Warning: thalidomide-related thrombotic risk potentially concerns patients with lupus

Thalidomide was  rst used as a sedative agent in the 1960s, but was rapidly banned due to its terrible teratogenic effects, mainly phocomelia. Later on, it appeared to be useful in the treatment of erythema nodosum leprosum and refractory aphthosis or cutaneous lupus erythematosus. More recently thalidomide use has expanded to malignancies, especially multiple myeloma, and diverse rheumatological and dermatological conditions.1 Although no randomized trial is available, the effectiveness of thalidomide in cutaneous lupus refractory to antimalarials in discoid lupus erythematosus (DLE) and/or subacute cutaneous lupus erythematosus (SCLE) has been underlined,2–4 and recently summarized in an excellent review article.5 Its serious potential toxicity, ie teratogenicity and peripheral neuropathy, has been clearly pointed out with subsequent strict recommendations for clinical use.5 We wish here to underline another recently recognized side-effect, ie thalidomide-associated thromboembolic events, and its particular clinical relevance in patients affected by lupus. Early foetal thrombosis induced by thalidomide was reported in mice as soon as 1977,6 and the development of thrombophlebitis was noted in one patient with Behçet’s syndrome receiving thalidomide by Genvo et al in 1984.7 However, the causal relationship between thalidomide treatment and the occurrence of thrombosis in humans was only suspected in 2000.8 These authors reported  ve patients including four with refractory cutaneous lupus erythematosus, within systemic lupus erythematosus (SLE) in two, all without previous history of vascular events, who developed severe arterial or venous thrombosis soon after onset of thalidomide treatment (50 – 100 mg daily). All of them had antiphospholipid antibodies (aPL). Data on contraception and possible smoking were not mentioned.8 The thrombotic risk associated with the use of thalidomide has been de nitely demonstrated in the peculiar setting of multiple myeloma by two recent studies. Zangari et al compared combined induction chemotherapy consisting of dexamethasone, vincristine, doxorubicin, cyclophosphamide, etoposide and cisplatin, with or without thalidomide (400 mg daily) in two similar groups of patients with newly diagnosed multiple myeloma.9 Deep-vein thrombosis (DVT) occurred during the  rst three cycles in 14 of 50 patients (28%) randomly assigned to receive thalidomide vs two of 50 (4%) not given this drug (P= 0.002). Similarly, Osman et al observed an unexpected 27% incidence of symptomatic DVT, including a case of fatal pulmonary embolism, among 15 previously untreated patients with stage 2 or 3 myeloma receiving doxorubicin, dexamethasone and thalidomide (100 mg daily for 2 weeks, then 200 mg), and therefore decided to suspend their phase 2 trial.10 A similar incidence of 28% DVT was recently reported in a series of 18 patients with refractory myeloma given thalidomide and chemotherapy.11 The occurrence of thrombosis has also been described in some patients treated by thalidomide for diverse non-malignant dermatological disorders, including a case of DLE associated with aPL.12,13 We have recently observed the development of saggital sinus thrombosis in a 16-year-old girl given thalidomide for complex aphthosis refractory to colchicine. Finally, in a randomized double-blind trial of thalidomide in Behçet’s syndrome,14 super cial thrombophlebitis occurred in 10 of 32 patients treated with 100 mg daily vs three of 32 patients in the placebo group (P= 0.06 by bilateral Fisher’s test). Although heterogeneous, these data strongly suggest that the use of thalidomide carries a serious risk of thrombotic events. The suspicion is con rmed by the recent US review of spontaneous postmarketing adverse events surveillance.15 Twenty-seven reports concerned venous thromboembolic events. Pulmonary embolism complicated DVT in one-third of cases. Except for one patient with Behçet’s syndrome, all others had various forms of malignancies, mostly myeloma. The mean duration of thalidomide treatment to thrombosis was 50 days (range 5–118). The mean daily thalidomide dose was 356 mg (range 100– 800). A past history of thromboembolic events was present in only 11% of patients. Besides malignancy, additional risk factors for thrombosis were rarely Lupus (2002) 11, 67 ±70