroscience Reports | Issue 10/2018

Login to get access

Abstract

Purpose of Review

In recent years, immune checkpoint inhibitors have been increasingly used in patients with metastatic cancers with favorable oncological outcomes; however, there have also been increasing number of cancer survivors who have developed immune-related adverse events. Little is known about PD-1 inhibitor-associated neuromuscular complications.

Recent Findings

Neuromuscular disorders are the most common neurological complication reported in PD-1 inhibitor-treated patients. Myasthenia gravis, immune-mediated myopathies, and Guillain-Barre syndrome are among commonly reported immune-related neuromuscular complications. HyperCKemia occurs frequently in patients with PD-1 inhibitor-associated myasthenia gravis, indicating coexisting myopathies or myocarditis. Oculobulbar weakness is a unique and common presentation of PD-1 inhibitor-associated immune-mediated myopathies with or without concomitant myasthenia gravis. High-dose steroid monotherapy may be associated with clinical deterioration in some patients with PD-1 inhibitor-associated myasthenia gravis, immune-mediated myopathies, or Guillain-Barre syndrome.

Summary

PD-1 inhibitor-associated neuromuscular complications have some characteristic features compared to their idiopathic counterparts. Although steroid monotherapy is commonly used in non-neuromuscular autoimmune disorders triggered by anti-PD-1 therapy, this may lead to unfavorable outcomes in some patients with PD-1 inhibitor-associated neuromuscular complications.
Literature
1.
2.
3.
4.
Sharpe AH, Pauken KE. The diverse functions of the PD1 inhibitory pathway. Nat Rev Immunol. 2018;18:153–67.CrossRefPubMed
5.
Jiang TT, Martinov T, Xin L, Kinder JM, Spanier JA, Fife BT, et al. Programmed death-1 culls peripheral accumulation of high-affinity autoreactive CD4 T cells to protect against autoimmunity. Cell Rep. 2016;17:1783–94.CrossRefPubMedPubMedCentral
6.
Garcia-Diaz A, Shin DS, Moreno BH, Saco J, Escuin-Ordinas H, Rodriguez GA, et al. Interferon receptor signaling pathways regulating PD-L1 and PD-L2 expression. Cell Rep. 2017;19:1189–201.CrossRefPubMedPubMedCentral
7.
8.
• Ribas A, Wolchok JD. Cancer immunotherapy using checkpoint blockade. Science. 2018;359:1350–5. A comprehensive review of cancer immunotherapy using immune checkpoint imhibitors. CrossRefPubMedPubMedCentral
9.
Zamani MR, Aslani S, Salmaninejad A, Javan MR, Rezaei N. PD-1/PD-L and autoimmunity: a growing relationship. Cell Immunol. 2016;310:27–41.CrossRefPubMed
10.
Weber JS, D’Angelo SP, Minor D, Hodi FS, Gutzmer R, Neyns B, et al. Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2015;16:375–84.CrossRefPubMed
11.
Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L, et al. Pembrolizumab versus Ipilimumab in advanced melanoma. N Engl J Med. 2015;372:2521–32.CrossRefPubMed
12.
•• Kao JC, Liao B, Markovic SN, Klein CJ, Naddaf E, Staff NP, et al. Neurological complications associated with anti-programmed death 1 (PD-1) antibodies. JAMA Neurol. 2017;74:1216–22. A series of patients with PD-1 inhibitor-associated neurologic complications highlighting the breadth, diversity, and frequency of neuromuscular complications. CrossRefPubMedPubMedCentral
