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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