REVIEW ARTICLE DOI 10.1111/j.1365-2133.2005.06747.x Thalidomide: dermatological indications, mechanisms of action and side-effects J.J. Wu,* D.B. Huang, §– K.R. Pang, S. Hsuà and S.K. Tyring**àà *Department of Dermatology, University of California, Irvine, Irvine, CA, U.S.A. Division of Infectious Diseases, Department of Medicine, and àDepartment of Dermatology, Baylor College of Medicine, Houston, TX, U.S.A. §Division of Infectious Diseases, Department of Medicine, –University of Texas at Houston School of Public Health, and **Department of Dermatology, University of Texas Health Science Center at Houston, Houston, TX, U.S.A. Department of Dermatology, Wayne State University School of Medicine, Detroit, MI, U.S.A. ààCenter for Clinical Studies, Houston, TX, U.S.A. Summary Correspondence Thalidomide was first introduced in the 1950s as a sedative but was quickly Stephen K. Tyring, removed from the market after it was linked to cases of severe birth defects. 2060 Space Park Drive, Suite 200, Houston, TX However, it has since made a remarkable comeback for the U.S. Food and Drug 77058, U.S.A. E-mail: [email protected] Administration-approved use in the treatment of erythema nodosum leprosum. Accepted for publication Further, it has shown its effectiveness in unresponsive dermatological conditions 13 February 2005 such as actinic prurigo, adult Langerhans cell histiocytosis, aphthous stomatitis, Behc¸et’s syndrome, graft-versus-host disease, cutaneous sarcoidosis, erythema Key words: multiforme, Jessner–Kanof lymphocytic infiltration of the skin, Kaposi sarcoma, dermatological uses, thalidomide lichen planus, lupus erythematosus, melanoma, prurigo nodularis, pyoderma Conflicts of interest: gangrenosum and uraemic pruritus. This article reviews the history, pharmacol- None declared. ogy, mechanism of action, clinical uses and adverse effects of thalidomide. There were no funding sources for this paper. This topic was presented as a poster at the American Academy of Dermatology 62nd Annual Meeting, Washington, DC, 6–11 February 2004. Thalidomide was first synthesized in West Germany in 1954 12 000 congenital birth defects, mostly in West Germany, and and was introduced to the German market as Contergan in to have incurred more than $27 million in legal expenses.5 1956 as an over-the-counter medication.1 Two years later it In 1965, it was given to patients with leprosy in Israel was marketed to other industrialized nations. In the U.K. it for use as a sedative to relieve ‘lepra suffering’.6 Researchers was known as Distaval. It was thought to be one of the safest noticed an unexpected clinical improvement in the signs sedatives ever produced as it was effective in small doses, was and symptoms of erythema nodosum leprosum (ENL). After not addictive, and did not have acute side-effects such as multiple reports from other countries confirmed the results, motor impairment.2,3 Accidental overdosing or deliberate sui- thalidomide emerged as an effective treatment for ENL. In cide attempts at doses as high as 14 g did not result in adverse Europe, thalidomide has not been approved by any health effects. Its use started to become widespread in the home and authority, but it has received orphan drug status. Pharmion, hospital, and it became popular among pregnant women to the pharmaceutical company producing thalidomide in Eur- reduce morning sickness.2 ope, filed for a Marketing Authorization Application (MAA) However, by 1960 it became clear that long-term thalido- for multiple myeloma and ENL to the European Agency for mide use was associated with polyneuritis.4 Further, rare con- the Evaluation of Medicinal Products. However, in May genital abnormalities such as phocomelia (Fig. 1) [courtesy of 2004 it withdrew the MAA for ENL to focus on the mul- the Thalidomide Victims Association of Canada (TVAC): tiple myeloma indication. In 1998, thalidomide was http://www.thalidomide.c./en/index.html] began to appear approved by the U.S. Food and Drug Administration (FDA) in infants born to women who used thalidomide during preg- for ENL and is classified as an orphan drug.7 The orphan nancy. In mid-1961, thalidomide was withdrawn from the drug status has led to its use in many currently unapproved world market due to the increasing numbers of infants born dermatological conditions that are refractory to other medi- with deformities. It was estimated to have caused more than cations. 