13.
•• Zimmer L, Goldinger SM, Hofmann L, Loquai C, Ugurel S, Thomas I, et al. Neurological, respiratory, musculoskeletal, cardiac and ocular side-effects of anti-PD-1 therapy. Eur J Cancer. 2016;60:210–25. A series of patients with PD-1 inhibitor-associated neurologic complications highlighting the breadth, diversity, and frequency of neuromuscular complications. CrossRefPubMed
14.
Spain L, Diem S, Larkin J. Management of toxicities of immune checkpoint inhibitors. Cancer Treat Rev. 2016;44:51–60.CrossRefPubMed
15.
•• Liewluck T, Kao JC, Mauermann ML. PD-1 inhibitor-associated myopathies: emerging immune-mediated myopathies. J Immunother. 2018;41:208–11. A series of patients with PD-1 inhibitor-associated immune-mediated myopathies highlighting a unique oculobulbar involvement in these patients, mimicking myasthenia gravis. CrossRefPubMed
16.
Lau KH, Kumar A, Yang IH, Nowak RJ. Exacerbation of myasthenia gravis in a patient with melanoma treated with pembrolizumab. Muscle Nerve. 2016;54:157–61.CrossRefPubMed
17.
Nguyen BH, Kuo J, Budiman A, Christie H, Ali S. Two cases of clinical myasthenia gravis associated with pembrolizumab use in responding melanoma patients. Melanoma Res. 2017;27:152–4.CrossRefPubMed
18.
Phadke SD, Ghabour R, Swick BL, Swenson A, Milhem M, Zakharia Y. Pembrolizumab therapy triggering an exacerbation of preexisting autoimmune disease: a report of 2 patient cases. J Investig Med High Impact Case Rep. 2016;4:2324709616674316.PubMedPubMedCentral
19.
Alnahhas I, Wong J. A case of new-onset antibody-positive myasthenia gravis in a patient treated with pembrolizumab for melanoma. Muscle Nerve. 2017;55:E25-E26.CrossRef
20.
Maeda O, Yokota K, Atsuta N, Katsuno M, Akiyama M, Ando Y. Nivolumab for the treatment of malignant melanoma in a patient with pre-existing myasthenia gravis. Nagoya J Med Sci. 2016;78:119–22.PubMedPubMedCentral
21.
Zhu J, Li Y. Myasthenia gravis exacerbation associated with pembrolizumab. Muscle Nerve. 2016;54:506–7.CrossRefPubMed
22.
Polat P, Donofrio PD. Myasthenia gravis induced by nivolumab therapy in a patient with non-small-cell lung cancer. Muscle Nerve. 2016;54:507.CrossRefPubMed
23.
Sciacca G, Nicoletti A, Rampello L, Noto L, Parra HJ, Zappia M. Benign form of myasthenia gravis after nivolumab treatment. Muscle Nerve. 2016;54:507–9.CrossRefPubMed
24.
Gonzalez NL, Puwanant A, Lu A, Marks SM, Zivkovic SA. Myasthenia triggered by immune checkpoint inhibitors: new case and literature review. Neuromuscul Disord. 2017;27:266–8.CrossRefPubMed
25.
Kimura T, Fukushima S, Miyashita A, Aoi J, Jinnin M, Kosaka T, et al. Myasthenic crisis and polymyositis induced by one dose of nivolumab. Cancer Sci. 2016;107:1055–8.CrossRefPubMedPubMedCentral
26.
Chang E, Sabichi AL, Sada YH. Myasthenia gravis after nivolumab therapy for squamous cell carcinoma of the bladder. J Immunother. 2017;40:114–6.CrossRefPubMed
27.
March KL, Samarin MJ, Sodhi A, Owens RE. Pembrolizumab-induced myasthenia gravis: a fatal case report. J Oncol Pharm Pract. 2017;1078155216687389.
