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Advances in dermatology and venereology Acta Dermato-Venereologica
PD-1 Antibody-induced Guillain-Barré Syndrome in a Patient with Metastatic Melanoma
Roland SCHNEIDERBAUER 1 # , Malessa SCHNEIDERBAUER 2 # , Wolfgang WICK 2 , Alexander H . ENK 1 , Holger A . HAENSSLE 1 and Jessica C . HASSEL 1
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Department of Dermatology and National Center for Tumor Diseases , University of Heidelberg , Im Neuenheimer Feld 440 , DE-69120 Heidelberg , 2 Depart ment of Neurology , University Hospital Heidelberg , Heidelberg , Germany . E-mail : Roland . Schneiderbauer @ med . uniheidelberg . de
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These authors contributed equally to this work and should be considered co-first authors . Accepted Oct 12 , 2016 ; Epub ahead of print Oct 14 , 2016
Guillain-Barré syndrome ( GBS ) presents as acute inflammatory demyelinating polyneuropathy , which leads to rapid-onset muscle weakness classically caused by immune-mediated damage to the peripheral nervous system .
We report here a case of GBS occurring during treatment with nivolumab . Nivolumab is a fully human IgG4 programmed death 1 ( PD-1 ) immune-checkpointinhibitor antibody that selectively blocks the interaction of the PD-1 receptor with its 2 known programmed death ligands , PD-L1 and PD-L2 . Nivolumab can thereby restore anticancer immune responses by abrogating PD-1 pathway-mediated T-cell inhibition ( 1 ). In addition , we discuss possible underlying disease mechanisms and treatment options .
CASE REPORT
A 51-year-old man was diagnosed with nodular melanoma with a tumour thickness of 2 mm on the right cheek and 2 positive cervical sentinel lymph nodes . After a neck dissection revealing one additional metastatic lymph node he received adjuvant treatment with high-dose intravenous interferon ( IFN ) -α 2b ( 20 mU / m 2 / day for 1 month , followed by 10 mU / m 2 3 times / week subcutaneously ). After 6 months treatment was discontinued because a submental lymph node metastasis occurred on the right side , which was excised . Two months later the patient developed distant metastases in the lung and liver ( Fig . S1a 1 ), the latter being histologically confirmed by a liver biopsy . The BRAF , NRAS and C-kit mutation status were wild-type . We included the patient in a doubleblind , randomized phase III study in which nivolumab was tested against dacarbazine . Staging procedures after 3 months of treatment showed “ stable disease ” ( Fig . S1b 1 ) with a decrease in the sum of target lesions of 30 % ( RECIST 1.1 ) and treatment was continued . While on treatment , S100 and LDH decreased from the initial 0.833 to 0.057 µ g / l , and from 279 to 194 U / l , respectively .
Five months after initiation of study medication the patient reported muscular weakness in both legs and peripheral paraesthesias . Besides the study medication the patient received levothyroxine ( 175 µ g / once daily )
1 https :// www . medicaljournals . se / acta / content / abstract / 10.2340 / 00015555-2548 and metoprolol ( 100 mg / once daily ). Neurological examination revealed formication in both hands , bilateral hypaesthesia of the legs up to the upper thigh , bilateral muscular weakness , and absent tendon reflexes in both legs . The patient was apyretic ; there were no clinical findings indicating infectious causes . Hepatitis A , B , and C and HIV were ruled out by repeated negative blood tests . The patient ’ s history concerning recent travel activities , vaccinations , or insect bites was negative . The patient was hospitalized and magnetic resonance imaging of the brain and the spinal cord were unremarkable . In addition , there were no pathological findings in serum auto-antibodies , including ganglioside M1 ( GM1 ) - , ganglioside Q1b ( GQ1b ) - , and myelin-associated glycoprotein ( MAG ) -antibodies . Further blood tests revealed neither active viral infections ( Epstein-Barr virus , cytomegalovirus , hepatitis A , B , and C and HIV ) nor any auto-immune related abnormalities ( antinuclear antibody , extractable nuclear antigens , anti-neutrophil cytoplasmic antibody , anti-DS DNA ). Cerebrospinal fluid ( CSF ) analysis showed an elevated protein level of 0.73 g / l ( normal range < 0.4 g / l ). Electroneurography ( ENG ) was diagnostic for an acute demyelinating sensorimotor polyneuropathy . These pathological findings were consistent with diagnosis of GBS ( Fig . S2a , b 1 ) and were rated as adverse event grade 3 according to the Common Terminology Criteria for Adverse Events ( CTCAE ). The patient was unblinded and found to have received nivolumab treatment ( 3 mg / kg bodyweight i . v . every 2 weeks ). Treatment with intravenous immunoglobulin ( IVIG ) ( 0.4 g / kg bodyweight ) for 5 days was initiated by Department of Neurology , as usual first choice in GBS , but did not lead to any clinical improvement . Hence , after consultation with the dermatologists and literature research a systemic corticosteroid therapy ( methylprednisolone , 1 mg / kg bodyweight ) was started . Clinical recovery started 48 h later and was nearly complete after 6 weeks , as confirmed by ENG ( normal F wave latency , no A waves , normal distal motor latency , no temporal dispersion ). Corticosteroids were tapered and then stopped after 8 weeks . ENG results suggested a stable remission 5 and 12 months after the initial examination for GBS ( Fig . S2c , d 1 ). Nivolumab was permanently discontinued and a partial response was documented , which , one year after initiation of nivolumab treatment , is still ongoing . To date , no other anti-tumoural treatment has been initiated .
This is an open access article under the CC BY-NC license . www . medicaljournals . se / acta Journal Compilation © 2017 Acta Dermato-Venereologica . doi : 10.2340 / 00015555-2548 Acta Derm Venereol 2017 ; 97 : 395 – 396