254 Ó 2005 British Association of Dermatologists • British Journal of Dermatology 2005 153, pp254–273 Thalidomide in dermatology, J.J. Wu et al. 255 Therapeutic use Although thalidomide is FDA-approved only for ENL, many dermatological conditions appear to be treated effectively with thalidomide (Table 2). In most of these situations, patients received thalidomide only after conventional treatment failed. The following diseases have been grouped into very effective, moderately effective, possibly effective and contraindicated when treated with thalidomide. Very effective Erythema nodosum leprosum ENL is a lepra reaction that occurs in lepromatous patients on multiple drugs or from interferon (IFN)-c intradermal injec- tions. It usually presents within the first year of multidrug therapy with both cutaneous and visceral manifestations.8 Skin reactions are erythematous nodules (Figs 2 and 3) associated with arthralgia, fever, iritis, malaise and neuritis. Visceral manifestations can include hepatosplenomegaly, nephritis, orchitis and pleuritis. ENL is the only approved indication for thalidomide. The first case report of six patients with ENL treated successfully with thalidomide 300 mg daily led to further clinical trials.6 In a crossover study, 44 patients received thalidomide for act- ive lepromatous leprosy and chronic ENL.9 Based on preven- tion of new ENL lesions and a temperature of less than 37Æ6 °C, 68% of patients treated with thalidomide responded to therapy, whereas none of the patients treated with placebo responded. Fig 1. A baby girl born in the late 1950s with phocomelia whose A double-blind trial of thalidomide vs. acetylsalicylic acid mother was given thalidomide during pregnancy. Courtesy of the was conducted by the World Health Organization.10 After the Thalidomide Victims Association of Canada: first course of treatment until the end of the 9-month study, http://www.thalidomide.c./en/index.html 48% of patients in the thalidomide group did not have any infectious reactions compared with 21% of patients in the ace- In preparing this manuscript, the following literature searches tylsalicylic acid group. Within 48 h of treatment, 75% of were performed over the course of July 2002 to September patients in the thalidomide group were afebrile compared 2004. Using the National Library of Medicine website at with 36% of patients in the acetylsalicylic acid group. Thalido- http://www.pubmed.org, the word combinations of ‘thalido- mide caused regression of skin lesions twice as often as did mide and dermatology’, ‘thalidomide and cutaneous’ and ‘tha- acetylsalicylic acid. lidomide and skin’ generated 20, 125 and 294 separate entries, Sheskin11 reviewed 4522 patients treated with thalidomide respectively. Each of these articles was examined to determine for ENL, and found that 4479 (99%) improved while only 43 relevance and suitability. Finally, to ensure that all relevant arti- (1%) had no change or worsened. The best initial dose cles had been cited, the word ‘thalidomide’ was used to gener- seemed to be 400 mg daily, with a maintenance dose of ate over 3700 entries, and all articles published after 1990 50–100 mg daily. The duration of therapy ranged from spor- (appropriately 2000 articles) were briefly scanned. This com- adic use to continuous use for greater than 6 years. As in the prehensive article reviews the pharmacology, adverse effects clinical studies, most skin lesions regressed after 24–48 h of and use of thalidomide in multiple dermatological conditions. therapy, and other signs and symptoms such as arthralgia, emesis, headache, myalgia, hepatosplenomegaly and orchitis Mechanism of action resolved quickly as well. Laboratory findings such as white blood cell count and erythrocyte sedimentation rate decreased. It appears that thalidomide may have several modes of action Patients with ENL also had rapid improvement in their various through its sedative, immunomodulatory and other properties neurological conditions, and neuropathy was found not to be (Table 1). a common side-effect.12 Ó 2005 British Association of Dermatologists • British Journal of Dermatology 2005 153, pp254–273 256 Thalidomide in dermatology, J.J. Wu et al. Table 1 Mechanism of action for thalidomide Sedative Activation of the sleep centre in the forebrain Immunomodulatory Inhibition of phagocytosis by neutrophils Inhibition of chemotaxis of monocytes and leucocytes Prevention of lymphocyte proliferation in response to mitogenic and antigenic stimuli by changing the lymphocytic response from T-helper 1 to 2 Decrease in the CD4 ⁄CD8 ratio by reducing the number of CD4+ cells and increasing the CD8+ cells Decrease the HIV binding to CD4+ cells by blocking the expression of CD26 on the T lymphocytes Suppression of the production of IgM antibodies Inhibition of tumour necrosis factor-a Inhibition of IL-8, IL-12 Enhancement of IL-2, IL-4, IL-5 Enhancement of interferon-c Downregulation of expression of class II MHC antigens and cellular adhesion molecules Inhibition of cytokine-induced NF-jB gene expression Increase in the expression of CD40L Decrease of B lymphocytes in the spleen Other