28.
Shirai T, Sano T, Kamijo F, Saito N, Miyake T, Kodaira M, et al. Acetylcholine receptor binding antibody-associated myasthenia gravis and rhabdomyolysis induced by nivolumab in a patient with melanoma. Jpn J Clin Oncol. 2016;46:86–8.CrossRefPubMed
29.
Mehta JJ, Maloney E, Srinivasan S, Seitz P, Cannon M. Myasthenia gravis induced by nivolumab: a case report. Cureus. 2017;9:e1702.PubMedPubMedCentral
30.
Loochtan AI, Nickolich MS, Hobson-Webb LD. Myasthenia gravis associated with ipilimumab and nivolumab in the treatment of small cell lung cancer. Muscle Nerve. 2015;52:307–8.CrossRefPubMed
31.
Makarious D, Horwood K, Coward JIG. Myasthenia gravis: an emerging toxicity of immune checkpoint inhibitors. Eur J Cancer. 2017;82:128–36.CrossRefPubMed
32.
Huh SY, Shin SH, Kim MK, Lee SY, Son KH, Shin HY. Emergence of myasthenia gravis with myositis in a patient treated with pembrolizumab for thymic cancer. J Clin Neurol. 2018;14:115–7.CrossRefPubMed
33.
Chen YH, Liu FC, Hsu CH, Chian CF. Nivolumab-induced myasthenia gravis in a patient with squamous cell lung carcinoma: case report. Medicine (Baltimore). 2017;96:e7350.CrossRef
34.
Chen JH, Lee KY, Hu CJ, Chung CC. Coexisting myasthenia gravis, myositis, and polyneuropathy induced by ipilimumab and nivolumab in a patient with non-small-cell lung cancer: a case report and literature review. Medicine (Baltimore). 2017;96:e9262.CrossRef
35.
Tan RYC, Toh CK, Takano A. Continued response to one dose of nivolumab complicated by myasthenic crisis and myositis. J Thorac Oncol. 2017;12:e90–1.CrossRefPubMed
36.
Fellner A, Makranz C, Lotem M, Bokstein F, Taliansky A, Rosenberg S, et al. Neurologic complications of immune checkpoint inhibitors. J Neuro-Oncol. 2018;137:601–9.CrossRef
37.
•• Suzuki S, Ishikawa N, Konoeda F, et al. Nivolumab-related myasthenia gravis with myositis and myocarditis in Japan. Neurology. 2017;89:1127-34. A well-designed study of myasthenia gravis in nivolumab-treated patients highlighting the differences between myasthenia gravis patients with and without nivolumab exposure and the myasthenia gravis-myositis-myocarditis overlap syndrome. CrossRefPubMed
38.
Agata Y, Kawasaki A, Nishimura H, Ishida Y, Tsubat T, Yagita H, et al. Expression of the PD-1 antigen on the surface of stimulated mouse T and B lymphocytes. Int Immunol. 1996;8:765–72.CrossRefPubMed
39.
Thibult ML, Mamessier E, Gertner-Dardenne J, Pastor S, Just-Landi S, Xerri L, et al. PD-1 is a novel regulator of human B-cell activation. Int Immunol. 2013;25:129–37.CrossRefPubMed
40.
Vallet H, Gaillet A, Weiss N, Vanhaecke C, Saheb S, Touitou V, et al. Pembrolizumab-induced necrotic myositis in a patient with metastatic melanoma. Ann Oncol. 2016;27:1352–3.CrossRefPubMed
41.
Suzuki S, Utsugisawa K, Yoshikawa H, Motomura M, Matsubara S, Yokoyama K, et al. Autoimmune targets of heart and skeletal muscles in myasthenia gravis. Arch Neurol. 2009;66:1334–8.CrossRefPubMed
42.
Santos E, Coutinho E, Martins da Silva A, Marinho A, Vasconcelos C, Taipa R, et al. Inflammatory myopathy associated with myasthenia gravis with and without thymic pathology: report of four cases and literature review. Autoimmun Rev. 2017;16:644–9.CrossRefPubMed
