nivolumab is an anti - programmed death 1 ( pd-1 ) monoclonal antibody and has been reported to be useful for treatment of cancers including malignant melanoma .
a recent case report documenting fatal nivolumab - related myasthenia gravis ( mg ) has caused concern about the risk of increased toxicity in patients with pre - existing mg who receive nivolumab for the management of metastatic melanoma .
it is unclear what will occur if a patient with pre - existing mg receives nivolumab .
a 79-year - old man began to receive immune checkpoint therapy with nivolumab at a dose of 2 mg / kg every 3 weeks for the management of submandibular lymph node metastasis from malignant melanoma , which arose in his forehead 3 years ago and was previously treated with cytotoxic chemotherapy .
the patient had a > 20-year history of ocular mg according to osserman s classification .
durable remission was maintained by treatment with oral corticosteroids ( 3 mg every other day ) .
a routine serum chemical test on day 43 , after the patient had received 2 doses of nivolumab , revealed a grade 3 elevation of the creatine phosphokinase ( cpk ) level to 1,627 iu / l ( institutional normal range , 62 to 287 iu / l ) ( fig .
the patient did not experience muscle pain , muscle weakness , or any other symptoms .
the cpk level decreased to 469 iu / l on day 100 and was at worst grade 1 subsequently .
however , after the third dose of nivolumab , the patient had diplopia , facial muscle weakness , and difficulty in drinking water on day 106 .
positive results of an acetylcholine receptor antibody test ( 20.0 nmol / l , normal range , 0.2 nmol / l ) supported the diagnosis .
. apparent shrinkage of the metastatic lymph nodes was observed on computed tomographic imaging after the patient had received 10 doses of nivolumab ( fig .
fdg - pet / ct before and after administration of nivolumab uptake of lymph node metastases decreased after ten doses of nivolumab .
anti - pd-1 antibodies enhance immune response to tumor cells and to normal host tissues as well , and cause adverse effects related to the autoimmune diseases .
other immune checkpoint inhibitors , anti - programmed death - ligand 1 ( pd - l1 ) antibodies and anti - cytotoxic t - lymphocyte - associated protein 4 ( ctla4 ) antibodies , also have been reported to cause immune - related diseases , such as myositis and myasthenia gravis .
the present case with pre - existing mg showed cpk elevation , and symptoms suggesting deterioration of mg such as diplopia and facial muscle weakness after nivolumab administration . after suspending nivolumab , cpk decreased and symptoms improved , and nivolumab was able to be administered safely . since cpk elevation is not usually observed in mg patients , we could not exclude the possibility the symptoms were caused by myositis but not by mg .
although it is not easy to distinguish symptoms of mg from those of myositis , the difference in the time of onset of cpk elevation and that of symptom exacerbation tends to indicate that the symptoms derived from mg rather than myositis . in a case previously reported , an acetylcholine receptor antibody test was low - titer positive ( 2.9 nmol / l ) before the onset of mg induced by nivolumab .
nmol / l one year and seven months prior to the beginning of nivolumab treatment , and it increased to 20 nmol / l when mg was exacerbated .
the antibody titer is considered to be useful to predict the onset of mg and to observe mg symptoms .
there are no clear criteria to decide whether nivolumab is allowed to be restarted after discontinuation of the administration due to adverse events such as cpk elevation or mg exacerbation .
we consider that the restart with careful observation might be allowed when the adverse events improved to mild symptoms , for instance , nci - ctcae grade 1 . despite the transient exacerbation of mg - associated symptoms , this patient - tolerated nivolumab therapy went well and provided substantial benefit , suggesting that the drug is not necessarily contraindicated in patients with preexisting mg .
nivolumab - related mg might have a distinct etiological background from that of primary mg .
yuichi ando received honoraria from ono pharmaceutical co. , ltd . , and has held a consultant / advisory role with ono pharmaceutical co. , ltd ..
 abstracta 79-year - old man with lymph node recurrence of malignant melanoma received nivolumab , an anti - programmed death 1 ( pd-1 ) monoclonal antibody . 
 he had pre - existing ocular myasthenia gravis ( mg ) and a continued small amount of corticosteroid . 
 grade 3 creatine phosphokinase elevation appeared after two doses of nivolumab , and the treatment was postponed until it improved to grade 1 . 
 after three doses of nivolumab , he experienced diplopia and facial muscle weakness which were consistent with an acute exacerbation of mg , and the symptoms relieved without additional treatment for mg . 
 he achieved shrinkage of metastasis after ten doses of nivolumab . 
 although a case who died due to mg after administration of nivolumab was reported recently , pre - existing mg is considered not to be always a contraindication of nivolumab . 
INTRODUCTION
CASE REPORT
DISCUSSION
CONFLICTS OF INTEREST