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Advances in dermatology and venereology Acta Dermato-Venereologica
Acute Lower Limb Ischaemia and Diabetes in a Patient Treated with Anti-PD1 Monoclonal Antibody for Metastatic Melanoma
Benjamin THOREAU 1, Flora GOUAILLIER-VULCAIN 2, Laurent MACHET 3, Christine MATEUS 4, Caroline ROBERT 4, Nicole FERREIRA- MALDENT 1, François MAILLOT 1 and Bertrand LIOGER 1, 5 *
1
Service de Medecine Interne, Hôpital Bretonneau, 2 Boulevard Tonnellé, FR-37044 Tours, 2 Service de Chirurgie Vasculaire, Hôpital Trousseau, CHRU of Tours, 3 Service de Dermatologie, Hôpital Trousseau, Tours, 4 Service de Dermatologie, Gustave Roussy campus cancer, Villejuif, and 5 Université François Rabelais, UMR GICC 7292, Tours, France. * E-mail: bertrand. lioger @ univ-tours. fr Accepted Jul 4, 2016; Epub ahead of print Jul 5, 2016
Therapeutic management of metastatic melanoma is undergoing a revolution, with the use of immune-checkpoint inhibitors, such as anti-cytotoxic T-lymphocyte antigen 4( CTLA-4) and anti-programmed cell death 1( PD-1) antibodies. Along with a significant durable efficacy of these therapies( 1 – 3) a new class of adverse events has emerged, namely immune-related adverse events( irAEs). Hypophysitis, thyroiditis, rashes, autoimmune colitis, and autoimmune hepatitis represent such side-effects. In safety studies, these severe irAEs have accounted for less than 15 % of overall side-effects( 4 – 6). We report here a case of arterial thrombosis and diabetes mellitus in a patient treated with anti PD-1 antibody pembrolizumab( MK-3475).
CASE REPORT
A 73-year-old man, who had a history of hypertension and right tibial venous thrombosis following a long journey 30 years ago, was admitted for an acute ischaemia of the left lower limb and a diabetic ketoacidosis while he was treated with pembrolizumab, 10 mg / kg / day, every 3 weeks for 26 weeks, for a stage IV melanoma of the scalp with lymph node, cutaneous, bone and liver metastases. He presented with a painful cyanotic and cold left foot( Fig. 1). Pedal and posterior tibial left pulses were abolished. Laboratory tests showed blood neutrophils 19 × 10 9 / l( normal 2.0 – 7.0 × 10 9 / l), platelets count 211 × 10 9 / l( normal 150-450 × 10 9 / l), C-reactive protein 37.1 mg / l( normal < 5 mg / l). Fibrinogen clotting tests were normal. Anticardiolipin antibodies, anti-beta2-glycoprotein 1 antibodies, and lupus anticoagulant test were negative and antithrombin III was normal. In terms of diabetes mellitus, metabolic
Fig. 1. Ischaemia of the left foot.
acidosis( pH: 7.15 and lactic acid: 2.1 mmol / l) and haemoglobin
A 1C of 8.5 % were found. Both anti-glutamic acid decarboxylase( GAD) and anti protein-tyrosine phosphatase-2( IA-2) antibodies were negative. Before this episode of diabetic ketoacidosis, the patient showed no sign of diabetes and glucose levels were normal. Computed tomography did not show pancreatitis or pancreas metastasis, but revealed an arterial thrombus floating in the infrarenal aorta( 12 × 5 mm) without atheroma plaque next or distally in the vicinity, associated with an arterial thrombosis from the left tibiofibular trunk to the left anterior tibial artery( Fig. 2). Other vascular axes were free of parietal atheroma, calcified plaque or aneurysm. Heart rate was sinus, and echocardiography was normal. Fogarty arterial embolectomy associated with anticoagulation allowed vascularization to recover. Pathological examination found a fibrin clot with no neoplastic cells.
Arterial Echo-Doppler at 3 months showed a complete disappearance of the thrombus. However, despite iloprost infusions and anticoagulation, a distal necrotic evolution of the foot led to a trans-phalangeal amputation. Pembrolizumab was stopped at the onset and has not been resumed to date. Follow-up, including clinical examination, fluorine-18 fluoro-2-deoxyglucose([( 18) F ] FDG) positron emission tomography / computed tomography scan every 3 months, revealed a partial melanoma remission with no thrombotic recurrence at 24 months. Diabetes mellitus still required daily insulin. Anticoagulation has been withdrawn at 6 months and arterial thromboembolism prevention with aspirin was started.
DISCUSSION
This report is the first description of an arterial thrombosis occurring concomitantly with fulminant type 1 diabetes in a patient treated with pembrolizumab for a
Fig. 2. Computed tomography revealed aortic thrombus floating and arterial thrombosis of the left tibiofibular trunk to the left anterior tibial artery( arrow). doi: 10.2340 / 00015555-2504 Acta Derm Venereol 2017; 97: 408 – 409
This is an open access article under the CC BY-NC license. www. medicaljournals. se / acta Journal Compilation © 2017 Acta Dermato-Venereologica.