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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 .