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

  • Justin C. Kao
  • Adipong Brickshawana
  • Teerin LiewluckEmail author
Nerve and Muscle (L H Weimer, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Nerve and Muscle


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.


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.


Myasthenia gravis Myositis Neuropathy Nivolumab Pembrolizumab Programmed cell death-1 (PD-1) inhibitors 


Compliance with Ethical Standards

Conflict of Interest

Justin C. Kao, Adipong Brickshawana, and Teerin Liewluck declare no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Burdick CG. William Bradley Coley 1862-1936. Ann Surg. 1937;105:152–5.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Chen L, Flies DB. Molecular mechanisms of T cell co-stimulation and co-inhibition. Nat Rev Immunol. 2013;13:227–42.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12:252–64.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Sharpe AH, Pauken KE. The diverse functions of the PD1 inhibitory pathway. Nat Rev Immunol. 2018;18:153–67.CrossRefPubMedGoogle Scholar
  5. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 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.CrossRefPubMedGoogle Scholar
  7. 7.
    Ribas A. Adaptive immune resistance: how cancer protects from immune attack. Cancer Discov. 2015;5:915–9.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 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. CrossRefPubMedGoogle Scholar
  9. 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.CrossRefPubMedGoogle Scholar
  10. 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.CrossRefPubMedGoogle Scholar
  11. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 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. CrossRefPubMedPubMedCentralGoogle Scholar
  13. 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. CrossRefPubMedGoogle Scholar
  14. 14.
    Spain L, Diem S, Larkin J. Management of toxicities of immune checkpoint inhibitors. Cancer Treat Rev. 2016;44:51–60.CrossRefPubMedGoogle Scholar
  15. 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. CrossRefPubMedGoogle Scholar
  16. 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.CrossRefPubMedGoogle Scholar
  17. 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.CrossRefPubMedGoogle Scholar
  18. 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.PubMedPubMedCentralGoogle Scholar
  19. 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.CrossRefGoogle Scholar
  20. 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.PubMedPubMedCentralGoogle Scholar
  21. 21.
    Zhu J, Li Y. Myasthenia gravis exacerbation associated with pembrolizumab. Muscle Nerve. 2016;54:506–7.CrossRefPubMedGoogle Scholar
  22. 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.CrossRefPubMedGoogle Scholar
  23. 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.CrossRefPubMedGoogle Scholar
  24. 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.CrossRefPubMedGoogle Scholar
  25. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 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.CrossRefPubMedGoogle Scholar
  27. 27.
    March KL, Samarin MJ, Sodhi A, Owens RE. Pembrolizumab-induced myasthenia gravis: a fatal case report. J Oncol Pharm Pract. 2017;1078155216687389.Google Scholar
  28. 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.CrossRefPubMedGoogle Scholar
  29. 29.
    Mehta JJ, Maloney E, Srinivasan S, Seitz P, Cannon M. Myasthenia gravis induced by nivolumab: a case report. Cureus. 2017;9:e1702.PubMedPubMedCentralGoogle Scholar
  30. 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.CrossRefPubMedGoogle Scholar
  31. 31.
    Makarious D, Horwood K, Coward JIG. Myasthenia gravis: an emerging toxicity of immune checkpoint inhibitors. Eur J Cancer. 2017;82:128–36.CrossRefPubMedGoogle Scholar
  32. 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.CrossRefPubMedGoogle Scholar
  33. 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.CrossRefGoogle Scholar
  34. 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.CrossRefGoogle Scholar
  35. 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.CrossRefPubMedGoogle Scholar
  36. 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.CrossRefGoogle Scholar
  37. 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. CrossRefPubMedGoogle Scholar
  38. 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.CrossRefPubMedGoogle Scholar
  39. 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.CrossRefPubMedGoogle Scholar
  40. 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.CrossRefPubMedGoogle Scholar
  41. 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.CrossRefPubMedGoogle Scholar
  42. 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.CrossRefPubMedGoogle Scholar
  43. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Juel VC. Myasthenia gravis: management of myasthenic crisis and perioperative care. Semin Neurol. 2004;24:75–81.CrossRefPubMedGoogle Scholar
  45. 45.
    Grob D, Brunner N, Namba T, Pagala M. Lifetime course of myasthenia gravis. Muscle Nerve. 2008;37:141–9.CrossRefPubMedGoogle Scholar
  46. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Gandiga PC, Wang AR, Gonzalez-Rivera T, Sreih AG. Pembrolizumab-associated inflammatory myopathy. Rheumatology (Oxford). 2018;57:397–8.CrossRefGoogle Scholar
  48. 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.CrossRefPubMedGoogle Scholar
  49. 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.CrossRefGoogle Scholar
  50. 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.CrossRefPubMedGoogle Scholar
  51. 51.
    Fox E, Dabrow M, Ochsner G. A case of nivolumab-induced myositis. Oncologist. 2016;21:e3.CrossRefPubMedPubMedCentralGoogle Scholar
  52. 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.CrossRefPubMedGoogle Scholar
  53. 53.
    Saini L, Chua N. Severe inflammatory myositis in a patient receiving concurrent nivolumab and azacitidine. Leuk Lymphoma. 2017;58:2011–3.CrossRefPubMedGoogle Scholar
  54. 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.CrossRefPubMedGoogle Scholar
  55. 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.CrossRefPubMedGoogle Scholar
  56. 56.
    Milone M. Diagnosis and management of immune-mediated myopathies. Mayo Clin Proc. 2017;92:826–37.CrossRefPubMedGoogle Scholar
  57. 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.CrossRefPubMedGoogle Scholar
  58. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  59. 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.PubMedGoogle Scholar
  60. 60.
    Yost MD, Chou CZ, Botha H, Block MS, Liewluck T. Facial diplegia after pembrolizumab treatment. Muscle Nerve. 2017;56:E20–1.CrossRefPubMedGoogle Scholar
  61. 61.
    Ong S, Chapman J, Young G, Mansy T. Guillain-Barre-like syndrome during pembrolizumab treatment. Muscle Nerve. 2018;58:E8-E10.CrossRefGoogle Scholar
  62. 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.CrossRefPubMedGoogle Scholar
  63. 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.CrossRefPubMedGoogle Scholar
  64. 64.
    de Maleissye MF, Nicolas G, Saiag P. Pembrolizumab-induced demyelinating polyradiculoneuropathy. N Engl J Med. 2016;375:296–7.CrossRefPubMedGoogle Scholar
  65. 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.CrossRefPubMedGoogle Scholar
  66. 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.CrossRefPubMedGoogle Scholar
  67. 67.
    Dimachkie MM, Saperstein DS. Acquired immune demyelinating neuropathies. Continuum (Minneap Minn). 2014;20:1241–60.Google Scholar
  68. 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.CrossRefPubMedGoogle Scholar
  69. 69.
    Sepulveda M, Martinez-Hernandez E, Gaba L, et al. Motor polyradiculopathy during pembrolizumab treatment of metastatic melanoma. Muscle Nerve. 2017;56:E162–7.CrossRefPubMedGoogle Scholar
  70. 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.PubMedGoogle Scholar

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© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Justin C. Kao
    • 1
  • Adipong Brickshawana
    • 2
  • Teerin Liewluck
    • 3
    Email author
  1. 1.Department of NeurologyAuckland City HospitalAucklandNew Zealand
  2. 2.Department of MedicineMontefiore Medical Center, Albert Einstein College of MedicineBronxUSA
  3. 3.Department of NeurologyMayo ClinicRochesterUSA

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