43.
Bilen MA, Subudhi SK, Gao J, Tannir NM, Tu SM, Sharma P. Acute rhabdomyolysis with severe polymyositis following ipilimumab-nivolumab treatment in a cancer patient with elevated anti-striated muscle antibody. J Immunother Cancer. 2016;4:36.CrossRefPubMedPubMedCentral
44.
Juel VC. Myasthenia gravis: management of myasthenic crisis and perioperative care. Semin Neurol. 2004;24:75–81.CrossRefPubMed
45.
Grob D, Brunner N, Namba T, Pagala M. Lifetime course of myasthenia gravis. Muscle Nerve. 2008;37:141–9.CrossRefPubMed
46.
Johnson DB, Balko JM, Compton ML, Chalkias S, Gorham J, Xu Y, et al. Fulminant myocarditis with combination immune checkpoint blockade. N Engl J Med. 2016;375:1749–55.CrossRefPubMedPubMedCentral
47.
Gandiga PC, Wang AR, Gonzalez-Rivera T, Sreih AG. Pembrolizumab-associated inflammatory myopathy. Rheumatology (Oxford). 2018;57:397–8.CrossRef
48.
Bourgeois-Vionnet J, Joubert B, Bernard E, Sia MA, Pante V, Fabien N, et al. Nivolumab-induced myositis: a case report and a literature review. J Neurol Sci. 2018;387:51–3.CrossRefPubMed
49.
Uchio N, Taira K, Ikenaga C, Unuma A, Kadoya M, Kubota A, et al. Granulomatous myositis induced by anti-PD-1 monoclonal antibodies. Neurol Neuroimmunol Neuroinflamm. 2018;5:e464.CrossRefPubMedCentral
50.
Yoshioka M, Kambe N, Yamamoto Y, Suehiro K, Matsue H. Case of respiratory discomfort due to myositis after administration of nivolumab. J Dermatol. 2015;42:1008–9.CrossRefPubMed
51.
52.
Diamantopoulos PT, Tsatsou K, Benopoulou O, Anastasopoulou A, Gogas H. Inflammatory myopathy and axonal neuropathy in a patient with melanoma following pembrolizumab treatment. J Immunother. 2017;40:221–3.CrossRefPubMed
53.
Saini L, Chua N. Severe inflammatory myositis in a patient receiving concurrent nivolumab and azacitidine. Leuk Lymphoma. 2017;58:2011–3.CrossRefPubMed
54.
Behling J, Kaes J, Munzel T, Grabbe S, Loquai C. New-onset third-degree atrioventricular block because of autoimmune-induced myositis under treatment with anti-programmed cell death-1 (nivolumab) for metastatic melanoma. Melanoma Res. 2017;27:155–8.CrossRefPubMed
55.
Min L, Hodi FS. Anti-PD1 following ipilimumab for mucosal melanoma: durable tumor response associated with severe hypothyroidism and rhabdomyolysis. Cancer Immunol Res. 2014;2:15–8.CrossRefPubMed
56.
Milone M. Diagnosis and management of immune-mediated myopathies. Mayo Clin Proc. 2017;92:826–37.CrossRefPubMed
57.
Moslehi JJ, Salem JE, Sosman JA, Lebrun-Vignes B, Johnson DB. Increased reporting of fatal immune checkpoint inhibitor-associated myocarditis. Lancet. 2018;391:933.CrossRefPubMedPubMedCentral
58.
Gordon SR, Maute RL, Dulken BW, Hutter G, George BM, McCracken MN, et al. PD-1 expression by tumour-associated macrophages inhibits phagocytosis and tumour immunity. Nature. 2017;545:495–9.CrossRefPubMedPubMedCentral
59.
Kahler KC, Hassel JC, Heinzerling L, et al. Management of side effects of immune checkpoint blockade by anti-CTLA-4 and anti-PD-1 antibodies in metastatic melanoma. J Dtsch Dermatol Ges. 2016;14:662–81.PubMed
