Abstract
Thalidomide is increasingly being used for the treatment of a variety of dermatologic conditions. Some of the risks associated with thalidomide use, however, are still being uncovered. Increased incidence of venous thrombosis following thalidomide use has recently been reported in the treatment of diseases with disease-related thrombotic risks, such as malignancy and lupus with antiphospholipid antibody syndrome. We report a case of venous thrombosis resulting from thalidomide use in a patient with cicatricial pemphigoid, illustrating the potential concern for increased thrombosis following thalidomide use in the dermatology setting.
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Case Report
A 64-year-old Caucasian woman presented to the dermatology clinic with a three-year history of cicatricial pemphigoid (CP) involving the oral mucosa, axilla, and vulva. Prior topical therapies included various topical steroid ointments and tacrolimus ointment without improvement. Systemic treatments included prednisone, dapsone, and mycophenolate, all with limited response. At the time of presentation she expressed considerable discomfort and frustration with the course of her disease. A repeat biopsy of lesional skin from the vulva demonstrated inflammatory subepidermal blistering with a prominent neutrophilic infiltrate and underlying dense scar formation consistent with CP. Direct immunofluoresence of normal perilesional skin revealed linear staining with IgG and C-3 along the dermal-epidermal junction, strongly suggestive of CP. Following this confirmation of the diagnosis, thalidomide was started by patient request at 100 mg bid after obtaining a negative pregnancy test, normal CBC, and normal nerve conduction study. She was informed of possible adverse effects in accordance with the S.T.E.P.S. program (System for Thalidomide Education and Perscribing Safety) and advised to discontinue use with the occurrence of any unusual side effects. At that time, her other daily medications included escitalopram, calcium supplement and a multivitamin. Past medical history was significant for depression and osteoporosis, she smoked 1/3 pack of cigarettes per day, and she had no history of previous thrombotic episodes.
She reported rapid improvement in her ulcerations after the initiation of thalidomide, but following one week of treatment she developed swelling and pain in her right leg, upon which she stopped the thalidomide and presented to her primary care physician. She was found to have a deep vein thrombosis (DVT) in the right popliteal vein by compression ultrasonography and was admitted to the hospital for anticoagulation with heparin and initiation of long-term coumadin anticoagulation. Laboratory panels to assess for thrombophilic factors were obtained and revealed the presence of heterozygous factor V Leiden mutation. Upon cessation of thalidomide her CP worsened, but it was decided that the risk of a thrombotic recurrence warranted her continued abstinence from the drug.
Comments
Thalidomide was originally marketed as a sedative in the 1960's and received much attention for the resulting limb defects discovered in infants born to mothers who had taken the drug during pregnancy. Since then, thalidomide has found an emerging niche in the investigational treatment of several difficult malignancies and dermatologic conditions, including multiple myeloma, renal cell carcinoma, Behcet's disease, graft vs. host disease, apthous ulcers, systemic lupus erythematosus and Langerhans cell histiocytosis (see Table 1) (1). Despite the many evolving investigational uses, thalidomide has only been approved for treatment of erythema nodosum leprosum. The efficacy of thalidomide in cicatricial pemphigoid was first described in one patient among a small open label case series (2). Its use in CP was recently reinforced in a case report involving a case of treatment-resistant CP (3). Given that our patient had failed several treatment regimens, a therapeutic trial of thalidomide was undertaken. The mechanism of action remains imperfectly defined and likely differs depending on the clinical entity treated, but it appears to have several immunomodulatory properties, including downregulation of TNF-[alpha], decrease in circulating helper T-cell to suppressor T-cell ratio, and inhibition of IFN-[alpha] (4), all of which may play a role in the treatment of cicatricial pemphigoid.
Thalidomide has been implicated in many adverse reactions but is probably best known for its potent teratogenicity. While multiple defects have been attributed to maternal use of thalidomide, the most commonly recognized effect is phocomelia (5). Limb defects have been shown to result from a single 100 mg dose administered within the first 35-50 days of pregnancy (6). The teratogenicity is widely appreciated but still incompletely understood; nevertheless, it is classified as pregnancy category X and requires pregnancy counseling and adequate birth control measures prior to initiation. The other major side effect of thalidomide that has been thoroughly described is a thalidomide-induced peripheral neuropathy. The clinical features of this sensory neuropathy include painful paresthesia of the hands and feet and loss of sensation in the extremities, usually following a symmetrical pattern and with characteristic electrophysiologic findings (7). This effect is particularly unsettling as it may be irreversible after discontinuation of the drug, and there remains controversy as to whether it is a dose-related effect or an idiosyncratic reaction (6). The incidence of this effect has been reported in different series and is widely variable, ranging from 1% to 70% (6). Due to the unpredictable nature of this potentially serious side effect, it is recommended that baseline electrophysiologic testing be performed and repeated in the event that clinical signs and symptoms of neuropathy develop during the course of treatment (4). Additional side effects of thalidomide include sedation, which is the most common effect and the initial indication for therapeutic use. This can manifest as drowsiness, dizziness, or mood changes, and all patients should be warned of the potential interaction with other sedative drugs and alcohol. Other effects that have been reported are listed in Table 2 (6).
While teratogenicity and peripheral neuropathy are the side effects of thalidomide that have garnered the most attention, a newly recognized side effect illustrated in this case is its thrombogenic property and the apparent increase in thrombotic events following use. It was not until 2000 that the causal role of thalidomide in these events was suggested, described in a report of five patients with lupus erythematosus and antiphospholipid antibody syndrome who developed deep vein thromboses shortly after beginning thalidomide (8). Following this report, there have been several reports in the oncology literature of increased incidence of venous thrombosis in patients receiving thalidomide for multiple myeloma and renal cell carcinoma, particularly in combination with other chemotherapeutic agents. In the setting of multiple myeloma, Zangari et al. found that the incidence of DVT in patients treated with thalidomide as part of their chemotherapy regimen was 28% compared to only 4% in those patients who did not receive thalidomide (9). Osman et al. report a phase II trial of thalidomide in multiple myeloma that was suspended due to the marked incidence of thrombotic events in the thalidomide treatment group, including one death secondary to pulmonary embolism (10).
It is increasingly clear that thalidomide plays a significant role in the formation of DVT during treatment of malignancy, and there is new concern expressed in an editorial by Piette et al. involving the potential for increased thrombotic events with thalidomide use in lupus patients (11). However, the potential for such events in the dermatology setting remains largely unheralded. We report on the development of DVT following thalidomide use in a patient without disease-related risk for thrombophilia who was subsequently found to have an inherited thrombophilia. Factor V Leiden is a mutation in clotting factor V that results in resistance to degradation by activated protein C, thus producing a greater likelihood for thrombosis (12). The heterozygous state of Factor V Leiden is the most common cause of inherited thrombophilia and is particularly prevalent among Caucasians, where it has been found at a frequency of 4.4% and appears to increase the risk of venous thrombosis by sevenfold over noncarriers of the gene (13).