60.
Yost MD, Chou CZ, Botha H, Block MS, Liewluck T. Facial diplegia after pembrolizumab treatment. Muscle Nerve. 2017;56:E20–1.CrossRefPubMed
61.
Ong S, Chapman J, Young G, Mansy T. Guillain-Barre-like syndrome during pembrolizumab treatment. Muscle Nerve. 2018;58:E8-E10.CrossRef
62.
Jacob A, Unnikrishnan DC, Mathew A, Thyagarajan B, Patel S. A case of fatal Guillain-Barre syndrome from anti-PD1 monoclonal antibody use. J Cancer Res Clin Oncol. 2016;142:1869–70.CrossRefPubMed
63.
Schneiderbauer R, Schneiderbauer M, Wick W, Enk AH, Haenssle HA, Hassel JC. PD-1 antibody-induced Guillain-Barre syndrome in a patient with metastatic melanoma. Acta Derm Venereol. 2017;97:395–6.CrossRefPubMed
64.
de Maleissye MF, Nicolas G, Saiag P. Pembrolizumab-induced demyelinating polyradiculoneuropathy. N Engl J Med. 2016;375:296–7.CrossRefPubMed
65.
Fukumoto Y, Kuwahara M, Kawai S, Nakahama K, Kusunoki S. Acute demyelinating polyneuropathy induced by nivolumab. J Neurol Neurosurg Psychiatry. 2018;89:435–7.CrossRefPubMed
66.
Supakornnumporn S, Katirji B. Guillain-Barre syndrome triggered by immune checkpoint inhibitors: a case report and literature review. J Clin Neuromuscul Dis. 2017;19:80–3.CrossRefPubMed
67.
Dimachkie MM, Saperstein DS. Acquired immune demyelinating neuropathies. Continuum (Minneap Minn). 2014;20:1241–60.
68.
Tanaka R, Maruyama H, Tomidokoro Y, Yanagiha K, Hirabayashi T, Ishii A, et al. Nivolumab-induced chronic inflammatory demyelinating polyradiculoneuropathy mimicking rapid-onset Guillain-Barre syndrome: a case report. Jpn J Clin Oncol. 2016;46:875–8.CrossRefPubMed
69.
Sepulveda M, Martinez-Hernandez E, Gaba L, et al. Motor polyradiculopathy during pembrolizumab treatment of metastatic melanoma. Muscle Nerve. 2017;56:E162–7.CrossRefPubMed
70.
Aya F, Ruiz-Esquide V, Viladot M, Font C, Prieto-González S, Prat A, et al. Vasculitic neuropathy induced by pembrolizumab. Ann Oncol. 2017;28:433–4.PubMed
Metadata
Title
Neuromuscular Complications of Programmed Cell Death-1 (PD-1) Inhibitors
Authors
Justin C. Kao
Adipong Brickshawana
Teerin Liewluck
Publication date
01-10-2018
Publisher
Springer US
Published in
Current Neurology and Neuroscience Reports / Issue 10/2018
Print ISSN: 1528-4042
Electronic ISSN: 1534-6293
DOI
https://doi.org/10.1007/s11910-018-0878-7

Other articles of this Issue 10/2018

Current Neurology and Neuroscience Reports 10/2018 Go to the issue

Stroke (H Diener, Section Editor)

Sleep-Wake Disorders in Stroke—Increased Stroke Risk and Deteriorated Recovery? An Evaluation on the Necessity for Prevention and Treatment

Headache (R B Halker, Section Editor)

The Neuralgias

Critical Care (SA Mayer, Section Editor)

Does Dexmedetomidine Ameliorate Postoperative Cognitive Dysfunction? A Brief Review of the Recent Literature

Sleep (M Thorpy and M Billiard, Section Editors)

Sleep in Parkinson’s Disease with Impulse Control Disorder

Sleep (M Thorpy and M Billiard, Section Editors)

Circadian Rhythm Disturbances in the Blind

Stroke (H Diener, Section Editor)

Detection of Atrial Fibrillation in Cryptogenic Stroke